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Background: This study aims to formulate and characterize sorafenib-loaded resealed erythrocytes (SoRE) and investigate their anticancer activity in a rat model of hepatocellular carcinoma. Methods: SoRE were prepared by hypotonic dialysis of red blood cells obtained from Wistar rats using a range of drug-containing dialysis mediums (2-10 mg/ml) and osmosis time (30-240 mins). Optimized SoRE (8 mg/mL and 240 mins) were characterized for size, morphology, stability, entrapment efficiency, in vitro release profiles, and in vivo efficacy evaluations. For efficacy studies, optimized SoRE were intravenously administered to Wistar rats having hepatocellular lesions induced by aflatoxin B and monitored for in vivo antineoplastic activity. Results: The amount of sorafenib entrapped was directly proportional to the drug concentration in the dialysis medium and duration of osmosis; highest for 10 mg/mL and 240 minutes and lowest for 2 mg/mL and 30 minutes, respectively. Optimized SoRE were biconcave with a size of 112.7 nm and zeta potential of -11.95 ± 2.25 mV. Osmotic and turbulence fragility were comparable with native erythrocytes. Conclusion: Drug release follows the first-order pattern. In vivo investigations reveal better anticancer activity of SoRE formulation compared to sorafenib standard preparation. Resealed erythrocytes loaded with sorafenib displayed first-order in vitro release and promising anticancer activity in a rat model of hepatocellular carcinoma.

Abstract: Elabela, a bioactive micropeptide, is recognized as the second endogenous ligand for Apelin receptor and is widely distributed in different tissues and organs. Elabela plays important role in various physiological processes such blood pressure control, heart morphogenesis, apoptosis, angiogenesis, cell proliferation, migration, etc. Elabela is also implicated in pathological conditions like cardiac dysfunctions, heart failure, hypertension, kidney diseases, cancer and CNS disorders. The association of Elabela with these disease conditions makes it a potential target for their therapy. This review summarizes physiological role of Elabela peptide as well as its implication in various disease conditions.

The plasma membrane of eukaryotic cells contains small flask-shaped invaginations known as caveolae that are involved in the regulation of cellular signaling. Caveolin-1 is a 21-24k- Da protein localized in the caveolar membrane. Caveolin-1 (Cav-1) has been considered as a master regulator among the various signaling molecules. It has been emerging as a chief protein regulating cellular events associated with homeostasis, caveolae formation, and caveolae trafficking. In addition to the physiological role of cav-1, it has a complex role in the progression of various diseases. Caveolin-1 has been identified as a prognosticator in patients with cancer and has a dual role in tumorigenesis. The expression of Cav-1 in hippocampal neurons and synapses is related to neurodegeneration, cognitive decline, and aging. Despite the ubiquitous association of caveolin-1 in various pathological processes, the mechanisms associated with these events are still unclear. Caveolin- 1 has a significant role in various events of the viral cycle, such as viral entry. This review will summarize the role of cav-1 in the development of cancer, neurodegeneration, glaucoma, cardiovascular diseases, and infectious diseases. The therapeutic perspectives involving clinical applications of Caveolin-1 have also been discussed. The understanding of the involvement of caveolin-1 in various diseased states provides insights into how it can be explored as a novel therapeutic target.

Despite various treatments available, there is still a high mortality rate in breast cancer patients. Thus, there exists an unmet need for new therapeutic interventions. Studies show that the Wnt/β-catenin signaling pathway is involved in breast cancer metastasis because of its transcriptional control on epithelial to mesenchymal transition.This comprehensive review explores the Wnt signaling pathway as a potential target for treating breast cancer and other breast cancer subtypes. We discuss the Wnt signaling pathway, its role in breast cancer metastasis, and its effect on breast cancer stem cells. Further, endogenous agents that cause Wnt pathway inactivation are outlined. Finally, various natural and chemical compounds modulating the Wnt pathway used in pre-clinical or clinical trials for breast cancer treatment are discussed.

