scholarly journals Therapeutic Modalities for Sars-Cov-2 (Covid-19): Current Status and Role of Protease Inhibitors to Block Viral Entry Into Host Cells

2020 ◽  
Vol 14 (3) ◽  
pp. 1695-1703
Author(s):  
Sarmad Ahmad Qamar ◽  
Kanta Basharat ◽  
Muhammad Bilal ◽  
Hafiz M.N. Iqbal
Keyword(s):  
Protease Inhibitors ◽  
Viral Entry ◽  
Host Cells ◽  
Type I Interferons ◽  
World Health ◽  
Current Status ◽  
Type I ◽  
Respiratory Pathway ◽  
Therapeutic Modalities ◽  
Health Organization

An acute respiratory disease (SARS-CoV-2, also recognized as COVID-19/2019-nCoV), caused by nCoV created a worldwide emergency. The World Health Organization declared the SARS-CoV-2 as epidemic of international concern on January 2020. After SARS-CoV in 2002 and MERS-CoV in 2012, the emergence of SARS-CoV-2 is marked as third highly pathogenic coronavirus of 21st century. Till now, various researches have been conducted, highlighting SARS-CoV-2 as β-coronavirus with high phylogenetic and genomic similarity with bat-CoV, indicating bats as natural reservoir of coronaviruses. It has also been confirmed that SARS-CoV-2 uses the same (ACE2) receptor for host cellular entry as of SARS-CoV, and primarily spread through respiratory pathway. Evidences shows continuous human-to-human viral transfer, with numerous worldwide exported cases. Currently, there is no specific approved drug available for the treatment of SARS-CoV-2, but various anti-parasitic and anti-viral drugs are being investigated. In this review, we have described several possible therapeutic modalities for SARS-CoV-2 infection based on (i) host protease inhibitors to block viral entry into the cell; (ii) gene silencing using siRNA-based RNAi and (iii) type I interferons (IFN1)-based therapeutics have been discussed in detail. Background knowledge on these strategies highlight them as potential therapeutic targets, which could be evaluated on urgent basis to combat COVID-19 epidemic.

scholarly journals Variable Clinical Manifestations of COVID-19; Viral and Human Genomes Talk

2020 ◽  
Author(s):  
Zeinab Imani-Saber ◽  
Hajar Vaseghi ◽  
Mojdeh Mahdian ◽  
Fatemeh Safari ◽  
Mohsen Ghadami
Keyword(s):  
Viral Entry ◽  
Drug Transport ◽  
Phylogenetic Analyses ◽  
Clinical Manifestations ◽  
Host Cells ◽  
World Health ◽  
Ongoing Research ◽  
Transmission Mechanisms ◽  
Human Genomes ◽  
Health Organization

The new coronavirus, known as “SARS-CoV-2”; is the cause of one of the most prevalent infectious viral diseases that was recently announced pandemic by the world health organization. Ongoing research in the fields of prevention, management, and therapy establishes a functional scaffold for clinics during the time of crisis. To obtain this goal, it is necessary that all pathophysiologic aspects of COVID-19 from infection to predisposing backgrounds of infection be identified, so that all the ambiguities of researchers regarding transmission mechanisms, variable clinical manifestation, and therapeutic response can be solved. Here, we firstly discuss about the homology screening between nCoV-2019 and beta-coronavirus family using phylogenetic analyses. Secondly, we analyzed the viral motifs to show that viral entry into the host cells requires a primary activation step performed by FURIN and FURIN-like-mediated enzymatic cleavage on the structural glycoprotein. The cleavage increases viral performance by 1000 folds. We then present a comprehensive view on host cells and the significance of gene variants affecting activation enzymes, supportive entry, and spread mechanisms in humans including renin-angiotensin-aldosterone system (RAAS) a pathway results in certain phenotypes or exacerbate infection-related phenotypes in different organs, hence causes variable clinical manifestations. This is followed by discussing about the importance of personalized medicine in nCoV-2019 exposure. Moreover, chemical drugs prescribed for individuals affected with COVID-19, as well as genes involved in drug transport and metabolisms are reviewed as a prelude to drug response. Finally, we suggest some therapeutic approaches developed based on new methods and technology such as anti-sense therapy and antibodies.

