Retinoblastoma

Regulating miRNAs Expression by Resveratrol: Novel Insights based on Molecular Mechanism and Strategies for Cancer Therapy

Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.

Research Progress of the Molecular Mechanism of Antithyroid Cancer Activity of Shikonin

Thyroid cancer is one of the most common endocrine neoplasms. Treatment methods include surgical resection, radioactive iodine therapy, inhibition of thyroid-stimulating hormone, and inhibition of kinase-based target therapies. These treatments induced adverse effects. Lithospermum officinale possesses antioxidant, anticancer, burn-healing, and anti-inflammatory activities, and Shikonin is the main ingredient. Antithyroid cancer studies of Shikonin discovered that it inhibited thyroid cancer cell migration and invasion by suppressing the epithelial-mesenchymal transition; induced cell cycle arrest; induced DNA damage and apoptosis by producing excessive reactive oxygen species; upregulated Bax; increased the stability of p53; decreased the expression of Mdm2; downregulated Slug and MMP-2, MMP-9, and MMP-14; repressed the phosphorylation of Erk and Akt; activated the p16/retinoblastoma protein pathway, leading to apoptosis; suppressed the expression of DNMT1; reduced the PTEN gene methylation; increased the expression of PTEN, leading to the inhibition of migration; increased LC3-II to induce autophagy and apoptosis of medullary thyroid carcinoma; and upregulated βII-tubulin in the cell to produce less resistance to cisplatin and paclitaxel, without cross-resistance to other anticancer agents. In vivo studies showed that it is safe in Sprague-Dawley rats, Beagle dogs, and nude mice.

Targeted Cancer Stem Cell Therapeutics: An Update

Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them.

Present Scenario and Future Prospects in the Management of Retinoblastoma: A Review

Retinoblastoma is the most common pediatric ocular cancer. This cancer occurs due to malignancy in retinoblast cells, which are precursors of photoreceptors, horizontal cells, amacrine cells, muller cells, and retinal progenitor cells in the retina of the eye. Genetic correlation has been observed in most cases of retinoblastoma. It is caused due to the suppression or mutation of the retinoblastoma 1 gene (RB1 gene), which is located at the 14th band of both alleles of the 13th human chromosome. RB1 gene is a tumour suppressor gene responsible for regulating cell growth and controlling abnormal cell division. In the last two decades, as accurate identification of characteristic features of cancer cells at various stages of retinoblastoma has been made, we can now plan more advanced and personalized management of the disease due to improved and focused therapeutic effects of cryotherapy, thermotherapy, radiotherapy, chemotherapy, and surgical interventions. These efforts can lead to a better survival rate with reduced damage to the non-cancerous cells in the eyeball, promoting better visual performance (better visual acuity and visual axis alignment). Based on studies published in PubMed and Google Scholar till 2023, current treatment options at various stages of retinoblastoma are reviewed to suggest the most promising treatment options. Based on this information, a clear treatment flowchart has been prepared. This review article can assist researchers, eye specialists, geneticists, and cancer specialists in determining the most promising method for treating retinoblastoma at various stages.

Generating Retinas through Guided Pluripotent Stem Cell Differentiation and Direct Somatic Cell Reprogramming

Retinal degeneration diseases affect millions of people worldwide but are among the most difficult eye diseases to cure. Studying the mechanisms and developing new therapies for these blinding diseases requires researchers to have access to many retinal cells. In recent years there has been substantial advances in the field of biotechnology in generating retinal cells and even tissues in vitro, either through programmed sequential stem cell differentiation or direct somatic cell lineage reprogramming. The resemblance of these in vitro-generated retinal cells to native cells has been increasingly utilized by researchers. With the help of these in vitro retinal models, we now have a better understanding of human retinas and retinal diseases. Furthermore, these in vitro-generated retinal cells can be used as donor cells which solves a major hurdle in the development of cell replacement therapy for retinal degeneration diseases, while providing a promising option for patients suffering from these diseases. In this review, we summarize the development of pluripotent stem cell-to-retinal cell differentiation methods, the recent advances in generating retinal cells through direct somatic cell reprogramming, and the translational applications of retinal cells generated in vitro. Finally, we discuss the limitations of the current protocols and possible future directions for improvement.

Effect of Raltitrexed on ECA109 Cellular Radiosensitivity and its Mechanism in Esophageal Cancer

Background: To investigate the effect of raltitrexed + X-ray irradiation on esophageal cancer ECA109 cells and analyze the potential action mechanism.

Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to analyze the inhibitory effect of raltitrexed on cell proliferation. The effect of raltitrexed on radiosensitivity was studied through a clone-forming experiment. The scratch assay and invasion test were performed to understand the cell migration and invasion abilities. The apoptosis rate change was measured using a flow cytometer, and Western Blotting was used to determine the expression of B cell lymphoma-2 (Bcl-2) and Bcl2-associated X protein (Bax) in each group.

Results: Raltitrexed significantly inhibited ECA109 proliferation in a time-dose-dependent manner; there were significant differences among different concentrations and times of action. The results of the clone-forming experiment showed a sensitization enhancement ratio of 1.65, and this demonstrated a radiosensitization effect. After the combination of raltitrexed with X-ray, the cell migration distance was shortened, and the number of cells penetrating the membrane was reduced.

Conclusion: Raltitrexed can inhibit the growth of esophageal cancer ECA109 cells and has a radiosensitization effect.

Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer

Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.

Curcuminoids as Cell Signaling Pathway Modulators: A Potential Strategy for Cancer Prevention

Despite substantial advancements in curative modern medicine in the last few decades, cancer risk and casualty rates have continued to mount globally. The exact reason for cancer's onset and progression is still unknown. However, skeletal and functional abnormalities in the genetic code are assumed to be the primary cause of cancer. Many lines of evidence reported that some medicinal plants can be utilized to curb cancer cell proliferation with a safe, fruitful, and cost-efficient perspective. Curcuminoid, isolated from Curcuma longa, have gotten a lot of focus due to their anticancer potential as they reduce tumor progression, invasion, and dissemination. Further, they modulated signal transduction routes like MAPK, PI3K/Akt/mTOR, JAK/STAT, and Wnt/β-catenin, etc., and triggered apoptosis as well as actuated autophagy in malignant cells without altering the normal cells, thus preventing cancer progression. Besides, Curcuminoid also regulate the function and expression of anti-tumor and carcinogenic miRNAs. Clinical studies also reported the therapeutic effect of Curcuminoid against various cancer through decreasing specific biomarkers like TNF-α, Bcl-2, COX-2, PGE2, VEGF, IκKβ, and various cytokines like IL-12p70, IL-10, IL-2, IFN-γ levels and increasing in p53 and Bax levels. Thus, in the present review, we abridged the modulation of several signal transduction routes by Curcuminoids in various malignancies, and its modulatory role in the initiation of tumor-suppressive miRNAs and suppression of the oncogenic miRNAs are explored. Additionally, various pharmacokinetic approaches have been projected to address the Curcuminoids bioavailability like the use of piperine as an adjuvant; nanotechnology- based Curcuminoids preparations utilizing Curcuminoids analogues are also discussed.

Enhancing the Antiproliferative Activity of Perillyl Alcohol against Glioblastoma Cell Lines through Synergistic Formulation with Natural Oils

Background: Due to its volatility, photostability, and gastrointestinal toxicity, Perillyl Alcohol (POH), a monoterpenoid component of various plant species, is a chemotherapeutic drug with insufficient efficacy. Many naturally occurring bioactive compounds have well-known antiproliferative properties, including sefsol, jojoba, tea tree, and moringa oils.

Objective: This study sought to develop an oil-based Self Nanoemulsifying Drug Delivery System (SNEDDS) using tween 80 as the surfactant and Dimethyl Sulfoxide (DMSO) or Polyethylene Glycol (PEG) 400 as the cosurfactant; the oils were used in a range of 10-20% to boost POH's anticancer efficacy.

Methods: The formulations' size, charge, and impact on the viability of glioma cell lines, ANGM-CSS and A172, were evaluated.

Results: The developed SNEDDS formulations ranged from 3 nm to 362 nm in size, with electronegative surface charges between 5.05 and 17.0 mV and polydispersity indices between 0.3 and 1.0.

Conclusion: The findings indicated that the antiproliferative effect of POH-loaded Nanoemulsion (NE) could be used as a possible anticancer therapy for glioblastoma in vitro, particularly when paired with the tested natural oils. Before asserting that this delivery technique is appropriate for glioblastoma therapy, additional in vitro and in vivo investigations are required.

Progress of Cancer Stem Cells in Retinoblastoma

The theory of cancer stem cells is a breakthrough discovery that offers exciting possibilities for comprehending the biological behavior of tumors. More and more evidence suggests that retinoblastoma cancer stem cells promote tumor growth and are likely to be the origin of tumor formation, drug resistance, recurrence, and metastasis. At present, some progress has been made in the verification, biological behavior, and drug resistance mechanism of retinoblastoma cancer stem cells. This article aims to review the relevant research and explore future development direction.

Crosstalk between Oxidative Stress and Inflammation Induced by Ionizing Radiation in Healthy and Cancerous Cells

Radiotherapy (RT) is a unique modality in cancer treatment with no replacement in many cases and uses a tumoricidal dose of various ionizing radiation (IR) types to kill cancer cells. It causes oxidative stress through reactive oxygen species (ROS) production or the destruction of antioxidant systems. On the other hand, RT stimulates the immune system both directly and indirectly by releasing danger signals from stress-exposed and dying cells. Oxidative stress and inflammation are two reciprocal and closely related mechanisms, one induced and involved by the other. ROS regulates the intracellular signal transduction pathways, which participate in the activation and expression of pro-inflammatory genes. Reciprocally, inflammatory cells release ROS and immune system mediators during the inflammation process, which drive the induction of oxidative stress. Oxidative stress or inflammation-induced damages can result in cell death (CD) or survival mechanisms that may be destructive for normal cells or beneficial for cancerous cells. The present study has focused on the radioprotection of those agents with binary effects of antioxidant and anti-inflammatory mechanisms IR-induced CD.

JHD205, A Novel Abemaciclib Derivative, Exerts Antitumor Effects on Breast Cancer by CDK4/6

Background: Efficient targeted molecular therapeutics are needed for the treatment of triple-negative breast cancer (TNBC), a highly invasive and difficult-to-treat form of breast cancer associated with a poor prognosis.

Objectives: This study aims to evaluate the potential of selective CDK4/6 inhibitors as a therapeutic option for TNBC by impairing the cell cycle G1 phase through the inhibition of retinoblastoma protein (Rb) phosphorylation.

Methods: In this study, we synthesized a compound called JHD205, derived from the chemical structure of Abemaciclib, and examined its inhibitory effects on the malignant characteristics of TNBC cells.

Results: Our results demonstrated that JHD205 exhibited superior tumor growth inhibition compared to Abemaciclib in breast cancer xenograft chicken embryo models. Western blot analysis revealed that JHD205 could dosedependently degrade CDK4 and CDK6 while also causing abnormal changes in other proteins associated with CDK4/6, such as p-Rb, Rb, and E2F1. Moreover, JHD205 induced apoptosis and DNA damage and inhibited DNA repair by upregulating Caspase3 and p-H2AX protein levels.

Conclusion: Collectively, our findings suggest that JHD205 holds promise as a potential treatment for breast carcinoma.

Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

Effect of Vitamin D on Retinoblastoma Protein in Prediabetic Individuals

About 50.8 million people were diagnosed with diabetes in 2011; the count has increased by 10 million in the last five years. Type-1 diabetes could occur at any age, but predominantly in children and young adults. The risk of developing type II diabetes mellitus in the offspring of parents with DM II is 40% if one parent has DM II and approaches 70% if both parents have DM II. The process of developing diabetes from normal glucose tolerance is continuous, with insulin resistance being the first stage. As prediabetes progresses slowly to DM II, it may take approximately 15-20 years for an individual to become diabetic. This progression can be prevented or delayed by taking some precautions and making some lifestyle amendments, e.g., reducing weight by 5-7% of total body weight if obese, etc. Retinoblastoma protein is one of the pocket proteins that act as crucial gatekeepers during the G1/S transition in the cell cycle. A loss or defect in single- cell cycle activators (especially CDK4 and CDK6) leads to cell failure. In diabetic or stress conditions, p53 becomes a transcription factor, resulting in the transactivation of CKIs, which leads to cell cycle arrest, cell senescence, or cell apoptosis. Vitamin D affects insulin sensitivity by increasing insulin receptors or the sensitivity of insulin receptors to insulin. It also affects peroxisome proliferator-activated receptors (PPAR) and extracellular calcium. These influence both insulin resistance and secretion mechanisms, undertaking the pathogenesis of type II diabetes. The study confines a marked decrement in the levels of random and fasting blood glucose levels upon regular vitamin D intake, along with a significant elevation of retinoblastoma protein levels in the circulatory system. The most critical risk factor for the occurrence of the condition came out to be family history, showing that patients with first-degree relatives with diabetes are more susceptible. Factors such as physical inactivity or comorbid conditions further aggravate the risk of developing the disease. The increase in pRB levels caused by vitamin D therapy in prediabetic patients directly influences blood glucose levels. pRB is supposed to play a role in maintaining blood sugar levels. The results of this study could be used for further studies to evaluate the role of vitamin D and pRB in regeneration therapy for beta cells in prediabetics.

Deciphering Potential Role of Hippo Signaling Pathway in Breast Cancer: A Comprehensive Review

Breast cancer is a heterogeneous disease and a leading malignancy around the world. It is a vital cause of untimely mortality among women. Drug resistance is the major challenge for effective cancer therapeutics. In contrast, cancer stem cells (CSCs) are one of the reasons for drug resistance, tumor progression, and metastasis. The small population of CSCs present in each tumor has the ability of self-renewal, differentiation, and tumorigenicity. CSCs are often identified and enriched using a variety of cell surface markers (CD44, CD24, CD133, ABCG2, CD49f, LGR5, SSEA-3, CD70) that exert their functions by different regulatory networks, i.e., Notch, Wnt/β-catenin, hedgehog (Hh), and Hippo signaling pathways. Particularly the Hippo signaling pathway is the emerging and very less explored cancer stem cell pathway. Here, in this review, the Hippo signaling molecules are elaborated with respect to their ability of stemness as epigenetic modulators and how these molecules can be targeted for better cancer treatment and to overcome drug resistance.

