Splenic Infarction

Intrahepatic Pseudoaneurysm Developing at the Confluence of Bilateral Biliary Drains Six Months Following a Procedure- A Case Report

Background: Hepatic artery aneurysms (HAAs) exhibit a notable risk of rupture, with both true aneurysms and pseudoaneurysms being exceptionally uncommon (incidence rate approximately 2 per 100,000). Symptoms include epigastric and right upper quadrant pain, jaundice, and potentially life-threatening bleeding upon rupture. This bleeding can extend into the portal vein, hepatic vein, biliary system, or abdominal cavity. While existing literature lacks reports of delayed post-therapeutic complications, this case report discusses a 27-year-old female who developed a pseudoaneurysm six months after bilateral biliary drain insertion, underscoring the potential for delayed complications.

Case Presentation: The patient underwent gastric endoscopy revealing an extensive lower esophageal varix protruding into the proximal stomach, subsequently treated with banding. The stomach and duodenum were found to contain fresh blood and blood clots indicating acute bleeding.

An urgent CT scan identified active bleeding (extravasation) at segment V and blood accumulation at the confluence of the right and left biliary drains. This was followed by celiac and selective hepatic digital subtraction angiography (DSA).

Conclusion: This case study outlines the occurrence of a hepatic artery pseudoaneurysm six months after percutaneous insertion of bilateral biliary drains. The pseudoaneurysm manifested precisely at the confluence of the right and left drains. The reported delayed complication may have resulted from friction between the drains at the confluence or erosion of the adjacent artery by the drains. The insights gained from this case shed light on the causes and preventive measures for potential delayed complications associated with percutaneous biliary drain placement.

Intrapancreatic Accessory Spleen Diagnosed by Size Reduction after Immunosuppressive Therapy: A Case Report

Background: Intrapancreatic accessory spleen (IPAS) is a congenital entity that can be confused with malignant distal pancreatic masses. Radiologic imaging and radionuclide imaging have an important place in the diagnosis of IPAS.

Case Report: Blood tests were performed on a 36-year-old female patient who presented with tachypnea, tachycardia, pain in the joints, and pain in the left abdominal quadrant. Laboratory test results were as follows: hemoglobin value 6.0 mg/dl, sedimentation 120, aspartate transaminase (AST) 150U/L, and alanine transaminase level (ALT) 110U/ L. Additional laboratory tests and ultrasonography were performed. The anti-doublestranded DNA (dsDNA) level was 800 IU/ml. C3 and C4 values were both 0.64 IU/ml, with anti-Ro-52 +++(three positive) and anti-Ro-60 ++ (two positive). A clinical diagnosis of systemic lupus erythematosus (SLE) was made. Ultrasonography and dynamic contrast-enhanced upper abdominal MRI showed lesions suggestive of multiple hemangiomas in the liver and a 29x18 mm lesion in the tail of the pancreas with a similar appearance as the spleen. SLE treatment was started. Scintigraphy was recommended for the diagnosis of IPAS. Scintigraphy was performed in the third week of the treatment. Uptake was not observed. In the second month of the treatment, a control upper abdominal MRI was performed, and a decrease in the size of the lesion was observed.

Conclusion: IPAS can be confused with pancreatic masses. Lack of uptake in scintigraphy may be due to treatment protocols that produce low phagocytic activity. If radiological imaging findings are compatible, a reduction in lesion size after immunosuppressive therapy can be accepted as evidence for the diagnosis of IPAS.

Mesenchymal Stem Cell Transplantation in Type 1 Diabetes Treatment: Current Advances and Future Opportunity

Type 1 Diabetes (T1D) is characterized by hyperglycemia, and caused by a lack of insulin secretion. At present there is no cure for T1D and patients are dependent on exogenous insulin for lifelong, which seriously affects their lives. Mesenchymal stem cells (MSCs) can be differentiated to β cell-like cells to rescue the secretion of insulin and reconstruct immunotolerance to preserve the function of islet β cells. Due to the higher proportion of children and adolescents in T1D patients, the efficacy and safety issue of the application of MSC’s transplant in T1D was primarily demonstrated and identified by human clinical trials in this review. Then we clarified the mechanism of MSCs to relieve the symptom of T1D and found out that UC-MSCs have no obvious advantage over the other types of MSCs, the autologous MSCs from BM or menstrual blood with less expanded ex vivo could be the better choice for clinical application to treat with T1D through documentary analysis. Finally, we summarized the advances of MSCs with different interventions such as genetic engineering in the treatment of T1D, and demonstrated the advantages and shortage of MSCs intervened by different treatments in the transplantation, which may enhance the clinical efficacy and overcome the shortcomings in the application of MSCs to T1D in future.

Advances in the Treatment of Kidney Disorders using Mesenchymal Stem Cells

Renal disease is a medical condition that poses a potential threat to the life of an individual and is related to substantial morbidity and mortality rates in clinical environments. The aetiology of this condition is influenced by multiple factors, and its incidence tends to increase with progressive aging. Although supportive therapy and kidney transplantation have potential advantages, they also have limitations in terms of mitigating the progression of KD. Despite significant advancements in the domain of supportive therapy, mortality rates in patients continue to increase. Due to their ability to self-renew and multidirectionally differentiate, stem cell therapy has been shown to have tremendous potential in the repair of the diseased kidney. MSCs (Mesenchymal stem cells) are a cell population that is extensively distributed and can be located in various niches throughout an individual's lifespan. The cells in question are characterised by their potential for indefinite replication and their aptitude for undergoing differentiation into fully developed cells of mesodermal origin under laboratory conditions. It is essential to emphasize that MSCs have demonstrated a favorable safety profile and efficacy as a therapeutic intervention for renal diseases in both preclinical as well as clinical investigations. MSCs have been found to slow the advancement of kidney disease, and this impact is thought to be due to their control over a number of physiological processes, including immunological response, tubular epithelial- mesenchymal transition, oxidative stress, renal tubular cell death, and angiogenesis. In addition, MSCs demonstrate recognised effectiveness in managing both acute and chronic kidney diseases via paracrine pathways. The proposal to utilise a therapy that is based on stem-cells as an effective treatment has been put forward in search of discovering novel therapies to promote renal regeneration. Preclinical researchers have demonstrated that various types of stem cells can provide advantages in acute and chronic kidney disease. Moreover, preliminary results from clinical trials have suggested that these interventions are both safe and well-tolerated. This manuscript provides a brief overview of the potential renoprotective effects of stem cell-based treatments in acute as well as chronic renal dysfunction. Furthermore, the mechanisms that govern the process of kidney regeneration induced by stem cells are investigated. This article will examine the therapeutic approaches that make use of stem cells for the treatment of kidney disorders. The analysis will cover various cellular sources that have been utilised, potential mechanisms involved, and the outcomes that have been achieved so far.

Comparison of Cell-based and Nanoparticle-based Therapeutics in Treating Atherosclerosis

Today, cardiovascular diseases are among the biggest public health threats worldwide. Atherosclerosis, a chronic inflammatory disease with complex aetiology and pathogenesis, predispose many of these conditions, including the high mortality rate-causing ischaemic heart disease and stroke. Nevertheless, despite the alarming prevalence and absolute death rate, established treatments for atherosclerosis are unsatisfactory in terms of efficacy, safety, and patient acceptance. The rapid advancement of technologies in healthcare research has paved new treatment approaches, namely cell-based and nanoparticle-based therapies, to overcome the limitations of conventional therapeutics. This paper examines the different facets of each approach, discusses their principles, strengths, and weaknesses, analyses the main targeted pathways and their contradictions, provides insights on current trends as well as highlights any unique mechanisms taken in recent years to combat the progression of atherosclerosis.

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.

Outlook of Ferroptosis-Targeted Lipid Peroxidation in Cardiovascular Disease

Lipid metabolism is a complex biochemical process that regulates normal cell activity and death. Ferroptosis is a novel mode of programmed cell death different from apoptosis, pyroptosis, and autophagy. Abnormal lipid metabolism may lead to lipid peroxidation and cell rupture death, which are regulated by lipoxygenase (LOX), long-chain acyl-coA synthases, and antioxidant enzymes. Alternatively, Fe²⁺ and Fe³⁺ are required for the activity of LOXs and ferroptosis, and Fe²⁺ can significantly accelerate lipid peroxidation in ferroptosis. Abnormal lipid metabolism is a certain risk factor for cardiovascular disease. In recent years, the important role of ferroptosis in developing cardiovascular disease has been increasingly reported. Reducing lipid accumulation could reduce the occurrence of ferroptosis, thus alleviating cardiovascular disease deterioration. This article reviews the relationship of lipid peroxidation to the general mechanism of ferroptosis and highlights lipid peroxidation as the common point of ferroptosis and cardiovascular disease.

Non-LGE Cardiac Magnetic Resonance Imaging in Patients with Cardiac Amyloidosis

Cardiac involvement is the leading cause of death in patients with cardiac amyloidosis. Early recognition is crucial as it can significantly change the course of the disease. Until now, the imaging modality of choice for diagnosing cardiac amyloidosis has been cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). LGE-CMR in patients with cardiac amyloidosis reveals characteristic LGE patterns that lead to a diagnosis while also correlating well with disease prognosis. However, LGE-CMR has numerous drawbacks that the newer CMR modality, T1 mapping, aims to improve. T1 mapping can be further subdivided into native T1 mapping, which does not require the use of contrast, and ECV measurement, which requires the use of contrast. Numerous T1 mapping techniques have been developed, each one with its own advantages and disadvantages when it comes to procedure difficulty and image quality. A literature review to identify relevant published articles was performed by two authors. This review aimed to present the value of T1 mapping in diagnosing cardiac amyloidosis, quantifying the amyloid burden, and evaluating the prognosis of patients with amyloidosis with cardiac involvement.

Atypical Debut of Granulomatosis with Polyangiitis as Acute Tonsilitis and Strawberry Gum: A Case Report

Abstract: Background: Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis characterized by necrosis, granulomatous inflammation, and vasculitis. It is characterized by the triad of the upper and lower respiratory system, lung, and kidney disease. Although it is usually a multisystemic disease, limited forms have also been described, and otolaryngological involvement is the first manifestation in up to 80-95% of the cases.

Case Presentation: In this report, we describe the case of an ANCA negative patient with a limited form of GPA that presented a necrotic lesion confined to the right tonsil compatible with granulomatosis with polyangiitis, which later presented positive ANCA antibodies. Oral lesions may be the initial manifestation of GPA, and systemic involvement can be presented within weeks or months. Although the oral manifestations have been well described, the initial presentation with oral lesions is very rare, and presentation with oropharyngeal manifestation is even rarer. This disease is generally characterized by anti-neutrophil cytoplasmic antibodies (ANCA); however, there are rare cases with negative ANCA.

Conclusion: The diagnosis was established based on the clinical presentation and the histopathological findings of the characteristic inflammatory pattern.

A Rare Case of Enteric Fever with Multiple Splenic Abscesses: Case Report

Background: Enteric fever is a common infection found in many developing countries around the world, which often has life-threatening complications if not treated promptly. One of the rarest complications of enteric fever is a splenic abscess.

Case Presentation: Our case is that of a 32-year-old male, admitted with febrile illness, diagnosed with typhoid fever (enteric fever) with rare complication- multiple splenic abscesses, after his travel to an endemic area, which was effectively treated with antibiotics under an inpatient setting.

Conclusion: Early diagnosis with imaging modalities such as computed tomography can lead to better treatment approaches. Splenic abscesses are often treated with antibiotics or conservative treatment; however, non-responsive cases may require splenectomy.

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.

The Role of Flavonoids in Inhibiting IL-6 and Inflammatory Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the synovial joints. RA has well-known clinical manifestations and can cause progressive disability and premature death along with socioeconomic burdens. Interleukin-6 (IL-6) has been implicated in the pathology of RA where it can stimulate pannus formation, osteoclastogenesis, and oxidative stress. Flavonoids are plant metabolites with beneficial pharmacological effects, including anti-inflammatory, antioxidant, antidiabetic, anticancer, etc. Flavonoids are polyphenolic compounds found in a variety of plants, vegetables, and fruits. Many flavonoids have demonstrated anti-arthritic activity mediated mainly through the suppression of pro-inflammatory cytokines. This review thoroughly discusses the accumulated data on the role of flavonoids on IL-6 in RA.