Objective: The objective of this study was to develop and optimize a microflora-triggered colon targeted sustained-release dosage form using Gum Ghatti (GG) and Hydroxypropyl Methylcellulose (HPMC K100). Methods: GG and HPMC K100 were used to prepare microflora triggered colon targeted sustained- release dosage form. For evaluation, two different tablets comprising metoprolol succinate and mesalamine as an active ingredient were used with the objective of developing a platform technology for various categories of drugs. The tablets were coated with Eudragit® L100 and Eudragit® S100 to provide enteric coating and evaluated for hardness, thickness, friability, weight variation, disintegration, and drug content. in vitro release studies for the prepared tablets were carried out mimicking the physiological transit time. Further, the effects of microflora were evaluated using rat cecal content. Results: The in vitro dissolution profile of coated matrix tablets showed that 86.03±0.43% of metoprolol succinate and 80.26±0.67% of mesalamine were released at the end of 12 h. The ex vivo dissolution profile of coated matrix tablets showed that 96.50±0.27% of metoprolol succinate and 92.58±0.39% of mesalamine were released at the end of 12 h in the presence of rat ceacal content. The developed formulation was stable when subjected to the standard ICH stability study conditions. Conclusion: The result of this study showed that gum ghatti together with hydroxypropyl methylcellulose could be successfully used for the preparation of microflora-triggered colon targeted matrix tablets.

The ubiquitin-proteasome pathway is responsible for the turnover of different cellular proteins, such as transport proteins, presentation of antigens to the immune system, control of the cell cycle, and activities that promote cancer. The enzymes which remove ubiquitin, deubiquitylating enzymes (DUBs), play a critical role in central and peripheral immune tolerance to prevent the development of autoimmune diseases and thus present a potential therapeutic target for the treatment of autoimmune diseases. DUBs function by removing ubiquitin(s) from target protein and block ubiquitin chain elongation. The addition and removal of ubiquitin molecules have a significant impact on immune responses. DUBs and E3 ligases both specifically cleave target protein and modulate protein activity and expression. The balance between ubiquitylation and deubiquitylation modulates protein levels and also protein interactions. Dysregulation of the ubiquitin-proteasome pathway results in the development of various autoimmune diseases such as inflammatory bowel diseases (IBD), psoriasis, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This review summarizes the current understanding of ubiquitination in autoimmune diseases and focuses on various DUBs responsible for the progression of autoimmune diseases.

Colorectal carcinogenesis involves various processes from the accumulation of genetic alterations to genetic and epigenetic modulations and chromosomal abnormalities. It also involves mutations in oncogenes and tumour suppressor genes. Genomic instability plays a vital role in CRC. Advances in modern biological techniques and molecular level studies have identified various genes involved in colorectal cancer (CRC). KRAS, BRAF, PI3K, and p53 genes play a significant role in different phases of CRC. Alteration of these genes leads to development or progression and metastasis colon cancer. This review focuses on the role of KRAS, BRAF, PI3KCA, and TP53 genes in carcinogenesis and their significance in various stages of CRC. It also provides insights on specific modulators acting on these genes. Further, this review discusses the mechanism of the pathways involving these genes in carcinogenesis and current molecules and treatment options under various stages of clinical evaluation.

Hypertrophic cardiomyopathy is a major cause of mortality worldwide. In this study, we hypothesized that the combination of Dantrolene and Polymyxin-B will provide cardioprotective action against isoproterenol-induced hypertrophic cardiomyopathy via attenuation of Calmodulin-dependent protein kinase II (CaMKII). Hypertrophic cardiomyopathy was induced in rats by subcutaneous administration of isoproterenol (5 mg/kg) for 14 days. Simultaneously, animals were treated with Polymyxin-B per se, Dantrolene per se, and Dantrolene and Polymyxin-B combination for 14 days. Hemodynamic parameters, biochemical parameters, and histological analysis were performed. Administration of isoproterenol for 14 days resulted in severe myocardial damage, characterized by cardiac hypertrophy and increase serum CK-MB, CK-Nac, LDH, AST, and ALT levels. It also caused alteration in electrocardiogram and blood pressure. A significant increase in CaMKII was observed in heart homogenate. Treatment with the Polymyxin-B and Dantrolene combination significantly ameliorated cardiac hypertrophy, biochemical parameters, ECG parameters, and heart histopathology. Further, significant attenuation in CaMKII levels was observed. The effect of the combination was more than per se treatment. Results of the current study showed that the combination of Polymyxin-B and Dantrolene prevented the development of isoproterenol-induced hypertrophic cardiomyopathy in rats via attenuation of the CaMKII.

Pneumonia of unknown etiology was detected in a few patients in Wuhan City, Hubei Province, China. The causative agent was named as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the World Health Organization (WHO). The disease caused by this virus was named as a new coronavirus disease: COVID-19. The disease has a global impact affecting more than 200 nations including the USA, India, Brazil, Russia, and Peru are the 5 most severely affected nations. The discovery of the genotype and phenotype of SARS-CoV-2 boosted the global efforts for the development of treatment options and vaccines for the COVID-19. As the transmission of the virus is rapid, to protect the global population, the development of an effective vaccine against the virus is very essential. The current review highlights the various platforms and technologies used globally for the development of the vaccine and also focuses on the current status of the vaccine candidates under development by organizations to combat the global threat of COVID-19 pandemic.