Nanoparticles Containing Oxaliplatin and the Treatment of Colorectal Cancer

Background: Colorectal cancer (CRC) is a highly widespread malignancy and ranks as the second most common cause of cancer-related mortality.

Objective: Cancer patients, including those with CRC, who undergo chemotherapy, are often treated with platinum- based anticancer drugs such as oxaliplatin (OXA). Nevertheless, the administration of OXA is associated with a range of gastrointestinal problems, neuropathy, and respiratory tract infections. Hence, it is necessary to devise a potential strategy that can effectively tackle these aforementioned challenges. The use of nanocarriers has shown great potential in cancer treatment due to their ability to minimize side effects, target drugs directly to cancer cells, and improve drug efficacy. Furthermore, numerous studies have been published regarding the therapeutic efficacy of nanoparticles in the management of colorectal cancer.

Methods: In this review, we present the most relevant nanostructures used for OXA encapsulation in recent years, such as solid lipid nanoparticles, liposomes, polysaccharides, proteins, silica nanoparticles, metal nanoparticles, and synthetic polymer-carriers. Additionally, the paper provides a summary of the disadvantages and limits associated with nanoparticles.

Results: The use of different carriers for the delivery of oxaliplatin increased the efficiency and reduced the side effects of the drug. It has been observed that the majority of research investigations have focused on liposomes and polysaccharides.

Conclusion: This potentially auspicious method has the potential to enhance results and enhance the quality of life for cancer patients undergoing chemotherapy. However, additional investigation is required to ascertain the most suitable medium for the transportation of oxaliplatin and to assess its efficacy through clinical trials.

Integrated Network Pharmacology and Cellular Assay to Explore the Mechanisms of Selenized Tripterine Phytosomes (Se@Tri-PTs) Alleviating Podocyte Injury in Diabetic Nephropathy

Aim: This work aimed to elucidate the mechanisms of Se@Tri-PTs in alleviating podocyte injury via network pharmacology and in vitro cellular assay.

Background: Selenized tripterine phytosomes (Se@Tri-PTs) have been confirmed to undertake synergistic and sensitized effects on inflammation, which may be curatively promising for diabetic nephropathy (DN). However, the mechanisms of Se@Tri-PTs in alleviating podocyte injury, a major contributor to DN, still remain unclear.

Objective: The objective of the study was to find out the underlying mechanisms of Se@Tri-PTs in alleviating podocyte injury in diabetic nephropathy.

Methods: The key components and targets of Tripterygium wilfordii (TW) significant for DN as well as the signaling pathways involved have been identified. A high glucose-induced podocyte injury model was established and verified by western blot. The protective concentration of Se@Tri-PTs was screened by CCK-8 assay. Podocytes cultured with high glucose were treated with Se@Tri-PTs under protective levels. The expression of key protective proteins, nephrin and desmin, in podocytes, was assayed by western blot. Further, autophagy- related proteins and factors, like NLRP3, Beclin-1, LC3II/LC3, P62, and SIRT1, were analyzed, which was followed by apoptosis detection.

Results: Network pharmacology revealed that several monomeric components of TW, especially Tri, act on DN through multiple targets and pathways, including the NLRP3-mediated inflammatory pathway. Se@Tri-PTs improved the viability of podocytes and alleviated their injury induced by high glucose at 5 μg/L or above. High-glucose induction promoted the expression of NLRP3 in podocytes, while a low concentration of Se@Tri-PTs suppressed the expression. A long-term exposure of high glucose significantly inhibited the autophagic activity of podocytes, as manifested by decreased Beclin-1 level, lower ratio of LC3 II/LC3 I, and up- regulation of P62. This abnormality was efficiently reversed by Se@Tri-PTs. Importantly, the expression of SIRT1 was up-regulated and podocyte apoptosis was reduced.

Conclusion: Se@Tri-PTs can alleviate podocyte injury associated with DN by modulating NLRP3 expression through the pathway of SIRT1-mediated autophagy.

Anticancer Tetrahydrocarbazoles: A Wide Journey from 2000 Till Date

Tetrahydrocarbazoles (THCz) are widespread in numerous indole alkaloids and have been reported since time for exhibiting profound pharmacological potential. Many pharmaceuticals drugs have tetrahydrocarbazole nucleus in their structure e.g. vinca alkaloids (Vincristine, Vinblastine, Vinorelbine), Frovatriptan, (R)-Ramatroban, Ondansetron, etc. that are used in various multifactorial diseases. In this review article, the anticancer potential of tetrahydrocarbazole based derivatives has been covered, enumerating their vast journey from the year 2000 to 2021. Since the last twenty-one years, tetrahydrocarbazoles have been a matter of focus among researchers worldwide, whereby several novel tetrahydrocarbazole derivatives have been synthesized and reported for their anticancer potential against various cancer cell lines. Tetrahydrocarabzole and its derivatives have exhibited profound anticancer potential mediated via various cancer pathways like apoptosis, cell cycle arrest, microtubule inhibition, Nrf2 Modulators, DNA intercalators, pERK and pRb phosphorylation, VEGF (Vascular Endothelial Growth Factor) and TNF-α inhibition, TPSO (translocator protein), Histone Deacetylase (HDAC) Inhibitors also discussed. The present review entails the synthesis, SAR studies, and anticancer mechanism of tetrahydrocarbazoles derivatives reported in review literature till date, and would provide a strong database to the medicinal chemist world over in discovering newer potential anticancer agent against various types of cancer diseases.

Application of Nanoparticles for Efficient Delivery of Quercetin in Cancer Cells

Quercetin (Qu, 3,5,7,3’, 4’-pentahydroxyflavanone) is a natural polyphenol compound abundantly found in health food or plant-based products. In recent decades, Qu has gained significant attention in the food, cosmetic, and pharmaceutic industries owning to its wide beneficial therapeutic properties such as antioxidant, anti-inflammatory and anticancer activities. Despite the favorable roles of Qu in cancer therapy due to its numerous impacts on the cell signaling axis, its poor chemical stability and bioavailability, low aqueous solubility as well as short biological half-life have limited its clinical application. Recently, drug delivery systems based on nanotechnology have been developed to overcome such limitations and enhance the Qu biodistribution following administration. Several investigations have indicated that the nano-formulation of Qu enjoys more remarkable anticancer effects than its free form. Furthermore, incorporating Qu in various nano-delivery systems improved its sustained release and stability, extended its circulation time, enhanced its accumulation at target sites, and increased its therapeutic efficiency. The purpose of this study was to provide a comprehensive review of the anticancer properties of various Qu nano-formulation to augment their effects on different malignancies. Various targeting strategies for improving Qu delivery, including nanoliposomes, lipids, polymeric, micelle, and inorganic nanoparticle NPs, have been discussed in this review. The results of the current study illustrated that a combination of appropriate nano encapsulation approaches with tumor-oriented targeting delivery might lead to establishing QU nanoparticles that can be a promising technique for cancer treatment.

The Meaningful Function of the Emerging Clinical Targets-lncRNA MEG3 in Gastric Cancer

LncRNA MEG3, a tumor suppressor gene, is related to reducing the proliferation, migration, and invasion as well as apoptosis abilities of gastric cancer (GC), which is a promising therapeutic target in patients. We conducted a comprehensive search of the literature on Pubmed using the keywords “lncRNA MEG3 and gas cancer” from 2014 to the present. Here, we provide a systematic and comprehensive summary of existing knowledge of the lncRNAs MEG3 and reveal its biological function and specific mechanisms in gastric cancer. MEG3 is involved in many molecular mechanisms that inhibit the development and progression of gastric cancer. For example, MEG3 can inhibit the proliferation of gastric cancer cells by inhibiting the expression of miR-21, miR-665, miR-148, miR-208, etc. MEG3 inhibits gastric carcinogenesis by inhibiting the negative regulator MDM2, regulating the expression of tumor suppressor genes p53 and Rb gene, and managing PI3K/Akt and Wnt/β-catenin signaling pathways. Additionally, gastric cancer patients with low MEG3 expression have poor prognosis, and transfection of MEG3 can improve the overall survival time of normal cells. Eventually, lncRNA MEG3 can be used as a biomarker or target for intervention, thereby providing new insights for gastric cancer therapy.

Advancement in Nanobiotechnology for Human Health Care: Focus on Ocular Diseases and Future Prospects

Nanotechnology involves the study of different materials on the nanometer scale, typically less than 100 nm in size. Nanomedicine is the creation of nanotechnology, a new science and technology area. Similarly, various nanomaterials, such as nanostructure, nanotubes, and nanoparticles, were also found to have significant applications in the human biological system at the molecular level to achieve healthcare advantage. Nanotechnology is rapidly expanding in the field of medicine with a special emphasis on ophthalmology. Nanotechnology advancements need to be translated into a new and exciting platform for diagnosis, treatment, and therapeutics for ocular disease. The application of nanotechnology in ocular disease and cancer, such as nanoparticle-based drug delivery system, drug development, gene therapy, and tissue engineering, helps overcome many ocular problems. In particular, one of the most important applications of the emerging nanoscience system is used in ocular cancer diagnosis and therapy with the help of carbon nanotubes, nanocrystals, nanowires, etc. Several approaches have been developed for treatment and therapy for ocular disease. Moreover, these tremendous approaches have been safely used and effective for a broad range of applications. In this study, the focus is to discuss recent findings and various constraints and summarize the applications of nanotechnology-mediated systems for treating various ocular diseases.

Pyrazolo[4,3-H]quinazolines as Cyclin-dependent Kinase Inhibitors for Treating Cancer

The application describes the synthesis of 1H-pyrazolo[4,3-H]quinazoline compounds for treating cell proliferation dysfunction and is a broad-spectrum and strongly- active inhibitor for a cell cyclin-dependent kinase (CDK).

From Basics of Coordination Chemistry to Understanding Cisplatin-analogue Pt Drugs

Background: Cisplatin, a platinum complex discovered by Rosenberg in 1969, has long been known as the first metal-based anticancer agent. Since then, various similar derivatives of cisplatin have been investigated for pharmacological activity, and the approved complexes have been applied as drugs.

Objectives: The aims of the current study are: 1) to summarize the advantages and dose-limiting effects of the approved and unapproved chemotherapy platinum cytostatics, 2) to develop new strategies for the development of platinum anticancer drugs, and 3) to clarify the important factors for the mechanism of action of platinum complexes.

Methods: A search was conducted in the literature databases, and the obtained information was summarized and analyzed.

Results: Myelosuppression is the main dose-limiting effect and the reason for the disapproval of platinum complexes, such as picoplatin, enloplatin, miboplatin, sebriplatin, zeniplatin, spiroplatin, iproplatin, and ormaplatin. From the basic point of view of inorganic coordination chemistry, such as theoretical calculations, crystal structures of model complexes, docking structures with nucleic acid molecules, spectroscopy, and biological aspects, the importance of physicochemical properties of inorganic platinum complexes for their mechanism of action has been indicated. Spectroscopic methods, such as FTIR, NMR, X-ray crystal structure analysis, and fluorescence microscopy, are important for the investigation of the conformational changes in the binding of platinum complexes and DNA.

Conclusion: In the development of platinum complexes, strong anti-cancer drug activity, low toxicity, and resistance can be obtained by the application of polynuclear platinum agents, complexes with targeted activity, and nanoparticle formulations. Electronic structure, stereochemical, and thermodynamic properties are essential for understanding the reaction mechanism of platinum complexes.

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.

YF343, A Novel Histone Deacetylase Inhibitor, Combined with CQ to Inhibit- Autophagy, Contributes to Increased Apoptosis in Triple- Negative Breast Cancer

Background: Compounds that target tumor epigenetic events are likely to constitute a prominent strategy for anticancer treatment. Histone deacetylase inhibitors (HDACis) have been developed as prospective candidates in anticancer drug development, and currently, many of them are under clinical investigation. We assessed the anticancer efficacy of a now hydroxamate-based HDACi, YF-343, in triple-negative breast cancer development and studied its potential mechanisms.

Methods: YF-343 was estimated as a novel HDACi by the HDACi drug screening kit. The biological effects of YF-343 in a panel of breast cancer cell lines were analyzed by Western blot and flow cytometry. YF-343 exhibited notable cytotoxicity, promoted apoptosis, and induced cell cycle arrest. Furthermore, it also induced autophagy, which plays a pro-survival role in breast cancer cells.

Results: The combination of YF-343 with an autophagy inhibitor chloroquine (CQ) significantly suppressed breast tumor progression as compared to the YF-343 treatment alone both in vitro and in vivo. Mechanistically, the molecular mechanism of YF-343 on autophagy was elucidated by gene chip expression profiles, qPCR analysis, luciferase reporter gene assay, chromatin immunoprecipitation assays, immunohistochemical analysis, and other methods. E2F7, a transcription factor, promoted the expression of ATG2A via binding to the ATG2A promoter region and then induced autophagy in triple-negative breast cancer cells treated with YF-343.

Conclusion: Our studies have illustrated the mechanisms for potential action of YF-343 on tumor growth in breast cancer models with pro-survival autophagy. The combination therapy of YF-343 and CQ maybe a promising strategy for breast cancer therapy.

Combating Childhood Cancer: Paediatric Patients Living with Neuroblastoma - Regulatory Ramifications and Roadblocks

This paper relates to Neuroblastoma (NBL), a rare, solid cancer affecting children and aims to describe regulatory obligations to adhere to during development, marketing authorisation application (MAA) and post-authorisation stage. The focus is on European Union (EU) paediatric legislation, although essential US Food and Drug Administration (FDA) elements are briefly outlined. Practical regulatory aspects and reporting requirements, players in the therapeutic area as well as clinical management are described. The feasibility and limitations of future harmonised clinical development are pointed out.