Immunopathology of Type 1 Diabetes and Immunomodulatory Effects of Stem Cells: A Narrative Review of the Literature

Type 1 Diabetes (T1D) is a complex autoimmune disorder which occurs as a result of an intricate series of pathologic interactions between pancreatic β-cells and a wide range of components of both the innate and the adaptive immune systems. Stem-cell therapy, a recently-emerged potentially therapeutic option for curative treatment of diabetes, is demonstrated to cause significant alternations to both different immune cells such as macrophages, natural killer (NK) cells, dendritic cells, T cells, and B cells and non-cellular elements, including serum cytokines and different components of the complement system. Although there exists overwhelming evidence indicating that the documented therapeutic effects of stem cells on patients with T1D are primarily due to their potential for immune regulation rather than pancreatic tissue regeneration, to date, the precise underlying mechanisms remain obscure. On the other hand, immune-mediated rejection of stem cells remains one of the main obstacles to regenerative medicine. Moreover, the consequences of efferocytosis of stem-cells by the recipients’ lung-resident macrophages have recently emerged as a mechanism responsible for some immune-mediated therapeutic effects of stem-cells. This review focuses on the nature of the interactions amongst different compartments of the immune systems which are involved in the pathogenesis of T1D and provides an explanation as to how stem cell- based interventions can influence immune system and maintain the physiologic equilibrium.

The Role of Angiotensin-Converting Enzyme in Immunity: Shedding Light on Experimental Findings

Abstract: Angiotensin-converting enzyme (ACE) is a zinc-dependent dicarboxypeptidase with two catalytic components, which has an important role in regulating blood pressure by converting angiotensin I to angiotensin II. ACE breaks down other peptides besides angiotensin I and has a variety of physiological effects together with renal growth and reproduction in men. ACE also acts on innate and acquired immune systems by affecting macrophage and neutrophil function, and these outcomes are exacerbated due to the overexpression of ACE. Overexpression of ACE in macrophages imposes antitumor and antimicrobial response, and it enhances the ability of neutrophils to produced super peroxide that has a bactericidal effect. ACE is also known to contribute to the expression of Major Histocompatibility Complex (MHC) class I and MHC class II peptides through enzymatic alterations of these peptides. Apprehending the expression of ACE and its effects on myeloid cell (myelogenous cells) activity can be promising in therapeutic interventions, including treatment of infection and malignancy.

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.

Targeting Brain-spleen Crosstalk After Stroke: New Insights Into Stroke Pathology and Treatment

The immune response following acute stroke has received significant attention. The spleen is an important immune organ, and more and more studies have shown that brain-spleen crosstalk after stroke plays an important role in its development and prognosis. There are many mechanisms of spleen activation after stroke, including activation of the sympathetic nervous system, the production of chemokines, and antigen presentation in the damaged brain. The changes in the spleen after stroke are mainly reflected in morphology, changes to immune cells, and cytokine production. Once activated, the spleen contracts, undergoes cellular changes, and releases inflammatory cytokines. Some studies have also shown that spleen cells specifically migrate to the site of primary brain injury. The size of the spleen is also negatively correlated with infarct volume — the more serious the spleen atrophy, the larger the infarct volume. Therefore, a comprehensive understanding of the dynamic response of the spleen to stroke will not only enable understanding of the evolution of ischemic brain injury but will also enable the identification of potential targets for stroke treatment. Here, we review recent basic and clinical drug studies on the spleen as a target for the treatment of stroke, focusing on therapeutic strategies for regulating the splenic response and inhibiting secondary brain injury.

Roles of Hematopoietic Stem and Progenitor Cells in Ischemic Cardiovascular Disease

Macrophage proliferation and skewed myelopoiesis-induced monocytosis, as well as neutrophils, enhance the generation of atherogenic inflammatory cells in a lesion area, leading to plaque formation and Cardiovascular Disease (CVD). Among all risk factors, accumulated data have shown that hyperlipidemia activates Hematopoietic Stem/Progenitor Cells (HSPCs) in the Bone Marrow (BM) niche. Recently, proliferation of Granulocyte-Monocyte Progenitors (GMPs) has been demonstrated to drive skewed myelopoiesis, while HSPCs remain quiescent. In this review, we discuss how HSPCs and GMPs participate in atherosclerosis of mice in terms of proliferation and cell mobilization from BM to peripheral blood and the lesion area. We also describe how the spleen, an extramedullary organ, is involved in skewed myelopoiesis and inflammation in atherosclerosis. We further summarize the clinical evidence of the relationship of HSPCs with coronary stenoses in patients with CVD. Ultimately, this review facilitates understanding the pathological roles of HSPCs and GMPs in atherosclerosis for future treatments.

Vascular and Cardiac Oxidative Stress and Inflammation as Targets for Cardioprotection

Cardiac and vascular diseases are often associated with increased oxidative stress and inflammation, and both may contribute to the disease progression. However, successful applications of antioxidants in the clinical setting are very rare and specific anti-inflammatory therapeutics only emerged recently. Reasons for this rely on the great diversity of oxidative stress and inflammatory cells that can either act as cardioprotective or cause tissue damage in the heart. Recent large-scale clinical trials found that highly specific anti-inflammatory therapies using monoclonal antibodies against cytokines resulted in lower cardiovascular mortality in patients with pre-existing atherosclerotic disease. In addition, unspecific antiinflammatory medication and established cardiovascular drugs with pleiotropic immunomodulatory properties such as angiotensin converting enzyme (ACE) inhibitors or statins have proven beneficial cardiovascular effects. Normalization of oxidative stress seems to be a common feature of these therapies, which can be explained by a close interaction/crosstalk of the cellular redox state and inflammatory processes. In this review, we give an overview of cardiac reactive oxygen species (ROS) sources and processes of cardiac inflammation as well as the connection of ROS and inflammation in ischemic cardiomyopathy in order to shed light on possible cardioprotective interventions.

Vascular Inflammation in Cardiovascular Disease: Is Immune System Protective or Bystander?

Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Chronic atherosclerosis induced vascular inflammation and perturbation of lipid metabolism is believed to be a major cause of CVD. Interplay of innate and adaptive Immune system has been interwined with various risk factors associated with the initiation and progression of atherosclerosis in CVD. A large body of evidence indicates a correlation between immunity and atherosclerosis. Retention of plasma lipoproteins in arterial subendothelial wall triggers the T helper type 1 (Th1) cells and monocyte-derived macrophages to form atherosclerotic plaques. In the present review, we will discuss the pathogenesis of CVD in relation to atherosclerosis with a particular focus on pro-atherogenic role of immune cells. Recent findings have also suggested anti-atherogenic roles of different B cell subsets. Therapeutic approaches to target atherosclerosis risk factors have reduced the mortality, but a need exists for the novel therapies to treat arterial vascular inflammation. These insights into the immune pathogenesis of atherosclerosis can lead to new targeted therapeutics to abate cardiovascular mortality and morbidity.

Advances in Sickle Cell Disease Treatments

Sickle Cell Disease (SCD) is an inherited disorder of red blood cells that is caused by a single mutation in the β -globin gene. The disease, which afflicts millions of patients worldwide mainly in low income countries, is characterized by high morbidity, mortality and low life expectancy. The new pharmacological and non-pharmacological strategies for SCD is urgent in order to promote treatments able to reduce patient’s suffering and improve their quality of life. Since the FDA approval of HU in 1998, there have been few advances in discovering new drugs; however, in the last three years voxelotor, crizanlizumab, and glutamine have been approved as new therapeutic alternatives. In addition, new promising compounds have been described to treat the main SCD symptoms. Herein, focusing on drug discovery, we discuss new strategies to treat SCD that have been carried out in the last ten years to discover new, safe, and effective treatments. Moreover, non-pharmacological approaches, including red blood cell exchange, gene therapy and hematopoietic stem cell transplantation will be presented.

Recent Progress on the Discovery of NLRP3 Inhibitors and their Therapeutic Potential

Background: Inflammation is the body’s immune system’s fast coordinating response to irritants caused by pathogens, external injuries, and chemical or radiation effects. The nucleotidebinding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. The dysfunction of NLRP3 inflammasome contributes to various pathogeneses of complex diseases, such as uncontrolled infection, autoimmune diseases, neurodegenerative diseases, and metabolic disorders. This review describes recent progress on the discovery of NLRP3 inflammasome inhibitors and their therapeutic potential.

Methods: Based on the mechanism of NLRP3 activation, several types of NLRP3 inhibitors are described and summarized according to their origins, structures, bioactivity, and mechanism of action. Structure-Activity Relationship (SAR) is also listed for different scaffolds, as well as effective pharmacophore.

Results: Over one-hundred papers were included in the review. The development of NLRP3 inhibitors has been described from the earliest glyburide in 2001 to the latest progress in 2019. Several series of inhibitors have been categorized, such as JC-series based on glyburide and BC-series based on 2APB. Many other small molecules such as NLRP3 inhibitors are also listed. SAR, application in related therapeutic models, and five different action mechanisms are described.

Conclusion: The findings of this review confirmed the importance of developing NLRP3 inflammasome inhibitors. Various NLRP3 inhibitors have been discovered as effective therapeutic treatments for multiple diseases, such as type II diabetes, experimental autoimmune encephalomyelitis, stressrelated mood disorders, etc. The development of a full range of NLRP3 inflammasome inhibitors is still at its foundational phase. We are looking forward to the identification of inhibitory agents that provide the most potent therapeutic strategies and efficiently treat NLRP3 inflammasome-related inflammatory diseases.

The Innate Immune System and Cardiovascular Disease in ESKD: Monocytes and Natural Killer Cells

Adverse innate immune responses have been implicated in several disease processes, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The monocyte subsets natural killer (NK) cells and natural killer T (NKT) cells are involved in innate immunity. Monocytes subsets are key in atherogenesis and the inflammatory cascade occurring in heart failure. Upregulated activity and counts of proinflammatory CD16+ monocyte subsets are associated with clinical indices of atherosclerosis, heart failure syndromes and CKD. Advanced CKD is a complex state of persistent systemic inflammation characterized by elevated expression of proinflammatory and pro-atherogenic CD14++CD16+ monocytes, which are associated with cardiovascular events and death both in the general population and among patients with CKD. Diminished NK cells and NKT cells counts and aberrant activity are observed in both coronary artery disease and end-stage kidney disease. However, evidence of the roles of NK cells and NKT cells in atherogenesis in advanced CKD is circumstantial and remains to be clarified. This review describes the available evidence regarding the roles of specific immune cell subsets in the pathogenesis of CVD in patients with CKD. Future research is expected to further uncover the links between CKD associated innate immune system dysregulation and accelerated CVD and will ideally be translated into therapeutic targets.

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.

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.

Cardiovascular Disease in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous, arterial or microvascular thrombosis or obstetric events in the presence of persistently positive antiphospholipid antibodies and constitutes a major cause of cardiovascular events in young people. Τhis review highlights the pathophysiology of cardiovascular complications in patients with APS and possible treatment options.

Patients with APS have endothelial dysfunction, accelerated endothelial proliferation and intimal hyperplasia, atherogenesis, platelet activation, inflammatory products secretion and coagulation-fibrinolytic dysregulation. Cardiovascular complications include accelerated atherosclerosis, acute coronary syndrome, Libman-Sacks endocarditis, cardiomyopathy and venous, arterial or intracardiac thrombi. Moreover, pulmonary hypertension and peripheral microvascular dysfunction are common findings.

Management of these patients is not well documented. The role of primary thrombosis prevention remains controversial in individuals with positive antiphospholipid antibodies. Treatment of traditional cardiovascular risk factors according to current guidelines for the prevention of cardiovascular disease in the general population is recommended for primary prevention of APS. Anticoagulation therapy with unfractionated or low-molecular-weight heparin overlapped with a vitamin K antagonist remains the mainstay of the treatment for APS patients with venous thrombosis, whereas direct oral anticoagulants are not yet recommended. Data are scarce regarding the secondary arterial thrombosis prevention and it is not clear whether dual or triple antithrombotic therapy is necessary. To date, it is recommended to follow current guidelines for the management of acute coronary syndrome in the general population. New treatment targets are promising options for patients with catastrophic APS.

Torsion of Wandering Spleen: Importance of Splenic Density and Liver-to- Spleen Attenuation Ratio on CT

Background: Wandering spleen (WS) is a rare clinical condition which may cause fatal complication like torsion with subsequent infarction. Determination of splenic parenchyma viability is very important in deciding whether splenopexy rather than splenectomy is an option. Contrast- enhanced computed tomography (CECT) is important for the diagnosis of WS and assessment of the viability of spleen.

