Screening of natural epigenetic modifiers for managing glycemic memory and diabetic nephropathy.

Short hyperglycaemic episodes trigger metabolic memory (MM) in which managing hyperglycaemia alone is not enough to tackle the progression of Diabetic nephropathy on the epigenetic axis. We used a structural similarity search approach to identify phytochemicals similar to natural epigenetic modifiers and docked with SIRT1 protein and did ADME studies. We found that UMB was 84.3% similar to esculetin. Upon docking, we found that UMB had a binding energy of -9.2 kcal/mol while the standard ligand had -11.8 kcal/mol. ADME showed UMB to be a good lead. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed it to be a good antioxidant with IC50 of 107 µg/mL and MTT stands for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) showed that it does not promote cell death. Oxidative biomarkers in vitro showed UMB was able to ameliorate glycemic memory induced by high glucose. Western blot revealed decreased histone acetylation under hyperglycaemic conditions and upon treatment with UMB along with DR, its levels increased. This led us to check our hypothesis of whether concomitant diet reversal (DR) together with UMB can alleviate high-fat diet-induced metabolic memory and diabetic nephropathy (DN) in SD rats. UMB was able to decrease blood glucose, lipid, renal, and liver profile concluding UMB was able to ameliorate DN and MM by increasing the histone acetylation level.

Biological macromolecules-based nanoformulation in improving wound healing and bacterial biofilm-associated infection: A review.

A chronic wound is a serious complication associated with diabetes mellitus and is difficult to heal due to high glucose levels, oxidative stress, and biofilm-associated microbial infection. The structural complexity of microbial biofilm makes it impossible for antibiotics to penetrate the matrix, hence conventional antibiotic therapies became ineffective in clinical settings. This demonstrates an urgent need to find safer alternatives to reduce the prevalence of chronic wound infection associated with microbial biofilm. A novel approach to address these concerns is to inhibit biofilm formation using biological-macromolecule based nano-delivery system. Higher drug loading efficiency, sustained drug release, enhanced drug stability, and improved bioavailability are advantages of employing nano-drug delivery systems to prevent microbial colonization and biofilm formation in chronic wounds. This review covers the pathogenesis, microbial biofilm formation, and immune response to chronic wounds. Furthermore, we also focus on macromolecule-based nanoparticles as wound healing therapies to reduce the increased mortality associated with chronic wound infections.

Guar gum-based nanoformulations: Implications for improving drug delivery.

Poorly soluble drugs are reported to easily degrade in the gastrointestinal tract and contribute in limiting the effect of drug to its targeted site. Oral administration of drug is one of the prominent ways to deliver a drug, although, it experiences barriers like acidic pH, presence of microflora and enzymes in the gastrointestinal tract. Collectively all of these participate in the degradation of drug before it reaches its target site and thus, they impede the sustained effect of drug. A quest of choosing a polymer with good stability profile and releasing the drug to its targeted site is always been a challenge for the scientists worldwide. Many polymers have been reported to prevent the degradation of drug and one such naturally occurring biocompatible polymer is guar gum. Guar gum-based nanoformulations have been extensively used in past decades to achieve controlled drug release which defines its importance. The coating of guar gum over the drug improves the bioavailability of the drug and thus helps in minimizing the risk of drug degradation. This review intends to highlight the beneficial role of guar gum-based nanoformulations to improve drug delivery by ameliorating the bioavailibility.

Pharmacological and Therapeutic Applications of Esculetin.

Esculetin is a coumarin compound, which belongs to the class of benzopyrone enriched in various plants such as Sonchus grandifolius, Aesculus turbinata, etc. Free radicals lead to the development of oxidative stress causing inflammation, arthritis, cancer, diabetes, fatty liver disease, etc. These further reduce the efficacy of anticancer drugs, activate inflammatory signaling pathways, degrade joints and cartilage, and disrupt the glycemic index and normal function of liver enzymes. For instance, the current treatment modalities used in arthritis such as non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs, and lipoxygenase inhibitors present limited efficacy and adverse effects. Thus, there is a constant need to find newer and safer alternatives. Esculetin has an immense antioxidative potential thereby alleviating arthritis, diabetes, malignancies, and hepatic disorders. Structurally, esculetin contains two hydroxyl groups, which enhance its ability to function as an antioxidant by inhibiting oxidative stress in pathological conditions. Leukotriene B4 synthesis, NF-κB and MPAK pathway activation, and inflammatory cytokine production are the main causes of bone and joint deterioration in arthritis, whereas esculetin treatment reverses these factors and relieves the disease condition. In contrast, lipid peroxidation caused by upregulation of TGF-ß-mediated expression and dysfunction of antioxidant enzymes is inhibited by esculetin therapy, thus reducing liver fibrosis by acting on the PI3K/FoxO1 pathway. Therefore, targeting NF-κB, pro-inflammatory cytokines, TGF-ß and oxidative stress may be a therapeutic strategy to alleviate arthritis and liver fibrosis.

