Hemostatic Disorders

DHA and EPA in Sickle Cell Disease Favor Clinical Improvement and Contribute to Better Quality of Life: A Qualitative Systematic Review

Background: Sickle cell disease is a severe genetic disorder, and searching for therapeutic strategies is indispensable for prolonged and improved life for people affected by this condition.

Objectives: This qualitative systematic review aimed to highlight the therapeutic potential of omega- 3 (n-3) in people with sickle cell disease.

Methods: The search was performed by combining sickle cell disease and n-3 descriptors in DeCS/ MeSH databases, including Scopus, PubMed, ScienceDirect, Web of Science, and Virtual Health Library. The risk of bias assessment in the primary studies was performed using the Cochrane risk of bias tool for randomized controlled trials. The evidence quality was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool.

Results: From the 187 records identified, seven were selected for data collection. Based on the evidence, n-3 supplementation contributes to lower activation of pro-inflammatory biomarkers, improves the concentration of docosahexaenoic and eicosapentaenoic acids in the erythrocyte membrane, provides better hemostatic response, and helps in vaso-occlusive crisis, pain episodes, and hospitalization reduction.

Conclusion: The findings suggest that n-3 adjuvant therapy favors the clinical and general aspects of people with sickle cell disease.

Some Versatile Medicinal Plants for Healing Wounds: A Review

The cellular and biochemical stages of the wound-healing process are interrelated and work to repair the wound. The body heals wounds in stages, and each stage that is postponed raises the risk of microbial infection. The time needed for healing can be sped up, and unwanted events can be reduced to improve wound healing. To aid in the healing of the wounds, the medications are administered locally or systemically. In order to promote wound healing, antibiotics, antiseptics, desloughing agents, extracts, etc. have been employed. Due to their adverse effects, several synthetic medications are subject to restrictions. Investigation, identification, and formulation of plants or plant-derived combinations are required for the management and therapy of wound healing. Because they have fewer adverse effects and have been used to treat wounds for a longer period, medicinal plants are becoming more popular for use in wound healing. According to studies, medicinal herbs help diabetic, infected, and opened wounds heal more quickly. It has been claimed that medicinal herbs can speed up wound healing through a variety of processes. Many medicinal plants, including Allium sativum, Commiphora myrrha, Curcuma longa (L.), Rauwolfia serpentia, and Vateria indica, have demonstrated the ability to treat wounds.

A Randomized Comparison of Transradial and Transfemoral Approach in Hepatic Arterial Infusion Chemotherapy

Introduction: Hepatic arterial infusion chemotherapy (HAIC) has been popular for treating unresectable hepatocellular carcinoma (HCC). However, there are few reports comparing the transradial approach (TRA) and transfemoral approach (TFA) in HAIC.

Objective: This study aimed to compare the duration of the hepatic artery catheterization, fluoroscopy time (FT), radiation exposure, safety, and quality of life associated with the procedure in patients undergoing HAIC via TRA and TFA.

Methods: This prospective, single-center, randomized, controlled study included 120 patients with unresectable HCC undergoing HAIC procedures. Patients were randomly assigned to group A (n = 60, TRA-HAIC) or group B (n = 60, TFA-HAIC). The hepatic artery catheterization time, FT, entrance surface dose (ESD), dose area product (DAP), procedure-related complications, and quality of life associated with the procedure were assessed between the two groups. Independent-sample t-test and analysis of variance (ANOVA) were used to assess differences. Statistical significance was set at P < 0.05.

Results: HAIC procedures were successfully performed in both groups. The hepatic artery catheterization time (19.35 ± 5.84 vs. 18.93 ± 5.62 minutes, P = 0.837), FT (2.35 ± 2.23 vs. 2.25 ± 2.16 minutes, P = 0.901), ESD (259.32 ± 167.46 vs. 250.56 ± 170.58 mGy, P = 0.449), and DAP (125.37 ± 60.65 vs. 120.56 ± 64.33 Gy.cm3, P = 0.566) were comparable between the two groups. The incidence of artery occlusion (10.0% vs. 0%, P < 0.001) in the TRA group was significantly higher than that in the TFA group. TRA was associated with a statistically significant (P < 0.05) improvement in the quality of life.

Conclusion: TRA to HAIC was associated with greater improvement in the quality of life associated with the procedure compared with TFA. Both approaches to HAIC had similar efficiency, safety, radiation exposure, and procedure duration.

Neurodevelopmental and Neuropsychiatric Perspectives on Respiratory Control: Understanding Congenital and Developmental Disorders

Breathing is an automatic process generated by the central nervous system, crucial for the homeostasis of several body processes. This vital process is underpinned by an intricate network in which distinct functional and anatomical factors and structures play a role. Transcription factors (i.e., PHOX2B and Pbx proteins), as well as neuromodulators (i.e., serotonin, noradrenaline, GABA, and glycine), have been demonstrated as implicated in the regulation of breathing. Besides, the several intertwined excitatory and inhibitory brainstem neural circuits comprising the so-called central pattern generator (CPG) have recently demonstrated a potential role of cerebellar structures and circuits in coordinating the complex and coordinated respiratory act in eupnea. A disruption affecting one of these components, which may also occur on a genetic basis, may indeed result in complex and heterogeneous disorders, including neurodevelopmental ones (such as Rett and Prader-Willi syndrome), which may also present with neuropsychiatric and breathing manifestations and potentially lead to sudden infant death syndrome (SIDS). Herein, we discuss the main factors and systems involved in respiratory control and modulation, outlining some of the associated neurodevelopmental disorders (NDDs) deriving from an impairment in their expression/ function. Further studies are needed to deepen our knowledge of the complexity underpinning “breathing” and the relation between respiratory implications and congenital and developmental disorders.

Network Pharmacology Study on Herb Pair Bletilla striata-Galla chinensis in the Treatment of Chronic Skin Ulcers

Background: Herb pair Bletilla striata-Galla chinensis (BS-GC) is a classic combination of topical traditional Chinese medicine formulae in the treatment of chronic skin ulcers (CSUs).

Objective: The aim of this study is to explore the effective active ingredients of BS-GC, as well as the core targets and signal transduction pathways of its action on CSUs.

Methods: The ingredients of BS-GC were obtained from TCMSP and HERB databases. The targets of all active ingredients were retrieved from the SwissTargetPrediction database. The targets of CSUs were obtained from OMIM, GeneCards, Drugbank, and DisGeNET databases. A drug-disease target protein-protein interaction (PPI) network was constructed to select the most core targets, and an herb-ingredient-target network was built by utilizing Cytoscape 3.7.2. Furthermore, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes database (KEGG) analysis and verified the results of network pharmacology through molecular docking.

Results: A total of 40 active ingredients from the herb pair BS-GC were initially screened, and a total of 528 targets were retrieved. Meanwhile, the total number of CSU targets was 1032. Then, the number of common targets between BS-GC and CSUs was 107. The 13 core targets of herb pair BS-GC with CSUs were filtered out according to the PPI network, including AKT1, TNF, EGFR, BCL2, HIF1A, MMP-9, etc. The 5 main core active ingredients were 1-(4-Hydroxybenzyl)-2-methoxy-9,10-dihydrophenanthrene-4,7-diol, 1-(4- Hydroxybenzyl)-4-methoxy-9,10-dihydrophenanthrene-2,7-diol, physcion, dihydromyricetin, and myricetin. The main biological processes were inflammation, oxidative stress, and immune response, involving the AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, NF-κB signaling pathway, and calcium signaling pathway. Molecular docking results showed good binding activity between the 5 main core active ingredients and 13 core targets.

Conclusion: This study predicted the core targets and signal transduction pathways in the treatment of CSUs to provide a reference for further molecular mechanism research.

Why have SGLT2 Inhibitors Failed to Achieve the Desired Success in COVID-19?

The SARS-CoV-2 virus emerged towards the end of 2019 and caused a major worldwide pandemic lasting at least 2 years, causing a disease called COVID-19. SARS-CoV-2 caused a severe infection with direct cellular toxicity, stimulation of cytokine release, increased oxidative stress, disruption of endothelial structure, and thromboinflammation, as well as angiotensin-converting enzyme 2 (ACE2) down-regulation-mediated renin-angiotensin system (RAS) activation. In addition to glucosuria and natriuresis, sodium-glucose transport protein 2 (SGLT2) inhibitors (SGLT2i) cause weight loss, a decrease in glucose levels with an insulin-independent mechanism, an increase in erythropoietin levels and erythropoiesis, an increase in autophagy and lysosomal degradation, Na⁺/H⁺-changer inhibition, prevention of ischemia/reperfusion injury, oxidative stress and they have many positive effects such as reducing inflammation and improving vascular function. There was great anticipation for SGLT2i in treating patients with diabetes with COVID-19, but current data suggest they are not very effective. Moreover, there has been great confusion in the literature about the effects of SGLT2i on COVID-19 patients with diabetes . Various factors, including increased SGLT1 activity, lack of angiotensin receptor blocker co-administration, the potential for ketoacidosis, kidney injury, and disruptions in fluid and electrolyte levels, may have hindered SGLT2i's effectiveness against COVID-19. In addition, the duration of use of SGLT2i and their impact on erythropoiesis, blood viscosity, cholesterol levels, and vitamin D levels may also have played a role in their failure to treat the virus. This article aims to uncover the reasons for the confusion in the literature and to unravel why SGLT2i failed to succeed in COVID-19 based on some solid evidence as well as speculative and personal perspectives.

A Critical Sojourn of Hyaluronic Acid-based Hydrogels in the Wound Healing Process: Current Advances and Future Prospects

\"Hyaluronic acid (HA), a non-sulfated glycosaminoglycan (GAG), is a significant component of the epidermal extracellular matrix (ECM). It plays multiple roles in the inflammatory response, cell adhesion, migration, proliferation, differentiation, angiogenesis, and tissue regeneration. Due to its inherent characteristics, including non-immunoreactivity, exceptional biocompatibility, biodegradability, native biofunctionality, hydrophilicity, and non-immunoreactivity, HA has found applications in the production of wound dressings. HA's synergistic role in enhancing deeper penetration into chronic wounds and its biofunctional properties in the healing process have been harnessed. HA-based wound dressings, often incorporating biomolecules or drugs to improve the dressing's biochemical performance during wound healing, have been developed. In this review, we explore the current state of knowledge regarding hydrogels based on HA, focusing on their biofunctional properties and delivery mechanisms. We present the latest developments in the research and development of HA-based hydrogels for the treatment of skin wounds.\"

Early-Life Lead Exposure: Risks and Neurotoxic Consequences

Background: Lead (Pb) does not have any biological function in a human, and it is likely no safe level of Pb in the human body. The Pb exposure impacts are a global concern for their potential neurotoxic consequences. Despite decreasing both the environmental Pb levels and the average blood Pb levels in the survey populations, the lifetime redistribution from the tissues-stored Pb still poses neurotoxic risks from the low-level exposure in later life. The growing fetus and children hold their innate high-susceptible to these Pb-induced neurodevelopmental and neurobehavioral effects.

Objective: This article aims to evaluate cumulative studies and insights on the topic of Pb neurotoxicology while assessing the emerging trends in the field.

Results: The Pb-induced neurochemical and neuro-immunological mechanisms are likely responsible for the high-level Pb exposure with the neurodevelopmental and neurobehavioral impacts at the initial stages. Early-life Pb exposure can still produce neurodegenerative consequences in later life due to the altered epigenetic imprints and the ongoing endogenous Pb exposure. Several mechanisms contribute to the Pb-induced neurotoxic impacts, including the direct neurochemical effects, the induction of oxidative stress and inflammation through immunologic activations, and epigenetic alterations. Furthermore, the individual nutritional status, such as macro-, micro-, or antioxidant nutrients, can significantly influence the neurotoxic impacts even at low-level exposure to Pb.

Conclusion: The prevention of early-life Pb exposure is, therefore, the critical determinant for alleviating various Pb-induced neurotoxic impacts across the different age groups.

Traditional Ayurvedic Treatment Practices by Vaidyas of the Northern Region of India

Aims: The present study aims to investigate the current scenario of utilization and importance of medicinal plants used by traditional Vaidyas. This study also provides information about the views and awareness of the current generation towards ayurvedic knowledge, which in turn explains the decline of traditional healthcare practices.

Background: Ayurvedic medicine is one of the oldest and most traditional healthcare systems in India. There is limited documentation available regarding the information of traditional medicinal uses of plants even though various rural folks and elders have long been using plant-based formulations for curing human ailments. Hence, there is an urgent need to document this traditional knowledge to endorse the Ayurveda or Indigenous medicinal system before such valuable knowledge becomes inaccessible and extinct.

Objective: The present study was carried out to profile the current status of medicinal plants used by Traditional Vaidya’s/practitioners/locals, and discuss the status of Ayurveda and indigenous systems in the Northern states of India i.e., Haryana and Rajasthan.

Methods: To study currently available medicinal plants used by traditional Vaidyas in Northern states of India such as Haryana and Rajasthan, a survey among 50 Vaidyas of each state was undertaken. Information was gathered through interview and questionnaires consisting of 20 questions regarding their knowledge, expertise, targeted ailments, herbal formulations, and preservation techniques.

Results: According to the collected information, these Vaidyas have almost 4 to 40 yrs. of experience and acquired their knowledge in a variety of ways, including from academic institutions or their ancestors. By feeling the pulse in the wrist, these Vaidyas were able to diagnose ailments associated with the three doshas (Vata, Pitta, and Kapha) with medical precision via sensing the wrist's pulse. Different illnesses associated with kidney, lungs, digestive system, leukosis, diabetes, blood pressure etc. were treated by these traditional Vaidyas. In addition to prescribing medicines, Vaidyas carefully observe the patient's routine, physical health and their age group for better medication. Several indigenous medicinal herbs such as Ashwagandha, safed musli, gokhru, garmunda, bawli ghans, giloy, triphala, ginger, patthar chatta, Aloe vera, Stevia, and many other herbs are being used by these traditional Vaidyas for their herbal formulations.

Conclusion: This survey highlights Ayurveda and its use of plants in the field of medicine, through validation based on knowledge of traditional Vaidyas. This article also highlights the indigenous system and some important Indian medicinal plants of Haryana and Rajasthan and their therapeutic use in daily life. This survey enlightens the traditional Vaidyas and their knowledge of the Ayurveda medicinal system. This step might strengthen the validity of these products and provide a lead to target new formulation preparations. Many high-profile formulations could be prepared in the future, if most of these reputed traditional Vaidyas get organized.

Exploring the Therapeutic Potential: Antiplatelet and Antioxidant Activities of Some Medicinal Plants in Morocco

Background: Thrombotic events and oxidative stress are major complications of certain ischemic disorders. The fight against these complications requires very intense research to develop new therapeutic agents of natural origin.

Objective: The general objective of this work is the scientific valorization of five medicinal plants: Rhus pentaphylla, Zizyphus lotus, Ammodaucus leucotrichus, Inula viscosa, and Cinnamomum zeylanicum by exploring their effects on rat platelet aggregation, antioxidant potential and determining their phytochemical composition.

Methodology: The aggregation test was monitored by stimulating isolated washed platelets suspension in the absence and presence of extracts. The antioxidant activity was conducted in vitro according to three methods: DPPH free radical scavenging activity, β-carotene bleaching test, and ferric reducing antioxidant power test. The quantitative determination of total polyphenols and flavonoids are determined respectively according to the Folin-Ciocalteu method and the colorimetric method with aluminum chloride.

