Exploring the Potential Mechanism of Action of Ursolic Acid against Gastric Cancer and COVID-19 using Network Pharmacology and Bioinformatics Analysis.

BACKGROUND: Patients with gastric cancer (GC) are more likely to be infected with 2019 coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the prognosis is worse. It is urgent to find effective treatment methods. OBJECTIVE: This study aimed to explore the potential targets and mechanism of ursolic acid (UA) on GC and COVID-19 by network pharmacology and bioinformatics analysis. METHODS: The online public database and weighted co-expression gene network analysis (WGCNA) were used to screen the clinical related targets of GC. COVID-19-related targets were retrieved from online public databases. Then, a clinicopathological analysis was performed on GC and COVID-19 intersection genes. Following that, the related targets of UA and the intersection targets of UA and GC/COVID-19 were screened. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome Analysis (KEGG) pathway enrichment analyses were performed on the intersection targets. Core targets were screened using a constructed protein-protein interaction network. Finally, molecular docking and molecular dynamics simulation (MDS) of UA and core targets were performed to verify the accuracy of the prediction results. RESULTS: A total of 347 GC/COVID-19-related genes were obtained. The clinical features of GC/COVID-19 patients were revealed using clinicopathological analysis. Three potential biomarkers (TRIM25, CD59, MAPK14) associated with the clinical prognosis of GC/COVID-19 were identified. A total of 32 intersection targets of UA and GC/COVID-19 were obtained. The intersection targets were primarily enriched in FoxO, PI3K/Akt, and ErbB signaling pathways. HSP90AA1, CTNNB1, MTOR, SIRT1, MAPK1, MAPK14, PARP1, MAP2K1, HSPA8, EZH2, PTPN11, and CDK2 were identified as core targets. Molecular docking revealed that UA strongly binds to its core targets. The MDS results revealed that UA stabilizes the protein-ligand complexes of PARP1, MAPK14, and ACE2. CONCLUSION: This study found that in patients with gastric cancer and COVID-19, UA may bind to ACE2, regulate core targets such as PARP1 and MAPK14, and the PI3K/Akt signaling pathway, and participate in antiinflammatory, anti-oxidation, anti-virus, and immune regulation to exert therapeutic effects.

Interaction of Biochemical Processes between Chronic Obstructive Pulmonary Disease (COPD), Pulmonary Arterial Hypertension (PAH), and Coronavirus Disease 2019 (COVID-19).

Both pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD) are risk factors for coronavirus disease 2019 (COVID-19). Patients with lung injury and altered pulmonary vascular anatomy or function are more susceptible to infections. The purpose of the study is to ascertain whether individuals with COPD or PAH are affected synergistically by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data sources for the construction of a protein-protein interaction (PPI) network and the identification of differentially expressed genes (DEGs) included three RNA-seq datasets from the GEO database (GSE147507, GSE106986, and GSE15197). Then, relationships between miRNAs, common DEGs, and transcription factor (TF) genes were discovered. Functional analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and other databases, as well as the forecasting of antiviral medications for COPD and PAH patients infected with SARS-CoV-2, were also performed. Eleven common DEGs were found in the three datasets, and their biological functions were primarily enriched in the control of protein modification processes, particularly phosphorylation. Growth factor receptor binding reflects molecular function. KEGG analysis indicated that co-DEGs mainly activate Ras, and PI3K-Akt signaling pathways and act on focal adhesions. NFKB1 interacted with HSA-miR-942 in the TF-miRNA-DEGs synergistic regulatory network. Acetaminophen is considered an effective drug candidate. There are some connections between COPD and PAH and the development of COVID-19. This research could aid in developing COVID-19 vaccines and medication candidates that would work well as COVID-19 therapies.

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.

Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism-Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer.

