SIRT6 in Regulation of Mitochondrial Damage and Associated Cardiac Dysfunctions: A Possible Therapeutic Target for CVDs.

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

The interplay of rheumatoid arthritis and osteoporosis: exploring the pathogenesis and pharmacological approaches.

Rheumatoid arthritis (RA) and osteoporosis are two chronic disorders that are often seen together. RA is an autoimmune disorder that causes pain and inflammation in the joints, while osteoporosis is a disorder in which the bones become weak and fragile. Risk factors for bone loss in RA include disease activity, longer disease duration, erosive disease, autoantibody positivity, and joint damage leading to impaired physical activity. Recent research has shown that there is a complex interplay between immune cells, cytokines, and bone remodeling processes in both RA and osteoporosis. The bone remodeling process is regulated by cytokines and immune system signaling pathways, with osteoclasts activated through the RANK/RANKL/OPG pathway and the Wnt/DKK1/sclerostin pathway. Understanding these mechanisms can aid in developing targeted therapies for treatment of osteoporosis in RA patients. Current pharmacological approaches include anti-osteoporotic drugs such as bisphosphonates, denosumab, teriparatide, abaloparatide, raloxifene, and romosozumab. Conventional disease-modifying antirheumatic drugs such as methotrexate and biologicals including TNF inhibitors, IL-6 inhibitors, rituximab, and abatacept lower disease activity in RA and can improve bone metabolism by reducing inflammation but have limited impact on bone mineral density. This review will shed light on the relationship between osteoporosis and rheumatoid arthritis as well as the various factors that influence the onset of osteoporosis in RA patients. We also explore several treatment approaches to effectively managing osteoporosis in RA patients.

Dextran-based Drug Delivery Approaches for Lung Diseases: A Review.

Respiratory disorders, such as tuberculosis, cystic fibrosis, chronic obstructive pulmonary disease, asthma, lung cancer, and pulmonary inflammation, are among the most prevalent ailments in today's world. Dextran, an exopolysaccharide formed by Leuconostoc mesenteroides (slimeproducing bacteria), and its derivatives are investigated for several therapeutic utilities. Dextranbased drug delivery system can become an innovative strategy in the treatment of several respiratory ailments as it offers numerous advantages, such as mucolytic action, airway hydration, antiinflammatory properties, and radioprotective effect as compared to other polysaccharides. Being biocompatible, flexible hydrophilic nature, biodegradable, tasteless, odourless, non-mutagenic, watersoluble and non-toxic edible polymer, dextran-based drug delivery systems have been explored for a wide range of therapeutic applications, especially in lungs and respiratory diseases. The present article comprehensively discusses various derivatives of dextran with their attributes to be considered for drug delivery and extensive therapeutic benefits, with a special emphasis on the armamentarium of dextran-based formulations for the treatment of respiratory disorders and associated pathological conditions. The information provided will act as a platform for formulation scientists as important considerations in designing therapeutic approaches for lung and respiratory diseases. With an emphasis on lung illnesses, this article will offer an in-depth understanding of dextran-based delivery systems in respiratory illnesses.

Microbiome Medicine: Microbiota in Development and Management of Cardiovascular Diseases.

The gut microbiome consists of trillions of bacteria and other microbes whose metabolic activities and interactions with the immune system go beyond the gut itself. We are all aware that bacteria and other microorganisms have a significant impact on our health. Also, the health of the bacteria directly reflects the health status of the body where they reside. Eventually, alterations in the microbiome at different sites of a body are associated with many different diseases such as obesity, IBD, malnutrition, CVD, etc. Microbiota directly or indirectly affects the heart with the formation of plaques in the blood vessels, and cell walls become prone to lesion development. This ultimately leads to heightening the overall inflammatory status via increased bacterial translocation. Metabolites derived from the gut microbial metabolism of choline, phosphatidylcholine, and L-carnitine directly contribute to CVD pathology. These dietary nutrients have trimethylamine (TMA) moiety, which participates in the development of atherosclerotic heart disease. The objective of this review was to examine various metabolic pathways regulated by the gut microbiome that appear to alter heart function and lead to the development and progression of cardiovascular diseases, as well as how to target the gut microbiome for a healthier heart. In this review, we also discussed various clinical drugs having crosstalk between microbiota and heart and clinical trials for the gut-heart microbiome.

Exploring New Drug Targets for Type 2 Diabetes: Success, Challenges and Opportunities.