Results: The results obtained show that the aqueous extract of the fruits of Rhus pentaphylla and the aerial part of Inula viscosa, as well as the stalk peel of Cinnamomum zeylanicum, significantly (p<0.001) inhibit thrombin-platelet aggregation, while the other plant extracts have a slightly, but significant effect. These extracts exert a remarkable antioxidant activity with the three methods used. But, their IC₅₀ values are still higher than those of the antioxidant references (ascorbic acid and butyl hydroxyanisole). Qualitative phytochemical analysis revealed the presence of secondary metabolites with varying contents. Additionally, the results of quantitative phytochemical analysis showed that the aqueous extracts of the leaves of Rhus pentaphylla and the aerial part of Inula viscosa contain the highest amount of polyphenols and flavonoids. These secondary metabolites are also present in the other extracts but in smaller quantities.

Conclusion: These results could contribute to the validation of the medical use of these extracts that exert an antiplatelet effect to treat hemostatic and thrombotic disorders.

Recent Trends in Electrospun Antibacterial Nanofibers for Chronic Wound Management

Chronic wounds and lesions have a severe impact on the socioeconomic status and compliance of patients all over the world. Diabetes-related chronic, non-healing lesions may necessitate amputation of the damaged limb or organ. These skin lesions are susceptible to microorganisms that cause infections that impede the healing process. Despite the advances in medication development and sophisticated formulations, treating persistent wound infections remains difficult. Electrospun antimicrobial wound dressings offer considerable potential for lowering the risk of infection and accelerating the healing of chronic wounds. Electrospinning is a cost-effective, reproducible, simple, and multifaceted technique for encapsulating hydrophobic and hydrophilic therapeutic molecules within polymeric carriers with wide-ranging applications. In this review, we have discussed extensively the recent advances in electrospun nanofiber formulation techniques for use as wound dressings, as well as the entrapment of various antibacterial biomolecules, such as synthetic antibiotics, phytoconstituents, and metal nanoparticles, which have been embedded into the electrospun nanofibers, highlighting bioactive antibacterial agents capable of enhancing wound healing. In addition, we focus on the challenges currently being faced in the area of biomedicine as well as the opportunities for electrospinning-based nanomaterials.

COVID-19 related Complications during Pregnancy: A Systematic Review

Background: The topic of COVID-19 (coronavirus disease)-associated complications during pregnancy is poorly postulated and remains an area that requires elucidation for the underlying pathophysiology mechanism in order to evaluate a new therapeutic strategy and optimize current therapies.

Aim: The study aimed to assess the proportion of associated complications with COVID-19 and the underlying pathophysiology in pregnant women.

Methods: The MedLine and Embase databases were searched for studies relevant to the study topic.

Results: Preterm delivery and C-section have been found to be the most frequently reported complications. Approximately, 28.55% of pregnant women with symptomatic COVID-19 have been reported to require a C-section and 8.8% preterm delivery. In addition, anxiety and depression have also been frequently reported in 57% and 37% of pregnant women, respectively.

Conclusion: Symptomatic pregnant women with COVID-19 have a high risk of preterm labor, mortality and morbidity rates, and C-section requirements. The underlying pathophysiology of COVID-19-associated complications during pregnancy includes homeostatic disturbances of the immune system, pulmonary system, and hemostatic system. In addition to endothelial dysfunction, excessive immune response, coagulopathy, hypoxemia, and hypotension are involved in the pathogenesis that negatively affects neonates' health outcomes.

Pathophysiology of Cardiac Cell Injury in Post-COVID-19 Syndrome

Recently, the scientific community has realized that COVID-19 effects are not limited to the acute period of infection but continue beyond that to cause more prolonged pathological changes. Post-COVID syndrome is a novel concept that describes the sequelae/persistent pathophysiological changes of post-COVID-19 infection. The current hypothesis suggests the involvement of severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) in cardiac arrhythmias, coronary artery aneurism, acute renal injury, central nervous system degenerative diseases, vascular endothelial cell dysfunction, and pulmonary dyspnea, as well as fibrotic lung damage. Therefore, COVID-19 has been identified as a poly-syndromic and polysystemic inflammatory disease. Post-COVID extrapulmonary complications have been observed in approximately 85% of hospitalized COVID-19 survivors and 35% of COVID-19 outpatients. Furthermore, 25% of hospitalised COVID-19 survivors developed myocardiopathy.

Anti-COVID-19 Vaccination, COVID-19, and Female Contraception: The Exacerbated Risks (Thromboembolism) of the Estrogen-progestin Pill

Significance of Beta-Blocker in Patients with Hypertensive Left Ventricular Hypertrophy and Myocardial Ischemia

Background: Arterial Hypertension (HTN) is a key risk factor for left ventricular hypertrophy (LVH) and a cause of ischemic heart disease (IHD). The association between myocardial ischemia and HTN LVH is strong because myocardial ischemia can occur in HTN LVH even in the absence of significant stenoses of epicardial coronary arteries.

Objective: To analyze pathophysiological characteristics/co-morbidities precipitating myocardial ischemia in patients with HTN LVH and provide a rationale for recommending beta-blockers (BBs) to prevent/treat ischemia in LVH.

Methods: We searched PubMed, SCOPUS, PubMed, Elsevier, Springer Verlag, and Google Scholar for review articles and guidelines on hypertension from 01/01/2000 until 01/05/2022. The search was limited to publications written in English.

Results: HTN LVH worsens ischemia in coronary artery disease (CAD) patients. Even without obstructive CAD, several pathophysiological mechanisms in HTN LVH can lead to myocardial ischemia. In the same guidelines that recommend BBs for patients with HTN and CAD, we could not find a single recommendation for BBs in patients with HTN LVH but without proven CAD. There are several reasons for the proposal of using some BBs to control ischemia in patients with HTN and LVH (even in the absence of obstructive CAD).

Conclusion: Some BBs ought to be considered to prevent/treat ischemia in patients with HTN LVH (even in the absence of obstructive CAD). Furthermore, LVH and ischemic events are important causes of ventricular tachycardia, ventricular fibrillation, and sudden cardiac death; these events are another reason for recommending certain BBs for HTN LVH.

Antioxidant and Antiangiogenic Effect of Homoleptic Palladium (II) Carboxamide Complex Loaded Chitosan Modified PLGA Nanoparticles: In vitro Evaluation and In vivo Chick Embryo Chorioallantoic Membrane (CAM) Assay

Background: Angiogenesis is a natural and complex mechanism that is regulated by biomolecules formed by the body. Medicinal inorganic chemistry is increasing in popularity due to metal-based compounds, offering significant chances and possibilities for building novel anti-cancer medicines with promising anti-angiogenic effects.

Objective: This study aimed to examine the successful results obtained from treatments with nanoparticle formulations of active drug substances.

Methods: The nanoprecipitation/solvent displacement approach, with some changes, was used to make PLGA-based NPs.

Result: The particle size obtained in the blank formulation was 82.4-473.9 nm, while the particle size in the API-loaded NPs was 193.2-678.0 nm. Among the formulations, NP-950-P, NP-390-P, and NP-350- CSP2 were found to have significant antioxidant potentials with IC50 values of 3.025, 5.198, and 7.4242 μg.mL^-1, respectively, when compared to Vit C. According to the microscopic evaluations, NP-950-P (including Pd(PyCrbx)₂Cl₂ as 50 μg.pellet-1) and NP-950-CSP2 (including Pd(PyCrbx)₂Cl₂ as 50 μg.pellet-1) showed strong anti-angiogenic effect whereas the other NP formulations showed weak antiangiogenic effect when compared with the positive control (±)-Thalidomide at the concentration of 50 μg.pellet^-1.

Conclusion: When the results were examined, it was found that nanoscale drug carrier systems were prepared, and high antioxidant activity and anti-angiogenesis activity were detected, especially in nanoparticles prepared with 950. As per our knowledge, it is the first study in this field that will bring a new perspective to cancer treatment.

An Overview of Thrombin Inhibitors in the Perspective of Structureactivity Relationships

Thrombosis is one of the most important pathogenic factors related to cardiovascular diseases. Presently, thrombin inhibitors have gradually gained prominence in clinical practice due to their unique potential, such as dabigatran. Nevertheless, the risk of bleeding is not completely eliminated, and the threats of gastrointestinal bleeding are even increased in some cases. Therefore, developing new oral thrombin inhibitors with low side effects is urgent. In this paper, we summarized recent advances in the newly synthesized and isolated thrombin inhibitors from 2000 to 2019 and their structure-activity relationships (SARs) along with structure-dependent pharmacokinetic parameters, guiding the next generation of oral thrombin inhibitors.

Effects of Exercise on Vascular Toxicity Associated with Breast Cancer Treatment: A Narrative Review

Breast cancer is the most common cancer among women worldwide, and its incidence is linearly associated with age. The development of cancer treatments has changed the prognosis of this disease. Despite effective treatments, cardiovascular complications in middle-aged and older women have become challenging. Physical exercise is a powerful tool to prevent senescence symptoms and diseases, besides being an essential component for cardiovascular diseases and cancer prevention and treatment. The present narrative review considers the vascular dysfunction associated with breast cancer treatment, specifically chemotherapy and radiotherapy, and the effects of exercise on vascular toxicity. We also explored the mechanisms involved in these responses. The search strategy involved three databases (Pubmed, Scielo, and Web of Science) with the following descriptors: breast cancer, vascular toxicity, physical exercise, chemotherapy, and radiotherapy. The evidence showed that breast cancer patients, especially those under chemotherapy and over 50 years old, have a potential risk of developing vascular dysfunction, which may persist in the long term. Decreases in nitric oxide bioavailability and increases in oxidative stress and pro-inflammatory cytokines might mediate the chemotherapy and radiotherapy- induced vascular dysfunction. Exercise seems to be a promising strategy for managing this risk. However, there is a need for well-constructed studies evaluating vascular toxicity in breast cancer, especially in middle-aged and elderly patients, to establish whether exercise is beneficial.

Tranexamic Acid and Plasminogen/Plasmin Glaring Paradox in COVID-19

Coronavirus disease 2019 (COVID-19) is caused by a severe acute respiratory syndrome, coronavirus type 2 (SARS-CoV-2), leading to acute tissue injury and an overstated immune response. In COVID-19, there are noteworthy changes in the fibrinolytic system with the development of coagulopathy. Therefore, modulation of the fibrinolytic system may affect the course of COVID-19. Tranexamic acid (TXA) is an anti-fibrinolytic drug that reduces the conversion of plasminogen to plasmin, which is necessary for SARS-CoV-2 infectivity. In addition, TXA has anti-inflammatory, anti-platelet, and anti-thrombotic effects, which may attenuate the COVID-19 severity. Thus, in this narrative review, we try to find the beneficial and harmful effects of TXA in COVID-19.

Self-Assembly of Short Amphiphilic Peptides and Their Biomedical Applications

A series of functional biomaterials with different sizes and morphologies can be constructed through self-assembly, among which amphiphilic peptide-based materials have received intense attention. One main possible reason is that the short amphiphilic peptides can facilitate the formation of versatile materials and promote their further applications in different fields. Another reason is that the simple structure of amphiphilic peptides can help establish the structure-function relationship. This review highlights the recent advances in the self-assembly of two typical peptide species, surfactant-like peptides (SLPs) and peptides amphiphiles (PAs). These peptides can self-assemble into diverse nanostructures. The formation of these different nanostructures resulted from the delicate balance of varied non-covalent interactions. This review embraced each non-covalent interaction and then listed the typical routes for regulating these non-covalent interactions, then realized the morphologies modulation of the self-assemblies. Finally, their applications in some biomedical fields, such as the stabilization of membrane proteins, templating for nanofabrication and biomineralization, acting as the antibacterial and antitumor agents, hemostasis, and synthesis of melanin have been summarized. Further advances in the self-assembly of SLPs and PAs may focus on the design of functional materials with targeted properties and exploring their improved properties.

Repurposing of Chemotherapeutics to Combat COVID-19

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is a novel strain of SARS coronavirus. The COVID-19 disease caused by this virus was declared a pandemic by the World Health Organization (WHO). SARS-CoV-2 mainly spreads through droplets sprayed by coughs or sneezes of the infected to a healthy person within the vicinity of 6 feet. It also spreads through asymptomatic carriers and has negative impact on the global economy, security and lives of people since 2019. Numerous lives have been lost to this viral infection; hence there is an emergency to build up a potent measure to combat SARS-CoV-2. In view of the non-availability of any drugs or vaccines at the time of its eruption, the existing antivirals, antibacterials, antimalarials, mucolytic agents and antipyretic paracetamol were used to treat the COVID-19 patients. Still there are no specific small molecule chemotherapeutics available to combat COVID-19 except for a few vaccines approved for emergency use only. Thus, the repurposing of chemotherapeutics with the potential to treat COVID-19 infected people is being used. The antiviral activity for COVID-19 and biochemical mechanisms of the repurposed drugs are being explored by the biological assay screening and structure-based in silico docking simulations. The present study describes the various US-FDA approved chemotherapeutics repositioned to combat COVID-19 along with their screening for biological activity, pharmacokinetic and pharmacodynamic evaluation.

Fresh Frozen Plasma Administration in the NICU: Evidence-based Guidelines

The use of FFP in neonatology should be primarily for neonates with active bleeding and associated coagulopathy. However, since there is limited and poor-quality evidence supporting neonatal FFP transfusion, considerable FFP usage continues to be outside of this recommendation, as documented by neonatal transfusion audits. This review updates the scientific evidence available on FFP use in neonatology and reports the best evidence-practice for the safety of neonates receiving FFP.

Utility of Fibrinogen Levels for Predicting Survival and Functional Outcomes in Patients with Acute Ischemic Stroke: A Meta-Analysis

Background and Objective: Studies on the association between blood fibrinogen levels and adverse outcomes in patients with acute ischemic stroke have produced controversial results. This meta-analysis aimed to examine the association of elevated fibrinogen levels with adverse outcomes in acute ischemic stroke patients.

Methods: Two authors comprehensively searched the articles indexed in PubMed and Embase databases until December 31, 2021. All cohort studies that assessed the value of fibrinogen level in predicting poor functional outcomes or all-cause mortality in acute ischemic stroke patients were included.

Results: Nine studies reporting on ten articles involving 16,998 patients met the inclusion criteria. For the highest versus lowest fibrinogen group, the pooled adjusted risk ratio (RR) was 1.48 (95% confidence intervals [CI] 1.17-1.87) for poor functional outcomes defined by the modified Rankin Scale ≥ 3. In addition, elevated fibrinogen was not significantly associated with an increased risk of all-cause mortality (RR 1.76; 95% CI 1.42-2.20). Subgroup analysis suggested that there was no clear association between elevated fibrinogen levels and PFO in younger acute ischemic stroke patients (RR 1.16; 95% CI 0.87-1.53).

Conclusion: Elevated fibrinogen level at baseline is possibly an independent predictor of short-term poor functional outcome and long-term all-cause mortality, particularly in elderly acute ischemic stroke patients. Blood fibrinogen level may serve as a useful biomarker for risk classification of acute ischemic stroke patients.