Probiotics, as Adjuvant Therapy and Preventive Measure on Progression, and Complications of Head and Neck Cancer

Background: Preclinical and clinical evidence implies that destructive therapies in local and malignant tissue are frequently used on patients with head and neck cancer. Consequently, the microbiome of the treated and adjacent regions is affected. Disruption of the normal microbiome plays an important role not only in the disease progression but also in its emergence, therefore new therapies involving probiotics, prebiotics, and synbiotics have been developed to control or regulate this microbial disruption.

Objective: This review aims to describe the current and potential uses of probiotics at different stages of development of head and neck squamous cell carcinoma, as an adjuvant therapy to prevent common complications such as radiation-induced oral mucositis (RIOM) and its role in other areas.

Methods: Currently, there is no widely effective strategy to treat or prevent this kind of cancer. Surgery, radiation therapy, and chemotherapy are the three main treatments for head and neck cancer. Some therapies can also cause long-term health problems, or complications which might change the way you eat, talk, hear and breathe.

Results: The main uses for which probiotics have been studied are: Prevention and reduction of severity of RIOM, change in dental plaque to reduce dysbiosis, and reduction of complications in post-operated patients. Potential uses of probiotics include the reduction of disease initiation and progression by reducing local inflammation caused by bacteria and other organisms.

Conclusion: The incidence and severity of RIOM may be lessened by probiotics. To establish its uses in additional clinical settings, though, more studies are necessary.

Cancer Proteomics for Cellular Dysfunction: Insights and Trends

Background: Cancer is an ailment with having a very low survival rate globally. Poor cancer prognosis is primarily caused by the fact that people are found to have the disease when it is already well advanced. The goal of this study is to compile information on new avenues of investigation into biomarkers that may facilitate the routine detection of cancer. Proteomic analysis has recently developed into a crucial technique for cancer biology research, working in tandem with genomic analysis. Mass spectrometry techniques are one of several proteome analysis techniques that allow for the highly precise quantitative and qualitative recognition of hundreds of proteins in small quantities from various biological materials. These findings might soon serve as the foundation for better cancer diagnostic techniques.

Methods: An exhaustive literature survey has been conducted using electronic databases such as Google Scholar, Science Direct, and PubMed with keywords of proteomics, applications of proteomics, the technology of proteomics, biomarkers, and patents related to biomarkers.

Result: Studies reported till 2021 focusing on cancer proteomics and the related patents have been included in the present review to obtain concrete findings, highlighting the applications of proteomics in cancer.

Conclusion: The present review aims to present the overview and insights into cancer proteomics, recent breakthroughs in proteomics techniques, and applications of proteomics with technological advancements, ranging from searching biomarkers to the characterization of molecular pathways, though the entire process is still in its infancy.

Protein Lysine Methyltransferases Inhibitors

Protein lysine methylation is a significant protein post-translational modification (PTMs) and has a key function in epigenetic regulation. Protein lysine methyltransferase (PKMTs) mainly catalyzes the lysine methylation of various core histones and a few non-histone proteins. It has been observed that aberrant activity of PKMTs has been found in many cancers and other diseases, and some PKMT inhibitors have been discovered and progressed to clinical trials. This field developed rapidly and has aroused great interest. In this paper, we reviewed the biochemical and biological activities of PKMTs and their association with various cancers. Selective small-molecule inhibitors, including their chemical structure, structure-activity relationship, and in vitro/vivo studies, are also described to provide ideas for the discovery of highly potent, selective PKMT inhibitors.

Involvement of Metabolites and Non-coding RNAs in Diseases

Non-coding RNAs have a role in gene regulation and cellular metabolism control. Metabolism produces metabolites which are small molecules formed during the metabolic process. So far, a direct relationship between metabolites and genes is not fully established; however, pseudogenes and their progenitor genes regulate health and disease states. Other non-coding RNAs also contribute to this regulation at different cellular processes. Accumulation and depletion of metabolites accompany the dynamic equilibrium of health and disease state. In this study, metabolites, their roles in the cell, and the link between metabolites and non-coding RNAs are discussed.

Cysteine Metabolism in Tumor Redox Homeostasis

Cysteine (Cys) is a semi-essential nutrient amino acid that plays an important role in cells through endogenous production and various transport systems. Intracellular Cys can be used as a precursor of protein synthesis to maintain cell homeostasis and to generate sulfur-containing substances, including glutathione (GSH), hydrogen sulfide (H2S), and taurine. There have been quite a few reports that Cys is related to tumor occurrence and development, and its level is closely related to tumor proliferation, invasion, and metastasis. Moreover, it helps in maintaining the tumor redox balance and increasing drug resistance. This review aims to summarize the production and metabolism of Cys and its role in tumors, with special emphasis on the potential therapeutic value of Cys in tumors to improve the quality of life of cancer patients.

ZFPM2-AS1: An Oncogenic Long Non-coding RNA in Multiple Cancer Types

Long non-coding RNA (lncRNA) is a novel kind of RNA transcript with lengths greater than 200 nucleotides. Functionally, lncRNAs lack the potential to encode peptides or proteins. Previous studies unveiled that lncRNA participated in numerous physiological and pathological processes, including cancer, aging, and immune responses. Newly discovered long noncoding RNA zinc finger protein, Friend of GATA (FOG) family member 2-antisense 1 (ZFPM2-AS1), located on the 8q23 chromosome, acts as a tumor stimulator in various cancer types, including Breast Cancer (BC), Colorectal Cancer (CRC), Esophageal Squamous Cell Carcinoma (ESCC), Gastric Cancer (GC), glioma, hepatocellular carcinoma (HCC), Lung Adenocarcinoma (LUAD), melanoma, non-small cell lung cancer (NSCLC), Retinoblastoma (RB), Small Cell Lung Cancer (SCLC) and thyroid cancer. Accumulative evidence also elucidated that ZFPM2-AS1 dysregulation was related to tumor proliferative, migratory, invasive, anti-apoptotic, and pro-epithelial-tomesenchymal Transition (EMT) effects, larger tumor volume, higher tumor weight, advanced tumor stage, high rates of lymphatic metastasis, distant metastasis, poor prognosis, histological differentiation, higher TNM (tumor, node, metastases) stage, depth of tumor invasion, reduced overall and disease- free survival, vein invasion, and shorter 5-year overall survival. Mechanistically, ZFPM2-AS1 acted as a ceRNA to play its oncogenic role. Thus, this study summarized the specific mechanisms of the lncRNA ZFPM2-AS1 in the aforementioned cancer types to reveal its novel application in cancer diagnosis, treatment, and prognosis.

The Regulatory Mechanisms and Clinical Significance of Lnc SNHG4 in Cancer

Background: LncRNAs have been reported to be involved in a variety of biological functions, including gene expression, cell growth, and differentiation. They may also serve as oncogenes or tumor suppressor genes in diseases. lncRNAs that can encode small nucleolar RNAs (snoRNAs) have been named small nucleolar RNA host genes (SNHGs).

Objective: In this review article, we readily review the regulatory mechanisms and clinical significance of Lnc SNHG4 in cancer.

Methods: We systematically investigated databases, like Scopus, PubMed, Embase, Google Scholar, and Cochrane Library database for all research articles, and have provided an overview regarding the biological functions and mechanisms of lncRNA SNHG4 in tumorigenesis.

Results: Compared to neighboring normal tissues, SNHG4 is significantly dysregulated in various tumor tissues. SNHG4 upregulation is mainly associated with advanced tumor stage, tumor size, TNM stage, and decreased overall survival. In addition, aberrant SNHG4 expression promotes cell proliferation, metastasis, migration, and invasion of cancer cells.

Conclusion: SNHG4 may serve as a new therapeutic target and prognostic biomarker in patients with cancer.

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.

A Reverse Structure-based Design of HPV E7 Inhibitor

Background: Human papillomavirus (HPV) is a small, non-enveloped double-stranded circular DNA virus. The high-risk types of HPV are claimed to be responsible for over 99% of cervical cancers. One of the essential HPV oncoproteins, E7, is responsible for escaping from G1/S cell cycle arrest in HPV-infected cells by binding to the retinoblastoma protein (pRb) through its LXCXE binding site.

Objective: To design a peptide inhibitor targeting HPV E7 through an in silico approach.

Methods: In this study, the LXCXE binding domain of pRb is used as a target to design peptide inhibitors using a reverse structure-based approach. The designed amino acid sequence from the B pocket of pRb, named peptide Y, was further investigated in vitro analysis. The cytotoxicity of the peptide was analysed in two cell lines, namely, CaSki, containing an integrated HPV16 genome, and HaCaT, an immortalized keratinocyte cell. Cell cycle analysis was also carried out in both cell lines treated with peptides.

Results: In the in silico approach, a 9-amino acids peptide sequence formed 4 conventional hydrogen bonds with LXCXE motif was selected for in vitro assay. Based on the cytotoxicity analysis, the peptide showed low toxicity in both cell lines, where the cell viability remained over 74% when treated with peptide Y. The peptide also caused an accumulation of cells in G0/G1 (+5.4%) and S phase (+10.2%) and a reduction of cells in the G2/M phase (-14.9%) in the CaSki cells with no significant effect on normal cells, indicating it is a potential HPV inhibitor.

Conclusion: A peptide inhibitor, peptide Y, that was designed from the LXCXE binding motif in pRb can inhibit HPV E7 by causing a cell accumulation effect in G0/G1, and S phases of the cell cycle in the HPV transformed cell lines. These findings could contribute to HPV E7 peptide inhibitor in the future.

MicroRNA-7 Regulates Insulin Signaling Pathway by Targeting IRS1, IRS2, and RAF1 Genes in Gestational Diabetes Mellitus

Background: Small non-coding micro RNAs (miRNAs) are indicated in various metabolic processes and play a critical role in disease pathology, including gestational diabetes mellitus (GDM).

Objective: The purpose of this study was to examine the altered expression of miRNAs and their target genes in placental tissue (PL), cord blood (CB), and maternal blood (MB) of matched non-glucose tolerant (NGT) and GDM mother.

Methods: In a case-control study, micro-RNA was quantified from forty-five serum (MB n = 15, CB n = 15, and PL n = 15) and matched placental tissue using stem-loop RT-qPCR followed by target prediction, network construction and functional and pathways enrichment analysis. Further, target genes were verified in-vitro through transfection and RT-qPCR.

Results: Five miRNAs, namely hsa-let 7a-5P, hsa-miR7-5P, hsa-miR9-5P, hsa-miR18a-5P, and hsamiR23a- 3P were significantly over-expressed (p < 0.05) in all three samples namely PL, CB, and MB of GDM patients. However, the sample-wise comparison reveals higher expression of miRNA 7 in MB while lowest in CB than control. Furthermore, a comparison of fold change expression of target genes discloses a lower expression of IRS1, IRS2, and RAF1 in MB while comparatively higher expression of NRAS in MB and CB. In-vitro validation reveals lower expression of IRS1/2 and RAF1 in response to overexpression of miR-7 and vice-versa. Thus it is evident that increased miRNA7 expression causes down-regulation of its target genes IRS1, IRS2, and RAF1 in GDM mother compared to control. Further, target prediction, pathway enrichment, and hormone analysis (significantly higher FSH & LH in MB of GDM compared to NGT) revealed insulin signaling, inflammatory and GnRH signaling as major pathways regulated by miRNA7.

Conclusion: Thus, an elevated level of miRNA7 may be associated with the progression of GDM by altering the multiple pathways like insulin, GnRH, and inflammatory signaling pathways via targeting IRS1, IRS2, and RAF1, implicating a new therapeutic target for GDM.

HPV-mediated Cervical Cancer: A Systematic Review on Immunological Basis, Molecular Biology, and Immune Evasion Mechanisms

Background: Human papillomavirus (HPV), one of the most frequently transmitted viruses, causes several malignancies, including cervical cancer.

Aim: Owing to its unique pathogenicity, the HPV virus can persist in the host organism for a longer duration than other viruses to complete its lifecycle. During its association with the host, HPV causes various pathological conditions affecting the immune system by evading the host's immune mechanisms, thereby leading to the progression of various diseases, including cancer.

Method: To date, ~ 150 serotypes have been identified, and certain high-risk HPV types are known to be associated with genital warts and cervical cancer. As of now, two prophylactic vaccines are in use for the treatment of HPV infection; however, no effective antiviral drug is available for HPVassociated disease/infections. Numerous clinical and laboratory studies have been conducted to formulate an effective and specific vaccine against HPV infections and associated diseases.

Result: As the immunological basis of HPV infection and associated disease progress persist indistinctly, deeper insights into immune evasion mechanism and molecular biology of disease would aid in developing an effective vaccine.

Conclusion: Thus, this systematic review focuses on the immunological aspects of HPV-associated cervical cancer by uncovering immune evasion strategies adapted by HPV.

The Emerging Role of EMT-related lncRNAs in Therapy Resistance and their Applications as Biomarkers

Cancer is the world's second-largest cause of death. The most common cancer treatments are surgery, radiation therapy, and chemotherapy. Drug resistance, epithelial-- to-mesenchymal transition (EMT), and metastasis are pressing issues in cancer therapy today. Increasing evidence showed that drug resistance and EMT are co-related with each other. Indeed, drug-resistant cancer cells possess enhanced EMT and invasive ability. Recent research has demonstrated that lncRNAs (long non-coding RNAs) are non-coding transcripts which play an important role in the regulation of EMT, metastasis, and drug resistance in different cancers. However, the relationships among lncRNAs, EMT, and drug resistance are still unclear. These effects could be exerted via several signaling pathways, such as TGF-β, PI3K-AKT, and Wnt/β-catenin. Identifying the crucial regulatory roles of lncRNAs in these pathways and processes leads to the development of novel targeted therapies. We review the key aspects of lncRNAs associated with EMT and therapy resistance. We focus on the crosstalk between lncRNAs and molecular signaling pathways affecting EMT and drug resistance. Moreover, each of the mentioned lncRNAs could be used as a potential diagnostic, prognostic, and therapeutic therapy resistancefor cancer. However, the investigation of lncRNAs for clinical applications still has several challenges.

