Amentoflavone derivatives significantly act towards the main protease (3CLPRO/MPRO) of SARS-CoV-2: in silico admet profiling, molecular docking, molecular dynamics simulation, network pharmacology.

SARS-CoV-2 is the foremost culprit of the novel coronavirus disease 2019 (nCoV-19 and/or simply COVID-19) and poses a threat to the continued life of humans on the planet and create pandemic issue globally. The 3-chymotrypsin-like protease (MPRO or 3CLPRO) is the crucial protease enzyme of SARS-CoV-2, which directly involves the processing and release of translated non-structural proteins (nsps), and therefore involves the development of virus pathogenesis along with outbreak the forecasting of COVID-19 symptoms. Moreover, SARS-CoV-2 infections can be inhibited by plant-derived chemicals like amentoflavone derivatives, which could be used to develop an anti-COVID-19 drug. Our research study is designed to conduct an in silico analysis on derivatives of amentoflavone (isoginkgetin, putraflavone, 4''''''-methylamentoflavone, bilobetin, ginkgetin, sotetsuflavone, sequoiaflavone, heveaflavone, kayaflavone, and sciadopitysin) for targeting the non-structural protein of SARS-CoV-2, and subsequently further validate to confirm their antiviral ability. To conduct all the in silico experiments with the derivatives of amentoflavone against the MPRO protein, both computerized tools and online servers were applied; notably the software used is UCSF Chimera (version 1.14), PyRx, PyMoL, BIOVIA Discovery Studio tool (version 4.5), YASARA (dynamics simulator), and Cytoscape. Besides, as part of the online tools, the SwissDME and pKCSM were employed. The research study was proposed to implement molecular docking investigations utilizing compounds that were found to be effective against the viral primary protease (MPRO). MPRO protein interacted strongly with 10 amentoflavone derivatives. Every time, amentoflavone compounds outperformed the FDA-approved antiviral medicine that is currently underused in COVID-19 in terms of binding affinity (- 8.9, - 9.4, - 9.7, - 9.1, - 9.3, - 9.0, - 9.7, - 9.3, - 8.8, and - 9.0 kcal/mol, respectively). The best-selected derivatives of amentoflavone also possessed potential results in 100 ns molecular dynamic simulation (MDS) validation. It is conceivable that based on our in silico research these selected amentoflavone derivatives more precisely 4''''''-methylamentoflavone, ginkgetin, and sequoiaflavone have potential for serving as promising lead drugs against SARS-CoV-2 infection. In consequence, it is recommended that additional in vitro as well as in vivo research studies have to be conducted to support the conclusions of this current research study.

Natural flavonoids effectively block the CD81 receptor of hepatocytes and inhibit HCV infection: a computational drug development approach.

Hepatitis C virus (HCV) infection is a major public health concern, and almost two million people are infected per year globally. This is occurred by the diverse spectrum of viral genotypes, which are directly associated with chronic liver disease (fibrosis, and cirrhosis). Indeed, the viral genome encodes three principal proteins as sequentially core, E1, and E2. Both E1 and E2 proteins play a crucial role in the attachment of the host system, but E2 plays a more fundamental role in attachment. The researchers have found the "E2-CD81 complex" at the entry site, and therefore, CD81 is the key receptor for HCV entrance in both humans, and chimpanzees. So, the researchers are trying to block the host CD81 receptor and halt the virus entry within the cellular system via plant-derived compounds. Perhaps that is why the current research protocol is designed to perform an in silico analysis of the flavonoid compounds for targeting the tetraspanin CD81 receptor of hepatocytes. To find out the best flavonoid compounds from our library, web-based tools (Swiss ADME, pKCSM), as well as computerized tools like the PyRx, PyMOL, BIOVIA Discovery Studio Visualizer, Ligplot+ V2.2, and YASARA were employed. For molecular docking studies, the flavonoid compounds docked with the targeted CD81 protein, and herein, the best-outperformed compounds are Taxifolin, Myricetin, Puerarin, Quercetin, and (-)-Epicatechin, and outstanding binding affinities are sequentially - 7.5, - 7.9, - 8.2, - 8.4, and - 8.5 kcal/mol, respectively. These compounds have possessed more interactions with the targeted protein. To validate the post docking data, we analyzed both 100 ns molecular dynamic simulation, and MM-PBSA via the YASARA simulator, and finally finds the more significant outcomes. It is concluded that in the future, these compounds may become one of the most important alternative antiviral agents in the fight against HCV infection. It is suggested that further in vivo, and in vitro research studies should be done to support the conclusions of this in silico research workflow.