Advances in Computational Methods to Discover New NS2B-NS3 Inhibitors Useful Against Dengue and Zika Viruses

The Flaviviridae virus family consists of the genera Hepacivirus, Pestivirus, and Flavivirus, with approximately 70 viral types that use arthropods as vectors. Among these diseases, dengue (DENV) and zika virus (ZIKV) serotypes stand out, responsible for thousands of deaths worldwide. Due to the significant increase in cases, the World Health Organization (WHO) declared DENV a potential threat for 2019 due to being transmitted by infected travelers. Furthermore, ZIKV also has a high rate of transmissibility, highlighted in the outbreak in 2015, generating consequences such as Guillain-Barré syndrome and microcephaly. According to clinical outcomes, those infected with DENV can be asymptomatic, and in other cases, it can be lethal. On the other hand, ZIKV has severe neurological symptoms in newborn babies and adults. More serious symptoms include microcephaly, brain calcifications, intrauterine growth restriction, and fetal death. Despite these worrying data, no drug or vaccine is approved to treat these diseases. In the drug discovery process, one of the targets explored against these diseases is the NS2B-NS3 complex, which presents the catalytic triad His⁵¹, Asp⁷⁵, and Ser¹³⁵, with the function of cleaving polyproteins, with specificity for basic amino acid residues, Lys- Arg, Arg-Arg, Arg-Lys or Gln-Arg. Since NS3 is highly conserved in all DENV serotypes and plays a vital role in viral replication, this complex is an excellent drug target. In recent years, computer-aided drug discovery (CADD) is increasingly essential in drug discovery campaigns, making the process faster and more cost-effective, mainly explained by discovering new drugs against DENV and ZIKV. Finally, the main advances in computational methods applied to discover new compounds against these diseases will be presented here. In fact, molecular dynamics simulations and virtual screening is the most explored approach, providing several hit and lead compounds that can be used in further optimizations. In addition, fragment-based drug design and quantum chemistry/molecular mechanics (QM/MM) provides new insights for developing anti-DENV/ZIKV drugs. We hope that this review offers further helpful information for researchers worldwide and stimulates the use of computational methods to find a promising drug for treating DENV and ZIKV.

The Role of NF-κB in Myocardial Ischemia/Reperfusion Injury

Acute myocardial infarction (AMI) is a threat to human life and physical health worldwide. Timely reperfusion is very important to limit infarct size and protect ischemic myocardium. Unfortunately, it has also caused severer myocardial damage, which is called “myocardial ischemia/ reperfusion injury (MIRI)”. There is no effective clinical treatment for it. Over the past two decades, biological studies of NF-κB have improved the understanding of MIRI. Nuclear Factor-κB (NF-κB) is a major transcription factor associated with cardiovascular health and disease. It is involved in the release of pro-inflammatory factors and apoptosis of cardiomyocytes. Recent studies have shown that inhibition of NF-κB plays a protective role in acute hypoxia and reperfusion injury. Here we review the molecular regulation of NF-κB in MIRI, better understanding of NF-κB signaling mechanisms related to inflammation and crosstalk with endogenous small molecules. We hope this review will aid in improving therapeutic approaches to clinical diagnosing. This review provides evidence for the role of NF-κB in MIRI and supports its use as a therapeutic target.

Extracellular Vesicles as Innovative Tools for Assessing Adverse Effects of Immunosuppressant Drugs

Background: Extracellular vesicles (EVs) are a heterogeneous family of small vesicles released by donor cells and absorbed by recipient cells, which represent important mediators with fundamental roles in both physiological and pathological conditions. EVs are present in a large variety of biological fluids and have a great diagnostic and prognostic value. They have gained the interest of the scientific community due to their extreme versatility. In fact, they allow us to hypothesize new therapeutic strategies since, in addition to being cell signal mediators, they play an important role as biomarkers, drug vehicles, and potential new therapeutic agents. They are also involved in immunoregulation, have the ability to transmit resistance to a drug from one cell to a more sensitive one, and can act as drug delivery systems.

Objective: The main reciprocal interactions between EVs and immunosuppressive drugs will be presented.

Results: The known interactions between EVs and immunosuppressive drugs, in particular cyclosporin, glucocorticoids, rapamycin, methotrexate, cyclophosphamide, eculizumab, infliximab, certolizumab, etanercept, glatiramer acetate, and fingolimod are presented.

Conclusion: This review provides relevant information on the links between EVs and immunosuppressive drugs with a focus on EVs' role as tools to assess the effects of immunosuppressants, suggesting innovative properties and new possible therapeutic uses.

Emerging Trends and their Impacts on Peptic Ulcer Diseases: Treatments and Techniques

Background: Peptic ulcer disease (PUD) is prevalent in almost all parts of the world. PUD complications are a major source of health care expenses; however, they are preventable. The major factors responsible for the incidence of PUD and its complication have changed over the past few decades after the identification of non-steroidal inflammatory drugs (NSAIDs) and Helicobacter pylori bacterial infection along with a marked increase in the use of proton-pump inhibitors (PPIs) as drug therapy. The management of PUD has become more complex and challenging due to antimicrobial resistance.

Objectives: The objective of the study was to highlight current therapy and novel techniques used in the treatment of peptic ulcer diseases.

Methods: An exhaustive literature search has been conducted across PubMed, Google, Scopus and Web of Science electronic databases to extract the crucial information from the relevant literature.

Results: In the present review, we have discussed PUD and its pathophysiology. The recent trends in PUD and possible treatments with novel techniques have also been discussed. The type and presence of ulcers cannot be predicted accurately based on symptoms. The available treatment approaches for peptic ulcers based on their clinical presentation and etiology are anti-secretory therapy, endoscopy to reveal ulcers, followed by drug therapy, and triple therapy for H. pylori infection.

Conclusion: Thus, the popular and effective methods are very beneficial in controlling PUD. The treatment based on diagnosis is the foremost requirement for ameliorating any disorder. In this article, the emerging techniques and advancements in the treatment and diagnosis of PUD have been reviewed.

Direct (New) Oral Anticoagulants (DOACs): Drawbacks, Bleeding and Reversal

Background and Objective: Direct (new) Oral Anticoagulants (DOACs) have emerged as a contemporary and promising option in the treatment of thromboses and VTE, while protecting the coagulation cascade against untoward bleeding events. They are used in the management and prophylaxis of Venous Thromboembolism (VTE) and other thrombotic diseases. The most prominent complication of these agents is bleeding. These agents have similar or lower rates of major intracranial hemorrhages, while they had a higher risk of major gastrointestinal bleeding when compared to warfarin. This manuscript is aimed to revise and update the literature findings to outline the side effects of DOACs in various clinical scenarios.

Methods: A narrative review of currently published studies was performed. Online database searches were performed for clinical trials published before July 2021, on the efficacy and adverse effects attributed to the anticoagulant treatment, especially DOACs. A literature search via electronic databases was carried out, beginning with the usage of the agents in the Western Languages papers. The search terms initially included direct (new) oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, idarucizumab, andexanet, prothrombin complex concentrates, and fresh frozen plasma. Papers were examined for methodological soundness before being included.

Results: Severe bleeding episodes require aggressive interventions for successful management. Therefore, bleeding should be evaluated in special regard to the location and rate of hemorrhage, and total volume of blood loss. Patient's age, weight and organ dysfunctions (e.g., kidney/liver failure or chronic respiratory diseases) directly affect the clinical course of overdose.

Conclusion: Management recommendations for hemorrhage associated with DOAC use vary, depending on the class of the culprit agent (direct thrombin inhibitor vs. FXa inhibitor), the clinical status of the patient (mild/ moderate vs. severe/life-threatening), and capabilities of the institution. Specific reversal agents (i.e., idarucizumab and andexanet alfa) can be used if available, while prothrombin complex concentrates, fresh frozen plasma and/ or tranexamic acid can also be employed as nonspecific replacement agents in the management of DOAC-related bleeding diathesis.

Relationship between Augmentation Index and Wall Thickening Fraction during Hypotension in an Animal Model of Myocardial Ischemia-Reperfusion and Heart Failure

Aims: Non-invasive indices to evaluate left ventricular changes during ischemic heart failure are needed to quantify the myocardial impairment and the effectiveness of therapeutic manoeuvres. The aims of this work were to calculate the Wall Thickening Fraction (WTF) and the Augmentation Index (AIx) and to assess the relationship between WTF and AIx using data obtained from an animal model with heart failure followed by a myocardial ischemia stage and a reperfusion stage.

Methods: Nine Corriedale sheep that had been monitored for 10 minutes during a basal stage underwent 5-minute myocardial ischemia, followed by 60-minute reperfusion. Seven of them were subjected to an induced heart failure through an overdose of halothane, two of which were treated with intra-aortic counterpulsation during the reperfusion stage. The remaining two animals were monitored during their ischemia-reperfusion stage.

Results: Data obtained in the 5 animals suffering from heart failure followed by myocardial ischemia showed that: a) heart failure induction determined decrease in cardiac output, cardiac index and systolic and diastolic aortic pressure (AoP) with respect to their basal values (p<0.05), b) myocardial ischemia decreased the WTF compared with basal and induced heart failure values (p<0.05), c) during the reperfusion stage accompanied by induced heart failure, WTF increased with respect to values observed during the ischemia induction stage (p<0.05); nevertheless, basal values were not recovered after reperfusion (p<0.05). During this 60-minute stage, systolic and diastolic AoP values were lower (p<0.05) than those at the basal stage.

Conclusion: AIx and WTF values calculated from synchronically recorded values of aortic pressure and left ventricular wall thickness during the reperfusion stage in all animals (n = 9) showed a negative correlation (p<0.05). Analysed data provided evidence of a negative relationship between a left ventricular index of myocardial function and an arterial index obtained from AoP waves.

HPMC- A Marvel Polymer for Pharmaceutical Industry-Patent Review

At the present time, designing of defined release dosage forms, either controlled, sustained, modified, are gaining much importance. For the development of such delivery systems, proper blend of polymers is required so that drug release occurs by polymer erosion, swelling, diffusion/ dissolution. HPMC (Hydroxypropyl Methylcellulose) is the most commonly used cellulosic polymer available in various grades to develop such types of systems. Depending upon the molecular weight and viscosity chosen, it can be applied for emulsification, adhesion, bonding, thickening, suspension, film forming and gelation. It consists of polymeric units linked together, which retain water, thereby acting as an excellent hydrophilic gel forming polymer. It generally hydrates on the outer surface to form a gelatinous layer. It swells, expands upon contact with water and releases the drug in predetermined manner initially and then forms viscous gel to control the release further. The objective of the present review is to overview the recent patents and articles of HPMC, its properties, grades and its use in various drug delivery systems and as a binder, dispersing agent, bioavailability enhancer and as capsule forming material have been identified and reviewed.

Review of the Biological Activity of Maslinic Acid

Since the discovery of (2α,3β)-2,3-dihydroxyolean-12-en-28-oic acid, also known as maslinic acid, many studies have examined its biological activity, which has been shown to promote health and resist various diseases. This article focuses on previous research on maslinic acid and mainly reviews its reported effects on cardiovascular diseases, neuroprotection, diabetes, cancer, inflammation, and pathogens. Maslinic acid exerts positive effects on both cell and animal models of disease. Although its mechanism of action has not yet been completely elucidated, maslinic acid is feasible as a nutritional additive and has the potential to be developed as a drug.

Achillea millefolium E.Mey: Phytochemistry and Pharmacological Profile

A staggering 80% of the population in developing countries relies on herbal medicine for treatment of various diseases and disorders. Among them, Achillea millifolium from Asteraceae family is one medicinally important plant called as “yarrow” and reported as being used in folklore medicine for ailments such as skin inflammations, spasmodic and gastrointestinal disorders, as well as hepatobiliary complaints. Therefore, a plethora of scientific studies have been conducted to give substance to its ethnomedicinal claims, and in addition to that, even more, biological functions such as its hypotensive, antioxidant, antimicrobial, vasoprotective, antiulcer and antis-permatogenic activities, scientifically established. Our review comprehensively collects recent phytochemical and pharmacological activities of Achillea millifolium and should, therefore, act a suitable reference for future research into the plant’s phytochemical profiling and overall pharmacological evaluation.

COVID-19 Related Coagulopathy: What is Known Up to Now

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has been a global challenge. The complicated forms of the Coronavirus Disease 2019 (COVID- 19) can evolve to multiple-organ failure, including several coagulopathies related to a sudden worsening of respiratory status. This article aimed to review studies about hematological and hemostatic laboratory disorders directly related to COVID-19 and to discuss how SARS-CoV- 2 causes these abnormalities. The coagulation cascade model is associated with both COVID- 19 and pulmonary involvement. Laboratory changes are relevant to evaluate the coagulation state - D-dimer, prothrombin time (PT), Activated Partial Thromboplastin Time (APTT), platelet count and fibrinogen. Pregnant women and patients in Extracorporeal Membrane Oxygenation (ECMO) need special attention. Prophylactic interventions for COVID-19 coagulopathy should consider patients at risk for thrombotic events and potential contraindications. The mechanisms exerted by SARS-CoV-2 that impairs hemostatic balance include endothelial injury, inflammation, and activation of the immune and complement systems. For diagnosis of coagulopathy, mainly D-dimer, but also PT, APTT and FDP, should be evaluated in COVID-19 patients. Intervention possibilities vary between low-molecular-weight heparin (LMWH) and Unfractionated Heparin (UFH). Until now, there is sufficient evidence that acutely-ill patients with risk factors for coagulopathies will benefit from thrombophylaxis during hospitalization and post-discharge, but not all patients.

Gene Expression Profiling Analysis to Identify Key Genes and Underlying Mechanisms in Meniscus of Osteoarthritis Patients

Background: Osteoarthritis (OA) is a degenerative joint disease that seriously affects the quality of life of elderly. Regrettably, the pathological mechanism for OA has not yet been fully elucidated.

Methods: This study is committed to distinguishing key genes and the underlying mechanisms for OA. Raw data was acquired from the Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs), hub genes, and key genes through bioinformatics analysis. Subsequently, we predicted the microRNAs (miRNAs) and circular RNAs (circRNAs) associated with these key genes that may play key roles in OA using web tools. We also constructed a protein- drug network and found potentially effective drugs by analyzing the relationships between the drugs and the key genes.

Results: The analysis revealed 360 DEGs, 24 hub genes, and 15 key genes enriched in many categories potentially related to the pathological mechanism of OA. hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p were predicted to be important miRNAs for OA, while hsa_circ_0025119, hsa_circ_0025113, hsa_circ_0009897, and hsa_circ_0002447 were predicted to be the most important circRNAs. Further studies indicated that Ocriplasmin and Collagenase clostridium histolyticum may be effective drugs for the treatment of OA. Finally, CD34 and VWF were inferred to be the most meaningful biomarkers for OA.

Conclusion: In conclusion, we determined the underlying key genes, miRNAs, and circRNAs for OA, predicted potentially effective drugs, and identified the most meaningful biomarkers for the disease. Our findings may provide insight into the pathological mechanism of OA and guide future research.

Isolation and Characterization of CD39-like Phosphodiesterase (Cc-PDE) from Cerastes cerastes Venom: Molecular Inhibitory Mechanism of Antiaggregation and Anticoagulation

Background: Cerastes cerastes venom contains several bioactive proteins with inhibitory potential of platelet aggregation and blood coagulation.

Objective: The current study deals with purification, characterization and determination of structural properties of Cc-PDE, the first phosphodiesterase from Cerastes cerastes venom.