Heterocycles in the Treatment of Neglected Tropical Diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Kush K. Maheshwari ◽  
Debasish Bandyopadhyay
Keyword(s):  
Developing Countries ◽  
Heterocyclic Compounds ◽  
Neglected Tropical Diseases ◽  
World Health ◽  
Current Status ◽  
Poor People ◽  
Tropical Diseases ◽  
Concise Review ◽  
The World ◽  
Health Organization

Background: Neglected tropical diseases (NTDs) affect a huge population of the world and majority of the victims belong to the poor community of the developing countries. Until now, the World Health Organization (WHO) has identified 20 tropical diseases as NTDs that must be addressed with high priority. However, many heterocyclic scaffolds have demonstrated potent therapeutic activity against several NTDs. Objective: There are three major objectives: (1) To discuss the causes, symptoms, and current status of all the 20 NTDs; (2) To explore the available heterocyclic drugs, and their mechanism of actions (if known) that are being used to treat NTDs; (3) To develop general awareness on NTDs among the medicinal/health research community and beyond. Methods: The 20 NTDs have been discussed according to their alphabetic orders along with the possible heterocyclic remedies. Current status of treatment with an emphasis on the heterocyclic drugs (commercially available and investigational) has been outlined. In addition, brief discussion of the impacts of NTDs on socio-economic condition is included. Results: NTDs are often difficult to diagnose and the problem is worsened by the unhealthy hygiene, improper awareness, and inadequate healthcare in the developing countries where these diseases primarily affect poor people. The statistics include duration of suffering, numbers affected, and access to healthcare and medication. The mechanism of actions of various heterocyclic drugs, if reported, have been briefly summarized. Conclusion: Scientists and pharmaceutical corporations should allocate more resources to reveal the in-depth mechanism of actions of many heterocyclic drugs that are currently being used for the treatment of NTDs. Analysis of current heterocyclic compounds and development of new medications can help in the fight to reduce/remove the devastating effects of NTDs. An opinion-based concise review has been presented. Based on available literature, this is the first effect to present all the 20 NTDs and related heterocyclic compounds under the same umbrella.

scholarly journals Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 675
Author(s):  
Samira Elmanfi ◽  
Mustafa Yilmaz ◽  
Wilson W. S. Ong ◽  
Kofi S. Yeboah ◽  
Herman O. Sintim ◽  
...  
Keyword(s):  
Immune Response ◽  
Periodontal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Vaccine Adjuvants ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

scholarly journals Promising Novel Biomarkers in Cardiovascular Diseases

2021 ◽  
Vol 11 (8) ◽  
pp. 3654
Author(s):  
Brigitte Sipos ◽  
Peter Jirak ◽  
Vera Paar ◽  
Richard Rezar ◽  
Moritz Mirna ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Diagnostic Yield ◽  
Accurate Estimate ◽  
World Health ◽  
Current Status ◽  
Fatty Acid Binding ◽  
Type Plasminogen Activator ◽  
Common Causes ◽  
Novel Biomarkers ◽  
Health Organization

Cardiovascular diseases remain the most common causes of death globally, according to the World Health Organization. In recent years, a great number of biomarkers have been investigated, whereas only some have gained value in the diagnosis, prognosis, and risk stratification of different cardiovascular illnesses. As numerous studies have investigated the diagnostic yield of novel biomarkers in various disease entities every year, this review aims to provide an overview of the current status of four promising representatives. In particular, this manuscript refers to soluble suppression of tumorigenicity 2 (sST2), heart-type fatty acid binding protein (H-FABP), growth differentiation factor (GDF-15) and soluble urokinase-type plasminogen activator receptor (suPAR). These markers are of special interest as they are thought to provide an accurate estimate of cardiovascular risk in certain patient populations, especially those with pre-existing diseases, such as obesity or diabetes mellitus. We sought to give an overview of their function, individual diagnostic and predictive value and determination in the laboratory. A review of the literature regarding the aforementioned cardiovascular biomarkers yielded manifold results with respect to their individual diagnostic and prognostic value. Yet, the clinical relevance of these findings remains unclear, warranting further studies to identify their optimal use in clinical routine.