Discussion: We reviewed the CT studies of four cases with WS. We measured the mean splenic and liver density and calculated liver-to-spleen attenuation ratio (LSAR). We also assessed the CT findings for each patient. Mean splenic density was measured as 40.77 Hounsfield Unit (HU) in cases with infarction, 127.1 HU in case without infarction. LSAR was calculated as 2.55 in cases with infarction, 0.99 in case without infarction. We detected whirlpool sign, intraperitoneal free fluid, splenic arterial enhancement in all patient, parenchymal and splenic vein enhancement in one patient without infarction, fat rim sign in three patients with infarction, capsular rim sign in one patient with infarction.

Conclusion: CECT should be obtained for the diagnosis of WS and assessment of the viability of spleen. CECT could suggest the diagnosis of infarction of the spleen with following findings; absence of parenchymal enhancement, very low density of spleen (<45 HU), and LSAR which is greater than 2.

Lipid Nanoparticles and Active Natural Compounds: A Perfect Combination for Pharmaceutical Applications

Phytochemicals represent an important class of bioactive compounds characterized by significant health benefits. Notwithstanding these important features, their potential therapeutic properties suffer from poor water solubility and membrane permeability limiting their approach to nutraceutical and pharmaceutical applications. Lipid nanoparticles are well known carrier systems endowed with high biodegradation and an extraordinary biocompatible chemical nature, successfully used as platform for advanced delivery of many active compounds, including the oral, topical and systemic routes. This article is aimed at reviewing the last ten years of studies about the application of lipid nanoparticles in active natural compounds reporting examples and advantages of these colloidal carrier systems.

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.

Fighting Type-2 Diabetes: Present and Future Perspectives

Background: Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic β cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects.

Methods: We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions.

Results: Glucagon-like peptide-1 receptor agonists stimulate β cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve β cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot.

Conclusion: A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.

Nanomedicine for Gene Delivery for the Treatment of Cardiovascular Diseases

Background: Myocardial infarction (MI) is the most severe ischemic heart disease and directly leads to heart failure till death. Target molecules have been identified in the event of MI including increasing angiogenesis, promoting cardiomyocyte survival, improving heart function and restraining inflammation and myocyte activation and subsequent fibrosis. All of which are substantial in cardiomyocyte protection and preservation of cardiac function.

Methodology: To modulate target molecule expression, virus and non-virus-mediated gene transfer have been investigated. Despite successful in animal models of MI, virus-mediated gene transfer is hampered by poor targeting efficiency, low packaging capacity for large DNA sequences, immunogenicity induced by virus and random integration into the human genome.

Discussion: Nanoparticles could be synthesized and equipped on purpose for large-scale production. They are relatively small in size and do not incorporate into the genome. They could carry DNA and drug within the same transfer. All of these properties make them an alternative strategy for gene transfer. In the review, we first introduce the pathological progression of MI. After concise discussion on the current status of virus-mediated gene therapy in treating MI, we overview the history and development of nanoparticle-based gene delivery system. We point out the limitations and future perspective in the field of nanoparticle vehicle.

Conclusion: Ultimately, we hope that this review could help to better understand how far we are with nanoparticle-facilitated gene transfer strategy and what obstacles we need to solve for utilization of nanomedicine in the treatment of MI.

Oxidative and Inflammatory Events in Prion Diseases: Can They Be Therapeutic Targets?

Prion diseases are a group of incurable infectious terminal neurodegenerative diseases caused by the aggregated misfolded PrPsc in selected mammals including humans. The complex physical interaction between normal prion protein PrPc and infectious PrPsc causes conformational change from the α- helix structure of PrPc to the β-sheet structure of PrPsc, and this process is repeated. Increased oxidative stress is one of the factors that facilitate the conversion of PrPc to PrPsc. This overview presents evidence to show that increased oxidative stress and inflammation are involved in the progression of this disease. Evidence is given for the participation of redoxsensitive metals Cu and Fe with PrPsc inducing oxidative stress by disturbing the homeostasis of these metals. The fact that some antioxidants block the toxicity of misfolded PrPc peptide supports the role of oxidative stress in prion disease. After exogenous infection in mice, PrPsc enters the follicular dendritic cells where PrPsc replicates before neuroinvasion where they continue to replicate and cause inflammation leading to neurodegeneration. Therefore, reducing levels of oxidative stress and inflammation may decrease the rate of the progression of this disease. It may be an important order to reduce oxidative stress and inflammation at the same time. This may be achieved by increasing the levels of antioxidant enzymes by activating the Nrf2 pathway together with simultaneous administration of dietary and endogenous antioxidants. It is proposed that a mixture of micronutrients could enable these concurrent events thereby reducing the progression of human prion disease.

Effect of Honey & Olive Oil Supplemented Bio-Yoghurt Feeding on Lipid Profile, Blood Glucose and Hematological Parameters in Rats

Background and Objective: Yoghurt, especially bio-yoghurt has long been recognized as a product with many health benefits for consumers. Also, honey and olive oil have considerable nutritional and health effects. So, the effect of administration of yoghurt made using ABT culture and fortified with honey (2 and 6%), olive oil (1 and 4%) or honey + olive oil (2+1 and 6+4% respectively) on some biological and hematological properties of rats was investigated.

Methods: The body weight gain, serum lipid level, blood glucose level, serum creatinine level, Glutamic Oxaloacetic Transaminase (GOT) activity, Glutamic Pyruvic Transaminase (GPT) activity, leukocytes and lymphocytes counts of rats were evaluated.

Results: Blending of bio-yoghurt with rats' diet improved body weight gain. Concentrations of Total plasma Cholesterol (TC), High-Density Lipoprotein cholesterol (HDL), Low-Density Lipoprotein cholesterol (LDL), Very Low-Density Lipoprotein cholesterol (VLDL) and Triglycerides (TG) significantly lowered in plasma of rats fed bio-yoghurt. Levels of TC, LDL, VLDL, and TG also decreased in rat groups feed bio-yoghurt supplemented with honey and olive oil. LDL concentrations were reduced by 10.32, 18.51, 34.17, 22.48, 43.30% in plasma of rats fed classic starter yoghurt, ABT yoghurt, ABT yoghurt contained 6% honey, ABT yoghurt contained 4% olive oil and ABT yoghurt contained 6% honey + 4% olive oil respectively. The blood glucose, serum creatinine, GOT and GPT values of rats decreased while white blood cells and lymphocytes counts increased by feeding bioyoghurt contained honey and olive oil.

Conclusion: The findings enhanced the multiple therapeutic effects of bio-yoghurt supplemented with honey and olive oil.

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.

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.

The Intriguing Occurrence of Segmental Arterial Mediolysis: Case Report and Concise Literature Review

Background: Segmental medial arteriolysis (SAM) is a unique arteriopathy highlighted by significant lytic changes in the medial wall of the blood vessels and can present from vague gastrointestinal discomfort to catastrophic abdominal bleeding and shock. We hereby present a concise review of this rare phenomenon with historic perspectives, epidemiology, and current concepts of etiology, pathogenesis, relevant clinical associations, treatment modalities, prognosis and future directions in SAM.

Conclusion: In addition, we present an interesting occurrence of this intriguing phenomenon in a forty-eight year old lady at our institution who presented with vague symptomatology and was an extremely challenging diagnosis. This highlights the importance of timely detection and institution of therapeutic or preventive strategies to minimize future catastrophic events.

Defensive and Offensive Cross-Reactive Antibodies Elicited by Pathogens: The Good, the Bad and the Ugly

Understanding how immunity to pathogens develops is crucial for progress in the quest for effective vaccines. Intraspecies and interspecies cross-reacting antibodies are produced in high frequency against immune-relevant and shared microbial epitopes. It has been confirmed that cross-reactive antigens may have a crucial role in natural epidemiology to a particular infection and that cross-protection may influence the outcome of natural infections. On the other hand, the action of cross-reactive antibodies may be very harmful for the host. In this review we discuss both the defensive and offensive capabilities of cross-reactive antibodies. The defensive properties are discussed with regard to the beneficial cross-protective interaction of these antibodies against various microorganisms including viruses, bacteria, fungi and protozoan parasites. We summarize the current knowledge of numerous effector functions of these antibodies such as agglutination, neutralization of infectivity, complement activation, phagocytosis enhancement, and antibody-dependent cellular cytotoxicity. We also discuss the offensive action of cross-reactive antibodies including their detrimental effects in exacerbation of the infective diseases, as well as autoimmune diseases and allergy as a result of inappriopriate or deleterious inflammatory response associated with host tissue destruction. The factors influencing cross-protective capacity of antibodies are also presented.

Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges

Background: The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases.

Objective: The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke.

Results: IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners.

Conclusion: IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders.

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.

Phosphoinositide-3-kinases as the Novel Therapeutic Targets for the Inflammatory Diseases: Current and Future Perspectives

Objective: To review the role of PI3K/AKT/mTOR signalling pathway, and the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc., laying special emphasis on the inflammatory diseases and associated cellular responses.

Background: Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The recent literature relating this pathway with these diseases is highlighted, with a hope, which remains for the progression of PI3K inhibitors in the market as a treatment option.

Result: With Idelalisib entering the market for cancer, PI3K/AKT signalling has also gained significance as an investigational target for various diseases, particularly for inflammation. Based on the pharmacological, genetic, and clinical data available, PI3K/AKT signalling can be designated as an outstanding target for their treatment.

Conclusion: Further exploration of this pathway may also uncover its involvement in these disorders, which may further contribute to developing the new treatments and can turn out to be an innovative brainwave in the field of experimental and clinical pharmacology in future.

CRH Receptor Signalling: Potential Roles in Pathophysiology

To maintain homeostatic equilibrium, living organisms have evolved complex adaptation systems that control an array of behavioural, autonomic, neuroendocrine and immune responses. One of the important switches of this system is the hypothalamic hormone corticotropin-releasing hormone (CRH), which together with a family of related peptides (urocortins, UCNs) orchestrate stress-coping responses that reinstate homeostasis. Persistent disturbances in the homeostatic equilibrium either due to inadequate or persistently uncontrolled responses have been associated with pathogenic mechanisms of disease. CRH and UCNs exert their actions by activating two receptors of the Class B1 GPCRs, CRH-R1 and CRH-R2. Their signalling versatility allows activation of multiple and diverse signalling pathways characterized by ‘cell-specific agonist-dependent signalling’ responses. Alternative mRNA splicing, interactions with intracellular protein partners and mechanisms that allow selective regulation of signalling potency and termination, provide additional levels of regulation to fine-tune cellular responses. Although understanding of CRH-R signalling is still incomplete, recent important advances in decoding CRH-R structure and signalling properties uncovered key important functions and roles in physiology and pathobiology.

Stem Cell Therapies for Intracerebral Hemorrhages

Background: An insult due to intracerebral hemorrhage (ICH) is critical to patients. So, breakthroughs in ICH treatment are very important.

Objective: Advances in the stem cell treatment of stroke have been remarkable. And stem cell experimentation on ischemic stroke, however, preceded such work on ICH and did not emphasized ICH therapy.

Method: We review recent stem cell treatments for ICH, an experimental model of ICH, the medical care of ICH, and several stem cell therapies for ICH along with future prospects.

Results: Stem cell therapy for ICH is effective in rodent or animal models. For humans, only a small number of clinical trials have been done, and significant functional recovery was recorded.

Conclusion: We need to reveal the mechanism of stem cell therapy and develop a reliable, definitive treatment strategy for treatment of ICH. In the future, several types of stem cells will be available for the treatment of ICH.

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.

The TLR9 Antagonist iCpG-ODN at Different Dosages Inhibits Cerebral Ischemia/Reperfusion Injury in Mice

Background: Inflammatory responses are important mechanisms that are involved in cerebral ischemia/reperfusion(I/R) injury. Whether toll-like receptor 9(TLR9), which belongs to the innate immune system, takes part in the inflammatory responses following cerebral I/R remains unclear.

Method: This study examined the effect of different dosages of the TLR9 antagonist inhibitory oligodeoxynucleotide (iCpG-ODN) on cerebral I/R injury by using a mouse model of transient middle cerebral artery occlusion. Neurological function, infarct size, splenocytes and the expression of TLR9 and the downstream products of the TLR9 pathways were determined after cerebral I/R for up to 72 hours.

Results: The Clark's focal symptom scoring showed iCpG-ODN improved neurological deficits following focal cerebral I/R. The iCpG-ODN administration significantly decreased the infarct size in a dose-dependent manner. RT-PCR showed that iCpG-ODN attenuated the I/R-induced RNA expression of TLR9. Immunoblot showed that iCpG-ODN prevented I/R-induced increases in NFκB and IRF7 levels and that it further downregulated the levels of IL-1β, TNF-α, and INF-β in the brain. iCpG-ODN did not alter the levels of TNF-α or INF-β in the peripheral blood or affect stroke-induced changes in the number of splenocytes.

