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).

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.

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.

Clinical Characterization and Outcomes of Patients with Hypercreatinemia Affected by COVID-19.

The present study evaluated the clinical presentation and outcome of COVID-19 patients with underlying hypercreatinemia at the time of hospitalization. A retrospective observational study was conducted from the 23rd of March 2020 to the 15th of April 2021 in 1668 patients confirmed positive for COVID-19 in the Chest Disease Hospital in Srinagar, India. The results of the present study revealed that out of 1668 patients, 339 with hypercreatinemia had significantly higher rates of admission to the intensive care unit (ICU), severe manifestations of the disease, need for mechanical ventilation, and all-cause mortality. Multivariable analysis revealed that age, elevated creatinine concentrations, IL-1, D-Dimer, and Hs-Crp were independent risk factors for in-hospital mortality. After adjusted analysis, the association of creatinine levels remained strongly predictive of all-cause, in-hospital mortality (HR-5.34; CI-4.89-8.17; p ≤ 0.001). The amelioration of kidney function may be an effective method for achieving creatinemic targets and, henceforth, might be beneficial for improving outcomes in patients with COVID-19.

Insight into Oncogenic Viral Pathways as Drivers of Viral Cancers: Implication for Effective Therapy.

As per a recent study conducted by the WHO, 15.4% of all cancers are caused by infectious agents of various categories, and more than 10% of them are attributed to viruses. The emergence of COVID-19 has once again diverted the scientific community's attention toward viral diseases. Some researchers have postulated that SARS-CoV-2 will add its name to the growing list of oncogenic viruses in the long run. However, owing to the complexities in carcinogenesis of viral origin, researchers across the world are struggling to identify the common thread that runs across different oncogenic viruses. Classical pathways of viral oncogenesis have identified oncogenic mediators in oncogenic viruses, but these mediators have been reported to act on diverse cellular and multiple omics pathways. In addition to viral mediators of carcinogenesis, researchers have identified various host factors responsible for viral carcinogenesis. Henceforth owing to viral and host complexities in viral carcinogenesis, a singular mechanistic pathway remains yet to be established; hence there is an urgent need to integrate concepts from system biology, cancer microenvironment, evolutionary perspective, and thermodynamics to understand the role of viruses as drivers of cancer. In the present manuscript, we provide a holistic view of the pathogenic pathways involved in viral oncogenesis with special emphasis on alteration in the tumor microenvironment, genomic alteration, biological entropy, evolutionary selection, and host determinants involved in the pathogenesis of viral tumor genesis. These concepts can provide important insight into viral cancers, which can have an important implication for developing novel, effective, and personalized therapeutic options for treating viral cancers.

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.

Mechanisms of Mitochondrial Malfunction in Alzheimer's Disease: New Therapeutic Hope.

Mitochondria play a critical role in neuron viability or death as it regulates energy metabolism and cell death pathways. They are essential for cellular energy metabolism, reactive oxygen species production, apoptosis, Ca++ homeostasis, aging, and regeneration. Mitophagy and mitochondrial dynamics are thus essential processes in the quality control of mitochondria. Improvements in several fundamental features of mitochondrial biology in susceptible neurons of AD brains and the putative underlying mechanisms of such changes have made significant progress. AD's etiology has been reported by mitochondrial malfunction and oxidative damage. According to several recent articles, a continual fusion and fission balance of mitochondria is vital in their normal function maintenance. As a result, the shape and function of mitochondria are inextricably linked. This study examines evidence suggesting that mitochondrial dysfunction plays a significant early impact on AD pathology. Furthermore, the dynamics and roles of mitochondria are discussed with the link between mitochondrial malfunction and autophagy in AD has also been explored. In addition, recent research on mitochondrial dynamics and mitophagy in AD is also discussed in this review. It also goes into how these flaws affect mitochondrial quality control. Furthermore, advanced therapy techniques and lifestyle adjustments that lead to improved management of the dynamics have been demonstrated, hence improving the conditions that contribute to mitochondrial dysfunction in AD.

Organoids: A new approach in toxicity testing of nanotherapeutics.

Nanotechnology has revolutionized diverse fields, which include agriculture, the consumer market, medicine, and other fields. Widespread use of nanotechnology-based products has led to increased prevalence of these novel formulations in the environment, which has raised concerns regarding their deleterious effects. The application of nanotechnology-based formulations into clinical use is hampered by the lack of the availability of effective in vitro systems, which could accurately assess their in vivo toxic effects. A plethora of studies has shown the hazardous effects of nanoparticle-based formulations in two-dimensional in vitro cell cultures and animal models. These have some associated disadvantages when used for the evaluation of nano-toxicity. Organoid technology fills the space between existing two-dimensional cell line culture and in vivo models. The uniqueness of organoids over other systems for evaluating toxicity caused by nano-drug formulation includes them being a co-culture of diverse cell types, dynamic flow within them that simulates the actual flow of nanoparticles within biological systems, extensive cell-cell, cell-matrix interactions, and a tissue-like morphology. Thus, it mimics the actual tissue microenvironment and, subsequently, provides an opportunity to study drug metabolism and toxico-dynamics of nanotechnology-based novel formulations. The use of organoids in the evaluation of nano-drug toxicity is in its infancy. A limited number of studies conducted so far have shown good predictive value and efficiently significant data correlation with the clinical trials. In this review, we attempt to introduce organoids of the liver, lungs, brain, kidney intestine, and potential applications to evaluate toxicity caused by nanoparticles.