The importance of the prevention and control of non-communicable diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer, is increasing as a requirement of the aging population in developed countries and the sustainability of healthcare. Similarly, the 2013-2030 action plan of the WHO for the prevention and control of non-communicable diseases seeks these achievements. Adequate lifestyle changes, alone or with the necessary treatments, could reduce the risk of mortality or the deterioration of quality of life. In our recent work, we summarized the role of two central factors, i.e., appropriate levels of vitamin D and SIRT1, which are connected to adequate lifestyles with beneficial effects on the prevention and control of non-communicable diseases. Both of these factors have received increased attention in relation to the COVID-19 pandemic as they both take part in regulation of the main metabolic processes, i.e., lipid/glucose/energy homeostasis, oxidative stress, redox balance, and cell fate, as well as in the healthy regulation of the immune system. Vitamin D and SIRT1 have direct and indirect influence of the regulation of transcription and epigenetic changes and are related to cytoplasmic signaling pathways such as PLC/DAG/IP3/PKC/MAPK, MEK/Erk, insulin/mTOR/cell growth, proliferation; leptin/PI3K-Akt-mTORC1, Akt/NFĸB/COX-2, NFĸB/TNFα, IL-6, IL-8, IL-1ß, and AMPK/PGC-1α/GLUT4, among others. Through their proper regulation, they maintain normal body weight, lipid profile, insulin secretion and sensitivity, balance between the pro- and anti-inflammatory processes under normal conditions and infections, maintain endothelial health; balance cell differentiation, proliferation, and fate; and balance the circadian rhythm of the cellular metabolism. The role of these two molecules is interconnected in the molecular network, and they regulate each other in several layers of the homeostasis of energy and the cellular metabolism. Both have a central role in the maintenance of healthy and balanced immune regulation and redox reactions; therefore, they could constitute promising targets either for prevention or as complementary therapies to achieve a better quality of life, at any age, for healthy people and patients under chronic conditions.

Human monkeypox infection threat: A comprehensive overview.

BACKGROUND: In addition to the COVID-19 waves, the globe is recently facing global monkeypox (MPX) outbreak. As the daily confirmed cases of MPX infection across epidemic and nonepidemic countries are increasing, taking measures to control global pandemic remains crucial. Therefore, this review aimed to provide fundamental knowledge for the prevention and control of future outbreaks of this emerging epidemic. METHODS: The review was conducted using PubMed and Google Scholar databases; the search terms used were "monkeypox," "MPX tropism," "replication signaling of MPX," "biology and pathogenicity of MPX," "diagnosis of MPX," "treatment of MPX," "prevention of MPX," etc. The update epidemic data were collected from the websites of the World Health Organization (WHO), United States Centers for Disease Control and Prevention (CDC), and Africa Center for Disease Control and Prevention (ADCC). High-quality research results published in authoritative journals were summarized and preferred cited. Excluding all duplicates, non-English published references, and irrelevant literature, totally 1,436 articles were assessed for eligibility. RESULTS: It is still difficult to diagnose the patient as MPX simply based on clinical manifestations; therefore, under this situation, employing polymerase chain reaction (PCR) technology to provide confirmed evidence for the diagnosis of MPX seems to be the preferred and indispensable strategy. The treatment approach for MPX infection is mainly symptomatic and supportive; anti-smallpox virus drugs including tecovirimat, cidofovir, and brincidofovir can be employed in severe cases. Timely identification and isolation of confirmed cases, cutting off dissemination routes, and vaccination of close contacts are effective measures to control MPX. Also, smallpox vaccines (JYNNEOS, LC16m8, and ACAM2000) can be under consideration due to their immunological cross-protection among Orthopoxvirus. Nevertheless, given the low quality and scarcity of relevant evidence of current antiviral drugs and vaccines, deeply seeking for the MAPK/ERK, PAK-1, PI3K/Akt signaling, and other pathways involved in MPX invasion may provide potential targets for the treatment, prevention, and control of the epidemic. CONCLUSIONS: In response to the current MPX epidemic, the development of vaccines and antiviral drugs against MPX, as well as the rapid and precise diagnostic methods are still urgently needed. Sound monitoring and detection systems should be established to limit the rapid spread of MPX worldwide.

Identification of berberine as a potential therapeutic strategy for kidney clear cell carcinoma and COVID-19 based on analysis of large-scale datasets.