Conclusion: These findings suggest that iCpG-ODN induced protection against cerebral I/R via inhibiting inflammatory responses in a dose-dependent manner and may be useful in therapy for stroke patients.

Diverse Functions and Mechanisms of Pericytes in Ischemic Stroke

Background: Every year, strokes take millions of lives and leave millions of individuals living with permanent disabilities. Recently more researchers embrace the concept of the neurovascular unit (NVU), which encompasses neurons, endothelial cells (ECs), pericytes, astrocyte, microglia, and the extracellular matrix. It has been well-documented that NVU emerged as a new paradigm for the exploration of mechanisms and therapies in ischemic stroke. To better understand the complex NVU and broaden therapeutic targets, we must probe the roles of multiple cell types in ischemic stroke. The aims of this paper are to introduce the biological characteristics of brain pericytes and the available evidence on the diverse functions and mechanisms involving the pericytes in the context of ischemic stroke.

Methods: Research and online content related to the biological characteristics and pathophysiological roles of pericytes is review. The new research direction on the Pericytes in ischemic stroke, and the potential therapeutic targets are provided.

Results: During the different stages of ischemic stroke, pericytes play different roles: 1) On the hyperacute phase of stroke, pericytes constriction and death may be a cause of the no-reflow phenomenon in brain capillaries; 2) During the acute phase, pericytes detach from microvessels and participate in inflammatory-immunological response, resulting in the BBB damage and brain edema. Pericytes also provide benefit for neuroprotection by protecting endothelium, stabilizing BBB and releasing neurotrophins; 3) Similarly, during the later recovery phase of stroke, pericytes also contribute to angiogenesis, neurogenesis, and thereby promote neurological recovery.

Conclusion: This emphasis on the NVU concept has shifted the focus of ischemic stroke research from neuro-centric views to the complex interactions within NVU. With this new perspective, pericytes that are centrally positioned in the NVU have been widely studied in ischemic stroke. More work is needed to elucidate the beneficial and detrimental roles of brain pericytes in ischemic stroke that may serve as a basis for potential therapeutic targets.

Carbon Nanotubes in the Treatment of Skin Cancers: Safety and Toxic ological Aspects

Background: Skin cancer is depicted to be the most common malignant disease across the globe that is frequently diagnosed in people bearing light skin. Three common forms of skin cancers are squamous cell carcinoma, basal cell carcinoma, and malignant melanoma. Treatment of skin cancers comprises of various forms of management strategies that can help in curing the disease including the use of several therapeutic agents. Though numerous therapies have been explored till date to deliver the active therapeutics, nanoparticulate based targeted therapy has garnered considerable interest and is a promising approach in treating skin cancers.

Objective: The present review aims to explore a novel nano-sized carrier, carbon nanotubes for the delivery of various actives researched for skin cancer treatment. The write up traces the pre-clinical and clinical reports on carbon nanotubes. The feasibility of the nanoparticulate system has been elaborated inclusive of the safety and toxicological aspects of the carrier system.

Conclusion: From the reviewed literature it can be concluded that carbon nanotubes are the emerging treatment modality in skin cancers as they offer targeted delivery to the cancerous cells, act selectively and provide better penetration in the neoplastic cells due to improved permeability and retention effect.

Cholinergic Anti-inflammatory Pathway and Stroke

Background: Stroke is devastating cerebrovascular event which is responsible for 6.7 million deaths each year worldwide. Inflammation plays an important role in the pathophysiology of stroke. Targeting inflammation after stroke is highly actual topic for both experimental and clinical research.

Methods: Research articles related to cholinergic anti-inflammatory pathway (CHAIP) and stroke were reviewed. The first part of review describes the basic characteristics of inflammatory response after stroke, main components and function of CHAIP. The second part reviews studies focused on CHAIP as a therapeutic target for ischemic and hemorrhagic stroke. Both pharmacological stimulation of α7 nAChR and vagus nerve stimulation after stroke are reviewed.

Results: Cholinergic anti-inflammatory pathway (CHAIP) is a physiological mechanism by which central nervous system regulates immune response and controls inflammation. Vagus nerve, spleen and α7 nicotinic acetylcholine receptor (α7 nAChR) are the main components of CHAIP.

Conclusion: Targeting cholinergic anti-inflammatory pathway is a promising way of immunomodulation which attenuates inflammation in a complex manner without causing immunosuppression.

Is there any Role for Splenectomy in Adulthood Onset Chronic Immun e Thrombocytopenia in the Era of TPO Receptors Agonists? A Critic al Overview

Background: Immune thrombocytopenia (ITP) in adulthood is characterized by chronic relapsing course. Despite the efficacious first line treatment (corticosteroid, intravenous immunoglobulin), majority of patients will enter the chronic phase warranting another treatment approach. Until recently, splenectomy performed in ITP chronic phase represented the standard of care with longterm remissions in more than 70% of patients, but it has never been tested in clinical trials. However, with the advances of our understanding of ITP pathophysiology and the shifting focus on megakaryocyte impairment, novel drugs were introduced in the treatment paradigm, mainly trombopoietin receptor agonists (TPO-RAs); romiplostim and eltrombopag.

Methods: These TPO-RAs were tested in randomized controlled trials resulting in adequate platelet response with few side effects and less need for additional therapy leading to approval of corresponding regulatory agencies and wide acceptance by hematological community, but however TPO-RAs must be taken continuously to maintain the response. With their onset, the rate of splenectomy in chronic ITP has diminished in modern era.

Conclusion: The main aim behind conducting this review is to evaluate the pros and cons of splenectomy compared to TPO-RAs treatment in order to provide the critical overview which may help the practicing clinician in managing often challenging cases of chronic ITP.

Inflammasome in Dendritic Cells Immunobiology: Implications to Diseases and Therapeutic Strategies

Background: An intricate interplay between innate and adaptive immune cells is crucial for an effective immune response during disease, infection and vaccination. This interplay is mainly performed by dendritic cells (DCs), which are professional antigen presenting cells with unparalleled capacity to translate innate to adaptive immunity. They effectively recognize and uptake antigens, migrate to lymphoid tissues, and activate naïve T-cells. Indeed, DCs have numerous germline encoded pattern recognition receptors (PRR) that recognize conserved pathogen associated molecular patterns (PAMPs) or danger associated molecular patterns (DAMPs). While some PRRs like Toll-like receptors (TLRs) recognize PAMPs and DAMPs at the cell surface and in endosomal/lysosomal compartments, others, such as NOD-like receptors (NLRs), act as cytosolic sensors. NLRs activation through recognition of PAMPs and DAMPs leads to the assembly of signaling multimeric protein complexes named inflammasomes. Inflammasomes are important regulators of caspase 1, the enzyme responsible for the proteolytically cleavage of precursors’ pro-IL-1β and pro-IL-18 into their active form.

Objective: To unveil how inflammasomes are related to maturation, migration, antigen presenting function and DCs ability to fine tune adaptive immune responses.

Conclusion: Several studies show that in danger/infectious scenarios NLR and TLR synergize to expand DCs maturation, migration, antigen presenting function and adaptive immune system activation. However, in the absence of a danger scenario, and without TLR engagement, inflammasome activation stimulates an immunosuppressive profile on DCs. Overall, it is clear from literature that activation of the inflammasome in DCs should not be viewed in isolation but rather considering its interconnections with the various PPRdriven pathways. Due to the increasing evidences of inflammasome involvement in multiple inflammatory and immune diseases, this information is of utmost importance since precise inflammasome pharmacological targeting could lead to considerable clinical utility through fine-tuned targeted therapies.

Ruptured Multiple Mycotic Aneurysms Following Infective Endocarditis: Effectiveness of Catheter-based Techniques Using N-butyl Cyanoacrylate in a Hemorrhage-induced Coagulopathy

Background: Visceral bleeding caused by ruptured mycotic aneurysms, especially intracerebral hematoma, is a most serious complication. In such cases, not only surgical techniques but also a variety of modalities such as catheter-based technique is required to comprehensively treat a patient with hemorrhage-induced coagulopathy.

Case Reports: We treated an infectious endocarditis (IE) patient with coagulopathy caused by ruptured multiple mycotic aneurysms who underwent endovascular embolization using n-butyl cyanoacrylate (NBCA) and successful surgical removal assisted with catheter-based hemostasis. We also reviewed published literatures about mycotic aneurysm treated using NBCA using PUBMED. Upon review of the existing literature, it was evident that there are only a very limited number of publications related to “infectious” or “mycotic aneurysm” treated using NBCA, and only three case references were retrieved.

Conclusion: Catheter-based techniques using n-butyl-2-cyanoacrylate (NBCA) which has been used as a liquid embolic agents is effective for patients with hemorrhage-induced coagulopathy caused by ruptured mycotic aneurysms before surgical treatment.

PDE7-Selective and Dual Inhibitors: Advances in Chemical and Biological Research

Phosphodiesterase 7 (PDE7) is an intracellular enzyme that specifically hydrolyzes the second messenger, cyclic-3’,5’-adenosine monophosphate (cAMP), into inactive noncyclic nucleotide, 5’-AMP. To date, many structurally diverse compounds with PDE7 inhibitory properties have been described, including selective PDE7 inhibitors, dual PDE4/PDE7, PDE7/PDE8, and PDE7/GSK-3 inhibitors, and non-selective PDE inhibitors with high affinity for PDE7. Inhibitors of PDE7 have provided beneficial effects in animal models of inflammatory and neurological disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and many others. This review is a comprehensive summary of the current state-of-the-art in the field of design and synthesis of PDE7 inhibitors, their physicochemical properties, biological evaluation, and structure-activity relationships as well as it highlights the updated evidence for a potential therapeutic utility of these compounds. Moreover, new approaches to obtain more effective and safer PDE7 inhibitors than those available now are presented.

Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application

The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders.

Pulmonary Disease in Beta-Thalassemia

The care of beta-thalassemia has improved dramatically over the last few decades mostly because of: i) improved blood transfusion regimens; ii) wide-spread use of deferoxamine; iii) surgical advances; and iv) allogeneic hematopoietic stem cell transplantation. Advanced healthcare standards, improved life expectancy, and complications specific to beta-thalassemia necessitate a renewed approach to the pulmonary issues of this disease.

While transfusion-related infections are expected, and Streptococcal, Staphylococcal, E. coli and Salmonella infections are common, a number of special problems are also reported. Mycoplasma pneumoniae infections associated with hemolytic anemia, Pneumocystis carinii pneumonia and necrotizing pneumonia caused by Klebsiella pneumoniae are indicative of the special susceptibility to infections in beta-thalassemia. The issue of immune function in the (non-transplanted) patient with thalassemia is brought up. Conditions associated with chronic airway inflammation, such as plastic bronchitis and allergic bronchopulmonary mycosis, are discussed as well as life-threatening complications.

In an attempt to organize the diagnostic approach to pulmonary disease in beta-thalassemia, four working entities are delineated, which, almost invariably, tend to overlap and aggravate each other: i) disorders inherent to the beta-thalassemia hemoglobinopathy; ii) chronic lung disease and its complications; iii) immunological corollaries of the therapy of beta-thalassemia, i.e. chronic transfusion, splenectomy and bone marrow transplantation; and iv) airway inflammation.

Functional Components from Nature-Derived Drugs for the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic disorder characterized by persistent synovitis and systemic inflammation. Currently, the widely used drugs for the treatment of RA are disease-modifying antirheumatic drugs, biological agents and glucocorticoids. But their clinical use has been limited because of their adverse effects with a high frequency and high cost of treatment. It is essential to find novel candidate agents. Traditional Chinese medicine (TCM) has been used for RA treatment for a long period of time. In recent years, significant amounts of studies have shown that some TCMs and their active ingredients have obvious therapeutic effects on RA. In this review, the compounds in TCMs that have an effect in clinic or animal experiments of RA are critically reviewed and summarized. Moreover, the relationship between chemical structures of the compound and their activities is analyzed. The relevant researches are described from the aspects of source, methods, result, and related mechanism analysis. The existing studies show that most effective compounds in TCM for RA treatment belong to alkaloids, flavonoids, terpenoids, phenols and quinines. It is hoped that the data summarized in this review will be beneficial to the screening of new nature-derived antirheumatic drugs.