Phytocompounds from the Medicinal and Dietary Plants: Multi-target Agents for Cervical Cancer Prevention and Therapy

Cervical cancer is the fourth leading cause of cancer death among women worldwide. Due to cervical cancer's high incidence and mortality, there is an unmet demand for effective diagnostic, therapeutic, and preventive agents. At present, the preferred treatment strategies for advanced metastatic cervical cancer include surgery, radiotherapy, and chemotherapy. However, cervical cancer is gradually developing resistance to chemotherapy, thereby reducing its efficacy. Over the last several decades, phytochemicals, a general term for compounds produced from plants, have gained attention for their role in preventing cervical cancer. This role in cervical cancer prevention has garnered attention on the medicinal properties of fruits and vegetables. Phytochemicals are currently being evaluated for their ability to block proteins involved in carcinogenesis and chemoresistance against cervical cancer. Chemoresistance to cancer drugs like cisplatin, doxorubicin, and 5-fluorouracil has become a significant limitation of drug-based chemotherapy. However, the combination of cisplatin with other phytochemicals has been identified as a promising alternative to subjugate cisplatin resistance. Phytochemicals are promising chemo-preventive and chemotherapeutic agents as they possess antioxidant, anti-inflammatory, and anti-proliferative potential against many cancers, including cervical cancer. Furthermore, the ability of the phytochemicals to modulate cellular signaling pathways through up and down regulation of various proteins has been claimed for their therapeutic potential. Phytochemicals also display a wide range of biological functions, including cell cycle arrest, apoptosis induction, inhibition of invasion, and migration in cervical cancer cells. Numerous studies have revealed the critical role of different signaling proteins and their signaling pathways in the pathogenesis of cervical cancer. Here, we review the ability of several dietary phytochemicals to alter carcinogenesis by modulating various molecular targets.

Belzutifan: A Narrative Drug Review

Von Hippel-Lindau disease is an autosomal dominant disorder characterised by renal cell carcinomas, pancreatic neuroendocrine tumours, central nervous system hemangioblastomas, retinoblastomas, and tumours of the reproductive tract. This disease results from loss of function mutations in the tumour suppressor gene known as the Von Hippel-Lindau gene, located on chromosome 3. Loss of function mutation in the Von Hippel-Lindau gene results in the accumulation of a protein known as a hypoxia-inducible factor, which promotes cellular proliferation and angiogenesis, leading to cancer. Belzutifan inhibits the hypoxia-inducible factor by binding to the Per-ARNT -Sim-B binding pocket on the hypoxia-inducible factor -2α, inhibiting cellular proliferation and angiogenesis. In our thorough literature review, we identified 37 relevant articles. Belzutifan showed clinically meaningful response rates for both Von Hippel-Lindau disease-associated renal cell carcinomas and non-renal cell cancers. The pharmacokinetic profile of belzutifan was much better than its congener molecules due to the optimisation of its dihalide groups from germinal to vicinal. The pharmacodynamic effect of belzutifan was confirmed by its ability to decrease serum erythropoietin, which is a direct result of hypoxia-inducible factor- 2α inhibition. The significant side effects observed were anaemia, hypoxia, fatigue, hypertension, visual impairment and weight gain. Multiple clinical trials are currently underway to determine the role of beluztifan as part of combination regimens in treating Von Hippel-Lindau diseaseassociated malignancies.

Non-histone Methylation of SET7/9 and its Biological Functions

Background: (su(var)-3-9,enhancer-of-zeste,trithorax) domain-containing protein 7/9 (SET7/9) is a member of the protein lysine methyltransferases (PLMTs or PKMTs) family. It contains a SET domain. Recent studies demonstrate that SET7/9 methylates both lysine 4 of histone 3 (H3-K4) and lysine(s) of non-histone proteins, including transcription factors, tumor suppressors, and membrane-associated receptors.

Objective: This article mainly reviews the non-histone methylation effects of SET7/9 and its functions in tumorigenesis and development.

Methods: PubMed was screened for this information.

Results: SET7/9 plays a key regulatory role in various biological processes such as cell proliferation, transcription regulation, cell cycle, protein stability, cardiac morphogenesis, and development. In addition, SET7/9 is involved in the pathogenesis of hair loss, breast cancer progression, human carotid plaque atherosclerosis, chronic kidney disease, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis.

Conclusion: SET7/9 is an important methyltransferase, which can catalyze the methylation of a variety of proteins. Its substrates are closely related to the occurrence and development of tumors.

Bridging Indigenous Knowledge and Scientific Evidence for Pharmacological Studies of Phaleria macrocarpa: A Systematic Review

Background: Phaleria macrocarpa (Scheff.) Boerl. (Thymelaeaceae), usually referred to as God’s crown, Mahkota dewa, Pau, grows all year long in tropical countries, including Malaysia, Indonesia, Papua New Guinea, and Australia. It is traditionally used to treat haemorrhoids, stroke, heart disease, tumour, impotence, diabetes, allergies, kidney and liver disorders, migraine, acne, and skin ailments.

Objective: The purpose of this systematic review is to provide important insight on P. macrocarpa’s traditional use, toxicity, classification of compounds, and pharmacological activities, thus identifying the gap in scientific analysis and potential analytical opportunities for future directions on this herb.

Methods: The related data for this systematic review were collected from renowned online databases, namely Wiley Online Library, Web of Science, Springer Link, PubMed, Science Direct, Scopus, and Google scholar.

Results: Around 48 compounds, including benzophenone, xanthonoids, norcucurbitacin derivatives, flavonoids, lignans, fatty acids and esters, phytosterols, aromatic acids, etc., were identified from different parts. These constituents and different solvent extracts using various identification techniques have been reported to show a broad range of pharmacological activities. Besides various traditional claims and pharmacological functions, scientific evidence on its ethnopharmacological aspects has been well-documented. Studies found that the plant demonstrates anti-diabetic, anti- oxidant, antimicrobial, anticancer, anti-hypercholesterolemia, and antihypertensive activities.

Conclusion: Despite various claims, there is still inadequate scientific evidence, particularly on P. macrocarpa’s benefit in the management of dysentery, asthma, skin diseases, and rheumatoid arthritis, necessitating future studies. There is also a need to test its pharmacokinetics and toxicological data on humans to verify its potential bioactive properties.

Genitourinary Tract Tumors in Children: An Update

Background: Genitourinary tract tumors in children are less common than in adults. Most of these tumors have different genetic backgrounds, clinical presentation, and oncologic behavior than their adult counterpart. As a result of low prevalence in children, some of the treatment approaches and recommendations are based on treatment experience in adult patients. However, thanks to scientific and technological development, survival rates have risen considerably.

Objective: This paper presents a review of the principal features of the tumors involving the genitourinary tract in children and an update in genetic background, diagnosis, and treatment.

Methods: A narrative review was performed on published literature about genitourinary tract tumors in pediatric patients. Papers presented in English and Spanish literature were reviewed. PubMed, Science Direct, and SciELO databases were used to collect information and present this article.

Results: Kidney tumors are the most common type of genitourinary tumors in children. Among those, Wilms tumor represents the majority of cases and shows the successful work of clinical trial groups studying this tumor type. Other tumors involving the genitourinary tract in children include Rhabdomyosarcoma, Transitional cell carcinoma, Testicular, and Adrenal tumors.

Conclusion: Genitourinary tract tumors in children represent significant morbidity and economic burden, so awareness in early diagnosis represents improvement in treatment, clinical, and oncological outcomes.

Nanoparticles Mediated Target-specific Drug Delivery in Prostate Cancer: An In-depth Review

Nanotechnology has been extensively exploited for its enormous therapeutic and diagnostic potential in the management of multiple disorders. It employs nanomaterials as drug carriers with enhanced efficacy and limited side effects on normal tissues. A lot of nanomaterials have been studied and produced, imminently reforming the treatment and diagnostics of numerous malignancies, including cancer. The purpose of the present study is to explore the role of nanotechnology-based devices/therapies that have a vital function in the therapeutics and diagnostics of cancer with potential impact at three levels: early detection, tumor imaging, and drug delivery methods. Concentrating on cancer, promising nanotechnology-based approaches have been planned to satisfy the need for targeted specificity of traditional agents of chemotherapeutics, in addition to early recognition of malignant and precancerous lesions. Prostate cancer is the fifth most wellknown cancer worldwide and the second most usually detected cancer in men. Therefore, there is a crucial need to improve therapeutic prospects for the diagnosis and treatment of prostate cancer via the exploitation of the potential of nanomaterials for cell-targeted specificity and improved primary diagnosis of precancerous tumors. The present review, therefore, focuses on summarizing all prospective applications of nanotechnology in the prognosis and diagnosis of prostate cancer, which would further help researchers to elucidate a more potent therapeutic approach for the better management of prostate cancer in the days ahead.

Intraocular Exosomes in Eye Diseases

Exosomes, nanosized extracellular vesicles with a size of 30–150nm, contain many biological materials, such as messenger RNA (mRNA), microRNA (miRNA), proteins, and transcription factors. It has been identified in all biological fluids and recognized as an important part of intercellular communication. While the role of exosomes in cancer has been studied in-depth, our understanding of their relevance for ocular tissues has just begun to evolve. Intraocular fluids, including aqueous humor and vitreous humor, play a role in nourishing eye tissues and in expelling metabolites. In the pathological state, intraocular exosomes can mediate pathological processes such as ECM remodeling, retinal inflammation, and blood-retinal barrier dysfunction. Herein, we reviewed the latest advances of intraocular exosomes in the research of several eye diseases, including glaucoma, age-related macular degeneration, myopia, and ocular tumors, and discuss how intraocular exosomes contribute to the pathogenesis and progression of multiple eye diseases.

Clinical Practice of Umbilical Cord Blood Stem Cells in Transplantation and Regenerative Medicine - Prodigious Promise for Imminent Times

The umbilical cord blood is usually disposed of as an unwanted material after parturition; however, today, it is viewed as a regenerative medication so as to create the organ tissues. This cord blood gathered from the umbilical cord is made up of mesenchymal stem cells, hematopoietic stem cells, and multipotent non-hematopoietic stem cells having many therapeutic effects as these stem cells are utilized to treat malignancies, hematological ailments, inborn metabolic problem, and immune deficiencies. Presently, numerous clinical applications for human umbilical cord blood inferred stem cells, as stem cell treatment initiate new research. These cells are showing such a boon to stem cell treatment; it is nevertheless characteristic that the prospect of conservation of umbilical cord blood is gaining impetus. Current research works have demonstrated that about 80 diseases, including cancer, can be treated or relieved utilizing umbilical cord blood stem cells, and every year, many transplants have been effectively done around the world. However, in terms of factors, including patient selection, cell preparation, dosing, and delivery process, the treatment procedure for therapy with minimally manipulated stem cells can be patented. It is also worth thinking about how this patent could affect cord blood banks. Meanwhile, the utilization of cord blood cells is controversial and adult-derived cells may not be as successful, so numerous clinicians have begun working with stem cells that are acquired from umbilical cord blood. This review epitomizes a change in outlook from what has been completed with umbilical cord blood cell research and cord blood banking on the grounds that cord blood cells do not require much in the method of handling for cryopreservation or for transplantation in regenerative medicine.

The Role of miR-129-5p in Cancer: A Novel Therapeutic Target

miRNA-129-5p belongs to the microRNA-129 (miRNA-129) family. miRNA-129-5p is expressed in many tissues and organs of the human body, and it regulates a wide range of biological functions. The abnormal expression of miRNA-129-5p is related to the occurrence and development of a variety of malignant tumors. miRNA-129-5p plays an important role in the tumorigenesis process and functions by promoting or inhibiting tumors. However, the role of miRNA-129-5p in cancer remains controversial. This article reviews the different biological functions of miRNA- 129-5p in cancer and provides ideas for research in this field to guide the development of targeted therapies and drugs for malignant tumors.

Nanomaterials and Stem Cell Differentiation Potential: An Overview of Biological Aspects and Biomedical Efficacy

Nanoparticles (NPs), due to their medical applications, are widely used. Accordingly, the use of mesenchymal stem cells is one of the most important alternatives in the tissue engineering field. NPs play effective roles in stem cells proliferation and differentiation. The combination of NPs and tissue regeneration by stem cells has created a new therapeutic approach towards humanity. Of note, the physicochemical properties of NPs determine their biological function. Interestingly, various mechanisms such as modulation of signaling pathways and generation of reactive oxygen species, are involved in NPs-induced cellular proliferation and differentiation. This review summarized the types of nanomaterials effective on stem cell differentiation, the physicochemical features, biomedical application of these materials and the relationship between nanomaterials and environment.

Unraveling Potential Candidate Targets Associated with Expression of p16^INK4a or p16 Truncated Fragment by Comparative Proteomics Analysis

Background: p16 is a tumor suppressor protein that is significantly involved in cycle regulation through the reduction of cell progression from the G1 phase to the S phase via CDK-cyclin D/p16^INK4a/pRb/E2F cascade. The minimum functional domain of p16 has been uncovered that may function comparable to wild type p16.

Objective: To expand the knowledge on molecules and mechanisms by which p16 or p16^66-156 fragment suppresses human fibrosarcoma cell line growth, differential proteome profiles of fibrosarcoma cells following p16 full length or the functional domain overexpression, were analyzed.

Methods: Following transfecting HT-1080 fibrosarcoma cells with p16 full length, p16^66-156 truncated form, and pcDNA3.1 empty vector, protein extract of each sample was harvested and clarified by centrifugation, and then the protein content was determined via Bradford assay. All protein extract of each sample was analyzed by two-dimensional gel electrophoresis. Immunoblot analysis was performed as further validation of the expression status of identified proteins.

Results: Expression of p16 or p16^66-156 fragment could induce mostly the common alterations (up/- down-regulation) of proteome profile of HT-1080 cells. Mass spectrometry identification of the differentially expressed protein spots revealed several proteins that were grouped in functional clusters, including cell cycle regulation and proliferation, cell migration and structure, oxidative stress, protein metabolism, epigenetic regulation, and signal transduction.