Treatments against Polymorphosal discrepancies in Glioblastoma Multiforme.

Glioblastoma (GB) are aggressive tumors that obstruct normal brain function. While the skull cannot expand in response to cancer growth, the growing pressure in the brain is generally the first sign. It can produce more frequent headaches, unexplained nausea or vomiting, blurred peripheral vision, double vision, a loss of feeling or movement in an arm or leg, and difficulty speaking and concentrating; all depend on the tumor's location. GB can also cause vascular thrombi, damaging endothelial cells and leading to red blood cell leakage. Latest studies have revealed the role of single nucleotide polymorphisms (SNPs) in developing and spreading cancers such as GB and breast cancer. Many discovered SNPs are associated with GB, particularly in great abundance in the promoter region, creating polygenetic vulnerability to glioma. This study aims to compile a list of some of the most frequent and significant SNPs implicated with GB formation and proliferation.

Melatonergic Receptors (Mt1/Mt2) as a Potential Additional Target of Novel Drugs for Depression.

A complex pathogenesis involving several physiological systems is theorized to underline the development of depressive disorders. Depression is accompanied by circadian regulation disruption and interaction with the functioning of both central and peripheral oscillators. Many aspects of melatonin function unite these systems. The use of drugs for circadian rhythm disorders could inspire a potential treatment strategy for depression. Melatonin plays an essential role in the regulation of circadian rhythms. It exerts effect by activating two types of melatonin receptors, type 1A (MT1) and 1B (MT2). These are G-protein-coupled receptors, predominantly located in the central nervous system. MT1/MT2 agonists could be a useful treatment approach according to all three prevalent theories of the pathogenesis of depression involving either monoamines, synaptic remodeling, or immune/inflammatory events. MT1/MT2 receptors can be a potential target for novel antidepressants with impact on concentrations of neurotrophins or neurotransmitters, and reducing levels of pro-inflammatory cytokines. There is an interesting cross-talk mediated via the physical association of melatonin and serotonin receptors into functional heteromers. The antidepressive and neurogenetic effects of MT1/MT2 agonists can also be caused by the inhibition of the acid sphingomyelinase, leading to reduced ceramide, or increasing monoamine oxidase A levels in the hippocampus. Compounds targeting MT1 and MT2 receptors could have potential for new anti-depressants that may improve the quality of therapeutic interventions in treating depression and relieving symptoms. In particular, a combined effect on MT1 and/or MT2 receptors and neurotransmitter systems may be useful, since the normalization of the circadian rhythm through the melatonergic system will probably contribute to improved treatment. In this review, we discuss melatonergic receptors as a potential additional target for novel drugs for depression.

Tuberculosis amidst COVID-19 in Pakistan: a massive threat of overlapping crises for the fragile healthcare systems.

Mycobacterium tuberculosis is the cause of tuberculosis (TB), a granulomatous illness that mostly affects the lungs. Pakistan is one of the eight nations that accounts for two-thirds of all new cases of developing TB. TB has long been an endemic disease in Pakistan. According to the World Health Organization (WHO) estimates, the nation has over 500 000 incident TB infections per year, with a rising number of drug-resistant cases. Recently, the coexistence of COVID-19 and TB in Pakistan has provided doctors with a problem. Fever or chills, cough, shortness of breath or difficulty breathing are all signs of COVID-19. After SARS-CoV-2 infection, cough might persist for weeks or months and it is frequently accompanied by persistent tiredness, cognitive impairment, dyspnoea or pain - a group of long-term consequences known as post-COVID syndrome or protracted COVID. Coughing with mucus or blood, and coughing that continues over 2 months are indications of TB. The same clinical presentation features make it difficult for healthcare personnel to effectively evaluate the illness and prevent the spread of these fatal diseases. Pakistan lacks the necessary healthcare resources to tackle two contagious diseases at the same time. To counteract the sudden increase in TB cases, appropriate management and effective policies must be implemented. Thus, in order to prevent the spread of these infectious diseases, it is critical to recognise and address the problems that the healthcare sector faces, as well as to create an atmosphere in which the healthcare sector can function at its full potential.

HIV epidemic amidst COVID-19 pandemic in India: a conundrum for the country's healthcare system.

