Study on active compounds from Maxingganshi decoction for treatment of novel coronavirus pneumonia (COVID-19) based on network pharmacology and molecular docking method

Aim To explore the active compound of Maxingganshi decoction in treatment of novel coronavirus pneumonia(COVID-19). Methods With the help of TCMSP database, the chemical components and action targets of ephedra, almond, licorice, and gypsum in Maxingganshi decoction were searched, and then a C-T network, protein interaction analysis, GO functional enrichment analysis, and KEGG pathway enrichment were constructed. Analysis was performed to predict its mechanism of action. Results A total of 120 compounds in Maxingganshi decoction corresponded to 222 targets. PTGS2, ESR1, PPARG, AR, NOS2, NCOA2 acted on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, T cell receptor signaling pathways, etc. The results of molecular docking showed that the affinity of quercetin, kaempferol, glabridin and other core compounds was similar to recommended drugs in treatment of COVID-19. Conclusions The active compounds of Maxingganshi decoction can target multiple pathways to achieve the therapeutic effect of COVID-19.Copyright © 2020 Publication Centre of Anhui Medical University. All rights reserved.

Bacterial Lysate from the Multi-Strain Probiotic SLAB51 Triggers Adaptative Responses to Hypoxia in Human Caco-2 Intestinal Epithelial Cells under Normoxic Conditions and Attenuates LPS-Induced Inflammatory Response.

Hypoxia-inducible factor-1α (HIF-1α), a central player in maintaining gut-microbiota homeostasis, plays a pivotal role in inducing adaptive mechanisms to hypoxia and is negatively regulated by prolyl hydroxylase 2 (PHD2). HIF-1α is stabilized through PI3K/AKT signaling regardless of oxygen levels. Considering the crucial role of the HIF pathway in intestinal mucosal physiology and its relationships with gut microbiota, this study aimed to evaluate the ability of the lysate from the multi-strain probiotic formulation SLAB51 to affect the HIF pathway in a model of in vitro human intestinal epithelium (intestinal epithelial cells, IECs) and to protect from lipopolysaccharide (LPS) challenge. The exposure of IECs to SLAB51 lysate under normoxic conditions led to a dose-dependent increase in HIF-1α protein levels, which was associated with higher glycolytic metabolism and L-lactate production. Probiotic lysate significantly reduced PHD2 levels and HIF-1α hydroxylation, thus leading to HIF-1α stabilization. The ability of SLAB51 lysate to increase HIF-1α levels was also associated with the activation of the PI3K/AKT pathway and with the inhibition of NF-κB, nitric oxide synthase 2 (NOS2), and IL-1ß increase elicited by LPS treatment. Our results suggest that the probiotic treatment, by stabilizing HIF-1α, can protect from an LPS-induced inflammatory response through a mechanism involving PI3K/AKT signaling.

Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro.

Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO.

Analysis of medication regularities of epidemic disease prescription in Treatise on Febrile Diseases and mechanism of core drugs in treatment of COVID-19