Background: Regarding the global coronavirus disease 2019 (COVID)-19 pandemic, kidney clear cell carcinoma (KIRC) has acquired a higher infection probability and may induce fatal complications and death following COVID-19 infection. However, effective treatment strategies remain unavailable. Berberine exhibits significant antiviral and antitumour effects. Thus, this study aimed to provide a promising and reliable therapeutic strategy for clinical decision-making by exploring the therapeutic mechanism of berberine against KIRC/COVID-19. Methods: Based on large-scale data analysis, the target genes, clinical risk, and immune and pharmacological mechanisms of berberine against KIRC/COVID-19 were systematically investigated. Results: In total, 1,038 and 12,992 differentially expressed genes (DEGs) of COVID-19 and KIRC, respectively, were verified from Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively, and 489 berberine target genes were obtained from official websites. After intersecting, 26 genes were considered potential berberine therapeutic targets for KIRC/COVID-19. Berberine mechanism of action against KIRC/COVID-19 was revealed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes with terms including protein interaction, cell proliferation, viral carcinogenesis, and the PI3K/Akt signalling pathway. In COVID-19 patients, ACOX1, LRRK2, MMP8, SLC1A3, CPT1A, H2AC11, H4C8, and SLC1A3 were closely related to disease severity, and the general survival of KIRC patients was closely related to ACOX1, APP, CPT1A, PLK1, and TYMS. Additionally, the risk signature accurately and sensitively depicted the overall survival and patient survival status for KIRC. Numerous neutrophils were enriched in the immune system of COVID-19 patients, and the lives of KIRC patients were endangered due to significant immune cell infiltration. Molecular docking studies indicated that berberine binds strongly to target proteins. Conclusion: This study demonstrated berberine as a potential treatment option in pharmacological, immunological, and clinical practice. Moreover, its therapeutic effects may provide potential and reliable treatment options for patients with KIRC/COVID-19.

Identifying potential pharmacological targets and molecular pathways of Meliae cortex for COVID-19 therapy.

Coronavirus disease-19 (COVID-19), caused by SARS-CoV-2, has contributed to a significant increase in mortality. Proinflammatory cytokine-mediated cytokine release syndrome (CRS) contributes significantly to COVID-19. Meliae cortex has been reported for its several ethnomedical applications in the Chinese Pharmacopoeia. In combination with other traditional Chinese medicines (TCM), the Meliae cortex suppresses coronavirus. Due to its phytoconstituents and anti-inflammatory capabilities, we postulated that the Meliae cortex could be a potential therapeutic for treating COVID-19. The active phytonutrients, molecular targets, and pathways of the Meliae cortex have not been explored yet for COVID-19 therapy. We performed network pharmacology analysis to determine the active phytoconstituents, molecular targets, and pathways of the Meliae cortex for COVID-19 treatment. 15 active phytonutrients of the Meliae cortex and 451 their potential gene targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and SwissTargetPrediction website tool, respectively. 1745 COVID-19-related gene targets were recovered from the GeneCards. 104 intersection gene targets were determined by performing VENNY analysis. Using the DAVID tool, gene ontology (GO) and KEGG pathway enrichment analysis were performed on the intersection gene targets. Using the Cytoscape software, the PPI and MCODE analyses were carried out on the intersection gene targets, which resulted in 41 potential anti-COVID-19 core targets. Molecular docking was performed with AutoDock Vina. The 10 anti-COVID-19 core targets (AKT1, TNF, HSP90AA1, IL-6, mTOR, EGFR, CASP3, HIF1A, MAPK3, and MAPK1), three molecular pathways (the PI3K-Akt signaling pathway, the HIF-1 signaling pathway, and the pathways in cancer) and three active phytonutrients (4,8-dimethoxy-1-vinyl-beta-carboline, Trichilinin D, and Nimbolin B) were identified as molecular targets, molecular pathways, and key active phytonutrients of the Meliae cortex, respectively that significantly contribute to alleviating COVID-19. Molecular docking analysis further corroborated that three Meliae cortex's key active phytonutrients may ameliorate COVID-19 disease by modulating identified targets. Hence, this research offers a solid theoretic foundation for the future development of anti-COVID-19 therapeutics based on the phytonutrients of the Meliae cortex.

