Comparison of disinfectants-induced gene expression profile: Potential adverse effects.

Despite their importance in combating the spread of the COVID-19 pandemic, adverse effects of disinfectants on human health, especially the respiratory system, have been of continuing concern to researchers. Considering that bronchi are the main target of sprayed disinfectants, we here treated the seven major active ingredients in disinfectant products accepted by the US EPA to human bronchial epithelial cells and determined the subtoxic levels. Then, we performed microarray analysis using total RNA obtained at the subtoxic level and designed a network representing disinfectant-induced cellular response using the KEGG pathway analysis technique. Polyhexamethylguanidine phosphate, a lung fibrosis inducer, was used as a reference material to verify the relationship between cell death and pathology. The derived results reveal potential adverse effects along with the need for an effective application strategy for each chemical.

Technologies for Direct Detection of Covalent Protein-Drug Adducts.

In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important to gather experimental evidence on the existence of a covalent protein-drug adduct. In this work, we review established methods and technologies for the direct detection of a covalent protein-drug adduct, illustrated with examples from (recent) drug development endeavors. These technologies include subjecting covalent drug candidates to mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties of the ligand upon covalent adduct formation. Alternatively, chemical modification of the covalent ligand is required to detect covalent adducts by NMR analysis or activity-based protein profiling (ABPP). Some techniques are more informative than others and can also elucidate the modified amino acid residue or bond layout. We will discuss the compatibility of these techniques with reversible covalent binding modes and the possibilities to evaluate reversibility or obtain kinetic parameters. Finally, we expand upon current challenges and future applications. Overall, these analytical techniques present an integral part of covalent drug development in this exciting new era of drug discovery.

Synthesis of 6″-Modified Kanamycin A Derivatives and Evaluation of Their Antibacterial Properties.

Aminoglycosides are one of the first classes of antibiotics to have been used clinically, and they are still being used today. They have a broad spectrum of antimicrobial activity, making them effective against many different types of bacteria. Despite their long history of use, aminoglycosides are still considered promising scaffolds for the development of new antibacterial agents, particularly as bacteria continue to develop resistances to existing antibiotics. We have synthesized a series of 6″-deoxykanamycin A analogues with additional protonatable groups (amino-, guanidino or pyridinium) and tested their biological activities. For the first time we have demonstrated the ability of the tetra-N-protected-6″-O-(2,4,6-triisopropylbenzenesulfonyl)kanamycin A to interact with a weak nucleophile, pyridine, resulting in the formation of the corresponding pyridinium derivative. Introducing small diamino-substituents at the 6″-position of kanamycin A did not significantly alter the antibacterial activity of the parent antibiotic, but further modification by acylation resulted in a complete loss of the antibacterial activity. However, introducing a guanidine residue led to a compound with improved activity against S. aureus. Moreover, most of the obtained 6″-modified kanamycin A derivatives were less influenced by the resistant mechanism associated with mutations of the elongation factor G than the parent kanamycin A. This suggests that modifying the 6″-position of kanamycin A with protonatable groups is a promising direction for the further development of new antibacterial agents with reduced resistances.

Herbs-derived phytochemicals - a boon for combating COVID-19.

The recent pandemic, the novel coronavirus (COVID-19), has put the whole world on alert with the threat of the virus that targets the human respiratory system. The disease has affected more than 633.6 million people globally and caused 6.5 million deaths since November 18, 2022. About 12.94 billion people are vaccinated as of November 18, 2022. Due to varied climatic conditions, SARS-CoV-2 has shown rapid mutation in recent years. Because of the lack of appropriate therapeutic drugs, inadequate diagnostic mechanisms, life-supporting medical facilities, and lack of awareness, the spread of SARS-CoV-2 has become severe. Thus, the most efficient strategy to control this disease is to follow preventive measures. However, treating SARS-CoV-2 cases in Wuhan using traditional Chinese herbs has set an example to show how traditional health can contribute to treating this novel virus. Medicinal herbs are known for their antimicrobial, antibacterial, antiviral, immunomodulatory, immunoadjuvant, and anti-inflammatory properties. These medicinal herbs are used during cooking and consumed regularly worldwide. In this view, medicinal herbs gained evident attention. These herbs can serve as a potential and economical remedy for combating the lethal effects of COVID-19. The present review highlights the phytochemicals and their mechanisms of action in preventing SARS-CoV-2. Supplementary Information: The online version contains supplementary material available at 10.1007/s42535-023-00601-9.