Objective To analyze the medication rules of related epidemic disease prescription in Treatise on Febrile Diseases based on data mining, and the mechanism of "Chaihu (Bupleuri Radix)-Huangqin (Scutellariae Radix)” as the core drugs in the treatment of coronavirus disease 2019 (COVID-19) by network pharmacology, in order to explore the contemporary value of classical prescriptions in the treatment of epidemic diseases. Methods The prescriptions for treating epidemic diseases in Treatise on Febrile Diseases were screened, and the medication rules such as drug frequency, flavor and meridian tropism as well as correlation, apriori algorithm were analyzed by using software such as R language. The mechanism of the core drugs in the medication pattern in the treatment of COVID-19 was explored by the network pharmacology. A "disease-drug-ingredient-target” network was constructed on the selected components and targets with Cytoscape. The key targets were introduced into String database for network analysis of protein-protein interaction (PPI), and gene ontology (GO) functional analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were conducted in R language. Results A total of 61 prescriptions for treating epidemic diseases in Treatise on Febrile Diseases were included, including 52 traditional Chinese medicines (TCMs). In the top 20 high-frequency drugs, warm drugs, spicy drugs and qitonifying drugs were mainly used, mostly in the spleen and lung meridian. Chaihu (Bupleuri Radix) and Huangqin (Scutellariae Radix) herb pair had the strongest correlation. A total of five clusters were excavated: supplemented formula of Xiaochaihu Decoction (小柴胡汤), Sini Decoction (四逆汤), supplemented formule of Maxing Shigan Decoction (麻杏石甘汤), Fuling Baizhu Decoction (茯苓白术汤) and Dachengqi Decoction (大承气汤). A total of 45 active ingredients, 189 action targets of Bupleuri Radix-Scutellariae Radix herb pair, and 543 targets of COVID-19 were obtained from TCMSP and Genecards, and 64 intersection targets were generated. The results of the network analysis showed that the main components of core drugs pair against COVID-19 may be quercetin, wogonin, kaempferol baicalein, acacetin etc., and the core targets may be VEGFA, TNF, IL-6, TP53, AKT1, CASP3, CXCL8, PTGS2, etc. A total of 1871 related entries and 164 pathways were obtained by GO and KEGG enrichment analysis, respectively. Conclusion In Treatise on Febrile Diseases, the treatment of epidemic diseases mainly chose pungent, warm, spleen-invigorating and qi-tonifying herbs, such as Xiaochaihu Decoction, Sini Decoction and Dachengqi Decoction, etc. It was found that Bupleuri Radix-Scutellariae Radix core herb pair prevent and treat COVID-19 through multi-target targets such as PTGS2, IL-6 and TNF. The ancient prescriptions for treating epidemic disease in Treatise on Febrile Diseases may have significant reference value for the prevention and treatment of new epidemic diseases today. © 2023 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.

Baicalin Ameliorates Preeclampsia In Vitro by Regulating the miRNA-19a/PTEN Axis

Baicalin is a kind of extraction from herb, and had treatment effects in some disease, however, it has been unclear that it's effects in preeclampsia (PE). The aim of our work was to evaluate baicalin's effects in PE treatment and relative mechanisms in vivo. Using hypoxia to make PE cell model. First step, using difference baicalin concentration to treat. Next step, transfecting si-miRNA-19a to discuss miRNA-19a's effects in baicalin's treatment to PE. Measuring cell proliferation, apoptosis, invasion and migration by CCK-8, flow cytometer, transwell and wound healing assay. Relative protein and gene expression by WB and RT-qPCR assay. Analysis correlation between miRNA-19a and PTEN by dual-luciferase reporter gene assay. Compared with NC, cell proliferation was significantly depressed with apoptosis significantly increasing and invasion cell number and wound healing rates were significantly down-regulation. miRNA-19a expression was significantly down-regulation, PTEN expression was significantly up-regulation, and p-AKT and p-PI3K expressions were significantly down-regulation. With baicalin supplement, the cell's biological activities including cell proliferation, invasion and migration were significantly up-regulation with miRNA-19a increasing. Meanwhile, PTEN protein expression was significantly depressed and p-AKT and p-PI3K proteins expression were significantly increased (p < 0.001, respectively). By dual-luciferase reporter gene assay, miRNA-19a could target PTEN in cell lines. Baicalin had effects to improve PE with miRNA-19a/PTEN axis in vivo study.

Network pharmacology to uncover potential anti-inflammatory and immunomodulatory constituents in Curcuma longa rhizome as complementary treatment in COVID-19

The immune status of patients plays an essential role in COVID-19. Herbal medicine with immunomodulatory and anti-inflammatory effect could have potential as a complementary therapeutic along with modern medicine. This study aims to investigate the anti-inflammatory and immunomodulatory constituents of Curcuma longa (C. longa) and its possible mechanisms in COVID-19. We systematically sorted the biochemical of C. longa rhizome from literature and repository. Next, we investigated targets related to COVID-19 in the selected active phytochemical constituents and analyzed the possible mechanisms against COVID-19 and performed molecular docking with four essential target proteins in COVID-19 for further verification. Ten active phytochemical constituents of C. longa were predicted to interact with four protein targets. The epidermal growth factor was the most interacted protein targeted by Calebin A, curcumin, cyclocurcumin, demethoxycurcumin, turmeronol a, turmeronol b, caffeic acid, and quercetin. Interferon-gamma was performed as the most critical protein targeted by 4-hydroxycinnamic acid. Curcumin was also predicted to interact with toll-like receptor 4 and Ar-turmerone with angiotensin II receptor type 2. We also reported four signaling pathways associated with target proteins-active phytochemical constituents against COVID-19: cytokine-cytokine receptor interaction, tolllike receptor signaling pathway, Jak-STAT signaling pathway, and PI3K-Akt signaling pathway. In conclusion, multi compounds in C. longa might act synergistically against COVID-19 by affecting the inflammatory and immune responses, and other pathological processes through multiple targets and pathways. Copyright © Indradi RB et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Possible Therapeutic Targets from Derivatives of Natural Marine Products Based on PI3K/AKT Dependent Inhibitors in Viral Infection COVID-19.

