Crosstalk between NLRP3 inflammasome and calpain in Alzheimer's disease.

Amyloid plaques are considered to be the pathological hallmark of Alzheimer's disease (AD). Neuroinflammation further aggravates the pathogenesis of Alzheimer's disease. Calpains and NOD-like receptor protein-3 (NLRP3) inflammasomes are involved in the neuroinflammatory pathway and affect the progression of Alzheimer's disease. Hyperactivation of calpains is responsible for the activation of NLRP3 inflammasome, thereby affecting each other's molecular mechanism and causing astrogliosis, microgliosis, and neuronal dysfunction. Further, calpain hyperactivation is also associated with calcium homeostasis that acts as one of the triggers in the activation of NLRP3 inflammasome. Calpain activity is required for the maturation of interleukin-1ß, a key mediator of neuroinflammatory responses. The membrane potential/calcium/calpain/caspase-1 axis acts as an unconventional regulator of inflammasomes. The complex crosstalk between NLRP3 inflammasome and calpain leads to a series of events. Targeting the molecular mechanism associated with calpain-NLRP3 inflammasome activation and regulation can be a therapeutic and prophylactic perspective towards Alzheimer's disease. This review discusses calpains and NLRP3 inflammasome crosstalk in the pathogenesis of AD.

Elabela Peptide: An Emerging Target in Therapeutics.

Elabela, a bioactive micropeptide, is recognized as the second endogenous ligand for the Apelin receptor and is widely distributed in different tissues and organs. Elabela plays an important role in various physiological processes, such as 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 the physiological role of Elabela peptide as well as its implication in various disease conditions.

Liver X receptor: a potential target in the treatment of atherosclerosis.

INTRODUCTION: Liver X receptors (LXRs) are master regulators of atherogenesis. Their anti-atherogenic potential has been attributed to their role in the inhibition of macrophage-mediated inflammation and promotion of reverse cholesterol transport. Owing to the significance of their anti-atherogenic potential, it is essential to develop and test new-generation LXR agonists, both synthetic and natural, to identify potential LXR-targeted therapeutics for the future. AREAS COVERED: This review describes the role of LXRs in atherosclerotic development, and provides a summary of LXR agonists and future directions for atherosclerosis research. We searched PubMed, Scopus, and Google Scholar for relevant reports, from last 10 years, using atherosclerosis, liver X receptor, and LXR agonist as keywords. EXPERT OPINION: LXRα has gained widespread recognition as a regulator of cholesterol homeostasis and expression of inflammatory genes. Further research using models of cell type-specific knockout and specific agonist-targeted LXR isoforms is warranted. Enthusiasm for therapeutic value of LXR agonists has been tempered due to LXRα-mediated induction of hepatic lipogenesis. LXRα agonism and LXRß targeting, gut-specific inverse LXR agonists, investigations combining LXR agonists with other lipogenesis-mitigating agents, like IDOL antagonists and synthetic HDL, and targeting ABCA1, M2 macrophages, and LXRα phosphorylation remain as promising possibilities.

Emerging targets signaling for inflammation in Parkinson's disease drug discovery.

Parkinson's disease (PD) patients not only show motor features such as bradykinesia, tremor, and rigidity but also non-motor features such as anxiety, depression, psychosis, memory loss, attention deficits, fatigue, sexual dysfunction, gastrointestinal issues, and pain. Many pharmacological treatments are available for PD patients; however, these treatments are partially or transiently effective since they only decrease the symptoms. As these therapies are unable to restore dopaminergic neurons and stop the development of Parkinson's disease, therefore, the need for an effective therapeutic approach is required. The current review summarizes novel targets for PD, that can be utilized to identify disease-modifying treatments.

Cytokine storm associated coagulation complications in COVID-19 patients: Pathogenesis and Management.

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.

SERCA stimulation: A potential approach in therapeutics.

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.

Neutrophilic Asthma and Potentially Related Target Therapies.

BACKGROUND: Neutrophilic asthma is generally associated with the absence of eosinophils and activation of non- predominant type 2 immunological pathways. It involves bronchial inflammation followed by different degrees of airway remodeling. Neutrophilic inflammation activates specific cellular and molecular pathways due to inhalation of environmental trigger factors such as exhaust fumes, cigarette smoke, occupation-related agents, and infections. OBJECTIVE: This review discusses the involvement of neutrophils in asthma and potentially related target therapies. RESULTS: Corticosteroid resistance is the hallmark of neutrophilic asthma which increases disease severity and leads to difficult-to-control asthma. Patients with neutrophil-dominant asthma are characterized by low levels of (or absence of) Th2 cytokines. Due to the shortage of effective treatments for neutrophilic asthma newer biologics are being developed that target type 2 asthma symptoms and phenotypes. Understanding different biomarkers, inflammatory pathways and treatment strategies involved in neutrophilic asthma will help to decrease adverse effects related to corticosteroid insensitivity. Better insight of targets involved in neutrophilic inflammation can lead to improved therapies. CONCLUSION: Further evaluation and clinical trials of emerging biologics involved in neutrophilic asthma needs to be performed before bringing them into clinical practice.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics.