Abstract: Gasdermins are novel pore forming proteins that comprise Gasdermin A, Gasdermin B, Gasdermin C, Gasdermin D, Gasdermin E and Pejvakin (DFNB59). Recently, pyroptosis has been redefined as "Gasdermin mediated necrosis", as gasdermins are key regulators of apoptosis, necrosis, and pyroptosis. The discovery of the gasdermin family has broadened the field of pyroptosis studies. Studies have correlated gasdermins with several diseases. This review summarizes the physiological roles and signal transduction of gasdermins. It further highlights the role of gasdermins in pathological conditions like autoimmune disease, kidney diseases, and central nervous system diseases.

Objective: Ischemic stroke is one of the leading causes of disability in adults worldwide. The present study was aimed to evaluate the efficacy of Narirutin-rich fraction (NRF), obtained from grape...

Treatment of osteochondral defects continues to pose a major challenge for patients and orthopedic surgeons due to the limited healing potential of articular cartilage. Mesenchymal stem cells (MSCs) possess therapeutic potential for the treatment of osteochondral pain and pathology. However, it is necessary to use proper labeling and imaging agent of stem cells that can decipher its role posttransplantation. A major limitation of routinely used contrast agents is signal dilution over a period of time which limits its use for further studies. At the same time, regeneration of fibrocartilage over native hyaline cartilage also limits the use of conventional therapies. The present study evaluates the efficacy of bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of osteochondral defect in rats with the regeneration of hyaline cartilage in situ and in vivo monitoring of the stem cells using L-lysine functionalized magnetic iron oxide nanoparticles (lys-IONPs). L-lysine stabilizes the iron oxide nanoparticles, enhances the biocompatibility, and provides functionalities for efficient stem cell labeling. in vitro toxic effects of lys-IONPs on mitochondrial impairment, morphological alterations, and actin cytoskeleton reveal minimum damage to BM-MSCs. Histological data (H and E, Masson's trichrome and immunohistochemistry) describe the early initiation of healing and regeneration of hyaline-like cartilage over fibrocartilage in stem cell treated groups. MR scans demonstrate generation of hypointense signals in lys-IONPs-BMSCs with improved signal intensity and minimum loss over 28 days revealing its use as a long-term stem cell labeling and imaging agent.

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

Bromodomains are a group of structurally diverse proteins characterized as readers of post-translational modifications. They bear unique structural topology and are known to have diverse cellular functions. As epigenetic readers of histone acetylation, bromodomains appear to have both physiological and pathological implications. Among the various types of bromodomain-containing proteins, BRD2 and BRD4 proteins are expressed ubiquitously and act as critical regulators of the cell cycle in normal mammalian cells. Therefore, they are increasingly involved in the process of oncogenesis. Bromodomains are the emerging novel epigenetic targets for the treatment of cancer. Various small molecules are proposed to target the bromodomain proteins as the readers of acetyl-lysine residues. In recent years, inhibiting the interaction of acetyl-lysine residues and bromodomain proteins on chromatin has served as an interesting target to regulate the expression of various pathological genes, including BCL-2, MYC, and NF-κB. The review summarizes bromodomains as potential targets in cancer and various bromodomain inhibitors in the early stages of the clinical trial.

Introduction SARS-CoV-2, the causative agent of COVID-19, attacks the immune system causing an exaggerated and uncontrolled release of pro-inflammatory mediators (cytokine storm). Recent studies propose an active role of coagulation disorders in disease progression. This hypercoagulability has been displayed by marked increase in D-dimer in hospitalized patients. Areas Covered This review summarizes the pathogenesis of SARS-CoV-2 infection, generation of cytokine storm, the interdependence between inflammation and coagulation, its consequences and the possible management options for coagulation complications like venous thromboembolism (VTE), microthrombosis, disseminated intravascular coagulation (DIC), and systemic and local coagulopathy. We searched PubMed, Scopus, and Google Scholar for relevant reports using COVID-19, cytokine storm, and coagulation as keywords. Expert Opinion A prophylactic dose of 5000–7500 units of low molecular weight heparin (LMWH) has been recommended for hospitalized COVID-19 patients in order to prevent VTE. Treatment dose of LMWH, based on disease severity, is being contemplated for patients showing a marked rise in levels of D-dimer due to possible pulmonary thrombi. Additionally, targeting PAR-1, thrombin, coagulation factor Xa and the complement system may be potentially useful in reducing SARS-CoV-2 infection induced lung injury, microvascular thrombosis, VTE and related outcomes like DIC and multi-organ failure.