Conclusion: The minimum functional domain of p16 could act in the same way as p16 full length. Also, these new findings can significantly enrich the understanding of p16 growth-suppressive function at the molecular level by the introduction of potential candidate targets for new treatment strategies. Furthermore, the present study provides strong evidence on the functional efficacy of the identified fragment of p16 for further attempts toward peptidomimetic drug design or gene transfer to block cancer cell proliferation.

Puerarin: A Review on the Pharmacological Activity, Chemical Properties and Pharmacokinetics of Main Isoflavonoid

Conventional drugs, as means of alternative medicine, have been in use in the Asian and African nations and some developed countries for the treatment of ailments and cure of diseases. Objective: Puerarin, a naturally occurring isoflavone in numerous plants, is one of the conventional medication that possess anti-inflammatory and immunoregulatory properties for the treatment of cardiac illnesses, osteonecrosis, Parkinson’s disease, Alzheimer’s disease, and other circulatory conditions. Puerarin is extensively distributed in numerous organs including the kidney, mammary gland, femur, tibia, stomach, liver, pancreas, brain, and lungs, but at a low rate because of its poor availability. However, when co-administered with compounds like gastrodin that can convey it into the cell, it shows a wide range of pharmacological properties, including antioxidant, antidiabetic, antimicrobial, antiviral, anti-inflammatory, anticancer, anti-Alzheimer’s, hepatoprotective, and neuroprotective activity. The biotransformation process of puerarin showed that it is well metabolized with daidzein, being the main hydrolyzed product. Puerarin is well tolerated in the body with a dosage of up to 250 mg/kg per day, does not initiate any toxic side effects but rather shows a wide range of beneficial and pharmacological properties.

A Comprehensive Review on Pharmacology and Toxicology of Bioactive Compounds of Lagerstroemia Speciosa(L.) Pers.

Background: Lagerstroemia speciosa (L.) Pers is one of the most valuable plants due to its ornamental and pharmacological relevance. It is known for its anti-diabetic activity with proved potent blood sugar-lowering activity. The anti-diabetic activity is due to the presence of its biologically active component, corosolic acid. Moreover, L.speciosa and its novel purified compounds are also well-known for their several biological activities with beneficial health benefit on the human being.

Objectives: This review provides a summary of pharmacokinetics, toxicity, and pharmacological properties of L.speciosa and its purified phytochemicals, which may help researchers for building up new research works in the near future.

Methods: The current article is prepared by collecting data through various online and offline databases. The preliminary source of study and data collection for outlining the review was research articles and reviews that have been already published by many reputed publishers, including Springer, Elsevier, Taylor & Francis imprints, BMC, Willy, The Norwegian Academy of Science and Letters, Environmental health prospective (EHP), and PLOS One.

Result: The available studies' results suggested that the L.speciosa and its phytochemicals exhibitedantidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiviral, anti-obesity, and cardio-protective activities. Pharmacokinetic studies suggested the low bioavailability of its purified compounds. However, nano-encapsulation can improve the bioavailability related issue and effectively potentiate the medicinal properties of its constituents.

Conclusion: Considering the worthy pharmacological properties, L.speciosa is considered a potent source of several novel drugs. Though, still preclinical and clinical studies are needed to reveal the targets, molecular mechanisms, bioavailability, and toxicity of its constituents.

Anticancer Effects of Ginsenoside Rh2: A Systematic Review

Background: As one of the effective pharmacological constituents of Ginseng Radix et Rhizoma, ginsenoside Rh2 (Rh2) exerts a remarkable anticancer effect on various cancer cell lines in vitro and strongly inhibits tumor growth in vivo without severe toxicity.

Objective: This article reviewed existing evidence supporting the anticancer effects of Rh2 to classify and conclude previous and current knowledge on the mechanisms and therapeutic effects of Rh2, as well as to promote the clinical application of this natural product.

Conclusion: This article reviewed the anticancer efficacies and mechanisms of Rh2, including the induction of cell cycle arrest and programmed cell death, repression of metastasis, alleviation of drug resistance, and regulation of the immune system. Finally, this paper discussed the research and application prospects of Rh2.

Selective Cytotoxic Effects of 5-Trifluoromethoxy-1H-indole-2,3-dione 3-Thiosemicarbazone Derivatives on Lymphoid-originated Cells

Aim: The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3- thiosemicarbazone derivatives. These compounds could be promising anticancer agents in leukemia treatment.

Background: Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to nonspecificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life.

Methods: In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt’s lymphoma P3HR1, acute promyelocytic leukemia HL60 cells, and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid-derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and the resulting apoptotic activities were demonstrated.

Results: All tested compounds have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC₅₀= 0.89-1.80 μM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistance. The most effective and selective compound is 4-bromophenyl substituted compound I (IC₅₀=0.96 and 0.89 μM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC₅₀=2.38 μM), while the allyl substituted compound C is effective on all cell lines (IC₅₀=1.13-2.21 μM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC₅₀=1.00-2.41 μM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC₅₀= 1.13 μM). Additionally, all compounds exhibited cytotoxic effects on lymphoidderived cells at 1μM concentration. These results are in accordance with the results obtained in lymphoma cells.

Conclusion: All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold potential for use in future treatments of leukemia.

Bladder Cancer: Update on Risk Factors, Molecular and Ultrastructural Patterns

Objective: The molecular mechanisms of bladder cancer development and progression are not clear. Bladder cancer is an important focus for epidemiological studies and understanding clinical implications.

Goal: The primary aim of prevention is achieved by limiting exposure to non-genetic risk factors, such as smoking, diet, arsenic in drinking water, or aromatic amines at work or elsewhere. Current therapies for bladder cancer are affected by tumor morphology and associated acquired genetic mutations.

Methods: A literature search was performed using PubMed, Scopus, ResearchGate, Google, MEDLINE, and ScienceDirect databases to find studies of bladder cancer published between 1984 and early 2020. The focus was articles that address epidemiological risk factors and underlying pathophysiological mechanisms. Articles were selected that enabled our review of these factors as well as molecular and structural patterns.

Results: There are multiple views of bladder cancer. The literature offers several novel insights regarding the development and progression of bladder cancer and possible biomarkers that may be useful in clinical and diagnostic practice.

Conclusion: There are several molecular pathways associated with bladder cancer that are frequently updated. In addition, genetic subtypes of bladder tumors are not distinguished clearly which requires future more detailed analysis.

Erdafitinib as a Novel and Advanced Treatment Strategy of Metastatic Urothelial Carcinoma

Urothelial carcinoma has become the ninth most common malignancy in the world. Since the 1980s, diverse studies and treatment methods came out with their possible effects along with certain limitations. Initially, platinum chemotherapy was considered as first-line treatment of the disease. Although it was proved to be effective initially, the most number of cases reported the reoccurrence of the disease. Furthermore, aberrant ligand- dependent and constitutive ligand-independent fibroblast growth factor receptor (FGFR) signaling has been reported in a large number of solid tumors, including urothelial carcinoma that became the basis for FGFR inhibition for the treatment of the disease. Erdafitinib is a pan-FGFR inhibitor that was recently approved in the USA for the treatment of locally advanced or metastatic FGFR3 or FGFR2 urothelial carcinoma. The drug is also being investigated as a treatment for other cancers, including cholangiocarcinoma, liver cancer, non-small cell lung cancer, prostate cancer, lymphoma cancer and oesophageal cancer. This article summarizes the various treatments that evolved for bladder cancer till now, a brief description of the biology of FGFR inhibition, clinical pharmacology, and various clinical trials of erdafitinib.

Therapeutic Potential of Natural Compounds in Lung Cancer

Lung cancer is a leading cause of cancer deaths worldwide. The management of lung cancer treatment is often ineffective as a result of the development of drug resistance, reactions to treatment, drug-drug interactions or non-specific targeting of the anticancer drugs. Natural compounds show promise and potential activity in lung cancer with very few side effects. While, the combinatorial action of an anti-cancer drug with a natural compound provides synergistic action which helps boost the overall therapeutic action against cancer cells. In cancer, there is a dysregulation of apoptosis which facilitates the cancer cell to survive, resulting in progression of cancer. Many cancer drugs cause mutations of genes that regulate cancer and should kill the cancer cell but lead to chemoresistance. There are many natural compounds that could specifically target different cell signalling pathways associated with cancer progression to provide a cytotoxic effect in the target cell. The importance of these compounds is emerging in many therapies developed with dual action often including a natural compound. In this review, we present a selection of these natural compounds and how they target lung cancer cells with a focus on the cell signalling pathways. Further work is required to delineate the potential action of natural compounds in the treatment against cancer.

Using Natural Compounds to Target KRAS Mutated Non-Small Cell Lung Cancer

Approximately 85% of all lungs cancer cases are classified as non-small cell lung cancer (NSCLC). Kirsten rat sarcoma (KRAS) viral oncogene homolog mutations frequently occur in NSCLC patients resulting in a decreased overall survival. Additionally, currently used chemotherapeutic drugs lack selectivity,and patients experience side effects. Therefore, potent therapeutic agents are urgently needed for these patients. Plant- based compounds could be a potential option to treat KRAS-mutated NSCLC. These compounds are reported to be effective against the KRAS-linked up-stream and downstream signaling pathways that are directly or indirectly linked with cell proliferation, division, and apoptosis. Additionally, plant phytochemicals also suppressed different cell cycle phases of KRAS-mutant NSCLC cells. Furthermore, phytochemicals have a wider therapeutic index compared to chemotherapeutic drugs. Therefore, phytochemicals could benefit NSCLC patients as sole agents or as a combination therapy with approved chemotherapies. The current review aims to summarize the potential benefit of natural compounds in KRAS-mutant NSCLC.

Targeted Therapies in Lung Cancers: Current Landscape and Future Prospects

Background: Lung cancer is the most common malignant cancer worldwide. Targeted therapies have emerged as a promising treatment strategy for lung cancers.

Objective: To evaluate the current landscape of targets and find promising targets for future new drug discovery for lung cancers, this research identified the science-technology-clinical development pattern and mapped the interaction network of targets.

Methods: Targets for cancers were classified into 3 groups based on a paper published in Nature. We searched for scientific pieces of literature, patent documents and clinical trials of targets in Group 1 and Group 2 for lung cancers. Then, a target-target interaction network of Group 1 was constructed, and the science-technology-clinical (S-T-C) development patterns of targets in Group 1 were identified. Finally, based on the cluster distribution and the development pattern of targets in Group 1, interactions between the targets were employed to predict potential targets in Group 2 for drug development.

Results: The target-target interaction (TTI) network of group 1 resulted in 3 clusters with different developmental stages. The potential targets in Group 2 are divided into 3 ranks. Level-1 is the first priority and level-3 is the last. Level-1 includes 16 targets, such as STAT3, CRKL, and PTPN11, that are mostly involved in signaling transduction pathways. Level-2 and level-3 contain 8 and 6 targets, respectively, related to various biological functions.

Conclusion: This study will provide references for drug development in lung cancers, emphasizing that priorities should be given to targets in Level-1, whose mechanisms are worth further exploration.

Resveratrol as an Enhancer of Apoptosis in Cancer: A Mechanistic Review

The resistance to therapy of cancer cells is a challenge for achieving an appropriate therapeutic outcome. Cancer (stem) cells possess several mechanisms for increasing their survival following exposure to toxic agents such as chemotherapy drugs, radiation, as well as immunotherapy. Evidences show that apoptosis plays a key role in the response of cancer (stem) cells and their multi-drug resistance. Modulation of both intrinsic and extrinsic pathways of apoptosis can increase the efficiency of tumor response and amplify the therapeutic effects of radiotherapy, chemotherapy, targeted therapy, and also immunotherapy. To date, several agents, as adjuvant, have been proposed to overcome the resistance of cancer cells to apoptosis. Natural products are interesting because of the low toxicity on normal tissues. Resveratrol is a natural herbal agent that has shown interesting anti-cancer properties. It has been shown to kill cancer cells selectively while protecting normal cells. Resveratrol can augment reduction/oxidation (redox) reactions, thus increases the production of ceramide and the expression of apoptosis receptors, such as Fas Ligand (FasL). Resveratrol also triggers some pathways which induce the mitochondrial pathway of apoptosis. On the other hand, resveratrol has an inhibitory effect on antiapoptotic mediators, such as Nuclear Factor κ B (NF-κB), Cyclooxygenase-2 (COX-2), Phosphatidylinositol 3– Kinase (PI3K), and mTOR. In this review, we explain the modulatory effects of resveratrol on apoptosis, which can augment the therapeutic efficiency of anti-cancer drugs or radiotherapy.

Potential Interactions between miRNAs and Hypoxia: A New Layer in Cancer Hypoxia

Hypoxia pathway and aberrant miRNA expression profile play crucial roles in the development of various cancers. Recent studies have emphasized that there are many collaborations in this cases because both of them are involved in cancer cell processes, including differentiation, metastasis, and cell proliferation and signaling pathways. Further studies have elucidated that miRNAs affect the hypoxia route, and more interestingly, the hypoxia pathway also affects miRNAs expression profile. The literature review summarizes the fundamental roles of hypoxia-related miRNAs in different cancers. The mutual interactions between miRNAs and hypoxia are a new layer of complexity in cancer hypoxia, which might be helpful in controlling cancer progression. It is also possible that the hypoxia pathway is initiated by miRNAs. In contrast, the hypoxia pathway regulates the expression of a large group of miRNAs. In this review for the first time, we discussed the significant interactions between hypoxia and miRNAs in order to determine new perspectives for new therapeutic aims in the field of cancer.