Material and Methods: The purification process consists of three successive chromatographies including G75-Sephadex size exclusion, DEAE exchange chromatography and affinity using Sildenafil as a main PDEs’ specific inhibitor. The amino acid sequence of purified Cc-PDE was determined by liquid chromatography coupled off line to MALDI-TOF/TOF. Modeling and structural features were obtained using several bioinformatics tools. In vivo and in vitro antiplatelet aggregation and anticoagulant assays were performed.

Results: Cc-PDE (73 506.42 Da) is a 654-residue single polypeptide with 1-22 signal peptide and it is characterized by the presence of predominant basic amino acids suitable to alkaline pI (8.17). Cc-PDE structure is composed of β-strands (17%) and α-helices (24%) and it shares a high identity with homologous snake venom PDEs. Cc-PDE hydrolyzes both Bis-p-nitrophenyl phosphate (Km = 2.60 ± 0.95 mM, Vmax = 0.017 ± 0.002569 μmol.min-1) and p-nitrophenyl phosphate (Km = 7.13 mM ± 0.04490 mM, Vmax = 0.053 ±0.012 μmol.min-1). Cc-PDE prevents ADP- and ATP-induced platelet aggregation by hydrolyzing ADP and ATP, reducing surface P-selectin expression and attenuating platelet function. In addition, Cc-PDE inhibits coagulation factors involved in the intrinsic pathway demonstrated by a significant prolongation of activated partial thromboplastin time and in vivo long-lasting anticoagulation.

Conclusion: The obtained results revealed that Cc-PDE may have a therapeutic potential and could be a remedy for thromboembolic diseases as an alternative of anticoagulant and antiplatelet aggregation chemical origins.

Nanomedicine against Alzheimer’s and Parkinson’s Disease

Alzheimer’s and Parkinson’s are the two most rampant neurodegenerative disorders worldwide. Existing treatments have a limited effect on the pathophysiology but are unable to fully arrest the progression of the disease. This is due to the inability of these therapeutic molecules to efficiently cross the blood-brain barrier. We discuss how nanotechnology has enabled researchers to develop novel and efficient nano-therapeutics against these diseases. The development of nanotized drug delivery systems has permitted an efficient, site-targeted, and controlled release of drugs in the brain, thereby presenting a revolutionary therapeutic approach. Nanoparticles are also being thoroughly studied and exploited for their role in the efficient and precise diagnosis of neurodegenerative conditions. We summarize the role of different nano-carriers and RNAi-conjugated nanoparticle-based therapeutics for their efficacy in pre-clinical studies. We also discuss the challenges underlying the use of nanomedicine with a focus on their route of administration, concentration, metabolism, and any toxic effects for successful therapeutics in these diseases.

Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio as Biomarkers for Cardiovascular Surgery Procedures: A Literature Review

Background: Neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) have been studied so far as prognostic factors of cardiovascular diseases. Their role interplayed with endothelial inflammation has emerged as optimal predictors for major cardiovascular disease events and prognostic factors for post-procedural outcomes.

Methods: A review of the current literature was undertaken to investigate the relationship between NLR and PLR with percutaneous, cardiac surgery, and vascular surgery procedures.

Results: Our findings show that perioperative NLR and PLR levels are significantly correlated with patient morbidity and mortality rates.

Conclusion: These biomarkers have several attractive characteristics, as they are inexpensive and quickly available, and they can contribute to the early identification of patients at high risk for periprocedural adverse events.

Snake Venom Proteins Isolated from Tunisian Vipers: Pharmacological and Therapeutic Overview

The venoms of Tunisian wildlife snakes are complex mixtures containing proteins/ peptides and non-protein molecules. Proteins and peptides are the most abundant compounds responsible for the biological effects of venoms. Snake venoms proteins have enzymatic or nonenzymatic activities, which are grouped into different families, including C-type lectin proteins, disintegrins (long, medium and short disintegrins), Kunitz-type serine protease inhibitors, natriuretic- like peptides, vascular endothelial growth factor-related proteins, L-amino acid oxidases, phospholipases A2 and serine proteinases. With technological advancements, the toxic effects of venoms were turned into potential benefits for clinical diagnosis, basic research and development of new research tools and drugs of potential clinical use. Our research team has shown that Macrovipera lebetina and Cerastes cerastes venom components of Tunisian wildlife snakes had great potential for the development of new drugs for the treatment of cancer, angiogenesis disorders or cardiovascular diseases. This review is an overview of snake venom proteins from Macrovipera lebetina and Cerastes cerastes and their biochemical, pharmacological and molecular characterization and their importance as protein resources with therapeutic potential.

Treatment Strategies Against Diabetic Foot Ulcer: Success so Far and the Road Ahead

Background: Diabetic foot ulcer (DFU) is one of the leading complications of type-2 diabetes mellitus. It is associated with neuropathy and peripheral arterial disease of the lower limb in patients with diabetes. There are four stages of wound healing, namely hemostasis phase, inflammatory phase, proliferative phase and maturation phase. In the case of DFU, all these stages are disturbed which lead to delay in healing and consequently to lower limb amputation. Conventional dosage forms like tablets, creams, ointments, gels and capsules have been used for the treatment of diabetic foot ulcer for many years.

Introduction: In this review, the global prevalence as well as etiopathogenesis related to diabetic foot ulcer have been discussed. The potential role of various synthetic and herbal drugs, as well as their conventional dosage forms in the effective management of DFU have been discussed in detail.

Methods: Structured search of bibliographic databases from previously published peer-reviewed research papers was explored and data has been represented in terms of various approaches that are used for the treatment of DFU.

Results: About 148 papers, including both research and review articles, were included in this review to produce a comprehensive as well as a readily understandable article. A series of herbal and synthetic drugs have been discussed along with their current status of treatment in terms of dose and mechanism of action.

Conclusion: DFU has become one of the most common complications in patients having diabetes for more than ten years. Hence, understanding the root cause and its successful treatment is a big challenge because it depends upon multiple factors such as the judicious selection of drugs as well as proper control of blood sugar level. Most of the drugs that have been used so far either belong to the category of antibiotics, antihyperglycaemic or they have been repositioned. In clinical practice, much focus has been given to dressings that have been used to cover the ulcer. The complete treatment of DFU is still a farfetched dream to be achieved and it is expected that combination therapy of herbal and synthetic drugs with multiple treatment pathways could be able to offer better management of DFU.

Anti-platelet Drug-loaded Targeted Technologies for the Effective Treatment of Atherothrombosis

Atherothrombosis results from direct interaction between atherosclerotic plaque and arterial thrombosis and is the most common type of cardiovascular disease. As a long term progressive disease, atherosclerosis frequently results in an acute atherothrombotic event through plaque rupture and platelet-rich thrombus formation. The pathophysiology of atherothrombosis involves cholesterol accumulation endothelial dysfunction, dyslipidemia, immuno-inflammatory, and apoptotic aspects. Platelet activation and aggregation is the major cause for stroke because of its roles, including thrombus, contributing to atherosclerotic plaque, and sealing off the bleeding vessel. Platelet aggregates are associated with arterial blood pressure and cardiovascular ischemic events. Under normal physiological conditions, when a blood vessel is damaged, the task of platelets within the circulation is to arrest the blood loss. Antiplatelet inhibits platelet function, thereby decreasing thrombus formation with complementary modes of action to prevent atherothrombosis. In the present scientific scenario, researchers throughout the world are focusing on the development of novel drug delivery systems to enhance patient’s compliance. Immediate responding pharmaceutical formulations become an emerging trend in the pharmaceutical industries with better patient compliance. The proposed review provides details related to the molecular pathogenesis of atherothrombosis and recent novel formulation approaches to treat atherothrombosis with particular emphasis on commercial formulation and upcoming technologies.

Hyaluronic Acid/Parecoxib-Loaded PLGA Microspheres for Therapy of Temporomandibular Disorders

Objective: This study aimed to fabricate Hyaluronic Acid (HA)/parecoxib-loaded PLGA microspheres for the treatment of Temporomandibular Disorders (TMD) and investigate the in vitro and in vivo effect of the microsphere system to solve the issues of poor drug delivery and short duration on drug concentration in conventional TMD therapy.

Methods: The microspheres were prepared by the double emulsion (w/o/w) method. Various formulations were compared in terms of particle size, drug loading rate and encapsulation rate. Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC) and FT-IR spectroscopy were performed to evaluate physicochemical properties. The drug release behavior of microspheres and toxicity assay on synovial cells were investigated. The in vitro anti-inflammatory effect on inflammatory markers, such as IL-1β, TNF-α and COX-2, was assessed by real-time PCR. Then, the in vivo therapeutic effect of microspheres was investigated using mechanically-induced rat synovitis model. Protein levels of inflammatory cytokines (IL-1β, TNF-α and COX-2) from TMJ periarticular tissues were quantified by Enzyme-Linked Immunosorbent Assay (ELISA).

Results: The results showed that microspheres were morphologically regular, smooth and non-cohesive. The average particle size of the microspheres was (25.32 ± 1.01) μm. The drug loading rate of parecoxib was 17.12%-20.95% with encapsulation efficiency reaching 51.9%-54.7%. In vitro drug release tests showed a successful sustained release over 28 days with a burst of 19.98% of the total drug substance. Treatment with HA/parecoxib-loaded PLGA microspheres declined the mRNA expression of IL-1β, TNF-α and COX-2 induced by LPS in articular synovial cells. Moreover, in vivo results demonstrated that the intra-articular microspheres significantly reduced protein levels of inflammatory cytokines (IL-1β, TNF-α and COX-2) for more than two weeks and stopped the mechanically-induced synovitis in its tracks in rat models.

Conclusion: The study presented new and potential insights into treatments of TMD using PLGA microspheres loaded with HA and parecoxib as a successful drug delivery system.

The Protective of Baicalin on Myocardial Ischemia-Reperfusion Injury

Background: The aim of this study was to explore the inhibitory effect of baicalin on myocardial apoptosis induced by Ischemia-Reperfusion (I/R).

Methods: Sprague Dawley rats' heart and myocardial cells I/R model were established in vivo and vitro, then 100 mg/kg and 10 μmol/l baicalin were administrated, respectively. The experiment was randomly divided into 4 groups (n=10): Control; I/R; IR+DMEM; and I/R+baicalin groups. Postoperation, the Left Ventricular (LV) End-Diastolic Pressure (LVEDP), the maximum velocity of LV contraction (dP/dtmax) and the maximum velocity of LV diastole (dP/dtmin) were recorded by the transthoracic echocardiography; the myocardial apoptosis percentage was analyzed by Annexin VFITC/ PI and TUNEL staining, and the apoptosis gene and protein were detected by RT-PCR and western blot. Furthermore, the protein expression of the calcium-sensing receptor (CaSR) and ERK1/2 phosphorylation were observed by western blot and Fura-2-acetoxymethyl ester. Moreover, primary rats’ cardiomyocytes were cultured and ERK1/2 specific inhibitor PD98059 was added to the culture medium. The cell survival rate, vitality and apoptosis were detected by MTT, lactate dehydrogenase (LDH) and TUNEL staining assay Kit, respectively.

Results: Our present study showed that baicalin significantly improved LV hemodynamic parameters and myocardial apoptosis in myocardial I/R injury rats. Furthermore, we found that baicalin could down-regulate the protein expression of CaSR, but up-regulate the protein expression of ERK1/2. Furthermore, when the cells were pretreated with ERK1/2 inhibitor PD98059, the cells survival rate significantly decreased, but LDH activity and apoptosis significantly increased. The results indicated that the effect of baicalin on myocardial I/R injury could be inhibited by ERK1/2 inhibitor.

Conclusion: In conclusion, our data suggests that baicalin attenuates I/R-induced myocardial injury maybe through the suppression of the CaSR/ERK1/2 signaling pathway.

‘Do not Do’ Recommendations in Hemophilia

Background: It is important to discard those practices that do not add value. As a result, several initiatives have emerged. All of them try to improve patient safety and the use of health resources.

Purpose: To present a compendium of "do not do recommendations" in the context of hemophilia.

Methods: A review of the literature and current clinical guidelines has been made, based on the best evidence available to date.

Results: The following 13 recommendations stand out: 1) Do not delay the administration of factor after trauma; 2) do not use fresh frozen plasma or cryoprecipitate; 3) do not use desmopressin in case of hematuria; 4) do not change the product in the first 50 prophylaxis exposures; 5) do not interrupt immunotolerance; 6) do not administer aspirin or NSAIDs; 7) do not administer intramuscular injections; 8) do not do routine radiographs of the joint in case of acute hemarthrosis; 9) Do not apply closed casts for fractures; 10) do not discourage the performance of physical activities; 11) do not deny surgery to a patient with an inhibitor; 12) do not perform instrumental deliveries in fetuses with hemophilia; 13) do not use factor IX (FIX) in patients with hemophilia B with inhibitor and a history of anaphylaxis after administration of FIX.

Conclusion: The information mentioned previously can be useful in the management of hemophilia, from different levels of care. As far as we know, this is the first initiative of this type regarding hemophilia.

Stroke Following Successful PTMC in a Patient with Severe Mitral Stenosis: A Case Report and Presenting A Simple Stepwise Approach to PTMC-related Stroke

Stroke following percutaneous trans-septal mitral commissurotomy (PTMC) is an unusual complication that could significantly affect the quality of life of the patients, particularly the young and active ones. We present a middle-aged woman who experienced stroke following PTMC and successfully treated with thrombolytic therapy regarding the potential adverse effects of this type of therapy. Also, we present a simple novel stepwise clinical approach for PTMC-related stroke.

The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury

Ginseng is a traditional medicine with a complex chemical composition, wide bioactivity and unique pharmacological action. Many studies have confirmed that ginsenosides are the active ingredients of ginseng, and ginsenosides have always been the focus of different researchers. With the development of modern separation and analysis technology, more than 150 kinds of ginsenosides have been isolated. The ginsenosides Rb1, Rb2, Rc, Rg1 and Re account for more than 80% of total ginsenosides, and other saponins, such as Rd, Rg3 and Rh2, which are minor constituents, accounting for only a small portion of the total amount. In recent years, ginsenosides have been found to possess strong pharmacological activities, such as antioxidation, clearing of oxygen free radicals, reducing calcium overload and anti-apoptosis. Ginsenosides play a protective role in ischemia-reperfusion injury. This paper reviews the protective effects of ginsenosides on myocardial ischemia and ischemiareperfusion injury.

Herbal Medicine for Slowing Aging and Aging-associated Conditions: Efficacy, Mechanisms and Safety

Aging and aging-associated diseases are issues with unsatisfactory answers in the medical field. Aging causes important physical changes which, even in the absence of the usual risk factors, render the cardiovascular system prone to some diseases. Although aging cannot be prevented, slowing down the rate of aging is entirely possible to achieve. In some traditional medicine, medicinal herbs such as Ginseng, Radix Astragali, Ganoderma lucidum, Ginkgo biloba, and Gynostemma pentaphyllum are recognized by the “nourishing of life” and their role as anti-aging phytotherapeutics is increasingly gaining attention. By mainly employing PubMed here we identify and critically analysed 30 years of published studies focusing on the above herbs' active components against aging and aging-associated conditions. Although many plant-based compounds appear to exert an anti-aging effect, the most effective resulted in being flavonoids, terpenoids, saponins, and polysaccharides, which include astragaloside, ginkgolide, ginsenoside, and gypenoside specifically covered in this review. Their effects as antiaging factors, improvers of cognitive impairments, and reducers of cardiovascular risks are described, as well as the molecular mechanisms underlying the above-mentioned effects along with their potential safety. Telomere and telomerase, PPAR-α, GLUTs, FOXO1, caspase-3, bcl-2, along with SIRT1/AMPK, PI3K/Akt, NF-κB, and insulin/insulin-like growth factor-1 pathways appear to be their preferential targets. Moreover, their ability to work as antioxidants and to improve the resistance to DNA damage is also discussed. Although our literature review indicates that these traditional herbal medicines are safe, tolerable, and free of toxic effects, additional well-designed, large-scale randomized control trials need to be performed to evaluate short- and long-term effects and efficacy of these medicinal herbs.