Repurposing of Mycobacterium indicus pranii for the severe form of COVID-19 patients in India: A cohort study.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induces the production of proinflammatory cytokines, which results in a cytokine storm, and immune-modulators like Mycobacterium indicus pranii (MIP) might ameliorate coronavirus disease of 2019 (COVID-19) related cytokine storm. Therefore, the present study evaluates whether MIP offers an advantage in the treatment of severe COVID-19 patients infected with SARS-CoV-2. A prospective MIP cohort study was conducted in chest disease hospitals in Srinagar, Jammu and Kashmir, India. In the present prospective, randomized clinical study, critically severe COVID-19 patients were divided into two groups, the MIP group (n = 105) and the best standard treatment (BST) group (n = 210). Procalcitonin, ferritin, high-sensitive C-reactive protein, D-dimer levels, and interleukin levels on 5th-day posttreatment were significantly reduced in the MIP group compared to the BST group. Compared to the BST group, 105 consecutive patients with severe COVID-19 in the MIP group reported early weaning off ventilation, resolution of chest architecture (computed tomography [CT] scan), a significant increase in SpO2 levels, and decreased mortality with a hazard ratio: 0.234 (95% confidence interval: 0.264-2.31) (p = 0.001). MIP restored SpO2 , immune/inflammatory response, normalized lung abnormalities (chest CT scan), and reduced mortality without any serious complications. However, there is a need for placebo-controlled double-blind and controlled clinical trials to confirm the efficacy.

An update on emerging therapeutics to combat COVID-19.

BACKGROUND: The COVID-19 pandemic has demanded effective therapeutic protocol from researchers and clinicians across the world. Currently, a large amount of primary data have been generated from several preclinical studies. At least 300 clinical trials are underway for drug repurposing against COVID-19; the clinician needs objective evidence-based medication to treat COVID-19. OBSERVATIONS: Single-stranded RNA viral genome of SARS-CoV-2 encodes structural proteins (spike protein), non-structural enzymatic proteins (RNA-dependent RNA polymerase, helicase, papain-like protease, 3-chymotrypsin-like protease) and other accessory proteins. These four enzymatic proteins on spike protein are rate-limiting steps in viral replications and, therefore, an attractive target for drug development against SARS-CoV-2. In silico and in vitro studies have identified various potential epitomes as candidate sequences for vaccine development. These studies have also revealed potential targets for drug development and drug repurposing against COVID-19. Clinical trials utilizing antiviral drugs and other drugs have given inconclusive results regarding their clinical efficacy and side effects. The need for angiotensin-converting enzyme (ACE-2) inhibitors/angiotensin receptor blockers and corticosteroids has been recommended. Western countries have adopted telemedicine as an alternative to prevent transmission of infection in the population. Currently, no proven, evidence-based therapeutic regimen exists for COVID-19. CONCLUSION: The COVID-19 pandemic has put tremendous pressure on researchers to evaluate and approve drugs effective against the disease. Well-controlled randomized trials should assess medicines that are not marketed with substantial evidence of safety and efficacy and more emphasis on time tested approaches for drug evaluation.

Ameliorative effects of Cuscuta reflexa and Peucedanum grande on letrozole induced polycystic ovary syndrome in Wistar rats.

OBJECTIVES: The current study was designed to examine the therapeutic role of hydroalcoholic extract of Cuscuta reflexa Roxb (CRE) and Peucedanum grande C.B. Clarke (PGE) on letrozole (1 mg/kg) induced polycystic ovary syndrome (PCOS) in female Wistar albino rats. METHODS: PCOS rats were treated with CRE (280 mg/kg), PGE (140 mg/kg) or CRE + PGE p.o. for 3 weeks. Vaginal smears for phase of estrous cycle determination, serum levels of sex androgens, lipid profile, oxidative stress parameters and histopathology of ovarian tissues were investigated. RESULTS: Diestrous cycle days treated with CRE (group III) or PGE (group IV) decreased significantly (p < 0.05) compared to PCOS control animals (group II). Moreover, weight of uteri in PCOS animals treated with the plant extracts also increased significantly (p < 0.05) compared to that of group II animals. Histopathological examination showed the protective effect of the CRE and PGE indicated by the disappearance of ovarian cyst. CONCLUSION: The study demonstrated that the CRE and PGE either alone or in combination hold a significant effect in letrozole induced PCOS rat models and could be useful in the management of reproductive and metabolic disorders related to PCOS.

Medicinal plants: Treasure for antiviral drug discovery.

The pandemic of viral diseases like novel coronavirus (2019-nCoV) prompted the scientific world to examine antiviral bioactive compounds rather than nucleic acid analogous, protease inhibitors, or other toxic synthetic molecules. The emerging viral infections significantly associated with 2019-nCoV have challenged humanity's survival. Further, there is a constant emergence of new resistant viral strains that demand novel antiviral agents with fewer side effects and cell toxicity. Despite significant progress made in immunization and regenerative medicine, numerous viruses still lack prophylactic vaccines and specific antiviral treatments that are so often influenced by the generation of viral escape mutants. Of importance, medicinal herbs offer a wide variety of therapeutic antiviral chemotypes that can inhibit viral replication by preventing viral adsorption, adhering to cell receptors, inhibiting virus penetration in the host cell, and competing for pathways of activation of intracellular signals. The present review will comprehensively summarize the promising antiviral activities of medicinal plants and their bioactive molecules. Furthermore, it will elucidate their mechanism of action and possible implications in the treatment/prevention of viral diseases even when their mechanism of action is not fully understood, which could serve as the base for the future development of novel or complementary antiviral treatments.