scholarly journals Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021

2021 ◽  
Vol 12 ◽  
Author(s):  
Safaet Alam ◽  
Taslima Binte Kamal ◽  
Md. Moklesur Rahman Sarker ◽  
Jin-Rong Zhou ◽  
S. M. Abdur Rahman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Case Series ◽  
Basic Knowledge ◽  
World Health ◽  
Current Status ◽  
Drug Candidates ◽  
Health Organization ◽  
Meta Analyses

COVID-19, transmitted by SARS-CoV-2, is one of the most serious pandemic situations in the history of mankind, and has already infected a huge population across the globe. This horrendously contagious viral outbreak was first identified in China and within a very short time it affected the world's health, transport, economic, and academic sectors. Despite the recent approval of a few anti-COVID-19 vaccines, their unavailability and insufficiency along with the lack of other potential therapeutic options are continuing to worsen the situation, with valuable lives continuing to be lost. In this situation, researchers across the globe are focusing on repurposing prospective drugs and prophylaxis such as favipiravir, remdesivir, chloroquine, hydroxychloroquine, ivermectin, lopinavir-ritonavir, azithromycin, doxycycline, ACEIs/ARBs, rivaroxaban, and protease inhibitors, which were preliminarily based on in vitro and in vivo pharmacological and toxicological study reports followed by clinical applications. Based on available preliminary data derived from limited clinical trials, the US National Institute of Health (NIH) and USFDA also recommended a few drugs to be repurposed i.e., hydroxychloroquine, remdesivir, and favipiravir. However, World Health Organization later recommended against the use of chloroquine, hydroxychloroquine, remdesivir, and lopinavir/ritonavir in the treatment of COVID-19 infections. Combining basic knowledge of viral pathogenesis and pharmacodynamics of drug molecules as well as in silico approaches, many drug candidates have been investigated in clinical trials, some of which have been proven to be partially effective against COVID-19, and many of the other drugs are currently under extensive screening. The repurposing of prospective drug candidates from different stages of evaluation can be a handy wellspring in COVID-19 management and treatment along with approved anti-COVID-19 vaccines. This review article combined the information from completed clinical trials, case series, cohort studies, meta-analyses, and retrospective studies to focus on the current status of repurposing drugs in 2021.

scholarly journals A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

2009 ◽  
Vol 206 (9) ◽  
pp. 1899-1911 ◽  
Author(s):  
Sarah M. McWhirter ◽  
Roman Barbalat ◽  
Kathryn M. Monroe ◽  
Mary F. Fontana ◽  
Mamoru Hyodo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Map Kinases ◽  
Second Messenger ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Host Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

Quality of Life of Parents of Children with Type I Diabetes Mellitus, Baghdad 2017

2021 ◽  
Vol 17 (2) ◽  
pp. 107-114
Author(s):  
Sadik Jaafar Shukur ◽  
Wijdan Akram Hussein ◽  
Nazik L. Kadhum
Keyword(s):  
Quality Of Life ◽  
Diabetes Mellitus ◽  
World Health Organization ◽  
World Health ◽  
Type I ◽  
Healthy Children ◽  
Social Domain ◽  
Chronic Hyperglycemia ◽  
Health Organization

Background: Diabetes is defined by the World Health Organization as a metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. Families are co-regulating systems in which the stresses and strains of one family member affect the well-being of another member of the family. Caregivers of children with chronic illness report experiencing more parental stress than parents of healthy children. Objective: A descriptive cross-sectional study had been conducted in four centers of endocrine diseases in Baghdad city and data was collected by using self-administered questionnaire regarding quality of life adapted from World Health Organization. The study was conducted on six hundred participants. Data analysis was done by using frequency, percentage and mean and analytical statistics using Chi Square test.  P value less than 0.05 was considered statistically significant. Results: The study showed that social domain had the highest mean score of (51.1) and that environmental domain had the lowest mean score of (38.9). The physical domain’s mean score was (40.2), while mean score of psychological domain was (46.2). The study reported that mothers of children with type 1 diabetes mellitus were more affected than fathers in physical, psychological and environmental domains. There was no difference between mothers and fathers in social domain of quality of life. Conclusion: It was concluded from the study that parents of diabetic children had generally poor quality of life that merits further investigations.