Recent Advancements for the Management of Pancreatic Cancer: Current Insights

One of the most fatal forms of cancer includes cancer of the pancreas And the most rapid malignancy is observed in PDAC (pancreatic ductal adenocarcinoma). The high lethality rate is generally due to very late diagnosis and resistance to traditional chemotherapeutic agents. Desmoplastic stromal barrier results in resistance to immunotherapy. Other reasons for the high lethality rate include the absence of effective treatment and standard screening tests. Hence, there is a need for effective novel carrier systems. “A formulation, method, or device that allows the desired therapeutic substance to reach its site of action in such a manner that nontarget cells experience minimum effect is referred to as a drug delivery system”. The delivery system is responsible for introducing the active component into the body. They are also liable for boosting the efficacy and desirable targeted action on the tumorous tissues. Several studies, researches, and developments have yielded various advanced drug delivery systems, which include liposomes, nanoparticles, carbon nanotubules, renovoCath, etc. These systems control rate and location of the release. They are designed while taking into consideration characteristic properties of the tumor and tumor stroma. These delivery systems overcome the barriers in drug deliverance in pancreatic cancer. Alongside providing palliative benefits, these delivery systems also aim to correct the underlying reason for the defect. The following review article aims and focuses to bring out a brief idea about systems, methods, and technologies for futuristic drug deliverance in pancreatic cancer therapy.

Bioinformatics Approach for Data Capturing: The Case of Breast Cancer

Background: With the rapid evolution in advanced computer systems and various statistical algorithms, it is now a days possible to analyze complex biological data. Bioinformatics is an interface between computational and biological assemblies. It is applied in various fields of biological as well as medical sciences.

Aim: The manuscript aims to summarize the developments in the field of breast cancer research through the applications of bioinformatics.

Methods: Various search engines like google, science direct, Scopus, PubMed, etc., were used for the literature survey.

Results: It describes the bioinformatics analysis tools and models, which include mainly artificial neural network models.

Conclusion: Bioinformatics is the evolutionary approach that is used for the capturing of data from the various case studies related to breast cancer.

An Intimate Alliance of DNA-Damage Response Network with Cell-Cycle Checkpoints Amid Events of Uncontrolled Cellular Proliferation: A Mini- Review

There is close interdependence between cell survival, cell senescence, events of the cell cycle, apoptosis, malignancy development, and tumor responses to cancer treatment. Intensive studies and elaborate researches have been conducted on the functional aspects of oncogenes, tumor suppressor genes, apoptotic genes, and members guiding cell cycle regulation. These disquisitions have put forward the existence of a highly organized response pathway termed as a DNA-damage response network. The pathways detecting DNA damage and signaling are intensively linked to the events of cell-cycle arrest, cell proliferation, apoptosis, and cell senescence. DNA damage responses are complex systems that incorporate specific “sensor” and “transducer” proteins, for assessment of damage and signal transmission, respectively. These signals are thereafter relayed upon various “effector” proteins involved in different cellular pathways. It may include those governing cell-cycle checkpoints, participating in DNA repair, cell senescence, and apoptosis. This review discusses the role of the tumour suppressor gene, oncogenes, cell cycle checkpoint regulators during DNA damage response and regulation.

New Insights Toward Nanostructured Drug Delivery of Plant-Derived Polyphenol Compounds: Cancer Treatment and Gene Expression Profiles

The increasing prevalence of cancer has led to expanding traditional medicine objectives for developing novel drug delivery systems. A wide range of plant-derived polyphenol bioactive substances have been investigated in order to explore the anti-cancer effects of these natural compounds and to promote the effective treatment of cancer through apoptosis induction. In this regard, plant-derived polyphenol compounds, including curcumin, silibinin, quercetin, and resveratrol, have been the subject of intense interest for anti-cancer applications due to their ability to regulate apoptotic genes. However, some limitations of pure polyphenol compounds, such as poor bioavailability, short-term stability, low-cellular uptake, and insufficient solubility, have restricted their efficiency. Nanoscale formulations of bioactive agents have provided a novel platform to address these limitations. This paper reviews recent advances in nanoformulation approaches of polyphenolic drugs and their effects on improving the delivery of chemotherapy agents to cancer cells.

Crosstalk of Long Non-coding RNAs and EMT: Searching the Missing Pieces of an Incomplete Puzzle for Lung Cancer Therapy

Background: Lung cancer has the first place among cancer-related deaths worldwide and demands novel strategies in the treatment of this life-threatening disorder. The aim of this review is to explore the regulation of epithelial-to-mesenchymal transition (EMT) by long non-coding RNAs (lncRNAs) in lung cancer.

Introduction: LncRNAs can be considered as potential factors for targeting in cancer therapy, since they regulate a bunch of biological processes, e.g. cell proliferation, differentiation and apoptosis. The abnormal expression of lncRNAs occurs in different cancer cells. On the other hand, epithelial-to-mesenchymal transition (EMT) is a critical mechanism participating in migration and metastasis of cancer cells.

Methods: Different databases, including Google Scholar, Pubmed and Science direct, were searched for collecting articles using keywords such as “LncRNA”, “EMT”, and “Lung cancer”.

Results: There are tumor-suppressing lncRNAs that can suppress EMT and metastasis of lung cancer cells. Expression of such lncRNAs undergoes down-regulation in lung cancer progression and restoring their expression is of importance in suppressing lung cancer migration. There are tumor- promoting lncRNAs triggering EMT in lung cancer and enhancing their migration.

Conclusion: LncRNAs are potential regulators of EMT in lung cancer, and targeting them, both pharmacologically and genetically, can be of importance in controlling the migration of lung cancer cells.

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.

High Expression of miR-483-5p Predicts Chemotherapy Resistance in Epithelial Ovarian Cancer

Background: Ovarian cancer is the most deadly cancer that requires novel diagnostics and therapeutics. MicroRNAs are viewed as essential gene regulatory elements involved in different pathobiological mechanisms of many cancers, including ovarian cancer.

Objective: This study examined the relationship between microRNA (miRNA) expression and response to platinum-based chemotherapy.

Methods: Genome-wide miRNA expression analysis was conducted using Epithelial Ovarian Cancer (EOC) tissues from 25 patients with 17 malignant tumors and eight benign ovarian tumors. Candidate miRNAs that respond to platinum-based chemotherapy were selected for validation by quantitative RT-PCR.

Results: Among 2,578 mature human miRNAs, high expression of miR-483-5p correlated with poor responses to platinum-based chemotherapy in EOC patients. Furthermore, high levels of miR-483-5p in the resistant group suppressed expression of the apoptotic regulator TAOK-1.

Conclusion: A possible marker for the prediction of chemotherapy response and resistance in patients may be miR-483-5p. Choosing the right treatment for each patient with EOC can avoid the risk of developing chemotherapy resistance.

A Review of DNA and Histone Methylation Alterations in the New Era of Diagnosis and Treatment of Retinal Diseases

Epigenetics has an important role in gene regulation and other cellular processes. DNA methylation, as one of the main mechanisms of epigenetics, is a type of post-replication modifications. Aberrant DNA methylation can alter gene expression patterns; so, it plays a considerable role in the pathogenesis of many diseases. DNA methylated alterations in the promoter of specific genes can be used for the diagnosis and proprietary targets acting as a “biomarker”. Early diagnosis and prevention may be possible due to these biomarkers. According to recent studies, DNA methylation abnormalities have an important role in the retinogenesis and pathogenesis of retinal diseases. Retinal diseases are the main cause of blindness and severe vision loss in the world, which will continue to increase. Also, they inflict an enormous burden on society and health care systems. Therefore, it is important to focus on the better recognition and prevention of retinal diseases and finding new targets for the treatment. DNA methylation is lionized as attractive therapeutic targets due to its reversibility. Epigenetic therapy has a high potency in the treatment of retinal diseases. Here, we reviewed the DNA and histone methylation alterations in common retinal diseases, focusing on agerelated macular degeneration (AMD), diabetic retinopathy, retinal detachment (RD), retinitis pigmentosa, retinal aging, and retinoblastoma. Then we surveyed some new approaches to epigenetic therapy in retinal disorders.

Differential Expression of miR-20a and miR-145 in Colorectal Tumors as Potential Location-specific miRNAs

Background: MicroRNAs (miRNAs), as tissue specific regulators of gene transcription, may be served as biomarkers for Colorectal Cancer (CRC).

Objective: This study aimed to investigate the potential role of the cancer-related hsa-miRNAs as biomarkers in Colon Cancer (CC) and Rectal Cancer (RC).

Methods: A total of 148 CRC samples (74 rectum and 74 colon) and 74 adjacent normal tissues were collected to examine the differential expression of selected ten hsa-miRNAs using quantitative Reverse Transcriptase PCR (qRT-PCR).

Results: The significantly elevated levels of miR-21, miR-133b, miR-18a, miR-20a, and miR-135b, and decreased levels of miR-34a, miR-200c, miR-145, and let-7g were detected in colorectal tumors compared to the healthy tissues (P<0.05). Hsa-miR-20a was significantly overexpressed in rectum compared to colon (p =0.028) from a cut-off value of 3.15 with a sensitivity of 66% and a specificity of 60% and an AUC value of 0.962. Also, hsa-miR-145 was significantly overexpressed in colon compared to the rectum (p =0.02) from a cut-off value of 3.9 with a sensitivity of 55% and a specificity of 61% and an AUC value of 0.91.

Conclusion: In conclusion, hsa-miR-20a and hsa-miR-145, as potential tissue-specific biomarkers for distinguishing RC and CC, improve realizing the molecular differences between these local tumors.

The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provides a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin-dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

The Synergistic Cytotoxic and Apoptotic Effect of Resveratrol and Naringenin on Y79 Retinoblastoma Cell Line

Background: Resveratrol is a phenolic natural product, which is found in red grapes and in Japanese knotweed root (Polygonum cuspidatum). Naringenin is one of the flavonoid compounds found in landing grape and other citrus fruits. Both agents exert antioxidant and anti-inflammatory properties.

Objective: In this study, the effect of Resveratrol and Naringenin in an in vitro model of retinoblastoma of the eye has been investigated.

Methods: XTT and trypan blue assays were used to evaluate the anti-proliferative/cytotixic effect of resveratrol and naringenin in Y79 cells. With the aid of AnnexinV/PI flow cytometry, the kind of cell death was investigated. To assess important gene expression levels at mRNA level involved in apoptosis, Real-time PCR was utilized.

Results: Naringenin and resveratrol significantly decreased proliferation and stimulated cell death (mostly apoptosis) in Y79 cells at 50 and 100 (μg/ml) after 24 and 48 hours. Additional cytotoxic effect was observed after 48 hours. Furthermore expression level of Bax and Bcl2 mRNAs altered significantly in all samples treated with 50 (μg/ml) of naringenin, resveratrol, or simultaneously with both. P21 mRNAs expression altered in all mentioned samples except those treated with 50 (μg/ml) of resveratrol.

Conclusion: Based on the results, it can be concluded that resveratrol and naringenin can decrease cell viability in retinoblastoma cells in an in vitro dose/time-dependent manner. Albeit more studies are needed to shed the light on the mechanism of action, our data reveal a potential synergistic cytotoxic effect of naringenin and resveratrol on Y79 cells in 48 hours.

Restoration of Chemoresistance Mechanism by Novel Drug Therapies in Breast Cancer Cell Lines

Chemoresistance is one of the biggest hurdles while treating cancer clinically. Due to its heterogeneous nature, complications of the chemoresistance mechanisms of breast cancer cannot be completely elucidated. Existing mechanisms of main-line drug treatment can slow down the process of malignancy with part and parcel called drug resistance. The combinatorial effect of several chemotherapeutic drugs, targeting different pathways at the same time, can work efficiently, yet the toxicity and drug-drug interaction remain intact.

To overcome this hurdle, a number of strategies have been discovered, such as novel agents, drug carriers, and combination treatment, etc., which target mediated drug delivery systems; nanomedicine and the use of phytocompounds can transfer the drug particularly to the cancerous cells with minimal side effects to the neighboring healthy cells. The cell cycle checkpoint proteins and genes induced to the deranged cells can inhibit the resistance mechanism towards the drug. Modification of cell signaling pathways can also help to treat breast cancer chemoresistance mechanisms in the long run. This article reviews the execution and onset of chemoresistance in various cancers and discusses potential therapeutic approaches to deal with the resistance mechanism.

This review summarizes the possible mechanisms and signaling pathways causing chemoresistance in breast cancer cell lines and discusses alternative therapy to overcome this issue under pre-clinical and clinical infrastructure.

Natural Products Targeting Cancer Stem Cells: A Revisit

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy.

Objective: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy.

Results: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure- activity relationships.

Conclusion: Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

Overview of PCTK3/CDK18: A Cyclin-Dependent Kinase Involved in Specific Functions in Post-Mitotic Cells

Cyclin-dependent kinases (CDKs) comprise a family of about 20 serine/threonine kinases whose catalytic activity requires a regulatory subunit known as cyclin; these enzymes play several roles in the cell cycle and transcription. PCTAIRE kinases (PCTKs) are a CDK subfamily, characterized by serine to cysteine mutation in the consensus PSTAIRE motif, involved in binding to the cyclin. One member of this class is PCTK3, which has two isoforms (a and b) and is also known as CDK18. After being activated by cyclin A2 or phosphorylation at Ser12 by PKA, PCTK3 can perform several functions. Among these functions, we may highlight the following: modulation of cargo transport in membrane traffic, p53-responsive gene, regulation of genome integrity. According to different studies, PCTK3 dysfunction is related to a wide range of diseases, such as metabolic diseases, cerebral ischemia, depression, cancer, neurological disorders, and Alzheimer's disease. Although this protein participates in different biological events, we may say that PCTK3 has received far less attention than other CDKs. There are thousands of published articles about other CDKs and less than two hundred articles related to PCTK3. The main objective of this review is to present the selected published studies about this protein. Our focus is on PCTK3 particularities compared to other CDKs. Here we give an overview of the biological functions of PCTK3 and explore its potential as a target for drug design.

Gamma Secretase Inhibitor: Therapeutic Target via NOTCH Signaling in T Cell Acute Lymphoblastic Leukemia

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a diseased condition of bone marrow and lymphoblast, mainly expressed on T-cell immune phenotype. Diagnosis of TALL patients shows the burden of a large tumour and leukemia cells in the peripheral blood vessel which often infiltrates into the central nervous system.