Effectiveness of hand sanitizers in the prevention of COVID-19 and related public health concerns: A review

The COVID-19 pandemic poses a severe threat to public health, resulting in high levels of mortality and morbidity. In response, there has been a significant usage of hand sanitizers in homes, public places, and healthcare systems. In the global panic, the market has a variety of products, and there are serious concerns about the safety and the potential of hand sanitization as the blue bullet for COVID-19. Therefore, this article presents a critical review of types of hand sanitizers available on the market, their active ingredients coupled with their mode of action in the wake of antiviral efficacies. In addition, the adoption of a culture of hand sanitization by society could raise the demand for hand sanitizers for an extended period. The continuous use of hand sanitizers might pose some safety concerns. Consequently, the review articulates potential dangers associated with hand sanitizer used to equip suppliers and manufacturers with knowledge on the safety of different ingredients and formulations, hence safeguarding the final users.Copyright © 2022 The Author(s). This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.0 license.

Do uncommon plant phenolic compounds have uncommon properties? A mini review on novel flavonoids

Unique plants and their properties, once considered synonymous to medicine, remain a potent source for new compounds in modern science. Plant polyphenols and natural products continue to be investigated for effective treatments for the most persistent of human ailments. In this review, fifty novel plant phenolic compounds have been compiled and briefly described from the previous five years. Select compounds and notable plant species from genus Morinda and Sophora are further expanded on. Traditional medicine plants often contain rich and diverse mixtures of flavonoids, from which rare compounds should receive attention. The bioactivity of crude plant extracts, purified compounds and mixtures can differ greatly, requiring that these interactions and mechanisms of action be investigated in greater detail. Novel applications of uncommon natural products, namely mimosine and juglone, are explored within this review. The 2019 coronavirus pandemic has resulted in abrupt spike of related scientific publications: speculation is made regarding plant natural products and future of antiviral drug discovery.

Discussion on the mechanism of Xiyanping injection in the treatment of human coronavirus infection based on network pharmacology and molecular docking

Objective: To explore the mechanism of Xiyanping injection in the treatment of human coronavirus infection based on network pharmacology and molecular docking method. Methods: The active components and targets of Xiyanping injection were screened by CNKI, SwissTarget Prediction and Targetnet. The Human Gene Database (Genecards), Online Human Mendelian Inheritance Database (OMIM) and Therapeutic Target Database (TTD) were searched to predict disease targets. Venny 2.1.0, Cytoscape 3.8.2 and STRING11.5 were used to construct "drug target-disease target Venn diagram", "drug-active ingredient-target-disease network" and "protein interaction network". The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Bioinformatics, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for the enrichment analysis and visualization. Finally, molecular docking was performed by AutoDock Vina and PyMOL. Results: The active ingredient of Xiyanping injection was andrographolide, andrographolide had 140 targets, 1 812 potential targets of human coronavirus infection, and 35 common targets of Xiyanping and human coronavirus infection;PPI network analysis and molecular docking showed that MAPK9, MAPK8, TYK2, CDKI and interleukin (IL)-6 among the 35 common targets might be the key targets of Xiyanping injection in the treatment of human coronavirus infection. Lactone was tightly bound;enrichment analysis showed that key targets were closely related to protein phosphorylation, cell signal transduction, and gene expression regulation, and key targets were NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, FOXO signaling pathway, there was also an important link in the TNF signaling pathway. Conclusion: The active ingredient of Xiyanping injection was andmgrapholide, and its treatment of human coronavirus infection might affect NOD-like receptor signaling pathway, Toll-like receptor signaling pathway and FOXO signaling by inhibiting the activities of MAPK9, MAPK8, TYK2, CDK1 and IL-6. The activation of the pathway and the TNF signaling pathway regulates protein phosphorylation, cell signal transduction and gene expression, thereby exerting anti-inflammatory effects.

A survey of mechanisms underlying current and potential COVID-19 vaccines.

The emergence of SARS-CoV-2 caught the world off guard resulting in a global health crisis. Even though COVID-19 have caused the death of millions of people and many countries are still battling waves of infections, the odds of the pandemic ending soon have turned significantly in our favor. The key has been the development and distribution of a broad range of vaccines in record time. In this survey, we summarize the immunology required to understand the mechanisms underlying current and potential COVID-19 vaccines. Furthermore, we provide an up to date (according to data from WHO 27th of May, 2022) overview of the vaccine landscape consisting of 11 approved vaccines in phase 4, and a pipeline consisting of 161 vaccine candidates in clinical development and 198 in preclinical development (1). Our focus is to provide an understanding of the underlying biological mode of action of different vaccine platform designs, their advantages and disadvantages, rather than a deep dive into safety and efficacy data. We further present arguments concerning why a broad range of vaccines are needed and discuss future challenges.