Antiphospholipid Antibody-Mediated Thrombotic Mechanisms in Antiphospholipid Syndrome: Towards Pathophysiology-Based Treatment

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by a persistently high titer of antiphospholipid antibodies (aPLs). In addition to pregnancy morbidity, arterial and/or venous thrombosis is another clinical feature of APS. Regardless of the type of APS, the thrombi formed by the induction of aPLs can lead to deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke and gangrene. Although the concept of APS was introduced approximately 32 years ago, its thrombogenic pathophysiology is still unclear. Therefore, patients are treated with anticoagulant and/or antiplatelet regimens just as in other thrombotic disorders even though the thrombotic pathophysiology is mainly aPLs-mediated. In this review, we provided an update of the cellular, auto-immune and genetic factors known to play important roles in the generation of thrombi. Current successful regimens are also outlined along with potential emerging treatment strategies that may lead to the optimum management of thrombotic APS patients.

Prognostic Significance of Asymptomatic Myocardial Ischemia in Women vs. Men

Background: Silent myocardial ischemia is a recognized but suboptimally studied condition in patients with and without known coronary artery disease. Limited work has focused on the association between silent myocardial ischemia and future prognosis however the majority of these analyses have focused mostly on male cohorts. As signs and symptoms of myocardial ischemia are known to be different in women, it is important to discuss and highlight any differences in association between silent myocardial ischemia and adverse cardiovascular outcomes based on gender. Methods: The aim of this review is to summarize the current literature available discussing silent myocardial ischemia and potential gender differences. We searched English language studies on PUBMED and the Cochrane Database of Systematic Reviews from the database start dates to November 2015. Conclusion: As data on the presence of silent myocardial ischemia in women is limited, whether a differential association based on gender between this condition and cardiovascular prognosis remains unknown. Future studies should target women especially those without epicardial coronary disease and suspected coronary microvascular dysfunction.

Allosteric Modulation of Nicotinic Acetylcholine Receptors: The Concept and Therapeutic Trends

Expressing functional nicotinic acetylcholine receptors (nAChRs) may be beneficial to central neurons and neuronal networks because activation of nAChRs enhances neuronal resistance to injury, improves attention, cognitive performance, and produces robust anti-inflammatory and analgesic effects in mammals. Although exogenous orthosteric nAChR ligands present valuable tools in treatment of age- and trauma-related neurological deficits, therapeutic approaches that could amplify the brain’s innate ability to maintain cholinergic homeostasis and resist injury may serve as intriguing and promising alternatives and have not been fully explored. One of these novel approaches utilizes positive allosteric modulators (PAMs) of nAChRs. Because of the ubiquitous expression of nAChRs in neuronal, glial and immune tissues, highly selective PAMs could amplify multiple endogenous neuroprotective, pro-cognitive, anti-inflammatory and anti-nociceptive cholinergic pathways to offset cholinergic hypofunction and generate therapeutic efficacy by targeting only a single player: i.e., nAChRs activated by endogenous cholinergic tone. In this article, I review the concept of allosteric modulation and current trends in therapeutic applications of nicotinic PAMs.

Platelet-derived Growth Factor Receptor-beta is Differentially Regulated in Primary Mouse Pericytes and Brain Slices

Pericytes are perivascular cells and have heterogenous roles in the brain, such as controlling blood flow and entry of immune cells or regulating the blood-brain barrier. Platelet-derived growth factor (PDGF) receptor-beta (PDGFRβ) is highly expressed in pericytes, representing the most selective biomarker. The aim of the present study was to culture primary mouse pericytes and to determine the expression pattern by Western Blot as well as immunostainings. We will study the effects of different exogenous stimuli (such as transforming growth factor-β (TGFβ1), PDGF-BB, oxygendeprivation, beta-amyloid or serumfree conditions) on the different pericyte markers. Using Western Blot analyses, we show that PDGFRβ is selectively expressed in pericytes as a 160 kDa protein. Nestin, although not exclusively specific, is also expressed by pericytes, but markedly downregulated under serum-free conditions. PDGF-BB and oxygen-deprivation dramatically reduced PDGFRβ expression, while TGF1 increased its expression. The expression of PDGFRβ was intracellular as shown by confocal microscopy. Using Western Blot analyses, we demonstrate that pericytes also contain a 100 kDa PDGFRβ protein. However, in contrast to cortex brain slices, pericytes do not express a phosphorylated (Y740) isoform. Interestingly, PDGF-BB markedly reduced the 160 kDa isoform of PDGFRβ. In conclusion, our data show a detailed expression of different forms of PDGFRβ in primary pericytes, which is different to brain slices. However, we suggest that PDGFR is a highly selective marker for pericytes.

Opinion Paper: A Cognitive-cultural Segregation and the Three Stages of Aging

There is no doubt that the world is divided and unequal, mostly with respect to wealth. However, the true obstacle preventing the progress of humanity is not the divide between the rich and the poor. It is the divide between the cognitive and the physical. Apart from the social and ethical issues associated with this, there are also medical ones. The implications of this divide have direct relevance to aging, both in research and in the clinical sense. We cannot simply apply the same ‘healthy aging’ guidelines to everybody, but we need to establish if our approach is specifically suited to the individual. Our research endeavours need to have this division in focus. In this Opinion paper I describe three separate groups of humanity, which are divided, not by economic criteria, but by a worldview of intellectual creativity. Each arbitrary group has its own health priorities. If we overlook these priorities we may, at best, give the wrong advice to our patients, or at worst waste resources and exacerbate the rate of age-related degeneration in many individuals. As our society becomes more reliant on technology, what is now considered ‘healthy’ may not be so, for many millions of people.

Diabetes and Pancreas: Why So Difficult? Potential Mechanisms of Elevated Serum Pancreatic Enzymes

Diabetes mellitus has been associated with a higher risk of exocrine pancreas disorders despite inconsistencies among studies, presumably due to the presence of several (often unmeasured) confounding factors. As a direct consequence of this uncertainty, the relationship between anti-diabetic therapies and pancreatic adverse reactions is difficult to evaluate and remains far from being clarified. Indeed, the on going debate on the safety of incretin-based therapies does not lie in any definite conclusion.

Serum level of amylases and lipase reflects the balance between production from different tissues and clearance, but it may be also influenced by numerous molecular, cellular, and systems mechanisms. The present review tries to provide an overview of potential biochemical pathways that may underlie pancreatic hyperenzymemia in health and diabetes mellitus.

Autonomic Nervous System in Viral Myocarditis: Pathophysiology and Therapy

Myocarditis, which is caused by viral infection, can lead to heart failure, malignant arrhythmias, and even sudden cardiac death in young patients. It is also one of the most important causes of dilated cardiomyopathy worldwide. Although remarkable advances in diagnosis and understanding of pathophysiological mechanisms of viral myocarditis have been gained during recent years, no standard treatment strategies have been defined as yet. Fortunately, recent studies present some evidence that immunomodulating therapy is effective for myocarditis. The immunomodulatory effect of the autonomic nervous system has raised considerable interest over recent decades. Studying the influence on the inflammation and immune system of the sympathetic and parasympathetic nervous systems will not only increase our understanding of the mechanism of disease but could also lead to the identification of potential new therapies for viral myocarditis. Studies have shown that the immunomodulating effect of the sympathetic and parasympathetic nervous system is realized by the release of neurotransmitters to their corresponding receptors (catecholamine for α or β adrenergic receptor, acetylcholine for α7 nicotinic acetylcholinergic receptor). This review will discuss the current knowledge of the roles of both the sympathetic and parasympathetic nervous system in inflammation, with a special focus on their roles in viral myocarditis.

Recent advances in the management of autoimmune myocarditis: insights from animal studies.

A growing body of evidence has been accumulating to demonstrate that human myocarditis and dilated cardiomyopathy involve a complex interaction with autoimmunity triggered by cardiotropic microbial infections. Animal experiments have provided direct evidence that infections with a particular microbe can incite autoimmune myocarditis, and this autoimmune response can be mimicked by immunization with the cardiac autoantigen, - myosin. Animal models greatly advanced our understanding of the molecular mechanisms of myocarditis, and various novel therapeutic strategies have been reported during the last two decades. In this review we present animal models of autoimmune myocarditis and describe the outlook of possible drug targets by showing the latest findings from animal studies.

Anti-inflammatory strategies in stroke: a potential therapeutic target

Stroke is an acute condition characterized by a sudden decrease in blood flow to brain tissue, resulting in immediate deprivation of both glucose and oxygen. Different mechanisms are involved in the pathogenesis of stroke, but increasing evidence suggests that one of the processes worsening clinical outcome is inflammation with the synthesis and the release of pro-inflammatory cytokines that activate several cells contributing to the progression of brain injury. Monoclonal antibody therapy has proved useful and safe for the treatment of several systemic diseases. In contrast, the evidence is limited for the treatment of stroke. More studies are needed in order to standardize the method of treatment and establish if it is safe and effective.

Pharmacotherapy of Sickle Cell Disease in Children

Sickle cell disease (SCD) is a potentially devastating and life threatening condition that is caused by an autosomal recessive inherited hemoglobinopathy which results in vaso-occlusive phenomena and hemolysis. The severity of this disorder is widely variable, but overall mortality is increased and life expectancy decreased when compared to the general population.

Care of patients with sickle cell disease is largely supportive. In fact, hydroxyurea is the only drug used that modifies disease pathogenesis. Painful vaso-occlusive events are the most common complication experienced by both children and adults with sickle cell disease and hydroxyurea is the only treatment option available to prevent the development of these events. Most events are managed with traditional supportive care measures (i.e. aggressive hydration, antiinflammatory and narcotic analgesics) that have not changed in decades. As such, there is an overwhelming need for both the development of new agents and new approaches to treatment with existing modalities for patients with sickle cell disease.

mTOR: A Novel Therapeutic Target for Diseases of Multiple Systems

Significant progress in the research of mammalian target of rapamycin (mTOR) in recent years, has greatly enhanced our understanding of the role and cellular pathways through which mTOR control cellular processes, such as translational initiation, actin organization, cell proliferation, and cell survival. mTOR is activated by phosphorylation and functions mainly through mTOR complex 1 or mTOR complex 2. mTORC1 is activated through tuberous sclerosis complex 1/2 dependent and independent mechanisms following the stimulation by growth factors, nutrient, amino acids, and other signaling pathways. The activity of mTOR is closely associated with cell proliferation and differentiation, apoptosis, and autophagy. Activation of mTOR prevents the induction of both apoptosis and autophagy through regulating its multiple targets. Given that the activity of mTOR has been involved in the pathogenesis of neurodegenerative disorders, cardiovascular abnormalities, metabolic diseases, renal transplantation, autoimmune abnormalities, and cancer, manipulating mTOR activation may represent as an innovative therapeutic strategy for these diseases. Yet, the role of mTOR in the body is complicated and therefore, its activity needs to be tightly regulated to achieve beneficial outcome in a specific pathological condition.

Signs and Related Mechanisms of Ethanol Hepatotoxicity

Ethanol is the most abused psychoactive substance. Accordingly to World Health Organization ethanol ranks among the top five risk factors for disease, disability and death (3.3 million/year) throughout the world. This manuscript highlights and critically analyses clinical and forensic signs related to hepatoxicity of ethanol that may lead to suspected of abuse. Namely, steatosis, jaundice, cirrhosis, hemorrhoids, esophageal varices caput medusae, ascites, petechiae, ecchymoses, splenomegaly, hemochromatosis, xanthelasma, nutritional deficiency, testicular atrophy, gynecomastia and dilated congestive cardiomyopathy are discussed and related to the toxic mechanism of ethanol.

Monocytes, Macrophages and Other Inflammatory Mediators of Abdominal Aortic Aneurysm

Macrophages early invade the forming abdominal aortic aneurysm (AAA) and greatly contribute to its pathogenesis. Recent findings have shown that Ly-6C^high and Ly-6C^low monocytes are rapidly mobilized from the splenic reservoir in response to angiotensin II infusion and sequentially infiltrate the abdominal aorta. The first wave of Ly-6C^high monocytes prevails in the aorta and promotes the accumulation of inflammatory macrophages, which most likely cause irreversible changes in the abdominal aorta. In this review, we discuss the current knowledge on the cellular mechanisms that initiate AAA in mice. We particularly focus on the role of monocyte and macrophage subsets during the early steps of the aneurysmal process.

Mesenchymal stem cell therapy for inflammatory bowel diseases: promise and challenge

Inflammatory Bowel Disease (IBD) is a complicated disease that arises as a consequence of the interaction among environment, genetic factors and autoimmunity. Available therapeutic interventions with pharmacological or biological drugs have a very selective action. Mesenchymal stem cells (MSCs) have been emerging as a promising cellular therapy for the treatment of IBD due to their multifaceted functions. This article summarizes recent progress in both preclinical studies and clinical trials employing MSCs in IBD treatment. We justify the use of MSC-based cell therapy as a novel strategy for IBD, discuss the biological roles that MSCs play underlying their therapeutic effects focusing on their immune-suppressive effects, illustrate methods to improve MSCs for better repair, and pinpoint the obstacles hindering their success and the challenges to overcome before their ultimate application.