Objective: Chemotherapy is considered the primary mode of treatment for this disease, but recent advancements in the molecular understanding of the disease, including NOTCH1 signaling, could offer some alternatives. NOTCH signaling undergoes a non-regulated mutation at NOTCH1 in most T-ALL. Gamma-secretase (GS) plays a key role in blocking of proteolytic activation of NOTCH receptors, which could potentially be a new targeted therapy for this type of leukaemia. This study mainly aims to outline the role of γ-secretase inhibitors via NOTCH signaling in TALL.

Results: The role of GSI (γ-secretase inhibitor) in most T-ALL cell lines has been linked to the targeting pathway of NOTCH signaling. Mutation at NOTCH1 has however not served as a predictor of γ-secretase inhibitor sensitivity because of several factors, including gene expression of NOTCH pathway activity. Therefore, despite the promising outcome of this approach in NOTCH-1 activated T-ALL, not all patients with this condition are expected to respond.

Conclusion: Long-term therapeutic success against cancerous cells is rarely achieved with monotherapy, and even targeting investigational pathways such as NOTCH may require a combination regimen. Ultimately, the optimised use of these new therapeutic agents may become the next tool in our search for an effective ‘individualized medicine’.

Genomic Instability in Cancer: Molecular Mechanisms and Therapeutic Potentials

DNA damage usually happens in all cell types, which may originate from endogenous sources (i.e., DNA replication errors) or be emanated from radiations or chemicals. These damages range from changes in few nucleotides to significant structural abnormalities on chromosomes and, if not repaired, could disturb the cellular homeostasis or cause cell death. As the most significant response to DNA damage, DNA repair provides biological pathways by which DNA damages are corrected and returned into their natural circumstance. However, an aberration in the DNA repair mechanisms may result in genomic and chromosomal instability and the accumulation of mutations. The activation of oncogenes and/or inactivation of tumor suppressor genes is a serious consequence of genomic and chromosomal instability and may bring the cells into a cancerous phenotype. Therefore, genomic and chromosomal instability is usually considered a crucial factor in carcinogenesis and an important hallmark of various human malignancies. In the present study, we review our current understanding of the most updated mechanisms underlying genomic instability in cancer and discuss the potential promises of these mechanisms in finding new targets for the treatment of cancer.

The Application of Chemometrics for Efficiency Enhancement and Toxicity Reduction in Cancer Treatment with Combined Therapy

Chemometrics is an important emerging discipline with unique charm formed by the intersection of mathematics, statistics, chemistry and computer science. The application of chemometrics in the field of pharmacy has injected fresh blood into the scientific research and clinical practice of medicine and has provided a sufficient scientific basis for drug analysis and content determination to solve the problem of cancer treatment with combined therapy in different ranges. This paper introduces the basic principles, advantages and disadvantages of several commonly used pattern recognition and multidimensional correction methods of chemometrics, reviews the application of chemometrics for efficiency enhancement and toxicity reduction in cancer treatment with combined therapy and summarizes its development and prospects in the future.

A Review on Natural Sources Derived Protein Nanoparticles as Anticancer Agents

Cancer notably carcinoma represents a prominent health challenge worldwide. A variety of chemotherapeutic agents are being used to deal with a variety of carcinomas. However, these delivering agents not only enter the targeted site but also affect normal tissues yielding poor therapeutic outcomes. Chemotherapeutic-associated problems are being attributed to drug non-specificity resulting from poor drug delivery systems. These problems are now being solved using nanomedicine, which entails using nanoparticles as drug delivery systems or nanocarriers. This nanoparticle-based drug delivery system enhances clinical outcomes by enabling targeted delivery, improving drug internalization, enhanced permeability, easy biodistribution, prolonged circulation and enhanced permeability rate, thereby improving the therapeutic effectiveness of several anticancer agents. Natural Protein-based Nanoparticles (PNPs) such as ferritin, lipoprotein, and lectins from natural sources have gained extensive importance at a scientific community level as nanovehicle for effective drug delivery and photo acoustic labeling replacing several synthetic nanocarriers that have shown limited therapeutic outcomes. The bioavailability of PNP, the chance of genetic engineering techniques to modify their biological properties made them one of the important raw material sources for drug delivery research. This current review highlighted different chemotherapeutic agents used in the treatment of some carcinomas. It also focused on the wide variety of natural protein sources derived nanoparticles (NPs) as anticancer delivery of agents for cancer therapy.

Lumiflavin Enhances the Effects of Ionising Radiation on Ovarian Cancer Stem-Like Cells by Inhibiting Autophagy

Background: The development of Cancer Stem-like Cells (CSCs) is one of the main causes of ovarian cancer tolerance to radiotherapy. Autophagy is an adaptive process by which cells damage due to radiation. As a metabolite of riboflavin, lumiflavin can enhance the chemotherapeutic effects of cisplatin on ovarian cancer CSCs.

Objective: This study aimed to investigate the synergistic effects of lumiflavin and ionising radiation on ovarian cancer CSCs and explore the association of this metabolite with autophagy.

Methods: CSCs of human ovarian cancer cell lines HO8910 were treated with lumiflavin and rapamycin and then subjected to irradiation at a cumulative dose of 8 Gy. Cell proliferation ability, clonal formation ability, apoptosis rate, autophagy changes and autophagy-related protein changes were detected.

Results: Lumiflavin and ionising radiation synergistically reduced cell vitality and clone formation and increased the apoptosis of CSCs compared with irradiation alone. In addition, ionising radiation increased autophagy and the expression of associated proteins, whereas lumiflavin reduced those changes in autophagy progression. Moreover, rapamycin, an autophagy inhibitor, was observed to block the synergistic effects of lumiflavin and ionising radiation on CSC apoptosis.

Conclusion: Lumiflavin can enhance the effects of ionising radiation on ovarian cancer CSCs. The mechanism by which these effects are exerted is related to blocking the autophagy pathway.

Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as a New Lead for Treating Breast and Ovarian Cancer

A serine/threonine-protein kinase, recognized as Glycogen Synthase Kinase-3 (GSK-3), is documented as a regulator of assorted cellular roles. GSK-3 activates by phosphorylation and thereby controls the action of many physiological, messenger, and membrane-bound structures. GSK-3α and GSK-3β are two vastly homologous forms of GSK-3 in mammals. Recent information has recommended that GSK-3β is a constructive controller of cancer cell proliferation and a promising key target against cancer cells. GSK-3 is overexpressed in various tumor types, including ovarian tumors. In human breast carcinoma, it has been revealed that the overexpression of GSK-3β was linked with breast cancer patients. The inhibition of GSK-3 or inhibitors of GSK-3 is a promising therapeutic tactic to overcome breast and ovarian cancer. This article features an important aspect of inhibitors of Glycogen Synthase Kinase-3 as a new lead for treating breast and ovarian Cancer.

Preclinical Studies of PROTACs in Hematological Malignancies

Incorrectly expressed or mutated proteins associated with hematologic malignancies have been generally targeted by chemotherapy using small-molecule inhibitors or monoclonal antibodies. But the majority of these intracellular proteins are without active sites and antigens. PROTACs, proteolysis targeting chimeras, are bifunctional molecules designed to polyubiquitinate and degrade specific pathological proteins of interest (POIs) by hijacking the activity of E3-ubiquitin ligases for POI polyubiquitination and subsequent degradation by the proteasome. This strategy utilizes the ubiquitin-proteasome system for the degradation of specific proteins in the cell. In many cases, including hematologic malignancies, inducing protein degradation as a therapeutic strategy offers therapeutic benefits over classical enzyme inhibition connected with resistance to inhibitors. Limitations of small-molecule inhibitors are shown. PROTACs can polyubiquitinate and mark for degradation of “undruggable“proteins, e.g. transcription factor STAT3 and scaffold proteins. Today, this technology is used in preclinical studies in various hematologic malignancies, mainly for targeting drug-resistant bromodomain and extraterminal proteins and Bruton tyrosine kinase. Several mechanisms limiting selectivity and safety of PROTAC molecules function are also discussed.

The Potential Use of RNA-based Therapeutics for Breast Cancer Treatment

Breast cancer is one of the most lethal cancers in women worldwide, and the development of efficient treatments faces several challenges. Breast cancer is characterized by histological and functional heterogeneity in aspects such as tumorigenesis, metastasis, and drug resistance. RNA therapy has emerged as a highly attractive class of drugs for the treatment and prevention of breast cancer. It might play remarkable regulatory roles in the treatment of targeted cells by either increasing or silencing expressions of specific proteins, and such features of RNA-based drugs cause high selectivity and low risk of off-target effect in breast cancer. RNA therapy exerts anti-proliferative and pro-apoptotic effects upon cell culture systems, animal models, and in clinical trials in most studies. In this mini-review, we outline the classifications, mechanisms, advantages, and challenges of RNA therapy and highlight its application in breast cancer treatment. Additionally, we summarize the clinical trials of RNA-targeting therapies and the development of anti-tumor RNA drugs and provide future directions for RNA therapeutics in breast cancer.

Neurokinin-1 Receptor (NK-1R) Antagonists: Potential Targets in the Treatment of Glioblastoma Multiforme

The current standard of care in glioblastoma multiforme (GBM), as the most morbid brain tumor, is not adequate, despite substantial progress in cancer therapy. Among patients receiving current standard treatments, including surgery, irradiation, and chemotherapy, the overall survival (OS) period with GBM is less than one year. The high mortality frequency of GBM is due to its aggressive nature, including accelerated growth, deregulated apoptosis, and invasion into surrounding tissues. The understanding of the molecular pathogenesis of GBM is, therefore, crucial for identifying, designing, and repurposing potential agents in future therapeutic approaches. In recent decades, it has been apparent that several neurotransmitters, specifically substance P (SP), an undecapeptide in the family of neuropeptides tachykinins, are found in astrocytes. After binding to the neurokinin-1 receptor (NK-1R), the SP controls cancer cell growth, exerts antiapoptotic impacts, stimulates cell invasion/metastasis, and activates vascularization. Since SP/NK-1R signaling pathway is a growth driver in many cancers, this potential mechanism is proposed as an additional target for treating GBM. Following an evaluation of the function of both SP and its NK-1R inhibitors in neoplastic cells, we recommend a unique and promising approach for the treatment of patients with GBM.

Cyclin-Dependent Kinase as a Novel Therapeutic Target: An Endless Story

Cyclin-Dependent Kinases (CDKs) are a family of enzymes that, along with their Cyclin partners, play a crucial role in cell cycle regulation at many biological functions such as proliferation, differentiation, DNA repair, and apoptosis. Thus, they are tightly regulated by a number of inhibitory and activating enzymes. Deregulation of these kinases’ activity either by amplification, overexpression or mutation of CDKs or Cyclins leads to uncontrolled proliferation of cancer cells. Hyperactivity of these kinases has been reported in a wide variety of human cancers. Hence, CDKs have been established as one of the most attractive pharmacological targets in the development of promising anticancer drugs. The elucidated structural features and the well-characterized molecular mechanisms of CDKs have been the guide in designing inhibitors to these kinases. Yet, they remain a challenging therapeutic class as they share conserved structure similarity in their active site. Several inhibitors have been discovered from natural sources or identified through high throughput screening and rational drug design approaches. Most of these inhibitors target the ATP binding pocket, therefore, they suffer from a number of limitations. Here, a growing number of ATP noncompetitive peptides and small molecules has been reported.

A Comprehensive Review on Cross-talk of Human Papilloma Virus Oncoproteins and Developmental/Self-Renewal Pathways During the Pathogenesis of Uterine Cervical Cancer

Cervical cancer, cancer arising from the uterine cervix, has been regarded as the fourth most frequent gynecological malignancy among females worldwide. Epidemiological reports have shown that uterine cervical cancer is a global health issue among women of especially developing countries and consequently creates an economic and medical burden in the society. The main causative agent of cervical carcinoma is high-risk human papilloma virus (HPV 16 and HPV 18). Molecular studies have revealed the expression of two viral genes E6 and E7, after HPV infection in the epithelial cells of the cervix. These gene products are known to inactivate the major tumor suppressors, p53 and retinoblastoma protein (pRB), respectively. Moreover, the role of self-renewal pathways, such as Hedgehog, Notch, and Wnt, has also been linked with drug resistance in cancer cells and epithelial mesenchymal transition during metastasis in the pathogenesis of cervical cancer. Although the mechanism of interaction of HPV E6 and E7 with each and every component of the above described developmental pathways is not elucidated yet, preliminary reports of their cross-talk have begun to emerge. Understanding the interplay between these oncoproteins and developmental/self-renewal pathways is highly important in terms of designing new and targeted therapeutic approaches against cervical cancer. Hence, this review cynosure the carcinogenesis of HPV with a brief description of its virology and also establishes the cross-talk between oncoproteins E6 and E7 and Hedgehog, Notch, and Wnt signaling pathway.

New Framework for the Discovery of PRC2 Inhibitors: Epigenetic Drugs

Over the past several years, remarkable progress towards the recognition of new therapeutic targets in tumor cells has led to the discovery and development of newer scaffolds of anti-tumor drugs. The exploration and exploitation of epigenetic regulation in tumor cells are of immense importance to both the pharmaceutical and academic biomedical literatures. Epigenetic mechanisms are indispensable for the normal development and maintenance of tissue-specific gene expression. Disruption of epigenetic processes to eradicate tumor cells is among the most promising intervention for cancer control. Polycomb repressive complex 2 (PRC2), a complex that methylates lysine 27 of histone H3 to promote transcriptional silencing, is involved in orchestrating significant pathways in a cell. Overexpression of PRC2 has been found in a number of cancerous malignancies, making it a major target for anti-cancer therapy. Despite its well-understood molecular mechanism, hyperactivation and drug resistance mutations in its subunits have become a matter of discussion. This review outlines the current understanding of the components of PRC2 in active complex formation and assesses their potential as a promising therapeutic target for cancer therapy. We also review the effects of mutations in the PRC2 components, in the purview of human cancers. Finally, we discuss some of the current challenges for therapeutic drug designs targeting the PRC2 complex.