Natural resources have long played a prominent part in conventional treatments as a parental source due to their multifaceted functions and lesser side effects. The diversity of marine products is a significant source of possible bioactive chemical compounds with a wide range of potential medicinal applications. Marine organisms produce natural compounds and new drugs with unique properties are produced from these compounds. A lot of bioactive compounds with medicinal properties are extracted from marine invertebrates, including Peptides, Alkaloids, Terpenoids, Steroids. Thus, it can be concluded that marine ecosystems are endowed with natural resources that have a wide range of medicinal properties, and it is important to examine the therapeutic and pharmacological capabilities of these molecules. So, finding particular inhibitors of the COVID-19 in natural compounds will be extremely important. Natural ingredients, in this light, could be a valuable resource in the progression of COVID-19 therapeutic options. Controlling the immunological response in COVID-19 patients may be possible by addressing the PI3K/Akt pathway and regulating T cell responses. T cell effector activity can be improved by preventing anti-viral exhaustion by suppressing PI3K and Akt during the early anti-viral response. The diversity of marine life is a significant supply of potentially bioactive chemical compounds with a broad range of medicinal uses. In this study, some biologically active compounds from marine organisms capable of inhibiting PI3K/AKT and the possible therapeutic targets from these compounds in viral infection COVID-19 have been addressed.

1,2,3,4,6-O-Pentagalloylglucose Protects against Acute Lung Injury by Activating the AMPK/PI3K/Akt/Nrf2 Pathway.

An acute lung injury (ALI) is a serious lung disease with a high mortality rate, warranting the development of novel therapies. Previously, we reported that 1,2,3,4,6-O-pentagalloylglucose (PGG) could afford protection against ALI, however, the PGG-mediated protective effects remain elusive. Herein, PGG (60 and 30 mg/kg) markedly inhibited the lung wet/drug weight ratio and attenuated histological changes in the lungs (p < 0.05). A pretreatment with PGG (60 and 30 mg/kg) reduced the number of total leukocytes and the production of pro-inflammatory cytokines IL-6 and IL-1ß in bronchoalveolar lavage fluid (p < 0.05). In addition, PGG (60 and 30 mg/kg) also attenuated oxidative stress by reducing the formation of formation and the depletion of superoxide dismutase to treat an ALI (p < 0.05). To further explore the PGG-induced mechanism against an ALI, we screened the PGG pathway using immunohistochemical analysis, immunofluorescence assays, and Western blotting (WB). WB revealed that the expression levels of adenosine monophosphate-activated protein kinase phosphorylation (p-AMPK), phosphoinositide 3-kinase (PI3K), protein kinase B phosphorylation (P-Akt), and nuclear factor erythroid 2-related factor (Nrf2) were significantly higher in the PGG group (60 and 30 mg/kg) than in the lipopolysaccharide group (p < 0.05); these findings were confirmed by the immunohistochemical and immunofluorescence results. Accordingly, PGG could be effective against an ALI by inhibiting inflammation and oxidative stress via AMPK/PI3K/Akt/Nrf2 signaling, allowing for the potential development of this as a natural drug against an ALI.

SARS-CoV-2 modulates inflammatory responses of alveolar epithelial type II cells via PI3K/AKT pathway.