There are substantial shortcomings in the drugs currently available for treatment of type 2 diabetes mellitus. The global diabetic crisis has not abated despite the introduction of new types of drugs and targets. Persistent unaddressed patient needs remain a significant factor in the quest for new leads in routine studies. Drug discovery methods in this area have followed developments in the market, contributing to a recent rise in the number of molecules. Nevertheless, troubling developments and fresh challenges are still evident. Recently, metformin, the most widely used first-line drug for diabetes, was found to contain a carcinogenic contaminant known as N-nitroso dimethylamine (NDMA). Therefore, purity and toxicity are also a big challenge for drug discovery and development. Moreover, newer drug classes against SGLT-2 illustrate both progress and difficulties. The same was true previously in the case of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Furthermore, researchers must study the importance of mechanistic characteristics of novel compounds, as well as exposure-related hazardous aspects of current and newly identified protein targets, in order to identify new pharmacological molecules with improved selectivity and specificity.

SARS-CoV-2 Infections, Impaired Tissue, and Metabolic Health: Pathophysiology and Potential Therapeutics.

The SARS-CoV-2 enters the human airways and comes into contact with the mucous membranes lining the mouth, nose, and eyes. The virus enters the healthy cells and uses cell machinery to make several copies itself. Critically ill patients infected with SARS-CoV-2 may have damaged lungs, air sacs, lining, and walls. Since COVID-19 causes cytokine storm, it damages the alveolar cells of the lungs and fills them with fluid, making it harder to exchange oxygen and carbon dioxide. The SARS-CoV-2 infection causes a range of complications, including mild to critical breathing difficulties. It has been observed that older people suffering from health conditions like cardiomyopathies, nephropathies, metabolic syndrome, and diabetes instigate severe symptoms. Many people who died due to COVID-19 had impaired metabolic health [IMH], characterized by hypertension, dyslipidemia, and hyperglycemia, i.e., diabetes, cardiovascular system, and renal diseases, making their retrieval challenging. Jeopardy stresses for increased mortality from COVID-19 include older age, COPD, ischemic heart disease, diabetes mellitus, and immunosuppression. However, no targeted therapies are available as of now. Almost two-thirds of diagnosed coronavirus patients had cardiovascular diseases and diabetes, out of which 37% were under 60. The NHS audit revealed that with a higher expression of ACE-2 receptors, viral particles could easily bind their protein spikes and get inside the cells, finally causing COVID-19 infection. Hence, people with IMH are more prone to COVID-19 and, ultimately, comorbidities. This review provides enormous information about tissue [lungs, heart, and kidneys] damage, pathophysiological changes, and impaired metabolic health of SARS-CoV-2 infected patients. Moreover, it also designates the possible therapeutic targets of COVID-19 and drugs which can be used against these targets.

Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19.

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.

In Situ Forming Depot as Sustained-Release Drug Delivery Systems.

In situ forming systems can serve as promising alternative to existing long acting injectables like disperse systems and microspheres, owing to their biocompatibility, stability, ease of administration and scale up. Microspheres based on long-acting parenteral systems pose challenges in scaling up and process changes with the drug and polymer selected. In situ gelling systems are having low viscosity which is very conducive during various manufacturing unit operations and passing the formulation through hypodermic needle with lower applied pressure. Different mechanisms such as physical or physiological stimuli and cross linking reactions are involved in the gelling of in situ forming systems at the site of injection. Drug release from in situ forming systems can be altered according to the need by using different polymers, lipids and fatty acids. In situ forming systems can be evaluated by sol-gel transition time, temperature and pH, rheology, gel strength, texture analysis, syringeability and injectability. The present paper is an overview of the various in situ gelling polymers and their application in the preparation of depot formulations. Numerous products based on in situ forming systems such as Eligard®, Atridox® are available in market.

Preparation and evaluation of floating tablets of pregabalin.

Floating tablets of pregabalin were prepared using different concentrations of the gums (xanthan gum and guar gum), Carbopol 974P NF and HPMC K100. Optimized formulations were studied for physical tests, floating time, swelling behavior, in vitro release studies and stability studies. In vitro drug release was higher for tablet batches containing guar and xanthan gum as compared to the batches containing Carbopol 974P NF. Tablet batches were subjected to stability studies and evaluated by different parameters (drug release, drug content, FTIR and DSC studies). The optimized tablet batch was selected for in vivo pharmacodynamic studies (PTZ induced seizures). The results obtained showed that the onset of jerks and clonus were delayed and extensor phase was abolished with time in treated groups. A significant difference (p > 0.05) was observed in control and treated group behavior indicating an excellent activity of the formulation for a longer period (>12 h).