Recent advances in ginsenosides against respiratory diseases: Therapeutic targets and potential mechanisms.

BACKGROUND: Respiratory diseases mainly include asthma, influenza, pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, lung fibrosis, and lung cancer. Given their high prevalence and poor prognosis, the prevention and treatment of respiratory diseases are increasingly essential. In particular, the development for the novel strategies of drug treatment has been a hot topic in the research field. Ginsenosides are the major component of Panax ginseng C. A. Meyer (ginseng), a food homology and well-known medicinal herb. In this review, we summarize the current therapeutic effects and molecular mechanisms of ginsenosides in respiratory diseases. METHODS: The reviewed studies were retrieved via a thorough analysis of numerous articles using electronic search tools including Sci-Finder, ScienceDirect, PubMed, and Web of Science. The following keywords were used for the online search: ginsenosides, asthma, influenza, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung fibrosis, lung cancer, and clinical trials. We summarized the findings and the conclusions from 176 manuscripts on ginsenosides, including research articles and reviews. RESULTS: Ginsenosides Rb1, Rg1, Rg3, Rh2, and CK, which are the most commonly reported ginsenosides for treating of respiratory diseases, and other ginsenosides such as Rh1, Rk1, Rg5, Rd and Re, all primarily reduce pneumonia, fibrosis, and inhibit tumor progression by targeting NF-κB, TGF-ß/Smad, PI3K/AKT/mTOR, and JNK pathways, thereby ameliorating respiratory diseases. CONCLUSION: This review provides novel ideas and important aspects for the future research of ginsenosides for treating respiratory diseases.

Interferon-inducible phospholipids govern IFITM3-dependent endosomal antiviral immunity.

The interferon-induced transmembrane proteins (IFITM) are implicated in several biological processes, including antiviral defense, but their modes of action remain debated. Here, taking advantage of pseudotyped viral entry assays and replicating viruses, we uncover the requirement of host co-factors for endosomal antiviral inhibition through high-throughput proteomics and lipidomics in cellular models of IFITM restriction. Unlike plasma membrane (PM)-localized IFITM restriction that targets infectious SARS-CoV2 and other PM-fusing viral envelopes, inhibition of endosomal viral entry depends on lysines within the conserved IFITM intracellular loop. These residues recruit Phosphatidylinositol 3,4,5-trisphosphate (PIP3) that we show here to be required for endosomal IFITM activity. We identify PIP3 as an interferon-inducible phospholipid that acts as a rheostat for endosomal antiviral immunity. PIP3 levels correlated with the potency of endosomal IFITM restriction and exogenous PIP3 enhanced inhibition of endocytic viruses, including the recent SARS-CoV2 Omicron variant. Together, our results identify PIP3 as a critical regulator of endosomal IFITM restriction linking it to the Pi3K/Akt/mTORC pathway and elucidate cell-compartment-specific antiviral mechanisms with potential relevance for the development of broadly acting antiviral strategies.

COVID-19 in patients with chronic lymphocytic leukemia: a multicenter analysis by the Czech CLL study group.

Patients with chronic lymphocytic leukemia (CLL) have a high risk of poor outcomes related to coronavirus disease 2019 (COVID-19). This multicenter cohort study evaluated the impact of COVID-19 infection on the population of CLL patients in the Czech Republic. Between March 2020 and May 2021, 341 patients (237 males) with CLL and COVID-19 disease were identified. The median age was 69 years (range 38-91). Out of the 214 (63%) patients with the history of therapy for CLL, 97 (45%) were receiving CLL-directed treatment at diagnosis of COVID-19: 29% Bruton tyrosine kinase inhibitor (BTKi), 16% chemoimmunotherapy (CIT), 11% Bcl-2 inhibitor, and 4% phosphoinositide 3-kinase inhibitor. Regarding the severity of COVID-19, 60% pts required admission to the hospital, 21% pts were admitted to the intensive care unit (ICU), and 12% received invasive mechanical ventilation. The overall case fatality rate was 28%. Major comorbidities, age over 72, male gender, CLL treatment in history, CLL-directed treatment at COVID-19 diagnosis were associated with increased risk of death. Of note, concurrent therapy with BTKi compared to CIT was not associated with better outcome of COVID-19.