Immunologic Modulations to Enhance Post-Stroke Recovery

Stroke is one of the leading causes of death and disability worldwide. The limited utility of current treatments, the increasing rates of stroke survivorship and subsequent long-term disability necessitate novel approaches to improve functional recovery after injury. The underlying immune mechanisms mediating inflammation and subsequent repair beyond the acute phase of injury remain understudied. The relative balance of injury and repair is dependent in part on the polarization state of microglia, the resident tissue macrophage of the central nervous system. Microglia can be classically activated to a pro-inflammatory phenotype, or alternatively activated to an immunomodulatory, tissue repair phenotype depending on the balance of local environmental cues. Once activated, they orchestrate a complex symphony of inflammation and repair, interacting with both the peripheral immune system and local cells such as astrocytes and neural stem cells to coordinate the resolution of inflammation and repair of damaged tissues. Furthermore, neural stem cells and astrocytes themselves appear to have intrinsic immunomodulatory properties which could be used in the development of future therapies. Enhancing these “reparative” functions with pharmacologic agents could open up exciting new avenues to improve long-term functional recovery in stroke patients.

Imaging of Chest and Abdominal Trauma in Children

Trauma is the commonest cause of death in children over a year old. The injuries sustained and management of these children differs to adults, due to differences in anatomy and physiology. Careful thought must also be given to exposing children to radiation, and CT scans should be performed only in select patients. This article reviews these important points and explains the imaging findings in chest and abdominal trauma.

Adult Stem Cells and Skeletal Muscle Regeneration

Satellite cells are unipotent stem cells involved in muscle regeneration. However, the skeletal muscle microenvironment exerts a dominant influence over stem cell function. The cell intrinsic complexity of the skeletal muscle niche located within the connective tissue between fibers includes motor neurons, tendons, blood vessels, immune response mediators and interstitial cells. All these cell types modulate the trafficking of stimuli responsible of muscle fiber regeneration. In addition, several stem cell types have been discovered in skeletal muscle tissue, mainly located in the interstitium. The majority of these stem cells appears to directly contribute to myogenic differentiation, although some of them are mainly implicated in paracrine effects. This review focuses on adult stem cells, which have been used for therapeutic purposes, mainly in animal models of chronic muscle degeneration. Emerging literature identifies other myogenic progenitors generated from pluripotent stem cells as potential candidates for the treatment of skeletal muscle degeneration. However, adult stem cells still represent the gold standard for future comparative studies.

The Toll-Like Receptor Radical Cycle Pathway: A New Drug Target in Immune-Related Chronic Fatigue

In this review we discuss that peripheral and central activation of the Toll-like receptor 2/4 (TLR2/4) Radical Cycle may underpin the pathophysiology of immune-related chronic fatigue secondary to other medical diseases and conditions. The TLR Radical Cycle plays a role in illnesses and conditions that are disproportionately commonly comorbid with secondary chronic fatigue, including a) neuroinflammatory disorders, e.g. Parkinson’s disease, stroke, depression, psychological stressors, and b) systemic disorders, e.g. (auto)immune disorders, chronic obstructive pulmonary disease, ankylosing spondylitis, chronic kidney disease, inflammatory bowel disease, cardiovascular disease, incl. myocardial infarction, cancer and its treatments. Increased TLR signaling is driven by activated immuneinflammatory and oxidative and nitrosative stress pathways, pathogen derived molecular patterns, including lipopolysaccharides, and damage associated molecular patterns (DAMPs). Newly formed redox-derived DAMPs, secondary to oxidative processes, may further activate the TLR complex leading to an auto-amplifying TLR Radical feedback loop. Increased gut permeability with translocation of gram negative bacteria and LPS, which activates the TLR Radical Cycle, is another pathway that may play a role in most of the abovementioned diseases and the secondary fatigue accompanying them. It is concluded that secondary fatigue may be associated with activation of the TLR Radical Cycle pathway due to activated immune-inflammatory pathways, classical and redox-derived DAMPs and PAMPs plays a role in its pathophysiology. Such an activation of the TLR Radical Cycle pathway may also explain why the abovementioned conditions are primed for an increased expression of secondary chronic fatigue. Targeting the TLR Radical Cycle pathway may be an effective method to treat TLR-Radical Cycle-related diseases such as secondary chronic fatigue.

microRNAs: Promising Biomarkers and Therapeutic Targets of Acute Myocardial Ischemia

microRNAs (miRNAs), small non-coding RNA molecules that act as negative regulators of gene expression, are involved in a wide range of biological functions and control several cellular processes. This review illustrates miRNA regulation and function in tissue response to acute ischemia, focusing on miRNA role in acute myocardial infarction and describing a subset of miRNAs de-regulated upon cardiac ischemia. These miRNAs may represent “master ischemic” miRNAs, playing a pathogenetic role in one of the different components of tissue response to ischemia. Moreover, circulating miRNAs correlated to myocardial infarction and examples of miRNA involvement in ischemic diseases different from cardiac ischemia are also discussed. The identification of specific miRNAs as key regulators of cell biology has opened new clinical avenues, and may allow new diagnostic and/or prognostic tools development, as much as innovative therapeutic strategies. Two paradigmatic reports, in which miRNAs have been targeted to improve cardiac function in pre-clinical models of myocardial infarction, are described in detail and confirmed the efficacy of these strategies.

Mouse Models of Autoimmune Diseases: Immune Thrombocytopenia

Immune thrombocytopenia or ITP is a debilitating and life-threatening disorder affecting more than 4 in every 10, 000 adults annually. Following a basic understanding of the immunopathology underlying ITP, namely that production of anti-platelet antibodies results in accelerated platelet clearance and thrombocytopenia, animal models of ITP were quickly developed. Rodent models that develop ITP spontaneously or by passive transfer of anti-platelet sera or antibodies have become instrumental in investigating the mechanisms responsible for the breakdown of tolerance in human ITP, understanding the immunopathology that underlies the progression of platelet destruction, elucidating the mechanism(s) of therapeutic amelioration of the ITP, and driving the development of new therapeutic modalities. This review aims to capture the development history and methodology of currently available ITP disease models, and review their advantages and limitations in the study of various aspects of ITP. We also review how closely the various ITP models reflect the pathobiology of human ITP and their usefulness in advancing the development of new therapeutics, which are particularly needed to address the unmet need of patients who are refractory to the currently available repertoire of interventions.

The Role of Adipocytokines in Atherogenesis and Atheroprogression

Research investigations on adipose tissue were focused for several decades on its “storage” function. Emerging evidence unveiled adipose tissue as an endocrine organ releasing a several mediators termed as adipokines. Adipokine-mediated functions include both physiological and pathophysiological roles such as regulation of energy metabolism, immune response and vascular homeostasis, as well as inflammatory and metabolic diseases (i.e. atherogenesis, diabetes and obesity clustered in the concept of metabolic syndrome). A dysregulation of adipokine levels has been also suggested as a potential common mechanism underlying these disorders. For instance, an unbalance between pro- and anti-inflammatory adipokines was positively associated with traditional risk factors (dyslipidaemia, hypertension, insulin resistance) in obesity, diabetes and atherogenesis. Adipokine-mediated activities particularly affected endothelial dysfunction/activation and intraplaque inflammation/vulnerability. The purpose of this narrative review is to provide an overview on the role of adipokines in atherogenesis. Evidence from basic research studies about adipokine-induced regulation of vascular and immune cell subsets will be discussed. Finally, conflicting results from clinical trials we be reported, with an attempt to better understand the reason why promising basic research results did not allow a speedy “into human” translation for clinical management of atherogenesis.

Granulocyte Colony-stimulating Factor and Bone Marrow Mononuclear Cells for Stroke Treatment in the Aged Brain

Ischemic stroke swiftly induces a wide spectrum of pathophysiological sequelae, particularly in the aged brain. The translational failure of experimental therapies, might partially be related to monotherapeutic approaches, not address potential counter-mechanisms sufficiently or within the best time window. For example, therapeutic effects relying on stem/progenitor cell mobilization by granulocyte-colony stimulating factor (G-CSF), require approximately a week to become manifest, which is potentially beyond the optimal timing. Here, We tested the hypothesis that treating post-stroke aged rats with the combination of bone marrow-derived mononuclear cells (BM MNC) and G-CSF improves the long term (56 days) functional outcome by compensating the delay before G-CSF effects come to full effect. 1x10⁶ syngeneic BM MNC per kg bodyweight (BW) with G-CSF (50µg/kg, given intraperitoneal by via the jugular vein to aged Sprague- Dawley rats, six hours post-stroke. This process was repeated daily, for a 28 day period. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunohistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period. Daily G-CSF treatment led to a robust and consistent improvement of neurological function, but did not alter final infarct volumes. The combination of G-CSF and BM MNC, did not further improve post-stroke recovery. The lack of an additional benefit may be due to interaction between both approaches, and to a lesser extent, in the insensitivity of the aged brains’ regenerative mechanisms. Also considering recent findings on other tandem approaches involving G-CSF in animal models featuring relevant co-morbidities, we conclude that such combination therapies are not the optimal approach to treat the acutely injured aged brain.

Programming Apoptosis and Autophagy with Novel Approaches for Diabetes Mellitus

According to the World Health Organization, diabetes mellitus (DM) in the year 2030 will be ranked the seventh leading cause of death in the world. DM impacts all systems of the body with oxidant stress controlling cell fate through endoplasmic reticulum stress, mitochondrial dysfunction, alterations in uncoupling proteins, and the induction of apoptosis and autophagy. Multiple treatment approaches are being entertained for DM with Wnt1 inducible signaling pathway protein 1 (WISP1), mechanistic target of rapamycin (mTOR), and silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1) generating significant interest as target pathways that can address maintenance of glucose homeostasis as well as prevention of cellular pathology by controlling insulin resistance, stem cell proliferation, and the programmed cell death pathways of apoptosis and autophagy. WISP1, mTOR, and SIRT1 can rely upon similar pathways such as AMP activated protein kinase as well as govern cellular metabolism through cytokines such as EPO and oral hypoglycemics such as metformin. Yet, these pathways require precise biological control to exclude potentially detrimental clinical outcomes. Further elucidation of the ability to translate the roles of WISP1, mTOR, and SIRT1 into effective clinical avenues offers compelling prospects for new therapies against DM that can benefit hundreds of millions of individuals throughout the globe.

Ischemic Colitis: Current Diagnosis and Treatment

Ischemic colitis (CI) is a common form of ischemic injury, which evolves as a consequence of decreased arterial blood flow to the colon. In general, CI is attributed to an elderly with multiple comorbidities; however, it may also occur in young or middle-aged individuals. The etiology of CI is multifactorial and the clinical presentation varies upon the severity of deprivation of the intestinal blood flow, and the development of the microvasculature plexus. Multiple case reports have associations with medications, vascular disorders, pathogens and hematologic diseases. Occlusive and nonocclusive diseases are the major mechanisms, which are simultaneously the causative factor of intestinal ischemia. In this review, we discuss major factors predisposing to occurrence of CI and analyze the mechanisms of action of several classes of medications currently used. We also suggest possible therapies and discuss the latest reports, which may lead to the discovery of novel pharmacological targets for future anti-CI drugs to be used in the clinical treatment.

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network

Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as posthemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the posthemorrhagic hydrocephalus affecting this vulnerable infant population.

Incidentally Detected Increased FDG Uptake in Bowel and its Correlation with Hystopathological Data: Our Experience in a Case Series Study

When an intense intestinal FDG accumulation occurs, especially if focal, it can be referred to either physiological intestinal activity or bowel disease, thus leading to a radical change in patient’s prognosis. Within a year, we recommended a colonoscopy to 103 of 7365 patients who were subjected to a total body FDG PET/CT. In a case-series study, we re-evaluated the patients and their lesions if already investigated with colonoscopy and biopsy. Only 18 patients were included in our study, but in none of them biopsy was negative and 3 adenocarcinomas, 8 adenomas, 5 inflammatory patterns, 1 hyperplastic polyp and 1 eosinophilic infiltrate were diagnosed. In 16 patients, no suspicion was present and diagnosis was absolutely incidental. Besides, among the three major groups (adenocarcinomas, adenomas and phlogosis), SUVmax values were significantly different. Adenocarcinomas are linked with high SUVmax values (ranging from 8.3 to 20.2) and large size (ranging from 26 to 43 mm). PET/CT sensitivity is low in detecting adenomas, being 71.4% if they are larger than 6 mm and 50% if SUVmax is lower than 4.9. SUVmax values in inflammatory lesions can range from 5.7 to 12. Colorectal cancer is still the second leading cause of cancer death, for this reason in many countries screening programs have been approved and colonoscopy is considered the golden standard. PET/CT cannot be considered as a screening test, but if it incidentally reveals intestinal abnormalities, this data cannot be underestimated and colonoscopy is highly recommended.