Background: SARS-CoV-2 infects through the respiratory route and triggers inflammatory response by affecting multiple cell types including type II alveolar epithelial cells. SARS-CoV-2 triggers signals via its Spike (S) protein, which have been shown to participate in the pathogenesis of COVID19. Aim: Aim of the present study was to investigate the effect of SARS-CoV2 on type II alveolar epithelial cells, focusing on signals initiated by its S protein and their impact on the expression of inflammatory mediators. Results: For this purpose A549 alveolar type II epithelial cells were exposed to SARS CoV2 S recombinant protein and the expression of inflammatory mediators was measured. The results showed that SARS-CoV-2 S protein decreased the expression and secretion of IL8, IL6 and TNFα, 6 hours following stimulation, while it had no effect on IFNα, CXCL5 and PAI-1 expression. We further examined whether SARS-CoV-2 S protein, when combined with TLR2 signals, which are also triggered by SARS-CoV2 and its envelope protein, exerts a different effect in type II alveolar epithelial cells. Simultaneous treatment of A549 cells with SARS-CoV-2 S protein and the TLR2 ligand PAM3csk4 decreased secretion of IL8, IL6 and TNFα, while it significantly increased IFNα, CXCL5 and PAI-1 mRNA expression. To investigate the molecular pathway through which SARS-CoV-2 S protein exerted this immunomodulatory action in alveolar epithelial cells, we measured the induction of MAPK/ERK and PI3K/AKT pathways and found that SARS-CoV-2 S protein induced the activation of the serine threonine kinase AKT. Treatment with the Akt inhibitor MK-2206, abolished the inhibitory effect of SARS-CoV-2 S protein on IL8, IL6 and TNFα expression, suggesting that SARS-CoV-2 S protein mediated its action via AKT kinases. Conclusion: The findings of our study, showed that SARS-CoV-2 S protein suppressed inflammatory responses in alveolar epithelial type II cells at early stages of infection through activation of the PI3K/AKT pathway. Thus, our results suggest that at early stages SARS-CoV-2 S protein signals inhibit immune responses to the virus allowing it to propagate the infection while in combination with TLR2 signals enhances PAI-1 expression, potentially affecting the local coagulation cascade.

Dissecting the molecular mechanism of cepharanthine against COVID-19, based on a network pharmacology strategy combined with RNA-sequencing analysis, molecular docking, and molecular dynamics simulation.

OBJECTIVES: Recently, it has been reported that cepharanthine (CEP) is highly likely to be an agent against Coronavirus disease 2019 (COVID-19). In the present study, a network pharmacology-based approach combined with RNA-sequencing (RNA-seq), molecular docking, and molecular dynamics (MD) simulation was performed to determine hub targets and potential pharmacological mechanism of CEP against COVID-19. METHODS: Targets of CEP were retrieved from public databases. COVID-19-related targets were acquired from databases and RNA-seq datasets GSE157103 and GSE155249. The potential targets of CEP and COVID-19 were then validated by GSE158050. Hub targets and signaling pathways were acquired through bioinformatics analysis, including protein-protein interaction (PPI) network analysis and enrichment analysis. Subsequently, molecular docking was carried out to predict the combination of CEP with hub targets. Lastly, MD simulation was conducted to further verify the findings. RESULTS: A total of 700 proteins were identified as CEP-COVID-19-related targets. After the validation by GSE158050, 97 validated targets were retained. Enrichment results indicated that CEP acts on COVID-19 through multiple pathways, multiple targets, and overall cooperation. Specifically, PI3K-Akt signaling pathway is the most important pathway. Based on PPI network analysis, 9 central hub genes were obtained (ACE2, STAT1, SRC, PIK3R1, HIF1A, ESR1, ERBB2, CDC42, and BCL2L1). Molecular docking suggested that the combination between CEP and 9 central hub genes is extremely strong. Noteworthy, ACE2, considered the most important gene in CEP against COVID-19, binds to CEP most stably, which was further validated by MD simulation. CONCLUSION: Our study comprehensively illustrated the potential targets and underlying molecular mechanism of CEP against COVID-19, which further provided the theoretical basis for exploring the potential protective mechanism of CEP against COVID-19.

Pinostrobin: An Adipogenic Suppressor from Fingerroot (Boesenbergia rotunda) and Its Possible Mechanisms.