Potential Mechanisms of Perillae folium Against COVID-19: A Network Pharmacology Approach.

In China, Perillae folium is widely used to treat colds, especially in the early stages of cold; the effect of taking P. folium is readily noticeable at that time. The active compounds and targets of P. folium were screened from Traditional Chinese Medicine Systems Pharmacology, Chinese Pharmacopoeia, and UniProt. Targets related to the initiation and progression of 2019 Coronavirus Disease (COVID-19) were retrieved from Online Mendelian Inheritance in Man and GeneCards. The potential therapeutic targets of P. folium on COVID-19 were the cross targets between them. Enrichment analysis of Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were conducted by using the Database for Annotation, Visualization and Integrated Discovery website. Molecular docking between key compounds and core targets was performed with AutoDock. The effects of P. folium extract and rosmarinic acid on inflammatory cytokines were tested by a cellular inflammatory model. The "Perillae folium-compound-target-COVID-19" network contained 11 kinds of compounds and 33 matching targets. There were 261 items in the GO functions (P < .05) and 67 items linked to the KEGG signaling pathways (P < .05). Luteolin and rosmarinic acid were key compounds of P. folium. Their docking with the core targets mitogen-activated protein kinase 1 (MAPK1) and chemokine (C-C motif) ligand 2 (CCL2), respectively, showed that they had good affinity with each other. Cell experiments demonstrated that P. folium extract had inhibitory effects on interleukin-6 and tumor necrosis factor (TNF)-α in cells, and was better than rosmarinic acid. Luteolin, rosmarinic acid, and other individual active compounds in P. folium, which may participate in PI3K-Akt, TNF, Jak-STAT, COVID-19, and other multisignaling pathways through multiple targets such as MAPK1 and CCL2, and play a therapeutic role in COVID-19.

Genome tumor profiling in endometrial cancer and clinical relevance in endometrial cancer management: a retrospective single-center experience.

OBJECTIVE: Next-generation sequencing (NGS) analysis has become an essential tool for endometrial carcinoma management. Moreover, molecular-driven therapies play an increasingly remarkable role in the era of precision oncology. This study aims to determine the clinical relevance of NGS testing in endometrial carcinoma management by analyzing the clinical benefit of NGS-driven targeted therapies. METHODS: A single-center retrospective study was conducted on 25 endometrial carcinoma patients who underwent Foundation Medicine CDx assay at Fondazione Policlinico Universitario Agostino Gemelli, IRCCS (Rome, Italy). Tumor samples were analyzed by Foundation One CDx. A descriptive analysis of tumor genome profiles was performed. Assessment of clinical benefit according to RECIST 1.1 criteria was analyzed for patients who received a tailored treatment according to actionable targets identified by NGS testing. RESULTS: Out of 25 endometrial carcinoma patients, 11 received targeted therapy. One patient was excluded from the clinical benefit assessment because of COVID-19-related death 1 month after starting the treatment. Eight of the remaining 10 patients benefited from targeted therapies, with an overall clinical benefit rate of 80%. A targeted agent belonging to the PI3K pathway was given to seven patients, with evidence of three partial responses (42.9%), three stable diseases (42.9%), and one progressive disease (14.2%) according to RECIST 1.1 criteria. One complete response (33.3%), one stable disease (33.3%), and one progressive disease (33.3%) were observed in the three patients treated with poly(ADP-ribose) polymerase (PARP) inhibitors according to their homologous recombination deficiency (HRD) status. CONCLUSION: This study highlights the importance of characterizing the mutation profile of patient tumors through NGS. Our findings suggest a clinical benefit of using NGS-driven targeted therapies in endometrial carcinoma patients. However, this personalized approach could benefit the health system in terms of cost-effectiveness by reducing the costs of inappropriate, ineffective, and often expensive treatments.