Isoform-Selective PI3K Inhibitors for Various Diseases

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

NAFLD in the 20’s. From Epidemiology to Pathogenesis and Management of Nonalcoholic Fatty Liver Disease

Anticancer Potential of Dietary Natural Products: A Comprehensive Review

Nature is a rich source of natural drug-like compounds with minimal side effects. Phytochemicals better known as “Natural Products” are found abundantly in a number of plants. Since time immemorial, spices have been widely used in Indian cuisine as flavoring and coloring agents. Most of these spices and condiments are derived from various biodiversity hotspots in India (which contribute 75% of global spice production) and form the crux of India’s multidiverse and multicultural cuisine. Apart from their aroma, flavor and taste, these spices and condiments are known to possess several medicinal properties also. Most of these spices are mentioned in the Ayurveda, the indigenous system of medicine. The antimicrobial, antioxidant, antiproliferative, antihypertensive and antidiabetic properties of several of these natural products are well documented in Ayurveda. These phytoconstituemts are known to act as functional immunoboosters, immunomodulators as well as anti-inflammatory agents. As anticancer agents, their mechanistic action involves cancer cell death via induction of apoptosis, necrosis and autophagy. The present review provides a comprehensive and collective update on the potential of 66 commonly used spices as well as their bioactive constituents as anticancer agents. The review also provides an in-depth update of all major in vitro, in vivo, clinical and pharmacological studies done on these spices with special emphasis on the potential of these spices and their bioactive constituents as potential functional foods for prevention, treatment and management of cancer.

Factors Affecting the Metabolite Productions in Endophytes: Biotechnological Approaches for Production of Metabolites

Since 1980, many species and different strains from endophytic genera of Phomopsis, Fusarium, Pestaliopsis and Aspergillus have been studied because of their ability to produce medicinal compounds found in their host plants. Some of these medicinal agents such as Taxol, Brefeldine A, Camptothecin and Podophyllotoxin are being produced in large-scale after an optimization process. However, the potential of fungal endophytes to produce host-like medicinal compounds remains largely unexplored.

A Comprehensive Review of the Genus Pyrola Herbs in Traditional Uses, Phytochemistry and Pharmacological Activities

Pyrola (Pyrolaceae), also known as Luxiancao/鹿衔草in China, was recorded in Sheng Nong’s Herbal Classic listed in top grade. Pyrola herbs were used as medicinal plants for a long history with wide-ranging activities such as nourishing kidney-yang, strengthening muscles and bones, activating blood, stopping bleeding, dispelling rheumatism, and eliminating dampness. Currently, the research on Pyrola plants is increasing year by year but there is no comprehensive and detailed review concerning genus Pyrola. This review aims to sum up the updated and comprehensive information about botany and traditional use, phytochemistry, pharmacological activities and safety by analyzing the information available on Pyrola plants via internationally accepted scientific databases. Collectively, more than 100 compounds have been isolated from the Pyrola plants. Furthermore, a total of 33 prescriptions containing Pyrola plants are compiled in this review. Pyrola plants are used as indispensable agents in traditional Chinese medicine due to its activities of antimicrobial, anti-inflammatory, antioxidant, lipidlowering, cardiovascular and cerebrovascular protection, proliferation of osteoblasts promoting, antineoplastic and etc. Further work should be developed on the elucidation of structure-function relationship, understanding of multi-target pharmacological effects, as well as developing its application both in clinical usage and functional food for research and development of Pyrola plants.

Role of Both Protein C and Antithrombin III as Predictors of Stage of Liver Disease in Chronic Viral Hepatitis B or C Infected Patients

Background & Aims: Chronic liver disease is characterized by complex hemostatic disorders because the liver is the site where most of the coagulation factors and their inhibitors are synthesized. The aim of this study was the evaluation of protein C and antithrombin III in different stages of chronic hepatitis B and C and to determine their possible role as markers of liver cell damage in different clinical stages.

Methods: The study included 60 subjects who were subdivided into 4 groups: (Group I): 15 patients diagnosed as chronic viral hepatitis B or C, (Group II): 15 patients with compensated liver cirrhosis, (Group III): 15 patients with decompensated liver cirrhosis, and (Group IV) (control group): 15 healthy individuals. History taking, clinical examination and abdominal ultrasonography were made for all subjects. Investigations were done in the form of liver function tests (ALT, AST, ALP, serum bilirubin, and serum albumin), PT, PTT, CBC. Plasma levels of Antithrombin III & protein C were estimated by automated Stago compact coagulation analyzer.

Results: In all patient groups, the mean value of Protein C showed significant decrease when compared to control group, mean value of antithrombin III showed a significant decrease in compensated and decompensated subjects when compared to chronic hepatitis and control groups. Antithrombin III and protein C showed a significant negative correlation with (ALT, AST, PT, PTT, INR). However, this correlation was positive with Albumin.

Conclusion: Antithrombin III and protein C are natural anticoagulants and can be considered as markers of different stages of chronic liver disease. This is supported further by the comparison between the levels of these parameters and clinical stages of liver disease. Protein C is more sensitive than ATIII as a marker of hepatocellular damage.

Herbal Medicine of the 21st Century: A Focus on the Chemistry, Pharmacokinetics and Toxicity of Five Widely Advocated Phytotherapies

Widely advocated for their health benefits worldwide, herbal medicines (HMs) have evolved into a billion dollar generating industry. Much is known regarding their wellness inducing properties, prophylactic and therapeutic benefits for the relief of both minor to chronic ailment conditions given their long-standing use among various cultures worldwide. On the other hand, their equally meaningful chemistry, pharmacokinetic profile in humans, interaction and toxicity profile have been poorly researched and documented. Consequently, this review is an attempt to highlight the health benefits, pharmacokinetics, interaction, and toxicity profile of five globally famous HMs. A systematic literature search was conducted by browsing major scientific databases such as Bentham Science, SciFinder, ScienceDirect, PubMed, Google Scholar and EBSCO to include 196 articles. In general, ginsenosides, glycyrrhizin and curcumin demonstrate low bioavailability when orally administered. Ginkgo biloba L. induces both CYP3A4 and CYP2C9 and alters the AUC and Cmax of conventional medications including midazolam, tolbutamide, lopinavir and nifedipine. Ginsenosides Re stimulates CYP2C9, decreasing the anticoagulant activity of warfarin. Camellia sinensis (L.) Kuntze increases the bioavailability of buspirone and is rich in vitamin K thereby inhibiting the activity of anticoagulant agents. Glycyrrhiza glabra L. displaces serum bound cardiovascular drugs such as diltiazem, nifedipine and verapamil. Herbal medicine can directly affect hepatocytes leading to hepatoxicity based on both intrinsic and extrinsic factors. The potentiation of the activity of concurrently administered conventional agents is potentially lethal especially if the drugs bear dangerous side effects and have a low therapeutic window.

Vasopressin & Oxytocin in Control of the Cardiovascular System: An Updated Review

Since the discovery of vasopressin (VP) and oxytocin (OT) in 1953, considerable knowledge has been gathered about their roles in cardiovascular homeostasis. Unraveling VP vasoconstrictor properties and V1a receptors in blood vessels generated powerful hemostatic drugs and drugs effective in the treatment of certain forms of circulatory collapse (shock). Recognition of the key role of VP in water balance via renal V2 receptors gave birth to aquaretic drugs found to be useful in advanced stages of congestive heart failure. There are still unexplored actions of VP and OT on the cardiovascular system, both at the periphery and in the brain that may open new venues in treatment of cardiovascular diseases. After a brief overview on VP, OT and their peripheral action on the cardiovascular system, this review focuses on newly discovered hypothalamic mechanisms involved in neurogenic control of the circulation in stress and disease.

Recognition of Plasminogen Activator Inhibitor Type 1 as the Primary Regulator of Fibrinolysis

The fibrinolytic system consists of a balance between rates of plasminogen activation and fibrin degradation, both of which are finely regulated by spatio-temporal mechanisms. Three distinct inhibitors of the fibrinolytic system that differently regulate these two steps are plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin, and thrombin activatable fibrinolysis inhibitor (TAFI). In this review, we focus on the mechanisms by which PAI-1 governs total fibrinolytic activity to provide its essential role in many hemostatic disorders, including fibrinolytic shutdown after trauma. PAI-1 is a member of the serine protease inhibitor (SERPIN) superfamily and inhibits the protease activities of plasminogen activators (PAs) by forming complexes with PAs, thereby regulating fibrinolysis. The major PA in the vasculature is tissue-type PA (tPA) which is secreted from vascular endothelial cells (VECs) as an active enzyme and is retained on the surface of VECs. PAI-1, existing in molar excess to tPA in plasma, regulates the amount of free active tPA in plasma and on the surface of VECs by forming a tPA-PAI-1 complex. Thus, high plasma levels of PAI-1 are directly related to attenuated fibrinolysis and increased risk for thrombosis. Since plasma PAI-1 levels are highly elevated under a variety of pathological conditions, including infection and inflammation, the fibrinolytic potential in plasma and on VECs is readily suppressed to induce fibrinolytic shutdown. A congenital deficiency of PAI-1 in humans, in turn, leads to life-threatening bleeding. These considerations support the contention that PAI-1 is the primary regulator of the initial step of fibrinolysis and governs total fibrinolytic activity.

Toxins of Animal Venoms and Inhibitors: Molecular and Biotechnological Tools Useful to Human and Animal Health

Venoms and Isolated Toxins from Snakes of Medical Impact in the Northeast Argentina: State of the Art. Potential Pharmacological Applications

Among the ophidians that inhabit the Northeast of Argentina, the genus Bothrops such as B. alternatus and B. diporus species (also known as yararás) and Crotalus durisus terrificus (named cascabel), represent the most studied snake venom for more than thirty years. These two genera of venomous snakes account for the majority of poisonous snake envenomations and therefore, constitute a medical emergency in this region. This review presents a broad description of the compiled knowledge about venomous snakebite: its pathophysiological action, protein composition, isolated toxins, toxin synergism, toxin-antitoxin cross-reaction assays. Properties of some isolated toxins support a potential pharmacological application.

Utilization of the Plant Clusia Fluminensis Planch & Triana Against Some Toxic Activities of the Venom of Bothrops jararaca and B. jararacussu Snake Venom Toxic Activities

Background: In Brazil, the Bothrops genus accounts for 87% of registered snakebites, which are characterized by hemorrhage, tissue necrosis, hemostatic disturbances, and death. The treatment recommended by governments is the administration of specific antivenoms. Although antivenom efficiently prevents venom-induced lethality, it has limited efficacy in terms of preventing local tissue damage. Thus, researchers are seeking alternative therapies able to inhibit the main toxic effects of venoms, without compromising safety.

Objective: The study aimed to test the ability of aqueous extracts of leaves, stems, and fruits of the plant Clusia fluminensis to neutralize some toxic effects induced by the venoms of Bothrops jararaca and Bothrops jararacussu.

Methods: The plant extracts were incubated with venoms for 30 min. at 25 °C, and then in vitro (coagulant and proteolytic) and in vivo (hemorrhagic, myotoxic, and edematogenic) activities were evaluated. In addition, the extracts were administered to animals (by oral, intravenous or subcutaneous routes) before or after the injection of venom samples, and then hemorrhage and edema assays were performed. In addition, a gel solution of the fruit extract was produced and tested in terms of reducing hemorrhage effects. A chemical prospection was performed to identify the main classes of compounds present in the extracts.

Results: All the extracts inhibited the activities of the two venoms, regardless of the experimental protocol or route of administration of the extracts. Moreover, the gel of the fruit extract inhibited the venom-induced-hemorrhage. The extracts comprised of tannins, flavonoids, saponins, steroids, and terpenoids.

Conclusion: Antivenom properties of C. fluminensis extracts deserve further investigation in order to gain detailed knowledge regarding the neutralization profile of these extracts.

Impaired Myocardial MIF/AMPK Activation Aggravates Myocardial Ischemia Reperfusion Injury in High-Fat Diet-Induced Obesity

Background: Obese patients are more sensitive to myocardial ischemia, which has been linked with high mortality rates. The following study investigates the effects of impaired macrophage Migration Inhibitory Factor (MIF)/AMP-Activated Protein Kinase (AMPK) activation on increased susceptibility to myocardial ischemia/reperfusion (I/R) in high-fat diet-induced obesity.

Methods: Male C57BL/6J mice were fed with a normal diet (10% kcal as fat, lean group) or a high-fat diet (60kcal as fat, obese group) for 12 consecutive weeks. To detect the MIF expression and AMPK activation in response to I/R in isolated hearts from lean and obese mice, myocardial samples were collected from left ventricular areas at different time points. To determine whether MIF supplementation is protective against I/R injury, recombined MIF (10 ng/mL) was applied before ischemia. Myocardial infarct size was estimated by triphenyltetrazolium staining. Western blot was used to detect myocardial MIF expression, AMPK activation and membrane glucose transporter 4 (Glut4) expression.

Results: The expression of MIF was remarkably higher in obese group compared to lean group. Ischemia increased myocardial MIF expression and phosphorylation of AMPK in lean mice, whereas it had no significant effect on obese mice. Furthermore, administration of recombinant MIF increased ischemic AMPK activation and membrane Glut4 expression in both lean and obese mice, while it reduced the infarct size in lean mice only.

Conclusion: An impaired MIF/AMPK activation response and consequent reduced membrane Glut4 expression may play an important role in increasing myocardial susceptibility to I/R in obesity.

Computational Protein-Protein Docking Reveals the Therapeutic Potential of Kunitz-type Venom against hKv1.2 Binding Sites

Background & Objective: Kunitz-type venoms are bioactive proteins isolated from a wide variety of venomous animals. These venoms are involved in protease inhibitory activity or potassium channel blocking activity. Therefore, they are reported as an important source for lead drug candidates towards protease or channel associated diseases like neurological, metabolic and cardiovascular disorders.

Methods: This study aimed to check the inhibitory action of Kunitz-type venoms against potassium channels using computational tools.

Results: Among potassium channels, Human Voltage-Gated Potassium Channel 1.2 (hKv1.2) was used as a receptor whereas Kunitz-type peptides from the venoms of various species were selected as ligand dataset.

Conclusion: This study helped in finding the binding interface between the receptor and ligand dataset for their potential therapeutic use in treating potassium channelopathies.

The Effects of Hemocoagulase on Coagulation Factors in an Elderly Patient with Upper Gastrointestinal Hemorrhage: A Case Report

Background: Hemocoagulase agkistrodon has been widely used for visceral bleeding, however, its adverse reaction has not been fully recognized.

Case Report: A 65-year-old female with upper gastrointestinal hemorrhage occurred severe coagulation disorder during her hospitalization. Transfusion of blood products can not improve coagulation function. Coagulation parameters returned to normal two days after discontinuation of hemocoagulase agkistrodon.