Targeting epigenetic regulators for treating diabetic nephropathy.

Diabetes is accompanied by the worsening of kidney functions. The reasons for kidney dysfunction mainly include high blood pressure (BP), high blood sugar levels, and genetic makeup. Vascular complications are the leading cause of the end-stage renal disorder (ESRD) and death of diabetic patients. Epigenetics has emerged as a new area to explain the inheritance of non-mendelian conditions like diabetic kidney diseases. Aberrant post-translational histone modifications (PTHMs), DNA methylation (DNAme), and miRNA constitute major epigenetic mechanisms that progress diabetic nephropathy (DN). Increased blood sugar levels alter PTHMs, DNAme, and miRNA in kidney cells results in aberrant gene expression that causes fibrosis, accumulation of extracellular matrix (ECM), increase in reactive oxygen species (ROS), and renal injuries. Histone acetylation (HAc) and histone deacetylation (HDAC) are the most studied epigenetic modifications with implications in the occurrence of kidney disorders. miRNAs induced by hyperglycemia in renal cells are also responsible for ECM accumulation and dysfunction of the glomerulus. In this review, we highlight the role of epigenetic modifications in DN progression and current strategies employed to ameliorate DN.

Polyol pathway and redox balance in diabetes.

Diabetes is a major public health disease that is globally approaching epidemic proportions. One of the major causes of type 2 diabetes is either a defect in insulin secretion or insulin action which is usually caused by a combination of genetic and environmental factors. Not only these factors but others such as deregulation of various pathways, and oxidative stress are also known to trigger the redox imbalance in diabetics. Increasing evidences suggest that there are tight interactions between the development of diabetes and redox imbalance. An alternate pathway of glucose metabolism, the polyol pathway, becomes active in patients with diabetes that disturbs the balance between NADH and NAD+ . The occurrence of such redox imbalance supports other pathways that lead to oxidative damage to DNA, lipids, and proteins and consequently to oxidative stress which further ascend diabetes and its complications. However, the precise mechanism through which oxidative stress regulates diabetes progression remains to be elucidated. The understanding of how antioxidants and oxidants are controlled and impact the generation of oxidative stress and progression of diabetes is essential. The main focus of this review is to provide an overview of redox imbalance caused by oxidative stress through the polyol pathway. Understanding the pathological role of oxidative stress in diabetes will help to design potential therapeutic strategies against diabetes.

Immunomodulation and immunotherapeutics of COVID-19.

Severe acute respiratory syndrome coronavirus-2 causes coronavirus disease 2019, a pandemic which was originated from Wuhan city of China. The pandemic has affected millions of people worldwide. The pathogenesis of SARS-CoV-2 is characterized by a cytokine storm in the blood (cytokinemia) and tissues, especially the lungs. One of the major repercussions of this inflammatory process is the endothelial injury-causing intestinal bleeding, coagulopathy, and thromboembolism which result in various sudden and unexpected post-COVID complications including kidney failure, myocardial infarction, or multiorgan failure. In this review, we have summarized the immune responses, biochemical changes, and inflammatory responses in the human body after infection with the SARS-CoV-2 virus. The increased amount of inflammatory cytokines, chemokines, and involvement of complement proteins in inflammatory reaction increase the risk of occurrence of disease.

An insight into the therapeutic applications of coumarin compounds and their mechanisms of action.

The coumarins are heterocyclic compounds belonging to the class of benzopyrone enriched in various plants like tonka beans. Coumarins and their derivatives exert a vast array of bioactive properties such as anticoagulant, antibacterial, anti-inflammatory, antioxidant, antitumor, antiviral, and enzyme inhibition. Higher doses of coumarin are found to be hepatotoxic however they exhibit beneficial effects by reducing the risk of cancer and other neuronal and cardiovascular ailments. Most of these effects can be attributed to their free radical scavenging effects. Coumarins such as umbelliferone, esculetin and quercetin show antioxidant properties and protect the cellular DNA from oxidative damage. The dicumarol shows anticoagulant properties by inhibiting the action of vitamin K, whereas angelmarin has been reported to be cytotoxic in pancreatic cancer. Coumarins also reduce edema and inflammation by inhibiting the prostaglandins biosynthesis. Hydroxyl aromatic substituted derivatives such as 5-hydroxycoumarin or vicinal dihydroxy coumarins have also been found to be potent anti-inflammatory agents. Some coumarins are approved by the FDA as drugs, and warfarin is one such example. It blocks the Vitamin K reductase enzyme thus disrupting the clotting mechanism. In conclusion, the coumarin class of phytomolecules has a lot of potential to be used as drugs for various diseases. Much work is needed to bring them at the stage of clinical trials for further approval. There is a lot of hope for this unexplored area of translational research.