sarco-endoplasmic reticulum Ca-ATPase (SERCA) is the major transporter present in sarco-endoplasmic reticulum (SR/ER), transporting calcium back into SR/ER from cytosol. The calcium-sequestering activity of SERCA facilitates relaxation in both cardiac and skeletal tissue. ER stress is one of the etiological factors in various diseases such as neurodegenerative diseases and diabetes. Disrupted calcium handling can cause ER stress. In the cardiac tissue, impairment of systolic and diastolic function can cause various cardiovascular diseases. SERCA ensures the proper calcium handling in cells and may act as a therapeutic target for the disease associated with dysregulation of calcium ions. This review examines the principle of calcium ion handling through SERCA and its role in various diseases.

Despite incessant research, colon cancer still is one of the most common causes of fatalities in both men and women worldwide. Also, nearly 50% of patients with colorectal cancer show tumor recurrence. Recent investigations have highlighted the involvement of colon cancer stem cells (CCSCs) in cancer relapse and chemoresistance. CCSCs deliver a significant protumorigenic niche through persistent overexpression of self-renewal capabilities. Moreover, CSCs cross network with stromal cells, immune infiltrates, and cyotokine-chemokine, which potentiate their aggressive proliferative potential. Targeting CCSCs through small molecule inhibitors, miRNAs, and monoclonal antibodies (mAbs) in in vivo studies has generated compelling evidence for the effectiveness of these various treatments. This review effectively compiles the role of CCSC surface markers and dysregulated and/or upregulated pathways in the pathogenesis of colorectal cancer that can be used to target CCSCs for effective colorectal cancer treatment.

Introduction Heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) chaperones are indispensable to lung cancer cells for their survival and proliferation. In this study we evaluated and compared anticancer potential of methylene blue (MB) as an Hsp70 inhibitor, novobiocin (NB) a well-known Hsp90 inhibitor and their combination. Methods In vitro evaluation was done by cell viability assays, fluorescent staining, and flow cytometry analysis using A549 non-small cell lung cancer cells. In vivo anticancer activity was investigated by evaluating oxidative stress, tumor biomarkers, weight, lung microarchitecture, and Hsp70 and Hsp90 inhibitions via immunoblotting in benzo[a]pyrene induced lung carcinogenesis mice model. Results Using A549 NSCLC cells, we found MB demonstrated lower cell viability versus NB. Together, MB + NB resulted in further decrease in cell viability. SRB assay revealed significantly superior and similar potency for MB versus NB and MB + NB (1:1) versus MB, respectively. Fluorescent staining and flow cytometry analysis displayed early apoptosis by MB (11.4%); early and late apoptosis by MB + NB (13.8%). In vivo, MB significantly inhibited Hsp70. Furthermore, MB significantly alleviated tumor biomarkers (ADA and LDH) and improved lung histopathological features more than NB. Additionally, MB significantly improved SOD, not more than MB + NB or NB and improved LPO. Conclusion MB demonstrated potent anticancer activity in vitro and in vivo via inhibition of Hsp70 in benzo[a]pyrene induced lung carcinogenesis in mice.

Despite the availability of various medications and prescribing combination therapies, uncontrolled blood pressure and resistance are observed in more than 40% of patients. The purpose of this review is to discuss emerging novel approaches for the treatment of hypertension and propose future research and clinical directions. Hypertension is a common disease of the cardiovascular system which may arise solely or as a comorbidity of other disorders. It is a crucial risk factor for cardiovascular diseases such as coronary artery disease, myocardial infarction, congestive heart failure, renal failure, and stroke. The results from current literature regarding the novel approaches showed several targets that could be explored as potential therapeutic options. These include toll-like receptor 4, a critical regulator of angiotensin II–induced hypertension; protease-activated receptor 2, which promotes collagen deposition and inflammatory responses; chemerin, which causes metabolic and obesity-associated hypertension; apelin receptor; transient receptor potential melastatin; urotensin-II; and Tie2 receptor. This review discusses various targets and pathways that could be emerging pharmacological therapies for hypertension.