India has the third-largest burden of human immunodeficiency virus (HIV) infection in the world. The coronavirus disease 2019 (COVID-19) pandemic has only exposed the cracks in the Indian healthcare infrastructure concerning HIV. The prevalence of HIV in India is more among the destitute or sections of society shrouded by years of social stigma such as prostitutes, truck drivers, transsexuals and intravenous drug users. National AIDS Control Organisation and The Joint United Nations Programme on HIV/AIDS (UNAIDS) organisation have many several efforts over the years to set up counselling and testing centres all over the country and spread awareness about HIV among the masses. COVID-19 pandemic has reversed years of progress made by the same. HIV patients are biologically more susceptible to COVID-19, and the lockdown has led to the loss of jobs, economic crises, shortage of drugs and necessities such as food and housing among this vulnerable population, which can result in lowered CD4-T cell counts in the coming months and make way for dangerous opportunistic infection outbreaks in this population increasing the overall HIV burden of India. This article explores how COVID-19 has impacted India's already existing HIV epidemic and tries to put forth recommendations based on the evidence found to be better prepared in treating the HIV-positive population in India in the face of another catastrophe like the COVID-19.

Unravelling the potential neuroprotective facets of erythropoietin for the treatment of Alzheimer's disease.

During the last three decades, recombinant DNA technology has produced a wide range of hematopoietic and neurotrophic growth factors, including erythropoietin (EPO), which has emerged as a promising protein drug in the treatment of several diseases. Cumulative studies have recently indicated the neuroprotective role of EPO in preclinical models of acute and chronic neurodegenerative disorders, including Alzheimer's disease (AD). AD is one of the most prevalent neurodegenerative illnesses in the elderly, characterized by the accumulation of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), which serve as the disease's two hallmarks. Unfortunately, AD lacks a successful treatment strategy due to its multifaceted and complex pathology. Various clinical studies, both in vitro and in vivo, have been conducted to identify the various mechanisms by which erythropoietin exerts its neuroprotective effects. The results of clinical trials in patients with AD are also promising. Herein, it is summarized and reviews all such studies demonstrating erythropoietin's potential therapeutic benefits as a pleiotropic neuroprotective agent in the treatment of Alzheimer's disease.

Role of extracellular vesicles in intercellular communication during reproduction.

The mammalian reproduction is a process of controlled cellular growth and development regulated by constant communication between the gametes, the subsequent embryo and the maternal system. Extracellular vesicles (EVs) are involved in these communications to a significant degree from the gamete production and maturation to fertilization, embryo development and implantation. They regulate the cellular physiology and the immune reaction to bring about a favourable environment for a successful pregnancy. Deciphering the mechanisms employed in EV-mediated embryo maternal communication could improve our knowledge in mammalian reproduction and increase the efficiency of animal breeding.

COVID-19 vaccination strategies and policies in India: The need for further re-evaluation is a pressing priority.

India is one of the worst-hit nations by the COVID-19 pandemic and witnessed a devastating impact across cities in the country. Although behavioral measures like wearing a face mask, maintaining social distance, and hand hygiene helped to control the spread of the disease initially, but a long-term action by vaccinating the population is a promising solution. On 16 January 2021, India undertook the challenge to vaccinate 300 million people by August 2021 against COVID-19, the largest vaccination campaign globally. India has been lauded by several prominent organizations around the world for its efforts. But catering to India's massive population is not without its own set of complex challenges. As of 29 July 2021, a mere 9.82 million (approximately 7.03 percent of the total Indian population) people have been fully vaccinated against COVID-19 with the first and second dose, and only 352.5 million (roughly 25.28 percent of the total Indian population) have been partly vaccinated with the first dose. This shows, India's current COVID-19 vaccination policies and plans are still inadequate and not undisputedly equitable even after several amendments in the guidelines. However, even with the second wave abating slowly and steadily in India, there is a need to further re-strategize the current vaccination policy and plans in India against COVID-19 to help achieve long-term positive outcomes in the shortest feasible time frame hoping to evade a third wave.

Polio amidst COVID-19 in Pakistan: Ongoing efforts, challenges, and recommendations.

Poliomyelitis is a crippling viral disease caused by poliovirus, a positive-stranded RNA virus that is a serotype of Enterovirus C. Pakistan remains one of the countries in the world where poliomyelitis is still prevalent, posing an obstacle to global poliomyelitis eradication. With the commencement of the COVID-19 pandemic, polio eradication campaigns have proven less feasible, resulting in an increase in polio cases across the country. Pakistan's healthcare system and socio-economic framework are incapable of dealing with two deadly viruses at the same time. As a result, effective measures for combating the destruction caused by the spread of the poliovirus are required.

Impact of COVID-19 pandemic on viral hepatitis in Africa: Challenges and way forward.