The Synthesis of Urolithins and Their Derivatives and the Modes of Antitumor Action.

Urolithins are microbial metabolites derived from berries and pomegranate fruits, which display anti-inflammatory, anti-oxidative, and anti-aging activities. There are eight natural urolithins (urolithin A-E, M5, M6 and M7) isolated by now. Structurally, urolithins are phenolic compounds and belong to 6H-dibenzo[b,d]pyran-6-one. They have drawn considerable attention because of their vast range of biological activities and health benefits. Recent studies also suggest that they possess anti-SARS-CoV-2 and anticancer effects. In this article, the recent advances on the synthesis of urolithins and their derivatives from 2015 to 2021 are reviewed. To improve or overcome the solubility and metabolism stability issues, the modifications of urolithins are mainly centered on the hydroxy group and lactone group, and some compounds are showing promising results and potential for further study. The possible modes of antitumor action of urolithin are also discussed. Several signaling pathways, including PI3K-Akt, Wnt/ß-catenin pathways, and multiple receptors (aryl hydrocarbon receptor, estrogen and androgen receptors) and enzymes (tyrosinase and lactate dehydrogenase) are involved in the antitumor activity of urolithins.

Network Pharmacological Investigation of Sinomenine Action Against Synovitis

Background and Objective: Synovitis is characterized as the inflammation of the synovial membrane, which often occurs in osteoarthritis. The incidence of this medical condition may be related to age, immunological responses and other co-morbidities. Therefore, the objective of the study was to elucidate the anti-Synovitis potential of sinomenine. Materials and Methods: The associated targets about sinomenine and synovitis were investigated in Homo sapiens, which was then elucidated by the PPI network construction via STITCH database. Furthermore, Cytoscape and its plugin were used for gene ontology (GO) analysis. Results: The literature survey and the network revealed 25 potential target proteins to be associated with sinomenine, of which many proteins such as OPRD1, CHRM1 and DAMGO were found to be significantly related to the bioactive action of sinomenine in Homosapiens. Moreover,the GO terms which were associated with the functioning of sinomenine for its anti-Synovitis potential were found to befour, analyzed by the functional annotation gene clusters and abundance values of the target proteins. Conclusion: The results of the study demonstrate the anti-Synovitis potential of sinomenine, where its action is dependent upon the molecular mechanisms that exert its beneficial role against synovitis. The core mechanisms that may be related to its anti-synovitis action may be adenylate cyclase-activating G-protein coupled receptor signalling pathway, regulation of smooth muscle contraction, adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signalling pathway and positive regulation of nitric oxide metabolic process.

Investigating the Potential Anti-SARS-CoV-2 and Anti-MERS-CoV Activities of Yellow Necklacepod among Three Selected Medicinal Plants: Extraction, Isolation, Identification, In Vitro, Modes of Action, and Molecular Docking Studies.

The anti-MERS-CoV activities of three medicinal plants (Azadirachta indica, Artemisia judaica, and Sophora tomentosa) were evaluated. The highest viral inhibition percentage (96%) was recorded for S. tomentosa. Moreover, the mode of action for both S. tomentosa and A. judaica showed 99.5% and 92% inhibition, respectively, with virucidal as the main mode of action. Furthermore, the anti-MERS-CoV and anti-SARS-CoV-2 activities of S. tomentosa were measured. Notably, the anti-SARS-CoV-2 activity of S. tomentosa was very high (100%) and anti-MERS-CoV inhibition was slightly lower (96%). Therefore, the phytochemical investigation of the very promising S. tomentosa L. led to the isolation and structural identification of nine compounds (1-9). Then, both the CC50 and IC50 values for the isolated compounds against SARS-CoV-2 were measured. Compound 4 (genistein 4'-methyl ether) achieved superior anti-SARS-CoV-2 activity with an IC50 value of 2.13 µm. Interestingly, the mode of action of S. tomentosa against SARS-CoV-2 showed that both virucidal and adsorption mechanisms were very effective. Additionally, the IC50 values of S. tomentosa against SARS-CoV-2 and MERS-CoV were found to be 1.01 and 3.11 µg/mL, respectively. In addition, all the isolated compounds were subjected to two separate molecular docking studies against the spike (S) and main protease (Mpr°) receptors of SARS-CoV-2.

Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry.

The entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells requires binding of the viral spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor, which triggers subsequent conformational changes to facilitate viral and cellular fusion at the plasma membrane or following endocytosis. Here, we experimentally identified selective and broad inhibitors of SARS-CoV-2 entry that share a tricyclic ring (or similar) structure. The inhibitory effect was restricted to early steps during infection and the entry inhibitors interacted with the receptor binding domain of the SARS-CoV-2 spike but did not significantly interfere with receptor (ACE2) binding. Instead, some of these compounds induced conformational changes or affected spike assembly and blocked SARS-CoV-2 spike cell-cell fusion activity. The broad inhibitors define a highly conserved binding pocket that is present on the spikes of SARS-CoV-1, SARS-CoV-2, and all circulating SARS-CoV-2 variants tested and block SARS-CoV spike activity required for mediating viral entry. These compounds provide new insights into the SARS-CoV-2 spike topography, as well as into critical steps on the entry pathway, and can serve as lead candidates for the development of broad-range entry inhibitors against SARS-CoVs.

MERS-CoV e protein induces autophagy in 293T cells

Objective: To investigate the molecular mechanism of the action by which the MERS-CoV E proxein induces autophagy in 293T cells.

Review of action mechanisms of acupuncture on post-traumatic stress disorder

Post-traumatic stress disorder(PTSD) is a kind of mental disorder caused by severe traumatic events. It has a high incidence, a serious of impacts on the physical and mental health of patients. Especially in the current situation of COVID-19, the researches on PTSD are particularly important, but the choice of drugs available for PTSD is limited and it is often accompanied by adverse reactions. In the field of acupuncture, there are many clinical research evidences suggested that PTSD is a predominant disease of acupuncture. However, its action mechanisms have not been fully elucidated, so the possible mechanisms of acupuncture in treating PTSD were discussed.

When Scent Becomes a Weapon—Plant Essential Oils as Potent Bioinsecticides

Crop protection still mostly relies on synthetic pesticides for crop pest control. However, the rationale for their continued use is shaded by the revealed adverse effects, such as relatively long environmental persistence that leads to water and soil contamination and retention of residues in food that brings high risks to human and animal health. As part of integrated pest management, biopesticides may provide crop protection, being eco-friendly and safe for humans and non-target organisms. Essential oils, complex mixtures of low-molecular-weight, highly volatile compounds, have been highlighted as major candidates for plant-derived bioinsecticides that are up to the sustainable biological standard. In this review, we screened the insecticidal activity of essential oils or their purified compounds, with focus given to their modes of action, along with the analyzed advantages and problems associated with their wider usage as plant-derived insecticides in agriculture.

The molecular mechanism behind the pathogenic action of the SARS-CoV-2 virus, the role of the ACE2 receptors in the creation of surfactant and in the protection of large functional surfaces

COVID-19 is caused by the SARS-CoV-2 virus. SARS-CoV-2 is different from other corona viruses due to the fact that it can intensely bind to the ACE2 receptor. Expression of ACE2 receptors is especially characteristic for the following cells: alveolar type 2 cells, endothelial cells of both small and large arteries, and the smooth muscle cells of the arteries, enterocytes of the small intestine, Leydig and Sertoli cells, proximal cells of the renal tubules and intestine cells. A common characteristic of these organs, tissues and cells, which have a high ACE2 expression, is that they have a "large functional surface". ACE2 receptor is critical in maintaining the integrity and stability of these so called "large functional surfaces". Production of surfactant in order for the ACE2 receptor to realize its protective function. Surfactants role in the stabilization and immunoprotection of large functional surfaces. People with a lower number of ACE2 receptors (the obese, elderly, people with comorbidities, males) are more susceptible to the virus occupying all avalaible ACE2 receptors and blocking the production of surfactant to such a degree that the antigens of ''large functional surfaces" become visible to the immune system and cause a massive inflammatory response in the COVID-19 cases. The molecular mechanism of the pathological action of the SARS-CoV-2 virus as explained from the aspect of ACE2 binding and the subsequent inhibition of surfactant production.