Obesity is a critical factor for chronic metabolic syndromes. The culinary plant fingerroot (Boesenbergia rotunda) has been reported for its anti-obesity activity. The anti-adipogenic effects of pandurantin A, a main component of fingerroot cultivated in Indonesia, have been studied. Nevertheless, the suppressive effect and related mechanisms of pinostrobin, a major constituent of Thai fingerroot, on adipogenesis have never been thoroughly investigated. This study aimed to evaluate the potential of pinostrobin to inhibit adipocyte differentiation. Culturing pre-adipocytes from both mouse (3T3-L1) and human (PCS-210-010) with pinostrobin at non-toxic concentrations (5-20 µM) for 48 h obviously hindered their differentiation into mature adipocyte as evidenced by reduced cellular lipid droplets. The lower levels of lipid metabolism-mediating proteins, namely C/EBPα, PPARγ, and SREBP-1c, as well as cellular triglyceride content were demonstrated in pinostrobin-treated 3T3-L1 cells when compared to the untreated control group. Additionally, pinostrobin modulated the signals of MAPK (p38 and JNK) and Akt (Akt/GSK3ß, Akt/AMPKα-ACC). These findings suggest the benefit of fingerroot as a source of phytopharmaceuticals for obesity prevention and management, with pinostrobin as the active principle.

Reproductive toxicity of ritonavir in male: Insight into mouse sperm capacitation.

Since COVID-19 began in 2019, therapeutic agents are being developed for its treatment. Among the numerous potential therapeutic agents, ritonavir (RTV), an anti-viral agent, has recently been identified as an important element of the COVID-19 treatment. Moreover, RTV has also been applied in the drug repurposing of cancer cells. However, previous studies have shown that RTV has toxic effects on various cell types. In addition, RTV regulates AKT phosphorylation within cancer cells, and AKT is known to control sperm functions (motility, capacitation, and so on). Although deleterious effects of RTV have been reported, it is not known whether RTV has male reproduction toxicity. Therefore, in this study, we aimed to investigate the effects of RTV on sperm function and male fertility. In the present study, sperm collected from the cauda epididymis of mice were incubated with various concentrations of RTV (0, 0.1, 1, 10, and 100 µM). The expression levels of AKT, phospho-AKT (Thr308 and Ser473), and phospho-tyrosine proteins, sperm motility, motion kinematics, capacitation status, and cell viability were assessed after capacitation. The results revealed that AKT phosphorylation at Thr308 and Ser473 was significantly increased, and the levels of tyrosine-phosphorylated proteins (at approximately 25 and 100 kDa) were significantly increased in a dose-dependent manner. In addition, RTV adversely affected sperm motility, motion kinematics, and cell viability. Taken together, RTV may have negative effects on sperm function through an abnormal increase in tyrosine phosphorylation and phospho-AKT levels. Therefore, individuals taking or prescribing RTV should be aware of its reproductive toxicity.

Donepezil Beyond Alzheimer’s Disease? A Narrative Review of Therapeutic Potentials of Donepezil in Different Diseases

Donepezil hydrochloride is an acetylcholine esterase inhibitor studied and approved to treat Alzheimer’s disease (AD). However, this drug can have positive therapeutic potential in treating different conditions, including various neurodegenerative disorders such as other types of dementia, multiple sclerosis, Parkinson’s disease, psychiatric and mood disorders, and even infectious diseases. Hence, this study reviewed the therapeutic potential of this drug in treating Alzheimer’s and other diseases by reviewing the articles from databases including Web of Science, Scopus, PubMed, Cochrane, and Science Direct. It was shown that donepezil could affect the pathophysiology of these diseases via mechanisms such as increasing the concentration of acetylcholine, modulating local and systemic inflammatory processes, affecting acetylcholine receptors like nicotinic and muscarinic receptors, and activating various cellular signaling via receptors like sigma-1 receptors. Despite many therapeutic potentials, this drug has not yet been approved for treating non-Alzheimer’s diseases, and more comprehensive studies are needed.

Mechanism of Huo-Xiang-Zheng-Qi in Preventing and Treating COVID-19: A Study Based on Network Pharmacology and Molecular Docking Techniques