With the overwhelming COVID-19 pandemic in Africa, many other severe epidemics have been given low priority, such as viral hepatitis. Patient mortality due to viral hepatitis has raised concern to COVID-19 patients due to compromise with undiagnosed hepatitis in Africa. The pandemic has worsened the control of the viral hepatitis epidemic as healthcare control facilities have moved their focus towards curbing COVID-19 infections. However, different challenges have arisen to viral hepatitis patients because of low health attention that declines the progress of already diagnosed hepatitis patients. Follow-up plans, routine testing and treatment plans for viral hepatitis are no longer as strict with the human resources transferred towards combating the pandemic. Thus, a global effort is required to abide by renewed recommendations to eradicate viral hepatitis in Africa that also fit the current picture of the COVID-19 pandemic. The article discusses the current challenges viral hepatitis patients faced during the COVID-19 pandemic and important recommendations that can see through these challenges in Africa.

Dengue and Coronavirus disease (COVID-19) syndemic: Double threat to an overburdened healthcare system in Africa.

Dengue fever (DF) is a significant public health problem in the African continent. The primary prevention strategy against the disease is vaccination and entomological control of vectors; however, implementing such a strategy in several countries in the continent is far below what is necessary to control the disease. The Coronavirus disease (COVID-19) pandemic further aggravated this situation and negatively impacted these measures, mainly the coverage of vaccination campaigns, due to restrictive measures to control the disease. Therefore, the most significant risk is that the incidence of DF in the continent will increase even more in the coming years, as a reflection of the negative impact of the pandemic on the control of the disease. To prevent another public health crisis, immediate and multidisciplinary approaches are required to address the epidemiological control of DF in African countries.

People living with mental disorder in Nigeria amidst COVID-19: Challenges, implications, and recommendations.

COVID-19 has become a global public health obstacle. This disease has caused negligence on mental health institutions, decreased trust in the healthcare system and traditional and religious beliefs, and has created a widespread stigma on people living with mental health illness, specifically in Nigeria. The increase of COVID-19 cases that have exhausted the healthcare system in Nigeria have brought further negligence to people living with mental disorder, thus increasing the burden of the disease on these patients. Overall, this article considerably highlighted the need for equal accessibility to healthcare resources, as well as the requirement of proper attention and care for mental health patients in Nigeria. This article discusses the challenges that surfaced because of the COVID-19 pandemic on people living with mental illness and their implications, as well as suggesting necessary actions and recommendations.

The risk of cutaneous mucormycosis associated with COVID-19: A perspective from Pakistan.

As a developing country, Pakistan reports a high burden of fungal diseases, of which cutaneous mucormycosis remains a prominent infection, presenting as a highly invasive disease with significant mortality. Apart from a high population of at-risk individuals, multiple factors have precipitated an increment in mucormycosis cases in the country following the COVID-19 pandemic. These include increased use of corticosteroids, immunosuppression following the viral infection, prolonged stays in the intensive care unit and sub-optimal laboratory testing available in the country. This article aims to assess the potential implications of a mucormycosis epidemic on a healthcare system already strained under the COVID-19 pandemic, and provides subsequent recommendations to weather the dual challenge of two deadly pathogens.

A Comprehensive Analysis and Anti-Cancer Activities of Quercetin in ROS-Mediated Cancer and Cancer Stem Cells.

Reactive oxygen species (ROS) induce carcinogenesis by causing genetic mutations, activating oncogenes, and increasing oxidative stress, all of which affect cell proliferation, survival, and apoptosis. When compared to normal cells, cancer cells have higher levels of ROS, and they are responsible for the maintenance of the cancer phenotype; this unique feature in cancer cells may, therefore, be exploited for targeted therapy. Quercetin (QC), a plant-derived bioflavonoid, is known for its ROS scavenging properties and was recently discovered to have various antitumor properties in a variety of solid tumors. Adaptive stress responses may be induced by persistent ROS stress, allowing cancer cells to survive with high levels of ROS while maintaining cellular viability. However, large amounts of ROS make cancer cells extremely susceptible to quercetin, one of the most available dietary flavonoids. Because of the molecular and metabolic distinctions between malignant and normal cells, targeting ROS metabolism might help overcome medication resistance and achieve therapeutic selectivity while having little or no effect on normal cells. The powerful bioactivity and modulatory role of quercetin has prompted extensive research into the chemical, which has identified a number of pathways that potentially work together to prevent cancer, alongside, QC has a great number of evidences to use as a therapeutic agent in cancer stem cells. This current study has broadly demonstrated the function-mechanistic relationship of quercetin and how it regulates ROS generation to kill cancer and cancer stem cells. Here, we have revealed the regulation and production of ROS in normal cells and cancer cells with a certain signaling mechanism. We demonstrated the specific molecular mechanisms of quercetin including MAPK/ERK1/2, p53, JAK/STAT and TRAIL, AMPKα1/ASK1/p38, RAGE/PI3K/AKT/mTOR axis, HMGB1 and NF-κB, Nrf2-induced signaling pathways and certain cell cycle arrest in cancer cell death, and how they regulate the specific cancer signaling pathways as long-searched cancer therapeutics.