Conclusion: So intravenous administration of hemocoagulase should be cautiously used for the treatment of gastrointestinal bleeding.

Chitosan Applications on Pharmaceutical Sciences: A Review

Background: Chitosan (CS) is a biomaterial derived from chitin, known for its excellent biological properties. One of the most interesting features of CS is its potential for chemical derivatization, which makes it a versatile material and allows to expand its applications. In the last years, the interest on this polymer and its pharmaceutical applications has notably increased. This biopolymer is being widely studied for its interesting properties, such as bioadhesion, antimicrobial activity, biocompatibility, and biodegradability. Other promising properties of CS include its modulation of immunological response, hemostasis, and wound and bone healing activity.

Objective: In this work, a critical review is performed covering its conventional and novel applications, specially focused on pharmaceutical area, providing a clear picture of the current state of art to serve as a basis to direct future research in this field.

Conclusion: Despite all the qualities of this polymer, there are only few CS-based products in the market, so it is a priority to enhance the research to develop new technologies and CS-based systems to enforce this biopolymer in the industry.

The Role of Traditional Chinese Herbal Medicines and Bioactive Ingredients on Ion Channels: A Brief Review and Prospect

Traditional Chinese Medicines (TCMs), particularly the Chinese herbal medicines, are valuable sources of medicines and have been used for centuries. The term “TCMs” both represents to the single drug agent like Salvia miltiorrhiza, Ligusticum chuanxiong and Angelica sinensis, and those herbal formulas like Jingshu Keli, Wenxin Keli and Danzhen powder. In recent years, the researches of TCMs developed rapidly to understand the scientific basis of these herbs. In this review, we collect the studies of TCM and their containing bioactive compounds, and attempt to provide an overview for their regulatory effects on different ion channels including Ca2+, K+, Na+, Cl- channels and TRP, P2X receptors. The following conditions are used to limit the range of our review. (i) Only the herbal materials are included in this review and the animal- and mineral-original TCMs are excluded. (ii) The major discussions in this review focus on single TCM agent and the herbal formulas are only discussed for a little. (iii) Those most famous herbal medicines like Capsicum annuum (pepper), Curcuma longa (ginger) and Cannabis sativa (marijuana) are excluded. (iv) Only those TCM herbs with more than 5 research papers confirming their effects on ion channels are discussed in this review. Our review discusses recently available scientific evidences for TCMs and related bioactive compounds that have been reported with the modulatory effects on different ion channels, and thus provides a new ethnopharmacological approach to understand the usage of TCMs.

HDL Dysfunction Caused by Mutations in apoA-I and Other Genes that are Critical for HDL Biogenesis and Remodeling

The “HDL hypothesis” which suggested that an elevation in HDL cholesterol (HDL-C) levels by drugs or by life style changes should be paralleled by a decrease in the risk for Cardiovascular Disease (CVD) has been challenged by recent epidemiological and clinical studies using HDL-raising drugs. HDL components such as proteins, lipids or small RNA molecules, but not cholesterol itself, possess various atheroprotective functions in different cell types and accumulating evidence supports the new hypothesis that HDL functionality is more important than HDL-C levels for CVD risk prediction. Thus, the detailed characterization of changes in HDL composition and functions in various pathogenic conditions is critically important in order to identify new biomarkers for diagnosis, prognosis and therapy monitoring of CVD. Here we provide an overview of how HDL composition, size and functionality are affected in patients with monogenic disorders of HDL metabolism due to mutations in genes that participate in the biogenesis and the remodeling of HDL. We also review the findings from various mouse models with genetic disturbances in the HDL biogenesis pathway that have been generated for the validation of the data obtained in human patients and how these models could be utilized for the evaluation of novel therapeutic strategies such as the use of adenovirus-mediated gene transfer technology that aim to correct HDL abnormalities.

Biomarkers of Atrial Fibrillation in Metabolic Syndrome

Whether the increased atrial fibrillation (AF) risk in metabolic syndrome (MetS) patients is due to the syndrome as a whole or simply the sum of the risks of its individual component parts is still obscure. These two clinical entities share many pathophysiological links and thus distinction between a casual observation and a significant association is difficult. Biomarkers associated with pathogenesis of AF in the context of MetS have the ability to refine future risk prediction. In the present review we identify circulating substances that could be regarded as potential biomarkers for prediction of incident AF, or of cardiovascular events in the setting of AF in patients with MetS. Cardiac myocyte injury and stress markers (troponin and natriuretic peptides), markers of renal function (glomeral filtration rate, cystatin-C), and inflammation markers/mediators (interleukin- 6, CRP) are promising biomarkers of patients with AF and MetS.

Perioperative Dental Management of Patients in The Background of Antithrombotic Use

Objectives: Treatment and perioperative dental management in patients on antithrombotic medications poses a serious challenge to dental professionals due to perceived risk of bleeding complications. This article aims to study the anticoagulant / antiplatelet drugs currently available on the market, review contemporary oral anti-thrombotic treatment and offer management guidelines in such situations based on the review of pertinent literature.

Material and Methods: Science Direct and Ovid databases, PubMed, Scopus and product literature were accessed to review relevant literature with respect to current anti-thrombotic drugs, indications for their use in medical conditions, complications related to their use and drug interactions. The search covered studies published in medical and dental journals in English with a relevant impact factor over a period of 10 years. Meta analyses, systematic reviews, randomized trials, cohort based and case-control studies and society-based guidelines were considered. Key words utilized in the search criteria included Warfarin, Coumarin, Aspirin, P2Y12 inhibitors, Prasugrel, Clopidogrel, Ticagrelor, Hemorrhage, Anti-thrombin, Platelet aggregation inhibitors and International Normalized Ratio (INR) and were validated by the MeSH dictionaries.

Results: Dental practitioners today, are faced with the challenge of conducting surgical procedures on patients who are on anti-thrombotic medications for a variety of medical/ surgical co-morbid conditions. Although there is consensus amongst various studies regarding continuation of warfarin in therapeutic ranges for dento-alveolar surgery, there is insufficient evidence to reach a consensus in those groups who are at intermediate or high risk of bleeding. However, most studies and published literature do agree that there is no real increased risk of bleeding complications during conduct of these procedures if the patient’s INR is less than 3.5 along with adequate haemostatic measures.

Conclusion: Regardless of the procedure to be performed, every case needs to be titrated on its individual merit based on both patient and surgical factors. Further, it is recommended that INR values should be established at least 72 hours prior to the surgery, which admits a margin of safety for dose modification if necessary. A meticulous case history with complementary hemostatic tests and adoption of adequate local hemostatic measures hold the key to not having the necessity to modify the antiplatelet or anticoagulation treatment in most cases. Additionally, the advent of newer anticoagulants and antiplatelets have raised the requirement of dedicated Randomized Clinical Trials to answer the specific clinical questions of bleeding risk versus thrombo-embolic complications in the perioperative management of such patients.

Medical Applications of Collagen and Collagen-Based Materials

Collagen and collagen-based materials have been successfully used in medicine for over 50 years. The number of scientific articles about the role of collagen in the construction of scaffolds for tissue engineering has risen precipitously in recent years. The review contains materials about historic and modern applications of collagen in medicine such as soluble collagen injections, solid constructs reconstructed from solution, and decellularized collagen matrices. The analysis of published data proves the efficacy of collagen material in the treatment of chronic wounds, burns, venous and diabetic ulcers, in plastic, reconstructive and general surgery, urology, proctology, gynecology, ophthalmology, otolaryngology, neurosurgery, dentistry, cardiovascular and bone and cartilage surgery, as well as in cosmetology. Further development of collagenoplasty requires addressing the problems of allergic complications, improvement of structure and maximizing therapeutic effects against pathological processes.

Chitosan in Biomedical Engineering: A Critical Review

Biomedical engineering seeks to enhance the quality of life by developing advanced materials and technologies. Chitosan-based biomaterials have attracted significant attention because of having unique chemical structures with desired biocompatibility and biodegradability, which play different roles in membranes, sponges and scaffolds, along with promising biological properties such as biocompatibility, biodegradability and non-toxicity. Therefore, chitosan derivatives have been widely used in a vast variety of uses, chiefly pharmaceuticals and biomedical engineering. It is attempted here to draw a comprehensive overview of chitosan emerging applications in medicine, tissue engineering, drug delivery, gene therapy, cancer therapy, ophthalmology, dentistry, bio-imaging, bio-sensing and diagnosis. The use of Stem Cells (SCs) has given an interesting feature to the use of chitosan so that regenerative medicine and therapeutic methods have benefited from chitosan-based platforms. Plenty of the most recent discussions with stimulating ideas in this field are covered that could hopefully serve as hints for more developed works in biomedical engineering.

Evaluation of Hemostatic Behavior of Micro and Nano Gelatin/Silica Hybrid in Severe Bleeding

Background: The pH variation of the injury site is an important factor in the failure of styptic and its structural damage. In this study, the behaviour of a gelatin-silica hybrid in severe bleeding was evaluated under different pH values. On the other hand, the effect of the hybrid particle size, which is one of the key physical properties of the hybrid, has been studied in rapid control of haemostasis.

Method: The hybrid haemostatic behaviour varied drastically by changing the particle size, so that the hybrid containing SiO2 with the average particle size of about 1 micro-meter (Hyb Gel-MSiO2) demonstrated very poor ability in platelet adhesion in neutral pH, about 24%. Also, the aPTT was not shorter than the normal time, whereas reduction of the particle size beyond a certain limit (with nanometer SiO2 for Hyb Gel-NSiO2) led to both increasing platelet adhesion to 32% and very considerable reduction of aPTT.

Results: Alignment of all results showed that the particle size reduction improves the haemostatic behaviour of the hybrid toward its best performance by controlling excessive bleeding. By changing the pH for a certain particle size, structural integrity, and thereby the hybrid haemostatic behaviour changed dramatically. Therefore, the nano-hybrid showed the most blood absorption (around 470%) in natural pH and acceded to a coherent structure. The results demonstrated that in alkaline or acidic environment, the hybrid haemostatic behaviour was limited. Based on the results of this study, it was found that changes in the hybrid behaviour in acidic pH were much more drastic than in alkaline pH, and also the hybrid with the optimum particle size (Hyb Gel-NSiO2) can maintain the structural integrity with rapid haemostasis (<3 seconds).

Conclusion: Based on the objective that the pH at the injury site change to the alkaline side, the resulting hybrid has an excellent ability to control excessive bleeding and can be proposed for further in vivo studies as a novel styptic.

Antimicrobial and Wound Healing Potential of Dietary Flavonoid Naringenin

Background: Naringenin belongs to the class flavanones, and chemically it is known as 5,7-dihydroxy-2-(4-hydroxyphenyl) chroman-4-one. It is one of the dietary poly-phenolic constituents of the citrus fruits and vegetables. Naringenin possesses excellent antioxidant, antiinflammatory, and antimicrobial activities. These activities promote wound healing activity. Naringenin has been incorporated in the gel base to be applied on the wounded skin. The wound healing property of naringenin gel has not been studied extensively in the literature to date.

Objective: The present study aims to unveil the wound healing property of naringenin gel formulation on excision and incision model.

Materials and Methods: 0.5% and 1% naringenin was incorporated in a carbopol gel base formulation and evaluated for physicochemical parameters. Incision and excision wound models were used to study wound contraction, tensile strength, healing index, the period of epithelization and histopathological parameters. Antimicrobial activity was performed using agar plate method.

Results: Naringenin (0.5% and 1%) treatment shows a significant increase in the percentage of wound contraction, good healing index and shorter epithelization period. Histopathology of naringenin gel treated wound tissue showed more fibroblasts, less macrophage infiltration, and wellformed collagen fibers as compared to control. In incision wound model, the animals were treated with 0.5% and 1% naringenin gel for nine days and showed a significant increase in the tensile strength. Naringenin exerts antimicrobial activity against fungus and E. coli.

Conclusion: The present study explored potent wound healing activity of naringenin gels.

New Sides of Aldosterone Action in Cardiovascular System as Potential Targets for Therapeutic Intervention

Aldosterone, the main mineralocorticoid hormone, plays a crucial role in the regulation of electrolyte homeostasis and blood pressure. Although this role is undoubtedly important, it is not a hormonal action that attracts the most attention. Aldosterone seems to be very important as a local messenger in the pathology of cardiovascular diseases (CVD). In the last few years, the attention was focused on the correlation between raised aldosterone level and increased risk of cardiovascular events. It has been demonstrated that aldosterone contributes to fibrosis, inflammation, endothelial dysfunction, fibrinolytic disorders, and oxidative stress leading to CVD development and progression. It used to be thought that the effects of aldosterone are mediated via classic nuclear receptors – mineralocorticoid receptors (MRs). Now we know that the mechanism of aldosterone action in the cardiovascular system (CVS) is much more complex since experimental and clinical studies indicate that MR blockade may be not sufficient to abolish aldosterone-induced harmful effects in CVS. Thus, the involvement of some other than MR, receptors, and factors is suggested. Moreover, in addition to the generally known genomic action of aldosterone, which involves MR activation, the nongenomic pathways are postulated in the mode of hormone action. More and more attention is focused on the membrane-coupled receptors, which mediate the rapid effects of aldosterone and have been already confirmed in different cells and tissues of CVS. Therefore, this brief review summarizes recent findings about new sides of aldosterone action in CVS that could be potential targets for therapeutic intervention.

Advances in the Development of Novel Factor Xa Inhibitors: A Patent Review

Development of new anticoagulants has been in constant demand throughout the world due to increasing rate of morbidity and mortality caused by thrombotic diseases. Factor Xa (FXa), one of the enzymes and validated target for anticoagulation, regulates the production of thrombin in the coagulation cascade. The importance of oral FXa inhibitors like rivaroxaban, apixaban and edoxaban in thromboembolic conditions is well supported by increasing number of patents and research publications during the recent years. Direct FXa inhibitors as antithrombotic agents offer selective, efficacious and orally active therapy with respect to the other traditional anticoagulants. Newly developed patented molecules are mainly structural bioisosteres of existing drugs and have exhibited better efficacy and safety profile. Development of antidotes for oral direct FXa inhibitors is in pipeline and their expected approval for therapeutic purposes will be further beneficial to anticoagulation therapy. This review is mainly focused on industrial and academic patents on the discovery of direct FXa inhibitors. The review covers patented compounds from December 2011 till date, describing various structural modifications along with biological activity data and advances in the process and formulation technologies of the reported FXa inhibitors.

An Update on Potential Molecular Mechanisms Underlying the Actions of Snake Venom L-amino Acid Oxidases (LAAOs)

Background: LAAOs (EC 1.4.3.2) are found in concentrations that vary according to each species of snakes; Viperidae, Crotalidae and Elapidae contain 1-9% of this enzyme in their venoms.

Methods: This review focuses on an update on molecular mechanisms, platelet activities, antimicrobial, antiprotozoal, induction of apoptosis and inflammatory potential underlying the actions of SVLAAOs.

Results: Snake venom LAAOs (SV-LAAOs) have become an interesting subject for pharmacological, structural and molecular studies.

Conclusion: Although the mechanisms of action of these enzymes are not well understood they are a subject of a variety of studies, because LAAOs are multifunctional enzymes exhibiting a wide range of pharmacological effects, including the inhibition or induction of platelet aggregation, hemolysis and hemorrhage, in addition to the stimulation of apoptosis, the activation of leukocytes and the formation of edema.