Objective: The Chinese herbal formula Huo-Xiang-Zheng-Qi (HXZQ) is effective in preventing and treating coronavirus disease 19 (COVID-19) infection;however, its mechanism remains unclear. This study used network pharmacology and molecular docking techniques to investigate the mechanism of action of HXZQ in preventing and treating COVID-19. Methods: The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to search for the active ingredients and targets of the 10 traditional Chinese medicines (TCMs) of HXZQ prescription (HXZQP). GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmacogenomics Knowledge Base (PharmGKB), Therapeutic Target Database (TTD), and DrugBank databases were used to screen COVID-19-related genes and intersect them with the targets of HXZQP to obtain the drug efficacy targets. Cytoscape 3.8 software was used to construct the drug-active ingredient–target interaction network of HXZQP and perform protein–protein interaction (PPI) network construction and topology analysis. R software was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Finally, AutoDock Vina was utilized for molecular docking of the active ingredients of TCM and drug target proteins. Results: A total of 151 active ingredients and 250 HXZQP targets were identified. Among these, 136 active ingredients and 67 targets of HXZQP were found to be involved in the prevention and treatment of COVID-19. The core proteins identified in the PPI network were MAPK1, MAPK3, MAPK8, MAPK14, STAT3, and PTGS2. Using GO and KEGG pathway enrichment analysis, HXZQP was found to primarily participate in biological processes such as defense response to a virus, cellular response to biotic stimulus, response to lipopolysaccharide, PI3K-Akt signaling pathway, Th17 cell differentiation, HIF-1 signaling pathway, and other signaling pathways closely related to COVID-19. Molecular docking results reflected that the active ingredients of HXZQP have a reliable affinity toward EGFR, MAPK1, MAPK3, MAPK8, and STAT3 proteins. Conclusion: Our study elucidated the main targets and pathways of HXZQP in the prevention and treatment of COVID-19. The study findings provide a basis for further investigation of the pharmacological effects of HXZQP.

Integrating network pharmacology and molecular docking to explore the potential mechanism of Xinguan No. 3 in the treatment of COVID-19

Xinguan No. 3 has been recommended for the treatment of coronavirus disease 2019 (COVID-19);however, its potential mechanisms are unclear. This study aims to explore the mechanisms of Xinguan No. 3 against COVID-19 through network pharmacology and molecular docking. We first searched the ingredients of Xinguan No. 3 in three databases (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Traditional Chinese Medicines Integrated Database, and The Encyclopedia of Traditional Chinese Medicine). The active components and their potential targets were predicted through the SwissTargetPrediction website. The targets of COVID-19 can be found on the GeneCards website. Protein interaction analysis, screening of key targets, functional enrichment of key target genes, and signaling pathway analysis were performed through Search Tool for the Retrieval of Interacting Genes databases, Metascape databases, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases. Finally, the affinity of the key active components with the core targets was verified by molecular docking. The results showed that five core targets had been screened, including MAPK1, NF-kappa B1, RELA, AKT1, and MAPK14. Gene ontology enrichment analysis revealed that the key targets were associated with inflammatory responses and responses to external stimuli. KEGG enrichment analysis indicated that the main pathways were influenza A, hepatitis B, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, and TNF signaling pathway. Therefore, Xinguan No. 3 might play a role in treating COVID-19 through anti-inflammatory, immune responses, and regulatory responses to external stimuli.

Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-ß Autocrine Stimulation.

Since the discovery of oncogenes, there has been tremendous interest to understand their mechanistic basis and to develop broadly actionable therapeutics. Some of the most frequently activated oncogenes driving diverse cancers are c-MYC, EGFR, HER2, AKT, KRAS, BRAF, and MEK. Using a reductionist approach, we explored how cellular proteomes are remodeled in isogenic cell lines engineered with or without these driver oncogenes. The most striking discovery for all oncogenic models was the systematic downregulation of scores of antiviral proteins regulated by type 1 interferon. These findings extended to cancer cell lines and patient-derived xenograft models of highly refractory pancreatic cancer and osteosarcoma driven by KRAS and MYC oncogenes. The oncogenes reduced basal expression of and autocrine stimulation by type 1 interferon causing remarkable convergence on common phenotypic and functional profiles. In particular, there was dramatically lower expression of dsRNA sensors including DDX58 (RIG-I) and OAS proteins, which resulted in attenuated functional responses when the oncogenic cells were treated with the dsRNA mimetic, polyI:C, and increased susceptibility to infection with an RNA virus shown using SARS-CoV-2. Our reductionist approach provides molecular and functional insights connected to immune evasion hallmarks in cancers and suggests therapeutic opportunities.

Combined exploration of the mechanism of Sang Xing Decoction in the treatment of smoke-induced acute bronchitis from protein and metabolic levels.