Anti-depressants and COVID-19: A New Ray of Hope.

The coronavirus disease pandemic has grown worldwide. As we understand the exact pathophysiology of the disease and how it affects the systems in the human body, we are in the process of discovering and repositioning drugs potentially effective in these regards. A few targets of these drugs are excessive inflammation following SARS-CoV-2 infection and sigma-1 receptor ER chaperone protein, which plays a role in replication. The recent discovery of antidepressants like fluvoxamine and clomipramine acting through these targets may provide a new ray of hope to decrease mortality and morbidity in severe COVID patients.

Viral infections amidst COVID-19 in Africa: Implications and recommendations.

Viral infections have been on the rise for the past decades. The impact of the viruses worsened amidst the pandemic burdening the already overwhelmed health care system in African countries. This article sheds light on how the coronavirus together with the already existing viral infections, some of which re-emerged, impacted the continent. The strategies in place such as immunization, education, will have to be strengthened in all African countries to reduce the burden. Furthermore, governments can further collaborate with other countries in creating guidelines to reduce co-infection of the diseases.

COVID-19 and mucormycosis syndemic: double health threat to a collapsing healthcare system in India.

In addition to the overwhelming and uncontrollable second wave of COVID-19 in India, the country is also dealing with an outbreak of mucormycosis, a deadly fungal infection, which is affecting thousands of COVID-19 patients. With the increasing number of cases of mucormycosis and a fatality rate of 50%, many Indian states and union territories have declared an epidemic of black fungus due to its unprecedented emergence, which has adversely affected the already debilitated health system of the country. The advent of the new fungal epidemic in the country is due to the overdosage, panic and injudicious use of corticosteroids among COVID-19 patients, as well as their pre-existing medical history of diabetes, given that India is the diabetes capital of the world. Thus, there is an urgent need to address this public health concern by having nationwide surveillance, diagnostic and management system of the disease, along with public awareness and education to combat the syndemic of COVID-19 and mucormycosis in the country.

The dilemma of treating the infected versus the wounded: Gaza's healthcare system is choked.

Gaza has been facing persistent disturbance since the last 14 years. Even before the pandemic, Gaza faced a dire healthcare consequence with prevalent instability, lack of adequate medical resources, and limited health-related infrastructure. Gaza continued to struggle while responding to the pandemic as the other nearby countries. However, the challenges were compounded with the onset of the conflict that affected Gaza's infrastructure and displaced tens of thousands to make-shift shelters. The testing capacity of Gaza is alarmingly low that makes any outbreak difficult to document. Additionally, all medical centres have been affected by the ongoing conflict. These centres, if not directly impacted, are severely overwhelmed with those injured during the conflict, shifting focus and resources away from coronavirus. Vaccinations in Gaza cover only 1.9% of the population and a great number of unvaccinated people now may act as vectors of transmission in overcrowded shelters. Furthermore, non-availability of clean water to maintain hygienic conditions has heightened the risk of an explosive surge in cases. Hence, beyond the ceasefire, further steps need to be taken to strengthen Gazan response to COVID-19 pandemic.

Resurgence of tuberculosis amid COVID-19 in Peru: Associated risk factors and recommendations.

Peru is one of the countries with the highest incidence of tuberculosis and multidrug-resistant tuberculosis in the world. Although public health measures adopted in the country have improved the care, diagnosis and management of patients with tuberculosis, there are still failures in the control of the disease in the country, especially of multidrug-resistant tuberculosis and among the prison population or people living with HIV. The COVID-19 pandemic has added a great burden to the Peruvian public health system, negatively impacting tuberculosis-focused health programs due to the diversion of resources to control the pandemic. Consequently, combat measures, epidemiological surveillance of tuberculosis cases were affected, and data point to an increase in the number of cases, especially of multidrug-resistant tuberculosis, and to the underdiagnosis of the disease. To deal with this problem and avoid a future catastrophe for the country's health system, multidisciplinary measures involving the population, health professionals and government bodies are needed. It is essential that education, diagnosis, contact screening and treatment programs are prioritised and given greater financial support. Furthermore, it is necessary to raise awareness in the population about the need for isolation and maintenance of treatment, especially among the most vulnerable populations.