Clinical status of potential drugs used for COVID-19 treatment and recent advances in new therapeutics – A review

COVID-19, a perilous disease caused by SARS-CoV-2, has brought a massive damage to humankind, and turned into a global catastrophe. It was first reported in Wuhan, China in December 2019 and since then has been a constant source of worry for the scientists and the medical world, due to the carnage it has caused globally. Extensive clinical studies are being carried to explore drug therapy and prophylaxis to combat this pestilence.  It is still an excessively big challenge for the scientists and pharmacological industry to develop potential drugs for the treatment of this deadly virus. At present though no specific drug has been identified as a perfect cure for this zoonotic disease, medical practitioners are using the therapy of repurposing of drugs for the treatment. Systemic research was carried out through e-resources to identify drugs for the treatment of COVID-19. A recent proposal of 2-DG drug as a cure for COVID-19 has also been discussed in this review.

Testosterone in the pathogenesis of tuberculosis

Tuberculosis is a leading cause of death from infectious diseases worldwide with more than 1.5 million deaths occurring annually. Males have been known to be more susceptible to tuberculosis than females. Sex hormones could be an important factor governing this gender bias. Here, we discuss the evidence that testosterone may be a crucial factor in male susceptibility to tuberculosis considering that testosterone impairs important factors which have a significant bearing on the outcome of tuberculosis. We also discuss possible underlying mechanisms through which testosterone modulates the immune response that is necessary for host resistance to tuberculosis. We discuss various models that have helped to uncover the role of testosterone in the outcome of infection by M. tuberculosis. Studying the role of testosterone on the various components that constitute the immune response to the disease have provided valuable insights into the sexual dichotomy observed in male bias in tuberculosis morbidity.

A comparative study of isothermal nucleic acid amplification methods for SARS-CoV-2 detection at point-of-care

COVID-19, caused by the novel coronavirus SARS-CoV-2, has put most of the world under lockdown. Despite approved vaccines, COVID-19 cases, hospitalizations, and deaths have remained on the rise. Rapid diagnosis and necessary public health measures are still key parts to contain the pandemic. Here, the colorimetric isothermal nucleic acid amplification tests (iNAATs) for SARS-CoV-2 detection based on loop-mediated isothermal amplification (LAMP), cross-priming amplification (CPA), and polymerase spiral reaction (PSR) were designed and compared in performance for the first time. The findings showed that, for the detection of SARS-CoV-2 genomic-RNA, LAMP outperformed both CPA and PSR, exhibiting the limit of detection (LOD) of roughly 43.14 copies/reaction. The results can be read with the naked eye within 45 minutes, without cross-reactivity to closely related coronaviruses. The direct detection of SARS-CoV-2 RNA in simulated specimens by iNAATs was also successful. Additionally, the lyophilized reagents for LAMP reactions maintained the sensitivity and LOD of the liquid assays. The colorimetric LAMP assay was validated using clinical samples, showing 98.1% sensitivity and 100% specificity upon using extracted samples and 82.4% sensitivity and 86.2% specificity upon using unextracted specimens. The results indicate that the direct colorimetric LAMP assay developed is highly suitable for detecting SARS-CoV-2 at point-of-care.

Immunoendocrine regulation of energy homeostasis and male reproduction

Human reproductive system involve a number of intricate complex interconnected physiological metabolic pathways and metabolites with involvement of overall health of different body organs. Overall health alterations mediated physiological conditions such as obesity, diabetes etc. bring about additional variations in expression and presence of metabolic constituents including kinases, hormones, proteins, peptides. The detailed analysis of various molecules like endocrine hormones, neuropeptides, immunity and inflammation associated kinases and proteins that have an end effect in cells and tissues, and might be playing a role in impacting male reproduction have been deliberated here. A deliberative collection of obesity and infertility related molecules including endocrine hormones, cytokines, adipokines, adiponectin, resistin, visfatin, ghrelin, orexins, leptin, adropin, chemerin, along with diabetes and age related physiological impact analysis on male reproductive system have been included in this selective compilation. An in-depth understanding of changes and introduction of new intermediate molecules for regulation of physiological phenomena like energy homeostasis in obesity regulation and their interlinked associated impact on the male fertility potential would provide a reflection for possible development of new therapeutics.

Resistin and visfatin: ‘connecting threads’ of immunity, energy modulations and male reproduction

Adipokines, mostly produced by white adipose tissues, have been established to be endocrine factors which are also essential in energy homeostasis. More recently, their contribution in fertility regulation has been recommended. Resistin as well as visfatin are unique adipocyte-derived signaling chemicals whose expressions enhance in advanced obesity and are implicated in insulin resistance as well as type-2 diabetes. They are also found to be immune modulators and may participate in aggravating inflammatory responses which may partly explain obesity-mediated systemic inflammation. They are yet much less explored adipokines with potential to regulate metabolic rate, immune homeostasis as well as fertility. These adipokines are shown to be expressed in the hypothalamus in an area in charge of energy balance. Evidence suggest that they can potentially affect the hypothalamo-pituitary-gonadal (HPG) axis thereby modulating reproductive functions. They are also found to be expressed highly by the testes. In rodents, resistin and visfatin may positively modulate Leydig cell number and steroidogenesis. Additionally, visfatin exists in the human spermatozoa and may play role in the sperm maturation. However, reports on the impact of resistin and visfatin on human male fertility are inconsistent. In this article, we review the available literature on the role resistin and visfatin on male reproduction and integrate the mechanisms to discuss if they act as sensor for body energy dyshomeostatis and modulate male reproductive functions as per the metabolic status.

