Identifying diseases associated with Post-COVID syndrome through an integrated network biology approach.

A growing body of research shows that COVID-19 is now recognized as a multi-organ disease with a wide range of manifestations that can have long-lasting repercussions, referred to as post-COVID-19 syndrome. It is unknown why the vast majority of COVID-19 patients develop post-COVID-19 syndrome, or why patients with pre-existing disorders are more likely to experience severe COVID-19. This study used an integrated network biology approach to obtain a comprehensive understanding of the relationship between COVID-19 and other disorders. The approach involved building a PPI network with COVID-19 genes and identifying highly interconnected regions. The molecular information contained within these subnetworks, as well as the pathway annotations, were used to reveal the link between COVID-19 and other disorders. Using Fisher's exact test and disease-specific gene information, significant COVID-19-disease associations were discovered. The study discovered diseases that affect multiple organs and organ systems, thus proving the theory of multiple organ damage caused by COVID-19. Cancers, neurological disorders, hepatic diseases, cardiac disorders, pulmonary diseases, and hypertensive diseases are just a few of the conditions linked to COVID-19. Pathway enrichment analysis of shared proteins revealed the shared molecular mechanism of COVID-19 and these diseases. The findings of the study shed new light on the major COVID-19-associated disease conditions and how their molecular mechanisms interact with COVID-19. The novelty of studying disease associations in the context of COVID-19 provides new insights into the management of rapidly evolving long-COVID and post-COVID syndromes, which have significant global implications.Communicated by Ramaswamy H. Sarma.

A deep learning and docking simulation-based virtual screening strategy enables the rapid identification of HIF-1α pathway activators from a marine natural product database.

Artificial Intelligence is hailed as a cutting-edge technology for accelerating drug discovery efforts, and our goal was to validate its potential in predicting pharmacological inhibitors of EGLN1 using a deep learning-based architecture, one of its subsidiaries. Egl nine homolog 1 (EGLN1) inhibition prevents poly ubiquitination-mediated proteosomal destruction HIF-1α. The pharmacological interventions aimed at stabilizing HIF-1α have the potential to be a promising treatment option for a range of human diseases, including ischemic stroke. To unveil a novel EGLN1 inhibitor from marine natural products, a custom-based virtual screening was carried out using a Deep Convolutional Neural Network (DCNN) architecture, docking, and molecular dynamics simulation. The custom DCNN model was optimized and further employed to screen marine natural products from the CMNPD database. The docking was performed as a secondary strategy for screened hits. Molecular dynamics (MD) and molecular mechanics/generalized Born surface area (MM-GBSA) were used to analyze inhibitor binding and identify key interactions. The findings support the claim that deep learning-based virtual screening is a rapid, reliable and accurate method of identifying highly contributing drug candidates (EGLN1 inhibitors). This study demonstrates that deep learning architecture can significantly accelerate drug discovery and development, and provides a solid foundation for using (Z)-2-ethylhex-2-enedioic acid [(Z)-2-ethylhex-2-enedioic acid] as a potential EGLN1 inhibitor for treating various health complications.Communicated by Ramaswamy H. Sarma.

Postischemic supplementation of folic acid improves neuronal survival and regeneration in vitro.

Supplementation of folic acid (FA) is beneficial to several neurological diseases because it promotes notch signaling and neurogenesis and reduces blood homocysteine levels. We hypothesized that postischemic supplementation of FA is beneficial for neuronal survival and regeneration. The objective of the present study was to determine the postischemic neuroprotective and neuroregenerative efficacy of FA supplementation and its effects on various cellular processes in vitro. This work benefited from the use of FA and glucose-free media to better assess the ischemic neuroprotection provided by FA supplementation. The postischemic supplementation of FA significantly improved cell viability, and the improvement was primarily by obstructing the oxygen-glucose deprivation (OGD)-activated apoptosis. Furthermore, postischemic treatment with FA significantly reduced the mitochondrial membrane depolarization and the formation of acidic organelles triggered by OGD. Moreover, FA's effect on neuroregeneration following OGD was evaluated by measuring the cell proliferation and neurite outgrowth length. Treatment with FA enhanced cell proliferation and neurite outgrowth significantly. Thus, these results revealed some of the mechanisms by which FA supplementation provided neuroprotection and neuroregeneration following ischemic injury and highlighted the need for further research into the potential of folic acid as a clinical drug for ischemic stroke.