Chemical profile of anti-epidemic sachet based on multiple sample preparation coupled with gas chromatography-mass spectrometry analysis combined with an embedded peaks resolution method and their action mechanisms.

The anti-epidemic sachet (Fang Yi Xiang Nang, FYXN) in traditional Chinese medicine (TCM) can prevent COVID-19 through volatile compounds that can play the role of fragrant and dampness, heat-clearing and detoxifying, warding off filth and pathogenic factors. Nevertheless, the anti-(mutant) SARS-CoV-2 compounds and the compounds related to the mechanism in vivo, and the mechanism of FYXN are still vague. In this study, the volatile compound set of FYXN was constructed by gas chromatography-mass spectrometry (GC-MS) based on multiple sample preparation methods, which include headspace (HS), headspace solid phase microextraction (HS-SPME) and pressurized liquid extraction (PLE). In addition, selective ion analysis (SIA) was used to resolve embedded chromatographic peaks present in HS-SPME results. Preliminary analysis of active compounds and mechanism of FYXN by network pharmacology combined with disease pathway information based on GC-MS results. A total of 96 volatile compounds in FYXN were collected by GC-MS analysis. 39 potential anti-viral compounds were screened by molecular docking. 13 key pathways were obtained by KEGG pathway analysis (PI3K-Akt signaling pathway, HIF-1 signaling pathway, etc.) for FYXN to prevent COVID-19. 16 anti-viral compounds (C95, C91, etc.), 10 core targets (RELA, MAPK1, etc.), and 16 key compounds related to the mechanism in vivo (C56, C30, etc.) were obtained by network analysis. The relevant pharmacological effects of key pathways and key compounds were verified by the literature. Finally, molecular docking was used to verify the relationship between core targets and key compounds, which are related to the mechanism in vivo. A variety of sample preparation methods coupled with GC-MS analysis combined with an embedded peaks resolution method and integrated with network pharmacology can not only comprehensively characterize the volatile compounds in FYXN, but also expand the network pharmacology research ideas, and help to discover the active compounds and mechanisms in FYXN.

Bioinformatics and systems biology approaches to identify the effects of COVID-19 on neurodegenerative diseases: A review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease (COVID-19), has been devastated by COVID-19 in an increasing number of countries and health care systems around the world since its announcement of a global pandemic on 11 March 2020. During the pandemic, emerging novel viral mutant variants have caused multiple outbreaks of COVID-19 around the world and are prone to genetic evolution, causing serious damage to human health. As confirmed cases of COVID-19 spread rapidly, there is evidence that SARS-CoV-2 infection involves the central nervous system (CNS) and peripheral nervous system (PNS), directly or indirectly damaging neurons and further leading to neurodegenerative diseases (ND), but the molecular mechanisms of ND and CVOID-19 are unknown. We employed transcriptomic profiling to detect several major diseases of ND: Alzheimer 's disease (AD), Parkinson' s disease (PD), and multiple sclerosis (MS) common pathways and molecular biomarkers in association with COVID-19, helping to understand the link between ND and COVID-19. There were 14, 30 and 19 differentially expressed genes (DEGs) between COVID-19 and Alzheimer 's disease (AD), Parkinson' s disease (PD) and multiple sclerosis (MS), respectively; enrichment analysis showed that MAPK, IL-17, PI3K-Akt and other signaling pathways were significantly expressed; the hub genes (HGs) of DEGs between ND and COVID-19 were CRH, SST, TAC1, SLC32A1, GAD2, GAD1, VIP and SYP. Analysis of transcriptome data suggests multiple co-morbid mechanisms between COVID-19 and AD, PD, and MS, providing new ideas and therapeutic strategies for clinical prevention and treatment of COVID-19 and ND.

A Concise Review on Dysregulation of LINC00665 in Cancers.