Rheumatoid arthritis is a complex disorder that is characterized by irreversible and progressive destructions of joints, but its exact etiology remains mainly unknown. The occurrence and the progression of the disease entirely depend on environmental and genetic factors. In recent years, various epigenetic changes involving DNA methylation, histone modification, miRNA, X-chromosome inactivation, bromodomain, sirtuin, and many others were identified that were found to be linked to the activation and the aggressive phenotype in rheumatoid arthritis. Epigenetics is found to be one of the root causes, which brings changes in the heritable phenotype and is not determined by changes in the DNA sequences and understanding these epigenetic mechanisms and the pathogenesis of the disease can help in understanding the disease and various other possible ways for its control and/or prevention. The various epigenetic modification occurring are reversible and can be modulated by drugs, diet, and environmental factors. This article focuses on various epigenetic factors involved in the pathogenesis of rheumatoid arthritis. Further, various epigenetic therapies that might be successful in inhibiting these epigenetic modifications are summarized. Several therapeutic agents alter the epigenetic modifications occurring in various diseases and many of the epigenetic therapies are under pre-clinical and clinical trial. However, exploring these epigenetic prognostic biomarkers would give a broader perspective and provide more ideas and knowledge regarding the process and pathways through which the diseases occur, and also combining various therapeutic agents would show more beneficial and synergistic effects.

Colorectal cancer is the third most common cancer in the world, affecting both men and women, and it is one of the leading causes of cancer related deaths worldwide. Current treatment modalities employed for colorectal cancer management have their own share of drawbacks, such as toxicity due to nonspecific action and chemoresistance that may develop during treatment. The quest and pursuit for newer drugs which can overcome these drawbacks has led to extensive research on plant derived phytoconstituents. Herbal molecules are known to have promising therapeutic efficacy and less toxicity as compared to the current chemotherapeutic drugs of allopathic regimen. However most of these herbal molecules have low bioavailability as a result their therapeutic efficacy gets compromised. Integration of modern delivery approaches with these herbal molecules and presenting them in the form of nanocarriers will help alleviate these drawbacks. This review describes herbal drugs that have potential for treatment of colorectal cancer and nanotechnology strategies widely investigated for the delivery of these herbal molecules. Targeted delivery methods include use of such components as polymeric nanoparticles, liposomes, dendrimers, magnetic nanoparticles, solid lipid nanoparticles, and nanoemulsions. The paper also discusses in detail the formulation aspects of herbal nanocarriers, their design development, and preclinical assessment.

Epilepsy is a neurological disorder that affects almost 70 million people worldwide of all socioeconomic groups. The currently available medications aim to restore the balance between excitatory and inhibitory neurotransmitters by acting on ion channels, receptors, transporters, and enzymes, thus providing symptomatic relief. Though most of the patients receive a lasting remission however, 30% of patients are still pharmacoresistant. The incidence of adverse effects and associated comorbidities are also common. To overcome these challenges, researchers are focusing on the development of drugs based on novel targets and signaling cascades. This review summarizes several experimental findings that could be explored to identify potential targets for anti-epileptic drug discovery.

Enicostema littorale blume (A. Raynal) is a traditional Indian plant belongs to the Gentianaceae family. A lot of research has been done on this plant for its antidiabetic activity. However, there are no reports on flavonoids from E. littorale for its antidiabetic activity and their mechanism of action. Thus, the aim of this study is to evaluate the antidiabetic activity of Swertisin rich flavonoid fraction (SRF) from Enicostema littorale blume and their mechanism of action.Type 2 Diabetes Mellitus rat model was established by inducing insulin resistance using high fat diet and low dose of streptozotacin injection and was authenticated by HOMA index. The antidiabetic effect of SRF was evaluated on diabetic rats to investigate its long term effects on fasting blood glucose, OGTT, weight of rats, insulin, liver profile, lipid profile, kidney profile, histopathology of liver and pancreas. In addition, antioxidant activity by lipid peroxidation and catalase assay, ex vivo assays and hepatic glycogen content were performed to determine its effect on glycogenesis and hepatic glucose production. Furthermore, the mechanism of action of SRF was evaluated by Real time PCR and the mRNA expression was quantified for Glucokinase (GCK), Insulin receptor substrate (IRS-1), Glucose transporter-2 (GLUT-2) and Glucose transporter-4 (GLUT-4) genes.Treatment of diabetic rats with SRF demonstrated significant (p0.0001) dose dependant hypoglycemic activity as compared to positive control metformin group. A decrease in liver, lipid and kidney function tests was seen as compared to diabetic control indicating normalization of organ function tests. Also, antioxidant activity showed significant decrease in malondialdehyde (MDA) content in liver (p0.001) as compared to pancreas and increased catalytic activity in liver, kidney, spleen and pancreas. The hepatic glycogen content was significantly (p0.001) increased in SRF treated rats indicating its inhibition of hepatic glucose production. Furthermore, ex vivo assays showed the significant (p0.05) increase in glucose uptake by diaphragm. The mRNA expression for GCK, IRS-1, GLUT-2 and GLUT-4 genes showed significant up regulation as compared to diabetic control indicating its mechanism via insulin signalling pathway.The studies suggest that SRF ameliorates the insulin resistance by increasing glucose uptake and sensitizing cells towards insulin via IRS1/PI3K/Akt2 pathway.