Supplementation of biotin to sperm preparation medium enhances fertilizing ability of spermatozoa and improves preimplantation embryo development.

PURPOSE: Motility of spermatozoa helps not only in planning the type of infertility treatment but also directly reflects the success rate in assisted reproductive technology (ART). Previously, biotin, a water-soluble vitamin, has been shown to increase the motility and longevity of cryopreserved human spermatozoa. The present study was designed to understand the molecular basis of the beneficial effects of presence of biotin in sperm wash medium on early embryo development. METHODS: The effect biotin supplementation to sperm wash medium on the sperm parameters were assessed in swim-up fraction of normozoospermic and asthenozoospermic ejaculates collected from infertile men. Fertilization and early embryo development was studied using Swiss albino mice. RESULTS: Even though both biotin and pentoxifylline (PTX) enhanced the motility of spermatozoa from normozoospermic and asthenozoospermic samples, biotin group exhibited higher in vitro survival. Using mouse model, we observed that presence of biotin or PTX in sperm wash medium improved the fertilization rate and blastocyst rate compared to control. Blastocysts from these groups had significantly higher total cell number (P < 0.01) and lower apoptotic index. In silico target prediction revealed that GTPase HRas (HRas), tyrosine-protein phosphatase nonreceptor type 1 (PTP1B), and glucokinase are the probable targets for biotin. Solution-state Nuclear Magnetic Resonance (NMR) studies confirmed that biotin interacts both with human HRas and PTP1B. CONCLUSION: Our results indicate that presence of biotin in sperm wash medium can improve the fertilization potential and preimplantation embryo development and can be considered as a safe alternate to PTX.

Post stroke depression: The sequelae of cerebral stroke.

Post-stroke depression (PSD) is the most common mental health issue, afflicting around 33% of stroke survivors. PSD has a negative impact on the rehabilitation, recuperation of motor and cognitive deficits following stroke and significantly increases the chances of relapsing neurovascular events. It has been demonstrated that biological and psychological factors have a significant role in PSD. Numerous endeavors have been made to discover the risk factors and predictors of PSD. Screening and diagnosis also have gained attention; however, a suitable tool is yet to be developed. Medications are chosen based on their viability and reaction profile in the patients. Besides pharmacotherapy, psychotherapy treatment is also highly valued by both psychiatrists and stroke patients. Additional research is needed to examine the pathophysiology of PSD. This review attempts to highlight the existing evidence and gaps in the present knowledge of the predictors of PSD, incidence, prevalence, and etiology. Further, it also discusses the screening and diagnostic approaches, therapeutic modalities and management of PSD and the impact of pre-stroke depression on PSD.

Computational repositioning and experimental validation of approved drugs for HIF-prolyl hydroxylase inhibition.

HIF stability and activation are governed by a family of dioxygenases called HIF prolyl-4-hydroxylases (PHDs). It has been identified as a new target to augment the adaptive machinery that governs cytoprotection in disorders associated with ischemia/reperfusion, inflammation, and oxidative stress. In this sense, PHD inhibition has been proposed to mimic, at least in part, the protective effects of exposure to hypoxia. Exploiting drug polypharmacology to identify novel modes of actions for drug repurposing has gained significant attention in the current era of weak drug pipelines. The present work plan aims at giving new purpose to some well-established FDA-approved drugs. Here, we propose that by combining the literature survey, docking, and manual interpretation altogether, we were able to perform virtual screening on FDA-approved drugs to identify potential PHD inhibitors. Upon screening of 1537 marketed drugs, a final set of six hits were selected for experimental testing. All six drugs were divers, and immuno blotting was carried out to evaluate their ability to upregulate HIF in order to validate our hypothesis. Out of the six, three drugs showed significant upregulation of HIF possibly by inhibiting the PHD. It is believed that the appropriate use of the literature survey, docking, manual interpretation, and experimental validation strategy in the drug design process should improve the ability to identify hits and confirm their potential to serve as basis for drug repurposing.