Antiviral properties of Cistus .. incanus L. Pandalis proven in SARS-CoV-2 in vitro

Due to lack of reliable therapy and insufficient available vaccines against SARS-CoV-2, researchers are looking for promising and effective therapy in substances that are already available. The objective of the current study is to investigate whether the herbal preparation Cystus Pandalis.. (CPE) has in vitro antiviral properties against SARS-CoV-2. CPE has already proved to be effective against several other viruses. At the Fraunhofer Institute for Cell Therapy and Immunology (IZI), cell cultures treated with Cystus Pandalis.. extract were infected with SARS-CoV-2, and the reduction in the infection rate was evaluated by comparing focus-forming units. An almost complete reduction in the CPE infection rate was observed at concentrations of greater than 15.6 ..g/ml with a calculated EC50 (mean effective concentration) of 1.94 ..g/ml. The mechanism of action of this extract may be based on the highly polymeric polyphenols that envelop certain viral epitopes, whereby CPE acts as an entry inhibitor. The high in vitro activity of CPE seems to make it a reasonable candidate for prophylaxis against SARS-CoV-2.

Pathophysiology of COVID-19: known and unknown

The corona virus disease 2019 caused by severe acute respiratory syndrome corona virus-2 starts as a respiratory infection but can progress to multi-organ involvement with some very unique and unusual clinical presentations. This can appear at times puzzling and can account for significant morbidity and mortality. Understanding the pathophysiology of this disease can help reveal the various mechanisms of the progress of the disease and can explain the clinical symptoms and offer hope for prevention and treatment modalities.

Suspected cardiovascular side effects of two COVID-19 vaccines

Fatalities or cardiovascular side effects of vaccines were rather uncommon in the past. So far, numerous reports of side effects and deaths associated with the COVID-19 vaccination have been accepted behind the background of the pandemic situation and the priority vaccinated elderly population at the beginning of the vaccination campaign. Cardiac and heart circulatory disturbances respectively cardiovascular side effects associated with the application of COVID-19 vaccines have not been recognized up to now with the exception of thrombotic/embolic side effects and cases of myo-/pericarditis. But the mechanism of action suggests that down regulation of ACE2 by non-neutralized spike proteins may have cardiovascular effects. The objective of this analysis was to determine the total number of reported adverse events and fatalities and to record suspected important cardiovascular adverse events up to the cut-off date in European countries. Therefore, a current review/analysis of spontaneously reported fatalities as well as of adverse events after application of COVID-19 vaccines has been performed. Data were retrieved from the EudraVigilance web reports of the European Medicines Agency (EMA), partly also from the safety reports of the German PEI. COVID-19 vaccine-associated suspected side effects and related deaths are alarming. Surprisingly, numerous cardiovascular reactions were reported, many of which were life-threatening. Cardiac and heart circulatory caused fatalities alone accounted for about 33% of all ComirnatyR vaccine-related deaths. The second most important side effects were vascular thrombotic/embolic side effects, often also associated with serious consequences. Based on their quality and quantity, these side effects seem to be characteristic for spike-producing vaccines and do not appear to be substance-specific. Further investigations are needed to clarify the approximately 3.5 times more frequent cases of sinus vein thrombosis and the some different frequent cases of thrombotic/embolic events after VaxzevriaR. The hypothesis could be confirmed. Because of their importance and their sometimes life-threatening consequences, cardiovascular side effects need to be better communicated. Limitations of the investigation result from the individual reporting and recording procedure, the lack of detailed individual information and the lack of an appropriate comparison population.

Coronavirus disease 2019 and hypertension: how anti-hypertensive drugs affect COVID-19 medications and vice versa

Introduction. Hypertension, as a medical problem, is one of the most common disorders in cardiovascular disease. High blood pressure has been identified as one of the most familiar risk factors for the ongoing COVID-19 pandemic. We planned to explore the possible interactions between antihypertensive agents and drugs targeting SARS-CoV-2 with broad investigations in the mechanism of action and adverse effects of these medications. Methods. The electronic databases (PubMed, Scopus, and Google scholar) were searched by two of the coauthors to collect the papers relevant to the subject. The keywords searched were angiotensin converting enzyme inhibitors (ACEI), angiotensin-II receptor blockers (ARBs), sympatholytic drugs (alpha-1 blockers, beta blockers), vasodilators (calcium channel blockers, nitrates, hydralazine), diuretics, chloroquine, hydroxychloroquine, lopinavir/ritonavir, remdesivir, favipiravir, interferons, azithromycin, anti-cytokine agents, glucocorticoids, anticoagulant agents, nitric oxide and epoprostenol. Results. QT prolongation, hypokalemia, arrhythmia and increase the serum level of drugs are the most risky adverse effects of medications in patients with COVID-19 on anti-hypertensive drugs. Conclusion. Interaction of the drugs used for COVID-19 patients with anti-hypertensive drugs is an important issue that this review addresses.