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.

Colon cancer stem cells: Potential target for the treatment of colorectal cancer.

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.

Targeting Matrix Metalloproteinases for Diabetic Retinopathy: The Way Ahead?

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.

Gastrointestinal hormones in regulation of memory.

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.

Experimental animal models for rheumatoid arthritis.

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.

Therapeutic Approaches for the Treatment of Epidermal Growth Factor Receptor Mutated Lung Cancer.

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.

Biomarkers for Parkinson's Disease: Recent Advancement.

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.

Neuropeptides: A promising target for treating seizures.

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.

Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells.

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.

Cyclin dependent kinase 5: A novel avenue for Alzheimer's disease.

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.

Herbal approach in the treatment of pancytopenia.

Pancytopenia is a health condition in which there is a reduction in the amount of leucocytes, erythrocytes and thrombocytes. If more than one of the blood cells is low then the condition is called as bicytopenia. The pancytopenic condition is observed in treatment of diseased conditions like thalassemia and hepatitis C. Iatrogenically pancytopenia is caused by some antibiotics and anti-HCV drugs. Medical conditions like aplastic anaemia, lymphoma, copper deficiency, and so forth can also cause pancytopenia. Pancytopenia can in turn decrease the immunity of the person and thereby can be fatal. Current therapies for pancytopenia include bone marrow stimulant drugs, blood transfusion and bone marrow transplant. The current therapies are very excruciating and have long-term side-effects. Therefore, treating these condition using herbal drugs is very important. Herbs like wheatgrass, papaya leaves and garlic are effective in treating single lineage cytopenias. The present review is focused on the potential effects of natural herbs for the treatment of pancytopenia.

Preparation, optimization, and evaluation of Zaltoprofen-loaded microemulsion and microemulsion-based gel for transdermal delivery.

CONTEXT: Zaltoprofen, a non-steroidal anti-inflammatory drug, has potent inhibitory action against nociceptive responses. However, gastrointestinal ulcer accompanied with anemia due to the bleeding are most cited side effects associated with it. Due to this, administration of Zaltoprofen is not suitable for individuals with gastric ulcer. Thus, there is unmet need to develop an alternative delivery system that will be easy to administer and can avoid ulcerogenic side effects associated with it. OBJECTIVE: Present study was aimed to prepare and evaluate microemulsion (ME) and microemulsion-based gel formulation of Zaltoprofen for transdermal delivery. MATERIALS AND METHODS: Pseudo-ternary phase diagrams were utilized to prepare ME formulations. Effect of surfactant and co-surfactant mass ratio on the ME formation and permeation of ME were evaluated and formulation was optimized. Permeation studies were performed using excised pigskin was studied. Efficacy of optimized formulations was evaluated in rat model of inflammation and pain. RESULTS: Composition of optimized formulation was 1% (w/w) Zaltoprofen, 20% (w/w) Capryol 90, 50% (w/w) Smix (2:1, Cremophor RH 40 and Transcutol P). Optimized formulation showed globule size of 22.11 nm, polydispersity index of 0.251 and zeta potential of -11.4 mV. ME gel was found safe in skin irritation study. Significant analgesic activity and anti-inflammatory activity of ME gel was observed in hot plate test and rat paw edema test, respectively. CONCLUSION: In conclusion, results of present study suggest that ME could be a promising formulation for transdermal administration of Zaltoprofen.

Management of bipolar depression with lamotrigine: an antiepileptic mood stabilizer.

The efficacy of lamotrigine in the treatment of focal epilepsies have already been reported in several case reports and open studies, which is thought to act by inhibiting glutamate release through voltage-sensitive sodium channels blockade and neuronal membrane stabilization. However, recent findings have also illustrated the importance of lamotrigine in alleviating the depressive symptoms of bipolar disorder, without causing mood destabilization or precipitating mania. Currently, no mood stabilizers are available having equal efficacy in the treatment of both mania and depression, two of which forms the extreme sides of the bipolar disorder. Lamotrigine, a well established anticonvulsant has received regulatory approval for the treatment and prevention of bipolar depression in more than 30 countries worldwide. Lamotrigine, acts through several molecular targets and overcomes the major limitation of other conventional antidepressants by stabilizing mood from "below baseline" thereby preventing switches to mania or episode acceleration, thus being effective for bipolar I disorder. Recent studies have also suggested that these observations could also be extended to patients with bipolar II disorder. Thus, lamotrigine may supposedly fulfill the unmet requirement for an effective depression mood stabilizer.