Seizures are serious neurological disorders affecting nearly 50 million people worldwide. Seizures are characterized by abnormal, repetitive and synchronised firing of the neurons which is produced as a result of imbalance in the levels of the excitatory and inhibitory neurotransmitters. Neuropeptides are found to regulate seizures by rectifying this imbalance. These neuropeptides are stored in the dense core synaptic vesicles, and are released on excitation. This review focuses on certain neuropeptides which can alleviate both, the effects of seizures as well as epileptogenesis. Thus making it an attractive target for the management of seizures.

As a multi-factorial degenerative disease, Parkinson's disease (PD) leads to tremor, gait rigidity, and hypokinesia, thus hampering normal living. As this disease is usually detected in the later stages when neurons have degenerated completely, cure is on hold, ultimately leading to death due to the lack of early diagnostic techniques. Thus, biomarkers are required to detect the disease in the early stages when prevention is possible. Various biomarkers providing early diagnosis of the disease include those of imaging, cerebrospinal fluid, oxidative stress, neuroprotection, and inflammation. Also, biomarkers, alone or in combination, are used in the diagnosis and evolution of PD. This review encompasses various biomarkers available for PD and discusses recent advances in their development.

Alzheimer's disease (AD) is one of the most frequently encountered diseases in adults with progressive loss of memory and behavioral changes. Inspite of there being an intense research in the field of AD, only a few chemical entities exhibiting anti-AD activity make it through the clinical trials and it is thus need of an hour to develop new drugs or repurpose the existing ones for better management of Alzheimer's disease. Novel therapeutic targets can influence drug discovery in the field of AD. Cyclin Dependent Kinase 5 (Cdk5) which is a serine/threonine kinase can prove to be an upcoming beneficial target to be studied for treating AD. Cdk5 is important for development of CNS and neuron movements, however in AD pathological stimuli cause Cdk5 hyperactivation which eventually results in hyperphosphorylation of various substrates such as amyloid precursor protein, tau and many more. This review provides an insight on Cdk5 as a target for treatment of AD and discuss therapeutic candidates for targeting it.

Despite incessant advancement in the therapeutic regimens against colorectal cancer (CRC), treatment failure, metastasis and serious side effects associated with the available therapeutic options demand specific targeted therapies that could help in improving the survival rate with significantly less toxicity, fewer untoward effects and improved efficacy. In-depth studies highlighted the potential of CRC to be immune-responsive, thereby opening a new door in the development of strategies to combat CRC. Immunotherapy has attracted a myriad of researchers with a hope that it could potentially increase the efficacy of the treatment regimens in parallel to the reduction of toxicity. Colorectal tumors undergo immune evasion, suppressing patients' immunity and making them susceptible to infections. Therefore, a viable option could be stimulating a patient's own immune system with the help of immune modulators to fight against CRC. This review briefly discusses the immune responsiveness of CRC as well as tumor-associated antigens in CRC, and highlights the current endeavors of the scientific community in the field of immune modulators against CRC that are under development including varied types of vaccines, checkpoint inhibitors and adoptive T-cell therapy.

One of the most common neurological disorders, which occurs among 1% of the population worldwide, is epilepsy. Therapeutic failure is common with epilepsy and nearly about 30% of patients fall in this category. Seizure suppression should not be the only goal while treating epilepsy but associated comorbidities, which can further worsen the condition, should also be considered. Treatment of such comorbidities such as depression, anxiety, cognition, attention deficit hyperactivity disorder and, various other disorders which co-exist with epilepsy or are caused due to epilepsy should also be treated. Novel targets or the existing targets are needed to be explored for the dual mechanism which can suppress both the disease and the comorbidity. New therapeutic targets such as IDO, nNOS, PAR1, NF-κb are being explored for their role in epilepsy and various comorbidities. This review explores recent therapeutic targets for the treatment of comorbidities associated with epilepsy.