Induction of HOXA3 by PRRSV inhibits IFN-I response through negatively regulation of HO-1 transcription

2021 ◽  
Author(s):  
Yingtong Feng ◽  
Xuyang Guo ◽  
Hong Tian ◽  
Yuan He ◽  
Yang Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Host Cells ◽  
Type I Interferons ◽  
Economic Losses ◽  
Heme Oxygenase 1 ◽  
Type I

Type I interferons (IFN-I) play a key role in the host defense against virus infection, but porcine reproductive and respiratory syndrome virus (PRRSV) infection does not effectively activate IFN-I response, and the underlying molecular mechanisms are poorly characterized. In this study, a novel transcription factor of the heme oxygenase-1 (HO-1) gene, homeobox A3 (HOXA3), was screened and identified. Here, we found that HOXA3 was significantly increased during PRRSV infection. We demonstrated that HOXA3 promotes PRRSV replication by negatively regulating the HO-1 gene transcription, which is achieved by regulating type I interferons (IFN-I) production. A detailed analysis showed that PRRSV exploits HOXA3 to suppress beta interferon (IFN-β) and IFN-stimulated gene (ISG) expression in host cells. We also provide direct evidence that the activation of IFN-I by HO-1 depends on its interaction with IRF3. Then we further proved that deficiency of HOXA3 promoted the HO-1-IRF3 interaction, and subsequently enhanced IRF3 phosphorylation and nuclear translocation in PRRSV-infected cells. These data suggest that PRRSV uses HOXA3 to negatively regulate the transcription of the HO-1 gene to suppress the IFN-I response for immune evasion. IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), caused by PRRSV, leads the pork industry worldwide to significant economic losses. HOXA3 is generally considered to be an important molecule in the process of body development and cell differentiation. Here, we found a novel transcription factor of the HO-1 gene, HOXA3, can negatively regulate the transcription of the HO-1 gene and play an important role in the suppression of IFN-I response by PRRSV. PRRSV induces the upregulation of HOXA3, which can negatively regulate HO-1 gene transcription, thereby weakening the interaction between HO-1 and IRF3 for inhibiting the type I IFN response. This study extends the function of HOXA3 to the virus field for the first time and provides new insights into PRRSV immune evasion mechanism.

scholarly journals Chemical and Biological Components of Urban Aerosols in Africa: Current Status and Knowledge Gaps

2019 ◽  
Vol 16 (6) ◽  
pp. 941 ◽  
Author(s):  
Egide Kalisa ◽  
Stephen Archer ◽  
Edward Nagato ◽  
Elias Bizuru ◽  
Kevin Lee ◽  
...  
Keyword(s):  
Management Strategies ◽  
Complex Mixture ◽  
Ambient Air ◽  
World Health ◽  
Current Status ◽  
Middle Income ◽  
Middle Income Countries ◽  
Polycyclic Aromatic ◽  
Nitro Derivatives ◽  
Health Organization

Aerosolized particulate matter (PM) is a complex mixture that has been recognized as the greatest cause of premature human mortality in low- and middle-income countries. Its toxicity arises largely from its chemical and biological components. These include polycyclic aromatic hydrocarbons (PAHs) and their nitro-derivatives (NPAHs) as well as microorganisms. In Africa, fossil fuel combustion and biomass burning in urban settings are the major sources of human exposure to PM, yet data on the role of aerosols in disease association in Africa remains scarce. This review is the first to examine studies conducted in Africa on both PAHs/NPAHs and airborne microorganisms associated with PM. These studies demonstrate that PM exposure in Africa exceeds World Health Organization (WHO) safety limits and carcinogenic PAHs/NPAHs and pathogenic microorganisms are the major components of PM aerosols. The health impacts of PAHs/NPAHs and airborne microbial loadings in PM are reviewed. This will be important for future epidemiological evaluations and may contribute to the development of effective management strategies to improve ambient air quality in the African continent.

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