Moreover, SV-LAAOs play an important role in bactericidal, cytotoxic, anti-parasitic, anti-tumor, and antiviral activities.

Connexin43 and Myocardial Ischemia-Reperfusion Injury

Background: Recently, the treatment and prevention of ischemic cardiomyopathy is one of the emerging research topics in the cardiovascular field. Gap junction is the basic structure of cardiac electrophysiology. Connexin is the basic unit of gap junctions. Connexin43(CX43) is the most abundant member of Cx family in the heart, the normal expression of Cx43 is important for heart development, electrically coupled cardiomyocytes activities and coordination of myocardial function. The connection between Cx43 and myocardial ischemia/reperfusion or reperfusion injury has become the focus of current research.

Methods: We undertook a structured search of bibliographic database for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyze the interventions and findings of included studies using a conceptual framework.

Results: Twenty-one papers were included in the review, eight papers outlined the relationship of Cx43 and reperfusion arrhythmias. Eight papers pointed out the effect on the infarct size of Cx43.

Conclusion: The findings of this review confirm that Cx43 is the most abundant member of Cx family in the heart and is vital for myocardial protection during ischemia/reperfusion process and for ischemia/reperfusion injury. Many of its mechanism are still not very clear and require future research in the future.

Commentary: Toward a Personalized Medicine in Wake-Up Stroke?

An Overview on Application of Natural Substances Incorporated with Electrospun Nanofibrous Scaffolds to Development of Innovative Wound Dressings

Conventional dressings are cost-effective and highly absorbent, but not effectual enough to promote hemostasis, adherence and in holding a moist wound bed. Thanks to the developments in the field of nanotechnology and bioengineering, one of the promising current trends is to move progress of innovative wound dressings, merging the application of traditional healing agents and modern products/ practices, such as hydrocolloids, hydrogels, films and nanofibers.

This review surveys on potentials of electrospun nanofibrous mats for wound dressing applications. Furthermore, loading of bioactive molecules and therapeutic agents into the nanofibrous mats especially natural compounds with the aim of fabrication novel bioactive electrospun nanofibrous mats for skin substitutes and wound dressings are discussed.

Systematic literature search was conducted to review all recent progress toward the potential of natural substances incorporated with electrospun nanofibrous scaffolds for wound dressing applications.

The electrospun nanofibers webs can provide the essential parameters require for wound dressing to heal wounds including absorptivity, oxygen permeability, and non-adherence to the healing tissue, barrier to bacteria, bioactivity and occlusivity. The modern wound dressings materials made of electrospun nanofibers contain various traditional healing agents such as plant derived compounds could be beneficial to the healing of wounds. Natural substances have been used in skin wound care for many years because of their therapeutic properties, including antimicrobial, antioxidant, anti-inflammatory and mitogenic activities.

A screening of natural substances with plant or animal sources having high wound healer activities and cooperating with electrospun nanofiber are an important step toward producing innovative bioactive wound dressings.

Cardioprotective Utility of Urocortin in Myocardial Ischemia- Reperfusion Injury: Where do We Stand?

Background: There has been a constant pursuit for development of newer therapies which can contribute to the relatively nascent field of cardioprotection in the setting of myocardial ischemiareperfusion injury. One novel cardioprotective agent among others, that has shown promising results in the limited number of research studies undertaken till now, is Urocortin. Urocortins are peptides belonging to the Corticotropin-Releasing Hormone family.

Results: Acting through a variety of downstream mechanisms, urocortin has been shown to alter cellular metabolism and modulate the mechanism of cell death occurring as a result of ischemia-reperfusion injury. New evidence continues to accumulate in support of urocortin’s beneficial role in cytoprotection.

Conclusion: We present here an updated review largely focused on the various mechanisms through which urocortin alters cellular metabolism, and discuss the clinical potential of urocortin’s cardioprotective ability in myocardial ischemia-reperfusion injury.

Impact of High Protein Intake on Viral Load and Hematological Parameters in HIV-infected Patients

Background: The impact of protein intake level leads to considerable alterations of the host essential amino acid profiles in the context of chronic viral infectious process. Amino acids play an important role in the pathogenesis of virus-related infections both as basic substrates for constant protein synthesis and as regulators in many metabolic pathways. The excess or deficiency of these host essential nutritional elements can play a limiting role in the life cycle of some viruses.

Objective: Our aim was to determine the changes of hematological parameters and viral load due to the high protein and L-lysine amino acid intake in HIV-infected patients.

Methods: Case-control study was performed in the Municipal Center of HIV/AIDS prophylaxis, Surgut, Russian Federation.

Results: The obtained data indicate that excess of dietary protein and L-lysine can increase the risk of high HIV replication, subsequent acceleration of immunosuppression and the disease progression. The present survey shows that HIV-infected Khanty indigenous people have the highest levels of plasma L-lysine and HIV-1 RNA and a more pronounced state of immunosuppression in comparison with the total patients' cohort.

Conclusion: There was evidence for an association between plasma L-lysine level and viral load. These findings are important for understanding the pathogenic impact of animal protein and Llysine consumption on the HIV-1 RNA levels and must be considered in further research for the development of new approaches in the treatment of HIV infection in era of HAART.

A Comprehensive Review on Phytochemistry and Pharmacological Effects of Stinging Nettle (Urtica dioica)

Background and Objective: Urtica dioica (stinging nettle), a member of the Urticaceae family, has been used in various traditional systems of medicines since ancient times especially for joint pain, arthritis and prostate problems. Its roots and leaves contain a wide variety of bioactive constituents like sterols, fatty acids, lectins terpenes, phenylpropanes, lignans and coumarins. The leaves and root extract shows various activities like hypoglycemic, anti-inflammatory, antiproliferative, antioxidant, hypolipemic, antirheumatic, anticarcinogenic and antiviral activity. It shows its effects through the inhibition of aromatase, 5 α-reductase, cell proliferation and Na+, K+-ATPase inhibition.

Conclusion: The article reviews the phytochemistry and phytopharmacology of the plant.

Clinical Uses of Melatonin in Neurological Diseases and Mental and Behavioural Disorders

Background: Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory “bench” are not always applicable to the patient's “bedside”.

Objective: In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology.

Conclusion: Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases.

Obesity and Inflammation and Altered Clopidogrel Pharmacokinetics and Pharmacodynamics

Background: Clopidogrel is a key antiplatelet drug that has substantial interpatient variability in pharmacodynamic response. Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk of cardiovascular events. Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction.

Results: A number of reports have demonstrated that obesity is a risk factor for a reduced clopidogrel pharmacodynamic response. The inflammatory state associated with obesity, particularly a metabolic endotoxemia, may set in motion, a number of mechanisms that increase platelet reactivity, suppress cytochrome P450 enzyme activity, and increase platelet turnover, all contributing to a poor clopidogrel response.

Conclusion: Comprehensive understanding of the mechanisms underlying obesity-related high onclopidogrel platelet reactivity will help in the optimization of antithrombotic therapy in this patient population.

Discovery of Chromen-7-yl Furan-2-Carboxylate as a Potent and Selective Factor XIa Inhibitor

Background: Direct inhibition of coagulation factor XIa (FXIa) carries a significant promise for developing effective and safe anticoagulants.

Method: In this report, we studied 4-methyl-2-oxo-2H-chromen-7-yl furan-2-carboxylate 1, a coumarin derivative, for direct FXIa inhibition.

Results: This small molecule was found to inhibit FXIa with an IC50 value of 0.77 µM. Coumarin 1 also displayed a moderate-to-high selectivity for FXIa inhibition over other coagulation, digestive, and fibrinolysis serine proteases. Coumarin 1 selectively doubled APTT of human plasma at a concentration of 72 µM. Insights about the structural features that contribute to the unique potential of such small molecule were deduced by profiling similar molecules in PubChem Open Chemistry Database as well as by performing a computational docking exercise.

Conclusion: Overall, chromen-7-yl furan-2-carboxylate 1 is expected to serve as an excellent fragmental lead for further anticoagulant design and development.

New Pharmacological Approaches to the Prevention of Myocardial Ischemia- Reperfusion Injury

Background: Early reperfusion of the blocked vessel is critical to restore the blood flow to the ischemic myocardium to salvage myocardial tissue and improve clinical outcome. This reperfusion strategy after a period of ischemia, however, may elicit further myocardial damage named myocardial reperfusion injury. The manifestations of reperfusion injury include arrhythmias, myocardial stunning and micro-vascular dysfunction, in addition to significant cardiomyocyte death. It is suggested that an overproduction of reactive oxygen species, intracellular calcium overload and inflammatory cell infiltration are the most important features of myocardial ischemia-reperfusion injury.

Objective: In this review, various pharmacological interventions to treat myocardial reperfusion injury including the antioxidant flavonols, hydrogen sulfide, adenosine, opioids, incretin-based therapies and cyclosporin A which targets the mitochondrial permeability transition pore are discussed.

Conclusion: The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic.

Nanotechnology Based Theranostic Approaches in Alzheimer's Disease Management: Current Status and Future Perspective

Background: Alzheimer's disease (AD), a cognitive dysfunction/dementia state amongst the elders is characterized by irreversible neurodegeneration due to varied pathophysiology. Up till now, anti-AD drugs having different pharmacology have been developed and used in clinic. Yet, these medications are not curative and only lowering the AD associated symptoms. Improvement in treatment outcome required drug targeting across the blood-brain barrier (BBB) to the central nervous system (CNS) in optimal therapeutic concentration. Nanotechnology based diagnostic tools, drug carriers and theranostics offer highly sensitive molecular detection, effective drug targeting and their combination. Over the past decade, significant works have been done in this area and we have seen very remarkable outocome in AD therapy. Various nanoparticles from organic and inorganic nanomaterial category have successfully been investigated against AD.

Conclusion: This paper discussed the role of nanoparticles in early detection of AD, effective drug targeting to brain and theranostic (diagnosis and therapy) approaches in AD's management.

Nanotechnology: A Promising Tool Towards Wound Healing

Nanotechnology is an exciting emerging field with multiple applications in skin regeneration. Nanofibers have gained special attention in skin regeneration based on their structural similarity to the extracellular matrix. A wide variety of polymeric nanofibers with distinct properties have been developed and tested as scaffolds for skin regeneration. Besides providing support for tissue repair, nanofibrous materials can act as delivery systems for drugs, proteins, growth factors, and other molecules. Moreover, the morphology, biodegradability, and other functionalities of nanofibrous materials can be controlled towards specific conditions of wound healing. Other nanostructured drug delivery systems, such as nanoparticles, micelles, nanoemulsions, and liposomes, have been used to improve wound healing at different stages. These nanoscale delivery systems have demonstrated several benefits for the wound healing process, including reduced cytotoxicity of drugs, administration of poorly water-soluble drugs, improved skin penetration, controlled release properties, antimicrobial activity, and protection of drugs against light, temperature, enzymes or pH degradation, as well as stimulation of fibroblast proliferation and reduced inflammation.

Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues

Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti-inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several biological in vitro and in vivo assays were performed in order to understand its mechanism of action. A set of analogues of BSL was prepared using low-cost synthetic procedures and further biologically investigated in zebrafish models. Compound 5c and 7e exhibited the best antiinflammatory activities and represent new promising anti-inflammatory agents for further preclinical development.

Climate Changes and Human Health: A Review of the Effect of Environmental Stressors on Cardiovascular Diseases Across Epidemiology and Biological Mechanisms

Background: Climate change is rapidly affecting all the regions of our planet. The most relevant example is global warming, which impacts on the earth’s ecosystems, threatening human health. Other effects include extreme variations in temperature and increases in air pollution. These events may negatively impact mortality and morbidity for cardiovascular diseases.

Methods: In this review, we discuss the main effects of climate changes on cardiovascular diseases, reporting the epidemiological evidences and the biological mechanisms linking climate change consequences to hypertension, diabetes, ischemic heart diseases, heart failure and stroke.

Results: Up to now, findings suggest that humans acclimate under different weather conditions, even though extreme temperatures and higher levels of air pollution can influence health-related outcomes. In these cases, climate change adversely affects cardiovascular system and the high-risk subjects for cardiovascular diseases are those more exposed.

Conclusion: Finally, we examine climate change implications on publich health and suggest adaptation strategies to monitor the high-risk population, and reduce the amount of hospital admissions associated to these events. Such interventions may minimize the costs of public health and reduce the mortality for cardiovascular diseases.

Laboratory Monitoring or Measurement of Direct Oral Anticoagulants (DOACs): Advantages, Limitations and Future Challenges

Background: The Direct Oral Anticoagulants (DOACs) represent a new generation of antithrombotic agents, providing direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa). Around the globe, their use is progressively rising, as these new agents replace the historical anticoagulants (heparin and vitamin K antagonists including warfarin) for various clinical conditions in medical practice. Other acronyms used to designate DOACs include TSOAC (target specific oral anticoagulants) and NOAC (novel; or non-vitamin K antagonist oral anticoagulants). Currently available DOACS include dabigatran (FIIa inhibitor), along with rivaroxaban, apixaban, edoxaban and betrixaban (FXa inhibitors).

Objective: This narrative review aims to briefly summarise the evidence concerning utility of different laboratory assays for qualitative or quantitative assessment of DOACs, emphasizing the difference between ‘drug monitoring’ and ‘drug measurement’ and ultimately discussing advantages and limitations of these processes.

Results and Conclusion: Recently, the dogma that these innovative anticoagulant agents will not necessitate laboratory testing has been challenged with the recognition that assessment of drug concentration or activity may be required in some circumstances, although this does not immediately translate to the concept of ‘drug monitoring’.

Pericyte: Potential Target for Hemorrhagic Stroke Prevention and Treatment

Background: Despite long-standing and worldwide efforts, hemorrhagic stroke remains a critical clinical syndrome that exerts a heavy toll on affected individuals and their families due to the lack of preventive and therapeutic targets.

Objective: To clarify the pathogenesis of hemorrhagic stroke and to identify novel therapeutic targets.

Method: Targeting pericytes, the typical mural cells of microvessels, could serve as a way to modulate microvascular permeability, development, and maturation by regulating endothelial cell functions and modulating tissue fibrosis and inflammatory responses.

Results: Pericytes in hemorrhagic stroke may exert the following functions: before bleeding, the morphological aberration and dysfunction of pericytes may lead to aneurysm formation, angiopsathyrosis, and hemodynamic disturbances, ultimately causing vasculature rupture. In the acute phase after hemorrhage, pericytes are faced with a complicated bleeding environment, which results in the death of pericytes, blood-brain barrier damage, pericyte-mediated inflammatory cascades, white matter impairment, and ultimately aggravated neural injury. In the recovery period post-hemorrhage, in situ pericytes are activated and differentiate into neurons, glia and endothelial cells to repair the neural vascular network. Moreover, many pericytes are recruited to the lesion and contribute to blood-brain barrier remodeling, thus facilitating neurovascular functional recovery after stroke.

Conclusion: Due to the multiple functions of pericytes in the development of vascular rupture and hemorrhagic stroke pathophysiology, additional drugs and trials targeting pericytes and evaluations of their effectiveness are required in future investigations to develop new strategies for the prevention and treatment of hemorrhagic stroke.