The Mad2-Binding Protein p31^comet as a Potential Target for Human Cancer Therapy

The spindle assembly checkpoint (SAC) is a surveillance mechanism that prevents mitotic exit at the metaphase-to-anaphase transition until all chromosomes have established correct bipolar attachment to spindle microtubules. Activation of SAC relies on the assembly of the mitotic checkpoint complex (MCC), which requires conformational change from inactive open Mad2 (OMad2) to the active closed Mad2 (C-Mad2) at unattached kinetochores. The Mad2-binding protein p31^comet plays a key role in controlling timely mitotic exit by promoting SAC silencing, through preventing Mad2 activation and promoting MCC disassembly. Besides, increasing evidences highlight the p31^comet potential as target for cancer therapy. Here, we provide an updated overview of the functional significance of p31^comet in mitotic progression, and discuss the potential of deregulated expression of p31^comet in cancer and in therapeutic strategies.

Functional Role of Glycosphingolipids in Cancer

Glycosphingolipids (GSLs) are ubiquitous components on animal cell membranes, and exposed on the outer surface. Various studies have demonstrated that they play key roles in cell proliferation, adhesion, motility and differentiation. Usually, the specific types of GSLs are expressed more highly in tumors than in normal tissues, which are known as tumorassociated antigens. It has been revealed that most tumor cells show altered GSLs patterns on their surface, abnormal GSLs signaling and biosynthesis, which together play a major role in tumor development. Tumor-associated GSL antigens have been used in the development of antitumor vaccines. There is no doubt that GSLs play a crucial role in tumor progression and would be a promising target for cancer treatment.

Evolution and Structure of API5 and Its Roles in Anti-Apoptosis

Apoptosis, also named programmed cell death, is a highly conserved physiological mechanism. Apoptosis plays crucial roles in many life processes, such as tissue development, organ formation, homeostasis maintenance, resistance against external aggression, and immune responses. Apoptosis is regulated by many genes, among which Apoptosis Inhibitor-5 (API5) is an effective inhibitor, though the structure of API5 is completely different from the other known Inhibitors of Apoptosis Proteins (IAPs). Due to its high expression in many types of tumors, API5 has received extensive attention, and may be an effective target for cancer treatment. In order to comprehensively and systematically understand the biological roles of API5, we summarized the evolution and structure of API5 and its roles in anti-apoptosis in this review.

Liposomes as Versatile Platform for Cancer Theranostics: Therapy, Bio-imaging, and Toxicological Aspects

Liposomes are nano-sized formulations having the benefits of site-specificity, biocompatibility, and biodegradability, which make them useful for the therapy and diagnosis of major diseases like cancer. In this review, various synthetic strategies of liposomes and their biomedical application in special concern to cancer are discussed. In context to the biomedical application, this article gives a detailed insight into subcellular targeted therapy and several therapeutic modifications like immunotherapy, receptor-based therapy, phototherapy, and combination therapy. The review also describes the liposome-based imaging platforms and the toxicity associated with liposomes. Owing to a significant amount of benefits of this carrier system, several products have been approved to be launched in the market and several others have already been marketed for clinical use.

Molecular Biomarkers for Lung Adenocarcinoma: A Short Review

Lung cancer is a disease with higher death rates and is responsible for around 2 million deaths per year worldwide. Recently, several breakthroughs have been made in the field of lung cancer that has led to a revolution in the management of lung cancer patients. Identification of molecular markers and the implication of respective targeted therapies has been a great success in the treatment of lung adenocarcinoma patients. Despite the fact that targeted therapy of lung adenocarcinomas represents one of the significant milestones in the treatment of lung cancer that resulted in increased survival rates even in advanced stages, the mortality rates of lung cancer still remain to be significantly high. This warrants further research for gaining better insights into molecular alterations that can lead to newer innovations in targeted drug therapy towards lung adenocarcinoma. In this review, we briefly summarized the literature on molecular markers that are already in use. We also consolidated newer molecular markers that are under study with the potential for being targeted for therapies in future.

Role of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Different Disease States: Recent Updates

Peroxisome proliferator-activated receptor (PPAR), a ligand dependant transcription factor, is a member of the nuclear receptor superfamily. PPAR exists in three isoforms i.e. PPAR alpha (PPARα), PPAR beta (PPARβ), and PPAR gamma (PPARγ). These are multi-functional transcription factors and help in regulating inflammation, type 2 diabetes, lipid concentration in the body, metastasis, and tumor growth or angiogenesis. Activation of PPARγ causes inhibition of growth of cultured human breast, gastric, lung, prostate, and other cancer cells. PPARγ is mainly involved in fatty acid storage, glucose metabolism, and homeostasis and adipogenesis regulation. A large number of natural and synthetic ligands bind to PPARγ and modulate its activity. Ligands such as thiazolidinedione, troglitazone, rosiglitazone, pioglitazone effectively bind to PPARγ; however, most of these were found to display severe side effects such as hepatotoxicity, weight gain, cardiovascular complications and bladder tumor. Now the focus is shifted towards the development of dual-acting or pan PPAR ligands. The current review article describes the functions and role of PPARγ in various disease states. In addition, recently reported PPARγ ligands and pan PPAR ligands were discussed in detail. It is envisaged that the present review article may help in the development of potent PPAR ligands with no or minimal side effects.

A Comprehensive Overview of Colon Cancer- A Grim Reaper of the 21st Century

A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

Background: Curcumin, an active compound of turmeric spice, is one of the most-studied natural compounds and has been widely recognized as a chemopreventive agent. Several molecular mechanisms have proven that curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as in the inhibition of the carcinogenesis process.

Objective: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents.

Methods: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed Central, and Google scholar for the implication of curcumin in cancer management, along with a special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com, and www.freshpatents.com.

Result: Recent studies based on cancer cells have proven that curcumin has potential effects against cancer cells as it prevents the growth of cancer and acts as a cancer therapeutic agent. Besides, curcumin exerted anti-cancer effects by inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion, and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells.

Conclusion: Accumulating evidences suggest that curcumin has the potential to inhibit cancer growth, induce apoptosis, and modulate various cell signaling pathway molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy, and safe dose in the management of various cancers.

Computational Analysis of Domains Vulnerable to HPV-16 E6 Oncoprotein and Corresponding Hot Spot Residues

Background: Human Papilloma Virus (HPV) is the primary cause of cancers in cervix, head and neck regions. Oncoprotein E6 of HPV-16, after infecting human body, alters host protein- protein interaction networks. E6 interacts with several proteins, causing the infection to progress into cervical cancer. The molecular basis for these interactions is the presence of short linear peptide motifs on E6 identical to those on human proteins.

Methods: Motifs of LXXLL and E/DLLL/V-G after identification on E6, were analyzed for their dynamic fluctuations by use of elastic network models. Correlation analysis of amino acid residues of E6 was also performed in specific regions of motifs.

Results: Arginine, Leucine, Glutamine, Threonine and Glutamic acid have been identified as hot spot residues of E6 which can subsequently provide a platform for drug designing and understanding of pathogenesis of cervical cancer. These amino acids play a significant role in stabilizing interactions with host proteins, ultimately causing infections and cancers.

Conclusion: Our study validates the role of linear binding motifs of E6 of HPV in interacting with these proteins as an important event in the propagation of HPV in human cells and its transformation into cervical cancer. The study further predicts the domains of protein kinase and armadillo as part of the regions involved in the interaction of E6AP, Paxillin and TNF R1, with viral E6.

Activation of Myosin Phosphatase by Epigallocatechin-Gallate Sensitizes THP-1 Leukemic Cells to Daunorubicin

Background: The Myosin Phosphatase (MP) holoenzyme is composed of a Protein Phosphatase type 1 (PP1) catalytic subunit and a regulatory subunit termed Myosin Phosphatase Target subunit 1 (MYPT1). Besides dephosphorylation of myosin, MP has been implicated in the control of cell proliferation via dephosphorylation and activation of the tumor suppressor gene products, retinoblastoma protein (pRb) and merlin. Inhibition of MP was shown to attenuate the drug-induced cell death of leukemic cells by chemotherapeutic agents, while activation of MP might have a sensitizing effect.

Objective: Recently, Epigallocatechin-Gallate (EGCG), a major component of green tea, was shown to activate MP by inducing the dephosphorylation of MYPT1 at phospho-Thr696 (MYPT1^pT696), which might confer enhanced chemosensitivity to cancer cells.

Methods: THP-1 leukemic cells were treated with EGCG and Daunorubicin (DNR) and cell viability was analyzed. Phosphorylation of tumor suppressor proteins was detected by Western blotting.

Results: EGCG or DNR (at sub-lethal doses) alone had moderate effects on cell viability, while the combined treatment caused a significant decrease in the number of viable cells by enhancing apoptosis and decreasing proliferation. EGCG plus DNR decreased the phosphorylation level of MYPT1^pT696, which was accompanied by prominent dephosphorylation of pRb. In addition, significant dephosphorylation of merlin was observed when EGCG and DNR were applied together.

Conclusion: Our results suggest that EGCG-induced activation of MP might have a regulatory function in mediating the chemosensitivity of leukemic cells via dephosphorylation of tumor suppressor proteins.

Cervical Cancer Diagnosis: Insights into Biochemical Biomarkers and Imaging Techniques

Cervical malignancy is known as one of the important cancers which is originated from cervix. This malignancy has been observed in women infected with papillomavirus who had regular oral contraceptives, multiple pregnancies, and sexual relations. Early and fast cervical cancer diagnosis is known as two important aspects of cervical cancer therapy. Several investigations indicated that early and fast detection of cervical cancer could be associated with better treatment process and increasing survival rate of patients with this malignancy. Imaging techniques are very important diagnosis tools that could be employed for diagnosis and following responses to therapy in various cervical cancer stages. Multiple lines of evidence indicated that utilization of imaging techniques is related to some limitations (i.e. high cost, and invasive effects). Hence, it seems that along with using imaging techniques, finding and developing new biomarkers could be useful in the diagnosis and treatment of subjects with cervical cancer. Taken together, many studies showed that a variety of biomarkers including, several proteins, mRNAs, microRNAs, exosomes and polymorphisms might be introduced as prognostic, diagnostic and therapeutic biomarkers in cervical cancer therapy. In this review article, we highlighted imaging techniques as well as novel biomarkers for the diagnosis of cervical cancer.

Analysis of Codon Usage Patterns in the Human Papillomavirus Oncogenes

Background: Persistent high-risk genital human papillomavirus (HPV) infection is a major cause of cervical cancer in women. The products of the viral transforming genes E6 and E7 in the high-risk HPVs are known to be similar in their amino acid composition and structure. We performed a comparative analysis of codon usage patterns in the E6 and E7 genes of HPVs.

Methods: The E6 and E7 gene sequences of eight HPV subtypes were analyzed to determine their nucleotide composition, relative synonymous codon usage (RSCU), effective number of codons (ENC), neutrality, genetic variability, selection pressure, and codon adaptation index (CAI). Additionally, a correspondence analysis (CoA) was performed.

Results: The analysis to determine the effects of differences in composition on the codon usage patterns revealed that there might be usage bias for ‘A’ nucleotides. This was consistent with the results of the RSCU analysis, which demonstrated that the selection of A/T-rich patterns and the preference for A/T-ended codons in HPVs are influenced by compositional constraints. Moreover, the results reveal that selection pressure plays an important role in the CoA results for the RSCU values, Tajima’s D tests, and neutrality tests.

Conclusion: The results of this study are consistent with previous findings that most papillomavirus genes are under purifying selection pressure, which limits changes to the encoded proteins. Natural selection and mutation pressures resulting in changes in the nucleotide composition and codon usage bias in the two tumor genes of HPV act differently during the evolution of the HPV subtype; thus, throughout the viral life cycle, HPV can constantly evolve to adapt to a new environment.

Stem Cells: In Sickness and in Health

Abstract: Stem cells are undifferentiated cells with the ability to proliferate and convert to different types of differentiated cells that make up the various tissues and organs in the body. They exist both in embryos as pluripotent stem cells that can differentiate into the three germ layers and as multipotent or unipotent stem cells in adult tissues to aid in repair and homeostasis. Perturbations in these cells’ normal functions can give rise to a wide variety of diseases. In this review, we discuss the origin of different stem cell types, their properties and characteristics, their role in tissue homeostasis, current research, and their potential applications in various life-threatening diseases. We focus on neural stem cells, their role in neurogenesis and how they can be exploited to treat diseases of the brain including neurodegenerative diseases and cancer. Next, we explore current research in Induced Pluripotent Stem Cells (iPSC) techniques and their clinical applications in regenerative and personalized medicine. Lastly, we tackle a special type of stem cells called Cancer Stem Cells (CSCs) and how they can be responsible for therapy resistance and tumor recurrence and explore ways to target them.

Potential of Photobiomodulation to Induce Differentiation of Adipose- Derived Mesenchymal Stem Cells into Neural Cells

Background: Given the minimal capacity and sometimes the failure of the mammalian nervous system to regenerate and repair itself after damage, strategies are required to help enhance this regenerative process. Adipose-derived Mesenchymal Stem Cells (ADMSCs) are likely candidates to assist in the recovery process due to their ability to differentiate into neural cells. Successful implementation of this intervention in a clinical setting would increase the rate of recovery following traumatic brain injury.

Review: Various strategies have been attempted to differentiate ADMSCs into neural cells for clinical use. Such methods have not been entirely successful in the development of functioning specialized cells for subsequent practical use. Therefore, the implementations of this differentiation technique in the clinical trial have not been effective. In this article, the potential of differentiating ADMSCs into neural cells and the various methods employed, including biological induction, chemical induction and photobiomodulation (PBM) will be discussed, where the combined use of transducers and PBM for neural differentiation of ADMSCs is also deliberated.

Conclusion: PBM shows promise as an avenue for effective ADMSCs differentiation into neural cells and their proliferation. Applying PBM with optimized biological factors and chemical inducers may prove to be an effective tool for clinical application.