Leptin in Energy homeostasis, Male reproduction, and Immune regulation

Discovery of leptin has changed the view of adipose tissue from energy storehouse to active neuroendocrine and immune organ. Adipokineleptin is a16 kDa amino acid protein, encoded by LEP gene, secreted by adipose tissue, and acts through leptin receptor which is a cytokine receptor. Leptin is a central regulator of energy homeostasis by regulating food intake, appetite, satiety and basal metabolism. Leptin acts at each level of hypothalamus pituitary gonadal axis (HPG) and has a key role in initiation, progression of pubertal events and sexual maturation. Leptin acts directly at testicular level and affects the spermatogenesis, sperm quality and capacitation thus have important role in male reproduction and fertility. Leptin receptors are present on every cell involved in innate and adaptive immunity and regulate the functions of these cells. Leptin acts as common link between energy homeostasis, reproduction, stress responses and immune system by modulating common complex neuronal circuits. Leptin is implicated in pathogenesis of multiple disorders like obesity, type 2 diabetes mellitus, Systemic Lupus Erythematosis, osteoarthritis, rheumatoid arthritis, male infertility and other chronic inflammatory disorders. Therapies based on modulating the functions of leptin can be the key area of research in future for treatment of these chronic disorders.

Journal: Chemical Biology Letters

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Lactobacillus casei and Bifidobacterium bifidum reduces postprandial hyperglycaemia, inhibits α-glucosidase activity and improve histology of pancreatic islets in streptozotocin induced diabetic rats

Lactobacillus and Bifidobacteria are generally accredited as potential anti-diabetic agents, but the mechanism of action is still not clear. This study aimed to investigate the result of administration of Lactobacillus casei and Bifidobacterium bifidum on α-glucosidase enzyme, postprandial blood glucose level, and histological changes that occur in the pancreatic β-cells in streptozotocin (STZ (50 mg/kg body weight)) induced diabetic rats. The experimental diabetic rats were treated with a single dose of L. casei and B. bifidum alone and combination for 28 days. The diabetic animals of a positive control group were treated with the standard hypoglycaemic drug, acarbose (10mg/kg body weight). Maltose and starch tolerance tests were performed. Treatment demonstrated significant hypoglycemic activity, lower postprandial blood glucose levels induced by maltose and starch loading in diabetic rats. The results demonstrated that L. casei and B. bifidum had α-glucosidase inhibitory activity and can reduce blood glucose level observed from the maltose and starch tolerance test. Histological analysis showed treatment prevented the function of pancreatic islets and regenerate degenerated cells.

Journal: Chemical Biology Letters

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Orexins: the ‘multitasking’ neuropeptides in the energy metabolism and immune regulation of male reproduction

Orexins are hypothalamus-derived neuropeptides with versatile functions. The most explored domains of orexins’ functions are their influence on the central nervous system (CNS) implicated in the regulation of sleep/wakefulness cycle, food intake behavior, energy homeostasis, and cognitive processes. Orexins reportedly bear two isoforms, orexin-A (OXA) and orexin-B (OXB), that act via their specific G protein-coupled receptor (GPCR), OX1R and OX2R. These peptides also play vital roles in various other peripheral organs where they regulate metabolism, neuroendocrine functions, blood pressure, as well as reproductive functions. Interestingly orexins also exhibit immuno-regulatory, anti-inflammatory properties and facilitate the mechanism of obesity resistance. Recent research has also shed light on significant role of orexins, in particular orexin A, in regulating reproductive functions in male since the Leydig cells, Sertoli cells, germ cells in various stages of the development, and even the epididymis and penis, manifest the OXA receptor. It will be intriguing to explore the properties of the orexins in reversing obesity, downregulation of inflammatory responses and mediation of male reproductive functions. The present article thus reviews these multitudinous properties of orexins and comprehends the possible connection among the behavioral, metabolic, anti-inflammatory functions of orexins with their roles in male reproduction.

Journal: Chemical Biology Letters

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Chemerin and male reproduction: ‘a tangled rope’ connecting metabolism and inflammation

Adipokines are peptides produced mainly by the fat tissue adipocytes and their levels are sensitive to alterations in metabolic state. While there is little known about the impact of adipokines on male reproductive control, both animal-based experimental data and clinical research suggest that they can influence numerous male fertility indices. Chemerin is a newly found adipokine which is generally recognized as a chemoattractant and chemokine. Chemerin has been correlated with inflammatory reactions and metabolic imbalances, as seen in various metabolic syndromes. A sex dimorphic chemerin expression pattern has also been shown with greater levels in men in comparison to women. Chemerin can thus be offered as a potential new candidate in the connection among metabolic disorders, inflammation and male reproduction. The present article explores the multidimensional metabolic and inflammatory roles of chemerin and discusses its impact upon the male reproduction.

Journal: Chemical Biology Letters

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An economic and efficient synthesis of acid-labile glycerol based β-thiopropionate esters for potential application in drug delivery

Acid labile linkers have been used widely for various biomedical applications with preferential applications in drug delivery. In this report, we have synthesized, glycerol based b-thiopropionate esters having an acid-labile β-thiopropionate linker with Michael addition reaction between hydrophobic thiol and hydrophilic tri-glycerol diacrylate. The solvent free reaction and purification by simply solvent extraction instead of any sophisticated chromatographic techniques provide an upper edge for their application in biomedical or other fields. These β-thiopropionate esters can potentially be used for the delivery and release of hydrophobic drugs at acidic sites particularly in cancer cells.

Journal Chemical Biology Letters