Novel Therapeutic Agents for Management of Diabetes Mellitus: A Hope for Drug Designing against Diabetes Mellitus.

Diabetes mellitus (DM) is characterized by an absolute decline in insulin secretion and peripheral resistance and is the most prevalent metabolic and endocrine disorder. However, the pathogenesis of DM also includes adipocyte insulin resistance, increased glucagon secretion, increased renal glomerular glucose absorption, and neurotransmitter dysfunction. Although there is a wide spectrum of therapeutics available for glycemic control, owing to the identification of various pathogenic determinants of DM, management of DM remains challenging and complex. Current therapeutic interventions against DM focus mostly on glycemic control without considering the other pathological determinants that eventually lead to treatment failure and the progression of DM. Furthermore, long-term use of these conventionally available anti-diabetic drugs leads to various side effects, henceforth development of novel drugs against DM remains an unending search strategy for researchers. Various studies conducted in various parts of the world have proposed that these novel therapeutic interventions target multiple and alternate pathogenic hotspots involved in DM. The current review article discusses novel therapeutic options that hold particular promise to support their safety and discuss the side effects resulting from their use so that these novel candidate drugs can be effectively fabricated into potential drugs for the treatment of DM.

The critical impacts of cytokine storms in respiratory disorders.

Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection to end-stage organ failure. Recently the novel coronavirus involved in COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with the pathological phenomenon of CS in critically ill patients. Furthermore, critically ill patients suffering from CS are likely to have a grave prognosis and a higher case fatality rate. Pathologically CS is manifested as hyper-immune activation and is clinically manifested as multiple organ failure. An in-depth understanding of the etiology of CS will enable the discovery of not just disease risk factors of CS but also therapeutic approaches to modulate the immune response and improve outcomes in patients with respiratory diseases having CS in the pathogenic pathway. Owing to the grave consequences of CS in various diseases, this phenomenon has attracted the attention of researchers and clinicians throughout the globe. So in the present manuscript, we have attempted to discuss CS and its ramifications in COVID-19 and other respiratory diseases, as well as prospective treatment approaches and biomarkers of the cytokine storm. Furthermore, we have attempted to provide in-depth insight into CS from both a prophylactic and therapeutic point of view. In addition, we have included recent findings of CS in respiratory diseases reported from different parts of the world, which are based on expert opinion, clinical case-control research, experimental research, and a case-controlled cohort approach.

Modulation of immune cum inflammatory pathway by earthworm granulation tissue extract in wound healing of diabetic rabbit model.

Regeneration is a rare occurrence in the animal kingdom, but the earthworm stands out as a remarkable example of this phenomenon. Recent research has highlighted the promising wound healing properties of extracts derived from earthworms. Therefore, we propose that earthworm granulation tissue extract (EGTE) may facilitate wound healing by regulating immune responses in a rabbit diabetic wound model. Electron microscopy reveals that 70 % EGTE possesses noteworthy porosity with spherical to irregularly oval configuration. Gas chromatography-mass spectrometry (GC-MS) Characterization of EGTE revealed higher levels of ergosta-5,7,22-trien-3-ol, (3. beta.,22E). In-Vitro studies revealed significant anti-oxidant, anti-inflammatory and anti-bacterial properties in dose dependent manner. Likewise, cytotoxicity assessments reveal that 70 % EGTE exhibits minimal harm to cells while displaying substantial antioxidant and anti-inflammatory activities. For In-Vivo studies excision wounds were created on the dorsal regions of the experimental animals and were divided as Group I (50 % EGTE), Group II (70 % EGTE), Group III (vehicle) and Group IV (distilled water). Over a 21-day observation period 70 % EGTE facilitated the early healing of wounds in the experimental animals, evident through prompt wound closure, granulation tissue formation, increased DNA content, enhanced tensile strength of the wound area and enhanced the expression/synthesis of wound healing markers/proteins. From these results it can be postulated that EGTE accelerates wound healing by immune modulation, dampening of inflammatory pathway and enhanced expression of growth markers. Henceforth making it promising candidate for therapeutic use in diabetic wound healing.

Aged garlic extract preserves beta-cell functioning via modulation of nuclear factor kappa-B (NF-κB)/Toll-like receptor (TLR)-4 and sarco endoplasmic reticulum calcium ATPase (SERCA)/Ca2+ in diabetes mellitus.