Emerging Therapy Options in Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening thrombotic complication of heparin, which is the result of platelet activation by anti-PF4/heparin antibodies. With lepirudin and danaparoid no longer available in the US, treatment options are limited to argatroban, fondaparinux (off-label use) and bivalirudin (for patients undergoing percutaneous coronary intervention). Both argatroban and bivalirudin are parenteral drugs and require close monitoring and hospitalization. Fondaparinux is contraindicated in patients with significant renal impairment and is associated with a small risk of HIT. Anticoagulants approved for thromboprophylaxis and management of thromboembolic conditions such as rivaroxaban, dabigatran, and apixaban have fixed oral dose, rapid onset of action and does not require monitoring. These novel agents do not interact with anti-PF4/heparin antibody and offer attractive therapy options for HIT. Their utility in HIT has been supported by a few clinical reports, however, larger studies are needed before they can be utilized in clinical practice. Therapeutic plasma exchange has been utilized with some success in patients with HIT, who need heparin reexposure for cardiac surgery but their safety and efficacy needs further exploration. 2-O, 3-O desulfated heparin, which lacks any anticoagulant effect, has been shown to reduce the development of HIT in murine models. Finally, novel targets based on the molecular pathogenesis of HIT are being studied for therapeutic drug development. We hope that the availability of novel therapies in the future will expand the options available for the management of HIT.

Tumor Dormancy and the Angiogenic Switch: Possible Implications of Bone Marrow- Derived Cells

Although escape from tumor dormancy has long been recognized as an important problem in the treatment of cancer, the molecular and cellular regulators underlying this transition remain poorly understood. The inability of the cancer cells to induce a complete and successful process of angiogenesis can result in tumor dormancy. In this case, the acquisition of sufficient angiogenic potential will result in the escape from indolence and in the initiation of tumor mass expansion. This stage in disease progression is known as the angiogenic switch. It is now becoming clear that the induction of the angiogenic switch is controlled by dynamic and complex biological processes involving the cancer cells, the associated stromal microenvironment and distant normal host cells, mostly from the bone marrow. Indeed, intricate tumor-host interactions are increasingly recognized as critical features of cancer. In particular, infiltrating cells of the immune system are crucial constituents of tumors and an important source of the growth stimulatory signals to the tumor cells. Tumor cells are surrounded by stromal cells, such as fibroblasts, lymphocytes, neutrophils, macrophages and mast cells, which communicate via a complex network of intercellular signaling pathways, mediated by surface adhesion molecules, cytokines and their receptors. However, the possible roles of these cells and molecules in the maintenance of micro-tumors in an occult state and in the induction of exit from the dormant state are not fully elucidated. In this review, we summarize recent findings and the current understanding of the role of bone marrow-derived cells, their recruitment into tumors and their interactive crosstalk with tumor cells, in leading to either the maintenance of, or exit from, tumor dormancy. Understanding the mechanisms of tumor growth and metastatic recurrence after periods of indolence is crucial for improving early detection, as well as increasing the cure rate for cancer patients.

Chronobiology of the Neuroimmunoendocrine System and Aging

The health maintenance depends on the preservation of the homeostatic systems, such as nervous, endocrine and immune system, and a proper communication between them. In this regard, the circadian system, which promotes a better physiological system functions and thus well being, could be considered part of that homeostatic complex, since the neuroimmunoendocrine system possesses circadian patterns in most variables, as well as circannual or seasonal variations. With aging, an impairment of the homeostatic systems occurs and an alteration of circadian system regulation has been demonstrated. In the immune system, several function parameters, which are good markers of health and of the rate of aging, change not only with age (immunosenescence) but also throughout the day and year. Indeed, with advancing age there is a modification of immune cell circadian function especially in lymphocytes. Moreover, immune functions at early afternoon correspond to more aged values than at morning, especially in mature subjects (60-79 years of age). In addition, these mature men and women showed a significant impaired immune cell function, which is especially remarkable in the winter. It is noteworthy the role of immunomodulatory hormones, such as melatonin, in the regulation of biological rhythms and their involvement in the aging process. Furthermore, the evidence of a neuroimmune regulation of the circadian system and its disturbance with aging, highlights the importance of proinflammatory cytokines in this complex cross-talk. The biological rhythms disruption with age and some diseases (jet lag, cancer and seasonal affective disorder), could contribute increasing the immune system impairment and consequently the loss of health.

Myocardial Ischemia/Reperfusion Injury: Potential of TRPV1 Agonists as Cardioprotective Agents

Myocardial Ischemia/Reperfusion (I/R) induced injury has widespread detrimental effects partially negating the benefits obtained from early revascularization in Acute Myocardial Infarction. Various complex mechanisms contribute to I/R injury and different agents targeting those specific mechanisms are being studied. Despite continued research and widespread interest, none of them have become incorporated into everyday practice. The TRPV1 (transient receptor potential vanilloid 1) channel is a non selective cation channel predominantly expressed in sensory neurons with the nerve fibers innervating the heart and blood vessels. Multiple studies have demonstrated the importance of the activation of TRPV1 and subsequent release of sensory neurotransmitters in cardioprotection. This review focuses on the role of TRPV1 in prevention of cardiac I/R injury, the work that has been done so far and future implications for TRPV1 agonists as cardioprotective agents.

Modulatory Effects of Peroxisome Proliferator-Activated Receptor-γ on CXCR3 Chemokines

An increasing body of evidence shows the importance of the chemokine (C-X-C motif) receptor (CXCR)3 and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10 and CXCL11 in the T helper 1 immune response, and in inflammatory diseases such as bowel inflammatory disorders, allograft rejection, thyroid autoimmune disorders, vascular and renal inflammation, and others. Peroxisome proliferator-activated receptor (PPAR)-γ agonists show a strong inhibitory effect on the expression and production of CXCR3 chemokines in vitro, in various kinds of cells, such as denditric cells, monocytes, macrophages, endothelial and vascular smooth muscle cells, intestinal cells, thyrocytes, fibroblasts, preadypocytes and mesangial cells, and in vivo in animal models. As rosiglitazone has recently been linked to a higher risk of heart failure, stroke, and all-cause mortality in old patients, it has been interrupted from the European market. On the contrary, the safety profile of pioglitazone seems favorable. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of the above mentioned inflammatory disorders, and many interesting patents have been recently applied.

Selective Acetyl- and Butyrylcholinesterase Inhibitors Reduce Amyloid-β Ex Vivo Activation of Peripheral Chemo-cytokines From Alzheimer's Disease Subjects: Exploring the Cholinergic Anti-inflammatory Pathway

Increasing evidence suggests that elevated production and/or reduced clearance of amyloid-β peptide (Aβ) drives the early pathogenesis of Alzheimer’s disease (AD). Aβ soluble oligomers trigger a neurotoxic cascade that leads to neuronal dysfunction, neurodegeneration and, ultimately, clinical dementia. Inflammation, both within brain and systemically, together with a deficiency in the neurotransmitter acetylcholine (ACh) that underpinned the development of anticholinesterases for AD symptomatic treatment, are invariable hallmarks of the disease. The inter-relation between Aβ, inflammation and cholinergic signaling is complex, with each feeding back onto the others to drive disease progression. To elucidate these interactions plasma samples and peripheral blood mononuclear cells (PBMCs) were evaluated from healthy controls (HC) and AD patients. Plasma levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and Aβ were significantly elevated in AD vs. HC subjects, and ACh showed a trend towards reduced levels. Aβ challenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) from AD vs. HC subjects, with IL-10 being similarly affected. THP-1 monocytic cells, a cell culture counterpart of PBMCs and brain microglial cells, responded similarly to Aβ as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning Aβ-induced changes in cytokine expression. As amyloid-β precursor protein expression, and hence Aβ, has been reported regulated by particular cytokines and anticholinesterases, the latter were evaluated on Aβ- and PHA-induced chemocytokine expression. Co-incubation with selective AChE/BuChE inhibitors, (-)-phenserine (AChE) and (-)-cymserine analogues (BuChE), mitigated the rise in cytokine levels and suggest that augmentation of the cholinergic anti-inflammatory pathway may prove valuable in AD.

Bridge Between Neuroimmunity and Traumatic Brain Injury

The pathophysiology of degenerative, infectious, inflammatory and traumatic diseases of the central nervous system includes a significant immune component. As to the latter, damage to the cerebral vasculature and neural cell bodies, caused by traumatic brain injury (TBI) activates innate immunity with concomitant infiltration of immunocytes into the damaged nervous system. This leads to proinflammatory cytokine and prostaglandin production and lost synaptic integrity and more generalized neurotoxicity. Engagement of adaptive immune responses follows including the production of antibodies and lymphocyte proliferation. These affect the tempo of disease along with tissue repair and as such provide a number of potential targets for pharmacological treatments for TBI. However, despite a large body of research, no such treatment intervention is currently available. In this review we will discuss the immune response initiated following brain injuries, drawing on knowledge gained from a broad array of experimental and clinical studies. Our discussion seeks to address potential therapeutic targets and propose ways in which the immune system can be controlled to promote neuroprotection.

The Role of P2Y₁₂ Receptor and Activated Platelets During Inflammation

Platelets play an important role not only during thrombosis, but also in modulating immune responses through their interaction with immune cells and by releasing inflammatory mediators upon activation. The P2Y₁₂ receptor is a Gicoupled receptor that not only regulates ADP-induced aggregation but can also dramatically potentiate secretion, when platelets are activated by other stimuli. Considering the importance of P2Y₁₂ receptor in platelet function, a class of antiplatelet drugs, thienopyridines, have been designed and successfully used to prevent thrombosis. This review will focus on the role of activated platelets in inflammation and the effects that P2Y₁₂ antagonism exerts on the inflammatory process. A change in platelet functions was noted in patients treated with thienopyridines during inflammatory conditions, suggesting that platelets may modulate the inflammatory response. Further experiments in a variety of animal models of diseases, such as sepsis, rheumatoid arthritis, myocardial infarction, pancreatitis and pulmonary inflammation have also demonstrated that activated platelets influence the inflammatory state. Platelets can secrete inflammatory modulators in a P2Y₁₂–dependent manner, and, as a result, directly alter the inflammatory response. P2Y₁₂ receptor may also be expressed in other cells of the immune system, indicating that thienopyridines could directly influence the immune system rather than only through platelets. Overall the results obtained to date strongly support the notion that activated platelets significantly contribute to the inflammatory process and that antagonizing P2Y₁₂ receptor can influence the immune response.

Therapeutic Potential and Mechanisms of Action of Mesenchymal Stromal Cells for Acute Respiratory Distress Syndrome

Mesenchymal stem/stromal cells (MSCs) have become the focus of intense research effort over the past 10 years, in an effort to harness their regenerative and immune-modulating capacity for a variety of clinical conditions. In Acute Respiratory Distress Syndrome (ARDS), pre-clinical studies point towards a therapy that modulates multiple aspects of a complex disease process. Almost universally, these cells have demonstrated an immune modulating phenotype, balancing protective host responses with a reduction in damaging inflammation, while enhancing bacterial killing. MSCs also lead to more efficient tissue repair, and MSC-mediated lung tissue repair and regeneration after ARDS are some of the exciting clinical prospects. Recent investigation into the role of endogenous MSCs has led to new insights into MSC physiology and its role in regulating the immune system. However, significant deficits remain in our knowledge regarding the mechanisms of action of MSCs, their efficacy in relevant pre-clinical models, and their safety in critically ill patients. These gaps need to be addressed before the enormous therapeutic potential of stem cells for ALI/ARDS can be realized.