Sang Xing decoction (SXD) is a typical prescription for treating "warm dryness" in traditional Chinese medicine (TCM), which is equivalent to respiratory diseases such as acute bronchitis in modern medicine. However, its mechanism of action remains unclear. In this study, the representative components of SXD were characterized using liquid chromatography-tandem mass spectrometry (LC-MS). The key targets, signaling pathways, and metabolic pathways associated with SXD in the treatment of acute bronchitis were identified via network prediction and metabolomics. A rat model of acute bronchitis was also established using mixed smoke, systematic in vivo experiments such as histopathological analyses, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, immunohistochemistry and western blotting were conducted to evaluate the network prediction results. An in-depth analysis of the targeted quantitative results was performed using the SIMCA software and MetaboAnalyst website. The results revealed that 50 active compounds and 45 key targets were screened and clustered with 20 approved drugs. The NF-κB signaling pathway, oxidative stress, and glutamine metabolism were associated with the therapeutic mechanism of SXD in acute bronchitis. In vivo experiments showed that SXD may maintain the production of inflammatory factors by regulating the PI3K/Akt/NF-κB signaling pathway, improving the metabolism of glutamine and glutamate to reduce oxidative stress, and inhibiting apoptosis. Simultaneously, the possibility of using SXD as an adjuvant drug for COVID-19 treatment was also revealed. This research will lay the foundation for the modern clinical application of SXD and promote the promotion and innovation of TCM.

PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy.

Coronavirus disease 2019 (COVID-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A single-stranded RNA virus from a ß-Coronaviridae family causes acute clinical manifestations. Its high death rate and severe clinical symptoms have turned it into the most significant challenge worldwide. Up until now, several effective COVID-19 vaccines have been designed and marketed, but our data on specialized therapeutic drugs for the treatment of COVID-19 is still limited. In order to synthesis virus particles, SARS-CoV-2 uses host metabolic pathways such as phosphoinositide3-kinase (PI3K)/protein kinase B (PKB, also known as AKT)/mammalian target of rapamycin (mTOR). mTOR is involved in multiple biological processes. Over-activation of the mTOR pathway improves viral replication, which makes it a possible target in COVID-19 therapy. Clinical data shows the hyperactivation of the mTOR pathway in lung tissues during respiratory viral infections. However, the exact impact of mTOR pathway inhibitors on the COVID-19 severity and death rate is yet to be thoroughly investigated. There are several mTOR pathway inhibitors. Rapamycin is the most famous inhibitor of mTORC1 among all. Studies on other respiratory viruses suggest that the therapeutic inhibitors of the mTOR pathway, especially rapamycin, can be a potential approach to anti-SARS-CoV-2 therapy. Using therapeutic methods that inhibit harmful immune responses can open a new chapter in treating severe COVID-19 disease. We highlighted the potential contribution of PI3K/Akt/mTOR inhibitors in the treatment of COVID-19.

Ivermectin-Induced Apoptotic Cell Death in Human SH-SY5Y Cells Involves the Activation of Oxidative Stress and Mitochondrial Pathway and Akt/mTOR-Pathway-Mediated Autophagy.

Ivermectin (IVM) could cause potential neurotoxicity; however, the precise molecular mechanisms remain unclear. This study explores the cytotoxicity of IVM in human neuroblastoma (SH-SY5Y) cells and the underlying molecular mechanisms. The results show that IVM treatment (2.5-15 µM) for 24 h could induce dose-dependent cell death in SH-SY5Y cells. Compared to the control, IVM treatment significantly promoted the production of ROS, mitochondrial dysfunction, and cell apoptosis. IVM treatment also promoted mitophagy and autophagy, which were charactered by the decreased expression of phosphorylation (p)-Akt and p-mTOR proteins, increased expression of LC3II, Beclin1, ATG5, PINK, and Pakin1 proteins and autophagosome formation. N-acetylcysteine treatment significantly inhibited the IVM-induced production of ROS and cell death in SH-SY5Y cells. Autophagy inhibitor (e.g., 3-methyladenine) treatment significantly inhibited IVM-induced autophagy, oxidative stress, and cell apoptosis. Taken together, our results reveal that IVM could induce autophagy and apoptotic cell death in SH-SY5Y cells, which involved the production of ROS, activation of mitochondrial pathway, and inhibition of Akt/mTOR pathway. Autophagy inhibition improved IVM-induced oxidative stress and apoptotic cell death in SH-SY5Y cells. This current study provides new insights into understanding the molecular mechanism of IVM-induced neurotoxicity and facilitates the discovery of potential neuroprotective agents.