BACKGROUND: Peripheral insulin resistance and compromised insulin secretion from pancreatic ß-cells are significant factors and pathogenic hallmarks of diabetes mellitus (DM). NF-κß/TLR-4 and SERCA/Ca2+ pathways have been identified as potential pathways regulating insulin synthesis by preserving pancreatic ß-cell functioning. The current study aimed to evaluate the therapeutic effect of aged garlic extract (AGE) against DM in a streptozotocin (STZ)-induced rat model with particular emphasis on pancreatic ß-cell functioning. METHODS: AGE was characterized by gas chromatography-mass spectrometry (GC-MS), Fourier-transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) to evaluate its physio-chemical characteristics followed by in-vitro anti-diabetic and antioxidant potential. This was followed by the induction of DM in laboratory animals for investigating the therapeutic action of AGE by evaluating the role of NF-κß/TLR-4 and the SERCA/Ca2+ pathway. The parameters assessed in the present experimental setup encompassed antioxidant parameters, metabolic indicators, insulin concentration, intracellular calcium levels, apoptotic markers (CCK-8 and Caspase Glo-8), and protein expression (P-62 and APACHE-II). RESULTS: AGE characterization by SEM, GC-MS, and X-ray diffraction (XRD) revealed the presence of phenylalanine, alliin, S-allylmercaptocysteine (SAMC), tryptophan, 1-methyl-1,2,3,4-tetrahydro-ß-carboline-3-carboxylic acid as major bioactive constituents of AGE. Metabolic studies, including intraperitoneal glucose tolerance test (IPGTT), revealed significantly lower blood glucose levels in the AGE group compared to the disease control group. In contrast, the intraperitoneal insulin tolerance test (ITT) exhibited no significant difference in insulin sensitivity between the AGE supplementation group and the DM control group. Interestingly, AGE was found to have no significant effect on fasting glucose and serum insulin levels. In contrast, AGE supplementation was found to cause significant hypoglycaemia in postprandial blood glucose and insulin levels. Importantly, AGE causes restoration of intracellular Ca2+ levels by modulation of SERCA/Ca2 functioning and inhibition NF-κB/TLR-4 pathway. AGE was found to interact with and inhibit the DR-5/ caspase-8/3 apoptotic complex. Furthermore, microscopic studies revealed degeneration and apoptotic changes in pancreatic ß-cells of the DM control group, while supplementation of AGE resulted in inhibition of apoptotic pathway and regeneration of pancreatic ß-cells. CONCLUSION: The current study suggests that AGE enhance glucose homeostasis by exerting their effects on pancreatic ß-cells, without ameliorating peripheral sensitivity. Moreover, AGEs promote an increase in ß-cell mass by mitigating the apoptosis of pancreatic ß-cells. These findings suggest that AGE could aid in developing a viable alternative therapy for diabetes mellitus (DM).

Evaluation of Convalescent Plasma in the Management of Critically Ill COVID-19 Patients (with No Detectable Neutralizing Antibodies Nab) in Kashmir, India.

BACKGROUND: For centuries, convalescent plasma (CP) has been recommended to treat a diverse set of viral diseases. Therefore, the present study was undertaken to evaluate the effectiveness of CP in critically ill COVID-19 patients. METHODS AND MATERIALS: From 23 March 2021 to 29 December 2021, an open-label, prospective cohort, single-centre study was conducted at Chest Disease Hospital, Jammu and Kashmir, Srinagar. Patients with severe manifestation of coronavirus disease 2019 (COVID-19) under BST (best standard treatment) +CP were prospectively observed in order to evaluate effectiveness of CP therapy and historical control under BST were used as the control group Results: A total of 1667 patients were found positive for COVID-19. Of these, 873 (52.4%), 431 (28.8%), and 363 (21.8%) were moderately, severely, and critically ill, respectively. On 35th day post-infusion of CP, all-cause mortality was higher in the BST (best standard treatment) +CP group 12 (37.5%) compared to 127 (35%) in the BST group with an odds ratio (OR) of 1.4 and hazard ratio (HR) (95% CI: 1.08-1.79, p = 0.06). Similarly, 7 (21.9) patients in the BST+CP group and 121 (33.3) patients in the BST group showed the transition from critically ill to moderate disease with subhazard ratio (s-HR 1.37) (95% CI: 1.03-2.9). CONCLUSIONS: In the present study, we could not find any significant difference in the CP group and BST +CP in primary outcome of reducing all-cause mortality in critically ill patients with negligible Nabs levels. However, beneficial results were observed with use of CP in a limited number of secondary outcomes which includes days of hospitalization, negative conversion of SARS-CoV-2 on basis of RT-PCR on 7th day and 14th day, need for invasive mechanical ventilation on 14th day post-CP treatment, and resolution of shortness of breath.

Treatment of Autism Spectrum Disorders by Mitochondrial-targeted Drug: Future of Neurological Diseases Therapeutics.

Autism is a neurodevelopmental disorder with a complex etiology that might involve environmental and genetic variables. Recently, some epidemiological studies conducted in various parts of the world have estimated a significant increase in the prevalence of autism, with 1 in every 59 children having some degree of autism. Since autism has been associated with other clinical abnormalities, there is every possibility that a sub-cellular component may be involved in the progression of autism. The organelle remains a focus based on mitochondria's functionality and metabolic role in cells. Furthermore, the mitochondrial genome is inherited maternally and has its DNA and organelle that remain actively involved during embryonic development; these characteristics have linked mitochondrial dysfunction to autism. Although rapid stride has been made in autism research, there are limited studies that have made particular emphasis on mitochondrial dysfunction and autism. Accumulating evidence from studies conducted at cellular and sub-cellular levels has indicated that mitochondrial dysfunction's role in autism is more than expected. The present review has attempted to describe the risk factors of autism, the role of mitochondria in the progression of the disease, oxidative damage as a trigger point to initiate mitochondrial damage, genetic determinants of the disease, possible pathogenic pathways and therapeutic regimen in vogue and the developmental stage. Furthermore, in the present review, an attempt has been made to include the novel therapeutic regimens under investigation at different clinical trial stages and their potential possibility to emerge as promising drugs against ASD.

Preclinical Evidence for the Pharmacological Actions of Glycyrrhizic Acid: A Comprehensive Review.

Glycyrrhiza glabra L. (Family: Fabaceae) is one of the important traditional medicinal plant used extensively in folk medicine. It is known for its ethnopharmacological value in curing a wide variety of ailments. Glycyrrhizin, an active compound of G. glabra, possesses anti-inflammatory activity due to which it is mostly used in traditional herbal medicine for the treatment and management of chronic diseases. The present review is focused extensively on the pharmacology, pharmacokinetics, toxicology, and potential effects of Glycyrrhizic Acid (GA). A thorough literature survey was conducted to identify various studies that reported on the GA on PubMed, Science Direct and Google Scholar.