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

Stem cells have been widely exploited as remedial agents in regenerative medicine due to its tremendous potential in treatment of various debilitating diseases. In spite of this fact, there is need of a reliable, clinically applicable cell tracker for deciphering the homing and distribution of stem cells post-transplantation. Researchers have proposed the use of superparamagnetic magnetite (Fe3O4) nanoparticles for in vivo and in vitro tracking and imaging of stem cells. However, there is not much understanding of the chemical coatings on the nanoparticles, which is very important for the sustainability of stem cells in biological system. For any biomedical applications, the surface properties and the core structure of nanoparticles play a significant role. This study reports surface modification of magnetic Fe3O4 nanofluid with biocompatible amino acids viz., arginine and histidine to maintain colloidal stability at neutral pH, impart least disruption when encountered with the biological system and allow labeling with mesenchymal stem cells (MSCs). The size of amino acids-modified magnetic nanoferrofluid (AA@MNFs) was restricted to 15–25 nm for enhanced uptake in stem cells. In vitro cytotoxicity profile of stem cells labeled AA@MNFs was estimated using various assays like MTT, LDH and AO/EtBr followed by detailed pre-clinical toxicity assessment of AA@MNFs which illustrated least toxicity effects in major tissues of the animals. In vitro MRI scans of the stem cells labeled AA@MNFs confirmed the suitability of the reported ferrofluids for the use as MR contrast agents.

Rheumatoid Arthritis (RA) affects approximately 1% of the total world population. Despite incessant research and development of new therapeutic agents, management of RA is still a troublesome affair. Histone Deacetylase 1 (HDAC1) is an epigenetic regulator which play important role in pathogenesis of RA. In present study, we hypothesized that Phenethyl isothiocyanate (PEITC), a potent inhibitor of HDAC1, may ameliorate RA. Efficacy of PEITC was evaluated in Complete Freund's Adjuvant (CFA) induced arthritis model in rats. CFA (0.1 ml) was injected subplantarly in the left hind paw on day 0 to all the groups except normal control. The administration of test drug PEITC (10, 24 & 50 mg/kg) and standard drug Ibuprofen started simultaneously and was continued for 21 days. Paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion were evaluated. Further, radiographic studies, TNF-alpha as well as HDAC1 levels in synovial tissue homogenate and histological analysis were performed. Prophylactic treatment of PEITC attenuated paw edema, total arthritic index, mobility score, stair climbing ability, behavioral parameters, and bone erosion in dose dependent manner. Furthermore, there was significant decrease in TNF-alpha as well as HDAC1 levels in synovial tissue homogenate. Histological analysis revealed no cartilage damage, bone erosion, hyperplasia at synovial lining as well as infiltration of inflammatory cells in treatment group. Results of this study suggest potent anti-rheumatoid arthritis activity of Phenethyl isothiocyanate in CFA induced RA model in rats.

Diabetic retinopathy (DR) is a severe sight-threatening complication of diabetes. It causes progressive damage to the retina and is the most common cause of vision impairment and blindness among diabetic patients. DR develops as a result of various changes in the ocular environment. Such changes include accelerated mitochondrial dysfunction, apoptosis, reactive oxygen species production, and formation of acellular capillaries. Matrix metalloproteinases (MMPs) are one of the major culprits in causing DR. Under physiological conditions, MMPs cause remodeling of the extracellular matrix in the retina, while under pathological conditions, they induce retinal cell apoptosis. This review focuses on the roles of various MMPs, primarily MMP-2 and MMP-9 in DR and also their participation in oxidative stress, mitochondrial dysfunction, and apoptosis, along with their involvement in various signaling pathways. This review also underscores different strategies to inhibit MMPs, thus suggesting that MMPs may represent a putative therapeutic target in the treatment of DR.

Rheumatoid Arthritis (RA) is an autoimmune systemic disorder of unknown etiology and is characterized by chronic inflammation and synovial infiltration of immune cells. RA is associated with decreased life expectancy and quality of life. The research on RA is greatly simplified by animal models that help us to investigate the complex system involving inflammation, immunological tolerance and autoimmunity. The animal models of RA with a proven track record of predictability for efficacy in humans include: collagen type II induced arthritis in rats as well as mice, adjuvant induced arthritis in rats and antigen induced arthritis in several species. The development of novel treatments for RA requires the interplay between clinical observations and studies in animal models. However, each model features a different mechanism driving the disease expression; the benefits of each should be evaluated carefully in making the appropriate choice for the scientific problem to be investigated. In this review article, we focus on animal models of arthritis induced in various species along with the genetic models. The review also discussed the similarity and dissimilarities with respect to human RA.

Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke. Chronic inflammation, aberrant immune response, and disturbances to key enzymes involved with lipid metabolism are characteristic features of atherosclerosis. Apart from targeting the derangements in lipid metabolism, therapeutic modulation to regulate chronic inflammation and the immune system response may prove to be very promising strategies in the management of atherosclerosis. In recent years, various targets have been studied for the treatment of atherosclerosis. PCSK9, a serine protease, actively targets the LDL-R and causes lysosomal degradation, which leads to excessive accumulation of LDL-C. Regulatory T cells (Tregs) and Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) affects the adaptive and innate immune response, respectively, and thus, therapeutic intervention of either of these targets would directly modulate disease progression. Advanced atherosclerotic lesions are characterized by an accumulation of apoptotic cells. Cluster of differentiation-47 (CD47), an anti-phagocytic known as the "don't eat me" signaling molecule, inhibits efferocytosis, which causes accumulation of cell debris in plaque. ADAMTS and Notch signaling potentially affect the formation of neointima by modulation of extracellular matrix components such as macrophages and vascular smooth muscle cells. This review provides insights on the molecular targets for therapeutic intervention of atherosclerosis, their effect at various stages of atherosclerosis development, and the therapies that have been designed and currently being evaluated in clinical trials.

The connection between the gastrointestinal hormones and the brain has been established many years ago. This relation is termed the gut-brain axis (GBA). The GBA is a bidirectional communication which not only regulates gastrointestinal homeostasis but is also linked with higher emotional and cognitive functions. Hypothalamus plays a critical role in the regulation of energy metabolism, nutrient partitioning and control of feeding behaviors. Various gut hormones are released inside the gastrointestinal tract on food intake. These hormones act peripherally and influence the different responses of the tissues to the food intake, but do also have effects on the brain. The hypothalamus, in turn, integrates visceral function with limbic system structures such as hippocampus, amygdala, and cerebral cortex. The hippocampus has been known for its involvement in the cognitive function and the modulation of synaptic plasticity. This review aims to establish the role of various gut hormones in learning and memory, through the interaction of various receptors in the hippocampus. Understanding their role in memory can also aid in finding novel therapeutic strategies for the treatment of the neurological disorders associated with memory dysfunctions.

Background Oxidative stress is one of the major mechanism involved in pathogenesis of myocardial infarction. Use of natural products as therapeutic approach for ischemic myocardial injury is gaining attention worldwide. Purpose This study was designed to investigate efficacy of Narirutin rich fraction (NRF), obtained from grape fruit peel, in the treatment of isoproterenol induced myocardial infarction in rats. Methods After 3-days pretreatment with NRF (100 mg/kg and 200 mg/kg, p.o.) myocardial injury was induced by subcutaneous administration of isoproterenol (85 mg/kg) for 2 days. Hemodynamic parameters, biochemical parameters, histological and ultrastructural changes were observed. Results Isoproterenol induced myocardial injury was evidenced by significant alterations in ECG, mean arterial pressure and left ventricular functions. Myocardial creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level were reduced while MDE levels were increased. Histological findings also showed severe changes. Treatment with NRF significantly attenuated these parameters in dose dependent manner. Conclusion Thus, present study provides evidences for efficacy of NRF against isoproterenol induced myocardial infarction in rats.

Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.

Lung cancer surfaces to be the predominant determinant of mortality worldwide constituting 13% and 19% of all new cancer cases and deaths related to cancer respectively. Molecular profiling has now become a regular trend in lung cancer to identify the driver mutations. Epidermal Growth Factor Receptor (EGFR) is the most regular driver mutation encountered in Non-Small Cell Lung Cancer (NSCLC). Targeted therapies are now available for the treatment of EGFR mutant NSCLC. EGFR mutation is more frequently expressed in adenocarcinoma than squamous cell carcinoma. This article presents a detailed molecular insight of the therapeutic approaches for the treatment of EGFR mutant lung cancer. The article delineates molecular mechanism of the drugs that are approved, the drugs that are in clinical trial and the drugs that have not entered a clinical trial but shows promising future in the treatment of EGFR mutant lung cancer. Furthermore, this article provides concise information on relevant combinational or monotherapy clinical trials that have been completed for various approaches.

Epilepsy is a common neurological disorder involving recurrent seizures and affecting about 1% of the population worldwide. Despite several antiepileptic drugs and effective therapies available for epilepsy, about 25% of the patients show therapeutic failure. Thus there exists an unmet need for newer antiepileptic drugs targeting newer targets with different mechanisms of action. Current research in epilepsy generally focuses on mechanisms that control neuronal excitability. Recently attention has been focussed on novel targets, their various interactions, and signalling cascades relating to epilepsy. This review summarizes several experimental and clinical findings from literature and explores potential targets which may play crucial role in epilepsy.