Remote Ischemic Conditioning Improves Cognitive Function During Cerebral Vascular Injury Through the Induction of Autophagy

Background: The most valid model for vascular cognitive impairment (VCI) is the mouse bilateral common carotid artery stenosis (BCAS), whose behavioral outcomes are supposedly affected by the remote ischemic conditioning (RIC) through the induction of autophgy. We hope to determine whether RIC contributes to the neuroprotection through the induction of autophagy.

Methods: Wastar male mice were randomized into three groups including the Sham, the BCAS and the RIC+BCAS groups. All the animals were submitted to 4 cycles of 5 min occlusion and 5 min reperfusion of both the femoral vessels performing RIC. Then the animal behaviors were recorded as well as the expression of proteins and the mRNA levels. Notably, the expression of proteins relates to autophagy. By this means, it is possible to estimate the cell death, the severity of pathology and the expression of proteins under different groups.

Results: Compared with the sham group, the expression of proteins increased for ATG7, Beclin-1, LC3, ATG5-ATG12 while decreased for P62 in the BCAS group. These changes were further promoted in the RIC+BCAS group, which indicates that the RIC can improve the cognitive function in the BCAS group. Moreover, RT-PCR demonstrated that the mRNA level of BECN1, Atg5, Atg7 in white matter (WM) and Hippocampus in BCAS group was higher than the sham group, while it was much greater in the RIC+BCAS group. This confirmed that the autophagy was activated in the BCAS and the RIC+BCAS groups, especially the RIC+BCAS group.

Conclusion: Improved cognition during vascular injury and RIC was associated with increased activity of autophagy.

Pharmacological Management Options to Prevent and Reduce Ischemic Hemorrhagic Transformation

Background: Hemorrhagic transformation (HT) is a common and natural complication after acute ischemic stroke. The only FDA-approved treatment so far for acute ischemic stroke is rapid reperfusion with recombinant tissue plasminogen activator (rtPA). Although it has been shown to exaggerate the risk and severity of HT and to be associated with increased morbidity and mortality.

Objective: The aim of this review is to discuss the multifactorial pathophysiology of hemorrhagic transformation, promising interventional targets, and pharmacological treatment options.

Results and Conclusion: Understanding HT is essential to restore cerebral blood flow to ischemic brain by reperfusion therapy without causing this complication and additional brain injury. Therefore methods for the prevention and treatment of HT are needed. Although experimental studies showed promising results, clinical translation remains unsatisfactory to date.

Hematoma Expansion: Clinical and Molecular Predictors and Corresponding Pharmacological Treatment

Background: Hematoma expansion is a detrimental event of intracerebral hemorrhage (ICH) which results in progressive neurologic deteriorations and poor outcomes. Objective: To summariz the current understanding of the mechanisms underlying hematoma expansion and discuss the potential approaches of treatment and prevention.

Results: Although the exact mechanism of hematoma expansion is unclear, accumulating evidences suggest that multiple clinical markers such as coagulation/hemostasis dysfunction, higher blood pressure and BRAIN scores, higher serum glucose and/or glycosylated hemoglobin A1c, serum creatinine, Factor XIII and international normalized ratio (INR), lower serum cholesterol or LDL cholesterol, and fibrinogen, may be correlated with incidents of hematoma expansion. Furthermore, activation of several molecular pathways (i.e. plasma kallikrein, von Willebrand factor, N-methyl-Daspartate and its receptor, cytokines/ adipokines, cellular fibronectin and apolipoprotein Eε2 allele) may lead to hematoma expansion.

Conclusion: Prospective study for hematoma expansion How to predict the patients Who are at highest risk of hematoma expansion is more challengeable than restricting hematoma expansion itself following acute ICH. Seeking and detecting risk markers in plasma that can be intervened appropriately is meaningful for patients with potential hematoma expansion, which may contribute to improve clinical outcomes in patients suffering from ICH.

Maintaining Plasma Fibrinogen Levels and Fibrinogen Replacement Therapies for Treatment of Intracranial Hemorrhage

Background: Intracranial hemorrhage is characterized by the blood vessel rupture and subsequent hematoma expansion. It is the least treatable stroke subtype, resulting in higher morbidity and mortality per incidence than ischemic stroke. Recent studies have observed lower than normal levels of plasma fibrinogen in patients of intracerebral hemorrhage. Furthermore, in other cases of severe hemorrhage, plasma fibrinogen levels have been identified as an indicator of prognosis. Current clinical management of cerebral hemorrhage includes adjunctive therapies and possible surgical evacuation. However, a possible therapeutic target for intracranial hemorrhage is fibrinogen. During intracranial hemorrhage with hematoma expansion, fibrinogen levels are rapidly depleted and thus are in need of replacement. Maintaining high levels of fibrinogen can promote rapid clotting and reduction of hematoma expansion.

Objectives: Within this review, we examine the role of fibrinogen in intracranial hemorrhage and evaluate the use of fibrinogen replacement therapies for maintaining normal levels of this key hemostatic protein. The pros and cons are discussed and an opinion of the most appropriate fibrinogen replacement therapy for intracranial hemorrhage is made.

Conclusion: It is concluded that fibrinogen concentrate seems to be the most suitable therapy for elevating plasma fibrinogen for the treatment of intracranial hemorrhage with hematoma expansion.

Von Willebrand Factor and Cardiovascular Disease: From a Biochemical Marker to an Attractive Therapeutic Target

Background: Despite recent advances, there is still an unmet need in antithrombotic therapy. New drugs have to overcome old targets, looking for new complementary strategies to counteract thrombus formation and propagation. Since its initial recognition in the 50’s, von Willebrand Factor (VWF) has proved to be a contributor in clot formation. The contribution of VWF to platelet adhesion and aggregation is pivotal at high shear rates (i.e. microcirculation and critical artery stenosis), where globular-inactive-VWF elongates in a long chain-active conformation. Particularly, at sites of plaque erosion/disruption the activation of VWF may contribute critically to post-stenotic thrombus formation. In this context, VWF is a potential target of antithrombotic therapies. The plasma concentration of VWF increases in high risk population and predicts cardiovascular (CV) outcome. VWF demonstrates an emerging role in different clinical settings; for example, in valvular heart disease where it has been recently proposed as a new fluido-dynamic marker of disease severity and a predictor of successful correction. Drugs used in daily clinical practice (LMWHs, statins, N-acetylcysteine, glycoprotein IIb/IIIa inhibitors) may have an unselective antagonism on the VWF-pathway. Recently, several “tailor-made” inhibitors of VWF have been investigated. In animal models and clinical studies monoclonal antibodies, aptamers and nanobodies have been demonstrated to directly interfere with the VWF pathway. These studies proved the powerful antithrombotic property and the acceptable level of safety of this strategy.

Conclusion: We provide an overview of the drugs that a have a role in VWF-antagonism, illustrating how they might become a potential option to overcome current limitations of antithrombotic therapy.

Snake Venom: From Deadly Toxins to Life-saving Therapeutics

Snakes are fascinating creatures and have been residents of this planet well before ancient humans dwelled the earth. Venomous snakes have been a figure of fear, and cause notable mortality throughout the world. The venom constitutes families of proteins and peptides with various isoforms that make it a cocktail of diverse molecules. These biomolecules are responsible for the disturbance in fundamental physiological systems of the envenomed victim, leading to morbidity which can lead to death if left untreated. Researchers have turned these life-threatening toxins into life-saving therapeutics via technological advancements. Since the development of captopril, the first drug that was derived from bradykininpotentiating peptide of Bothrops jararaca, to the disintegrins that have potent activity against certain types of cancers, snake venom components have shown great potential for the development of lead compounds for new drugs. There is a continuous development of new drugs from snake venom for coagulopathy and hemostasis to anti-cancer agents. In this review, we have focused on different snake venom proteins / peptides derived drugs that are in clinical use or in developmental stages till to date. Also, some commonly used snake venom derived diagnostic tools along with the recent updates in this exciting field are discussed.

Low-Density Lipoprotein Cholesterol (LDL-C): How Low?

Low-density lipoprotein cholesterol (LDL-C) is a well-established major cardiovascular (CV) risk factor supported by clinical evidence showing decreased atherosclerotic disease events when LDL-C is therapeutically lowered. A reasonable approach is to tailor each patient’s LDL-C target level depending on the initial LDL-C level and the perceived risk. Multiple clinical entities such as the newborn, hypobetalipoproteinemia, proprotein convertase subtilisin/kexin type 9 (PCSK9) missense mutations, and an unexpected excess response to a statin or other medications, are associated with very low LDL-C levels in otherwise healthy individuals. Therefore, an issue of major interest to clinicians who buy into “lower is better” for LDL-C in the high-risk CV patient is how low can and should the LDL-C be taken? Available information is discussed and placed into context. A definite safe lowest LDL-C level cannot be specified but there appears to be support that a level as low as 20 mg/dL (0.52 mmol/l) can be justified in the highest CV risk patients with extensive atherosclerosis where plaque stabilization and regression are necessary.

Potential Role for Dendritic Cells in Endothelial Dysfunction, Diabetes and Cardiovascular Disease

Background: Endothelial dysfunction (ED) is a pathophysiological mechanism present in patients affected by type 2 diabetes (T2DM) supporting the development of cardiovascular disease. Among immune- and inflammatory cells accelerating atherosclerosis, dendritic cells (DC) play a pivotal role, however their pathogenetic mechanism has not been fully clarified, at present. The aim of our review is to explore the relationship between ED, DCs and cardiovascular events.

Methods: We analysed the literature in Medline database under ‘‘endothelial function OR dysfunction OR vasodilatation’’, AND ‘‘dendritic cells” OR “innate immunity” OR “adaptive immunity” AND “diabetes” AND “cardiovascular disease” OR “atherosclerosis”. Research articles, systematic reviews and clinical trials have been screened.

Results: Both conventional DCs (cDCs) and plasmacytoid cells (pDCs) have been found in the atherosclerotic lesions, together with other pro-inflammatory cells, leading to increase local inflammation. This inflammatory state drives DC interaction with dysfunctional endothelium activating vascular smooth muscle cells. Clinical studies have reported a dysregulation in circulating DC number and function in T2DM patients, especially in those with macrovascular complications, and a significant correlation between reduction in pDCs, TNF-α production and poor glycemic control has been reported.

Conclusion: Several studies have proven the prognostic significance of endothelial function and the accumulation of cDCs and pDCs in the arterial intima, thus suggesting their pathogenetic role in atherogenesis. A lack of clinical results is evident, since most observations on human studies are based on circulating measurements despite the fact that different DCs, residing in different tissues, were not detectable in peripheral blood samples. Further preclinical and clinical studies are needed, which should include the measurement of both circulating and tissueresiding DCs simultaneously.

Pretreatment Serum Fibrinogen Levels are Associated with Postoperative Distant Metastasis and Prognosis of Resected Lung Cancer Patient: A Retrospective Study

Objective: Lung cancer is one of the main causes of cancer-related mortality. The identification of early diagnostic biomarkers improved outcomes for lung cancer patients. This study investigated the correlation of preoperative plasma fibrinogen level with distant metastasis and prognosis in lung cancer patients.

Methods: A total of 139 lung cancer patients who underwent curative surgery between January 2009 and November 2010 were enrolled in this study. In addition to clinical and pathological prognostic factors, we evaluated the prognostic value of plasma fibrinogen on distant metastasis and relapse. Univariate analysis was performed using the Kaplan-Meier survival analysis and multivariate analysis was performed using the Cox regression model in order to measure 5-year distant metastasisfree survival (DMFS), locoregional relapse-free survival (LRFS), relapse-free survival (RFS), and overall survival (OS).

Results: Median plasma fibrinogen level was 3.59 g/L (range: 1.92-8.73 g/L). A total of 86 patients (61.9%) had normal plasma fibrinogen levels (<4 g/L) and 53 patients (38.1%) had hyperfibrinogenemia (>4 g/L). Pearson’s chi-square test showed that plasma fibrinogen level was significantly associated with age (P=0.047), tumor stage (P<0.001), and lymph node status (P=0.037) whereas there was no significant association between plasma fibrinogen level and gender, smoking, alcohol, tumor size, and tumor differentiation. Median follow-up time was 37 months. The 5-year DMFS, LRMFS, RFS, and OS rates were 26.40, 18.90, 7.50, and 28.30% with hyperfibrinogenemia respectively. Multivariate analysis showed that lymph node status (P=0.001, HR=0.397 with 95% CI=0.233-0.677) and plasma fibrinogen level (P=0.002, HR=0.410 with 95% CI=0.234-0.718) were significantly related to LRFS. RFS was significantly related to plasma fibrinogen level (P=0.036, HR=0.596 with 95% CI=0.368- 0.966) and lymph node status (P<0.001, HR=0.405 with 95% CI=0.260-0.631). DMFS was also significantly related to lymph node stage (P=0.006, HR=0.501 with 95% CI=0.307-0.817) and plasma fibrinogen level (P=0.001, HR=0.399 with 95% CI=0.236-0.674).

Conclusion: Preoperative increased plasma fibrinogen level was a predictor of distant metastasis and was independently associated with the prognosis of lung cancer patients.

Antiplatelet and Anticoagulation Treatment in Patients with Thrombocytopenia

Thrombocytopenia (TP) is a common finding in patients hospitalized for cardiovascular causes and needing antiplatelet and anticoagulant therapies. However, TP is not only a numeric parameter, but mostly a dynamic condition affected by the patients’ underlying disorders and concomitant treatments. Platelets are important players in the hemostatic process, taking part to both primary and secondary hemostasis. Although both TP and antithrombotic treatment contribute to the risk of bleeding, the complexity of the pathogenesis of bleeding events makes it difficult to predict them accurately simply based on these two parameters. It should be considered that, under certain clinical conditions, TP may be associated with an increased risk of thrombosis. In order to manage antithrombotic therapies in patients with TP, the frail balance between bleeding and thrombotic complications needs to be estimated. A joint hematological and cardiological evaluation is mandatory in order to avoid stopping an otherwise lifesaving treatment and to decrease the individual patient risk for both thrombotic and/or bleeding events, in each different setting. The purpose of this review is to describe an operative work flow aimed at helping clinicians to face this challenging issue.

Recombinant Activated Factor VII (Eptacog Alfa Activated, NovoSeven®) in Patients with Rare Congenital Bleeding Disorders. A Systematic Review on its Use in Surgical Procedures

In the absence of definite guidelines in the area, we have carried a systemic review to provide a thorough overview concerning the efficacy and safety of recombinant activated factor VII (rFVIIa, NovoSeven®, Novo Nordisk A/S, Bagsværd, Denmark) in patients with Glanzmann’s thrombasthenia (GT) and FVII deficiency, undergoing surgical procedures. PubMed, Web of Science, Scopus and EMBASE databases was employed for the search. Three multicenter registries were identified: the Glanzmann’s Thrombasthenia Registry (GTR), the Seven Treatment Evaluation Registry (STER), and a German post-marketing surveillance registry (the WIRK study). In addition, data from 10 case-series and/or single-center experiences have been summarized. We have found that the following; perioperatively, the hemostatic effectiveness of rFVIIa was high in GT patients and in those with FVII deficiency undergoing both minor and major surgical procedures. Moreover, in all studies, rFVIIa was well tolerated. Thus, the current evidence shows an optimal perioperative safety/efficacy profile of rFVIIa in the setting of these rare bleeding disorders, and provides the rationale for further studies aimed at evaluating the optimal perioperative anti-hemorrhagic prophylaxis with rFVIIa in GT and in FVII deficient patients.