Understanding the Multifaceted Role of Inflammatory Mediators in Ischemic Stroke

The evolution of ischemic brain damage is strongly affected by an inflammatory reaction that involves soluble mediators, such as cytokines and chemokines, and specialized cells activated locally or recruited from the periphery. The immune system affects all phases of the ischemic cascade, from the acute intravascular reaction due to blood flow disruption, to the development of brain tissue damage, repair and regeneration. Increased endothelial expression of adhesion molecules and blood-brain barrier breakdown promotes extravasation and brain recruitment of blood-borne cells, including macrophages, neutrophils, dendritic cells and T lymphocytes, as demonstrated both in animal models and in human stroke. Nevertheless, most anti-inflammatory approaches showing promising results in experimental stroke models failed in the clinical setting. The lack of translation may reside in the redundancy of most inflammatory mediators, exerting both detrimental and beneficial functions. Thus, this review is aimed at providing a better understanding of the dualistic role played by each component of the inflammatory/immune response in relation to the spatio-temporal evolution of ischemic stroke injury.

The Renin-angiotensin System as a Target of Novel Anticancer Therapy

The role of the renin-angiotensin system (RAS) in the development of various malignancies has recently been extensively examined and, since it has been shown to significantly influence many aspect of cancer initiation and progression, the idea of RAS-targeted anticancer therapy has arisen. This article reviews the mechanisms underlying RAS-induced physiological and pathological responses related to cancer biology, including tumor growth, cell proliferation, apoptosis, angiogenesis, inflammation, and protein degradation, emphasizing the associated cellular transduction schemes activated by main RAS effectors. Also the dual nature of RAS-dependent effects, resulting from its complex physiology has been commented. Finally, based on the available data from clinical trials and experimental studies, the possibilities of the introduction of RAS-modulating drugs into standard clinical practice in oncology have been discussed with the focus on both, positive and negative effects associated with the administration of various classes of pharmaceuticals to cancer patients.

Genetics of the First Seven Proprotein Convertase Enzymes in Health and Disease

Members of the substilisin/kexin like proprotein convertase (PCSK) protease family cleave and convert immature pro-proteins into their biologically active forms. By cleaving for example prohormones, cytokines and cell membrane proteins, PCSKs participate in maintaining the homeostasis in a healthy human body. Conversely, erratic enzymatic function is thought to contribute to the pathogenesis of a wide variety of diseases, including obesity and hypercholestrolemia. The first characterized seven PCSK enzymes (PCSK1-2, FURIN, PCSK4-7) process their substrates at a motif made up of paired basic amino acid residues. This feature results in a variable degree of biochemical redundancy in vitro, and consequently, shared substrate molecules between the different PCSK enzymes. This redundancy has confounded our understanding of the specific biological functions of PCSKs. The physiological roles of these enzymes have been best illustrated by the phenotypes of genetically engineered mice and patients that carry mutations in the PCSK genes. Recent developments in genome-wide methodology have generated a large amount of novel information on the genetics of the first seven proprotein convertases. In this review we summarize the reported genetic alterations and their associated phenotypes.

Interactions of Iron Oxide Nanoparticles with the Immune System: Challenges and Opportunities for their Use in Nano-oncology

Iron oxide (IO) nanoparticles hold great promise as diagnostic and therapeutic agents in oncology. Their intrinsic physical properties make IO nanoparticles particularly interesting for simultaneous drug delivery, molecular imaging, and applications such as localized hyperthermia. Multiple non-targeted IO nanoparticle preparations have entered clinical trials, but more exciting, new tumortargeted IO nanoparticle preparations are currently being tested in preclinical settings. This paper will analyze the challenges faced by this new theranostic modality, with a specific focus on the interactions of IO nanoparticles with the innate and adaptive immune systems, and their effect on nanoparticle biodistribution and tumor targeting. Next, we will review the critical need for innovative surface chemistry solutions and strategies to overcome the immune interactions that prevent existing tumor-targeted IO preparations from entering clinical trials. Finally, we will provide an outlook for the future role of IO nanoparticles in oncology, which have the promise of becoming significant contributors to improved diagnosis and treatment of cancer patients.

Naoxintong Protects against Atherosclerosis through Lipid-lowering and Inhibiting Maturation of Dendritic Cells in LDL Receptor Knockout Mice fed a High-fat Diet

Naoxintong (NXT), a Chinese Materia Medica standardized product, extracted from 16 various kinds of Chinese traditional herbal medicines including Salvia miltiorrhiza, Angelica sinennsis, Astragali Radix, is clinically effective in treating atherosclerosisrelated diseases. Here, we tested the hypothesis that the anti-atherosclerosis effects of NXT might be mediated by suppressing maturation of dendritic cells (DCs) in a mice model of atherosclerosis. LDLR^-/- mice fed a high-fat diet were treated with placebo, NXT (0.7g/kg/d, oral diet) or simvastatin (100mg/kg/d, oral diet) for 8 weeks, respectively. NXT treatment significantly reduced plasma triglyceride (112±18 mg/dl vs. 192±68 mg/dl, P<0.05) and total cholesterol (944±158 mg/dl vs. 1387±208 mg/dl, P<0.05) compared to placebo treatment. Vascular lesions were significantly smaller and macrophage content and amount of DCs in plaques were significantly less in NXT and simvastatin groups than in placebo group (all P<0.05). In addition, expressions of splenic DC membrane molecules (CD40, CD86 and CD80) and the plasma level of IL-12p70 were significantly lower in NXT and simvastatin groups than in placebo group. In conclusion, NXT protects against atherosclerosis through lipid-lowering and inhibiting DCs maturation in this mice model of atherosclerosis.

Dendritic Cells in Atherosclerosis

It is recognized that the development of atherosclerosis involves many elements of an inflammatory process, involving components of both the innate and adaptive immune systems. The presence and roles of macrophages and T-cells in atherogenesis are wellestablished. More recently dendritic cells have been identified in the vasculature and in atherosclerotic lesions. This review summarises our current understanding of the roles of dendritic cells in the development and regression of atherosclerosis.

Augmentation Therapy with Alpha1-antitrypsin: Novel Perspectives

SERPINA1, α-antitrypsin (AAT) is an acute phase protein, a member of the serpin (serine protease inhibitor) super family and one of the most abundant protease inhibitors in the circulation. The clinical importance of AAT is emphasized in persons with inherited AAT deficiency who exhibit high risk of developing early onset pulmonary emphysema, neonatal hepatitis, liver cirrhosis, which may appear at any age, and in rare cases panniculitis and vasculitis. The most common and severe AAT deficiency is associated with the Z (Glu342 to Lys) mutation. It is also well established that Z AAT deficiency results from the polymerization and accumulation of the misfolded AAT protein. Consequently, low levels of circulating Z AAT are assumed to be inadequate to neutralize elastolytic activity and to prevent lung tissue damage. Novel studies, however, are expanding the link between AAT and human diseases. Associations are shown between reduced AAT levels and HIV type 1 infection, hepatitis C infection, diabetes mellitus, vasculitis, panniculitis and other diseases. Given the importance of the protease/antiprotease imbalance in causing emphysema, augmentation of circulating AAT is used as a specific therapy for patients with AAT deficiency-related emphysema but not for those with liver diseases. According to the novel findings, therapy with AAT possesses antiinflammatory and immuno-modulatory effects across a broad spectrum of experimental models of systemic and local inflammation. Hence, in this article we will discuss putative new directions for the clinical use of therapy with AAT.

Catastrophic Antiphospholipid Syndrome - 20 Years Later

The catastrophic variant of the antiphospholipid syndrome (APS) is the most severe and acute form of APS with multiorgan involvement. Patients with this condition have the following features in common: a) clinical evidence of multiple organ involvement developed over a very short time period; b) histopathological evidence of multiple small vessel occlusions, and c) laboratory confirmation of the presence of antiphospholipid antibodies, usually in high titer.

The two key pathobiologic mechanisms that cause the clinical manifestations of catastrophic APS are the development of thrombosis and the systemic inflammatory response syndrome. A precipitating factor is reported in more than half of patients.

A combination of anticoagulants, corticosteroids, intravenous immunoglobulins and/or plasma exchanges are the treatment modalities advocated for all patients with this severe condition. Unfortunately, its mortality is still high (around 30%) despite therapy. However relapse is uncommon.

Systemic and Biophase Bioavailability and Pharmacokinetics of Nanoparticulate Drug Delivery Systems

The development of the vectorized delivery systems combining advantages of the colloidal carriers, with active targeting to the receptors sites suggests that nanoparticles have a considerable potential for treatment after biophase internalization and pharmacokinetics, as for example gene therapy. Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting. Examples of passive targeting were presented: organ targeting by the Enhanced Permeability and Retention (EPR) effect; targeting the mononuclear phagocitic system; organ targeting by chemoembolization or local (organ) administration;sterical stabilization of nanoparticles (PEGylation). A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest. The source for biophase bioavailability can be the systemic bioavailability following common routes of adminstration (generally for systemic delivery of medicines), or directly the site specific biophase bioavailability for the formulations capable of cellular or nuclear drug internalization where the drug release only will take place (for nanoparticulate drug delivery systems, DDS). Once the pharmaceutical nanosystem was internalized, begins the release of the active moiety by different mechanisms, as for example the escape from endosome, or biodegradation of the polymer carrier or liberation of the active peptide or gene from a biological construct in the nucleus, etc. The presentation will discusses the pharmacokinetics of drugs after systemic administration but especially the biophase bioavailability and pharmacokinetics after the administration of biotechnology origin of therapeutic proteins like monoclonal antibodies, gene transfer products, plasmid DNAs, nucleotides, antisense oligonucleotides (AODNs) or small interfering RNAs (siRNA).

Recent Advances in Perioperative Anesthetic Management Update in the Perioperative Support of Patients with Septic Shock and the Effect on Outcomes

Septic shock during the perioperative period imparts significant challenges for anesthetic management. There is increasing support for standardization of care using evidence-based, international consensus guidelines, such as the Surviving Sepsis Campaign. This review will highlight practices in the supportive management relevant to the perioperative care of patients with severe sepsis or septic shock and their effect on clinical outcomes. It will address the epidemiological data of sepsis, the diagnostic criteria, and the role of routine, goal-directed hemodynamic resuscitation. Furthermore, it will review other options for support, including antibiotics, intensive insulin therapy, and intensive care sedation in this high risk patient population.

Advances in Drug Safety

The operating room offers a unique setting where anesthetics, preoperative medications, patient comorbidities, and surgery all merge. Anesthesiologists are responsible for combining these concerns into a dependable and safe approach. From formulation to administration, enhancements in nearly every aspect of a given drug have improved the ability of anesthesiologists to accomplish this. Some of these methodologies, including novel anesthetics and analgesics, drug delivery and administration including infusion pumps, antithrombotics, and a reappraisal of previous medications are highlighted in this review.

While these advancements are significant, patients and healthcare systems globally are rightfully demanding safer application of drugs at every level. On May 1, 2012, a report issued by the Institute of Medicine advised the United States Food and Drug Administration to undertake a much more rigorous patient-centered effort to evaluate a drug’s safety over its entire life-cycle. This recommendation is in agreement with the objectives of the Anesthesia Patient Safety Foundation. With these mutual goals shared by many stakeholders and their continued efforts, the future of the estimated 200 million global surgeries to be undertaken this year hopefully provides a safer experience while under anesthesia.

P2X7 Receptors: Channels, Pores and More

Purine nucleotides are well established as extracellular signaling molecules. P2X7 receptors (P2X7Rs) are members of the family of ionotropic ATP-gated receptors. Their activity can be found in a limited number of cell types, but is readily detectable in cells of hemopoietic lineage including macrophages, microglia, and certain lymphocytes, and mediates the influx of Ca2+ and Na+ as well as the release of pro-inflammatory cytokines. Amongst P2X receptors, P2X7Rs behave as a bifunctional molecule. The binding of ATP induces within milliseconds the opening of a channel selective for small cations, and within seconds a larger pore opens which allows permeation by molecules with a mass of up to 900 Da. In humans at least, the P2RX7 gene is highly polymorphic, and genetic differences within P2X7R affect receptor pore formation and channel function. ATP can act as a neurotransmitter, while the presence of P2X7Rs on immune cells suggests that they also regulate immune function and inflammatory responses. In addition, activation of the P2X7R has dramatic cytotoxic properties. The role of extracellular ATP and purinoceptors in cytokine regulation and neurological disorders is, in fact, the focus of a rapidly expanding area of research. P2X7Rs may affect neuronal cell death by regulating the processing and release of interleukin-1β, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7Rs provides an inflammatory stimulus, and P2X7R-deficient mice display a marked attenuation of inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X7R activity, by regulating the release of pro-inflammatory cytokines, may be involved in the pathophysiology of neuropsychiatric disorders. The P2X7R may thus represent a critical communication link between the nervous and immune systems, while providing a target for therapeutic exploitation. In this review we discuss current biology and pharmacology of the P2X7R, as well as insights into the role for this receptor in neurological/psychiatric diseases.