Long Intergenic Non-Protein Coding RNA 665 (LINC00665) is an RNA gene located on the minus strand of chromosome 19. This lncRNA acts as a competing endogenous RNA for miR-4458, miR-379-5p, miR-551b-5p, miR-3619-5p, miR-424-5p, miR-9-5p, miR-214-3p, miR-126-5p, miR-149-3p, miR-379-5p, miR-665, miR-34a-5p, miR-186-5p, miR-138-5p, miR-181c-5p, miR-98, miR-195-5p, miR-224-5p, miR-3619, miR-708, miR-101, miR-1224-5p, miR-34a-5p, and miR-142-5p. Via influencing expression of these miRNAs, it can enhance expression of a number of oncogenes. Moreover, LINC00665 can influence activity of Wnt/ß-Catenin, TGF-ß, MAPK1, NF-κB, ERK, and PI3K/AKT signaling. Function of this lncRNA has been assessed through gain-of-function tests and/or loss-of-function studies. Furthermore, diverse research groups have evaluated its expression levels in tissue samples using microarray and RT-qPCR techniques. In this manuscript, we have summarized the results of these studies and categorized them in three sections, i.e., cell line studies, animal studies, and investigations in clinical samples.

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.

Thymol protects against bleomycin-induced pulmonary fibrosis via abrogation of oxidative stress, inflammation, and modulation of miR-29a/TGF-ß and PI3K/Akt signaling in mice.

Idiopathic pulmonary fibrosis is a terminal lung ailment that shares several pathological and genetic mechanisms with severe COVID-19. Thymol (THY) is a dietary compound found in thyme species that showed therapeutic effects against various diseases. However, the effect of THY against bleomycin (BLM)-induced lung fibrosis was not previously investigated. The current study investigated the ability of THY to modulate oxidative stress, inflammation, miR-29a/TGF-ß expression, and PI3K/phospho-Akt signaling in lung fibrosis. Mice were divided into Normal, THY (100 mg/kg, p.o.), BLM (15 mg/kg, i.p.), BLM + THY (50 mg/kg, p.o.), and BLM + THY (100 mg/kg, p.o.) groups and treated for four weeks. The obtained results showed that BLM + THY (50 mg/kg) and BLM + THY (100 mg/kg) reduced fibrotic markers; α-SMA and fibronectin, inflammatory mediators; TNF-α, IL-1ß, IL-6, and NF-kB and oxidative stress biomarkers; MDA, GSH, and SOD, relative to BLM group. Lung histopathological examination by H&E and Masson's trichrome stains confirmed the obtained results. Remarkably, expression levels of TGF-ß, PI3K, and phospho-Akt were decreased while miR-29a expression was elevated. In conclusion, THY effectively prevented BLM-induced pulmonary fibrosis by exerting significant anti-oxidant and anti-inflammatory effects. Our novel findings that THY upregulated lung miR-29a expression while decreased TGF-ß and PI3K/Akt signaling are worthy of further investigation as a possible molecular mechanism for THY's anti-fibrotic actions.

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.

Tocotrienol-Rich Fractions Offer Potential to Suppress Pulmonary Fibrosis Progression.

Although pulmonary fibrosis (PF) is considered a rare disease, the incidence thereof has increased steadily in recent years, while a safe and effective cure remains beyond reach. In this study, the potential of tocotrienol-rich fractions (TRF) and carotene to alleviate PF was explored. PF was induced in Sprague-Dawley rats via a single intratracheal bleomycin (BLM) (5 mg/kg) instillation. These rats were subsequently treated with TRF, carotene, pirfenidone (Pir) and nintedanib (Nin) for 28 days via gavage administration, whereafter histopathological performance, biochemical functions and molecular alterations were studied in the lung tissues. Our results showed that TRF, carotene, Nin and Pir all ameliorated PF by reducing inflammation and resisting oxidative stress to varying degrees. The related mechanisms involved the TGF-ß1/Smad, PI3K/Akt and NF-κB signaling pathways. Ultimately, our findings revealed that, when combined with TRF, the therapeutic effects of Nin and Pir on PF were enhanced, indicating that TRF may, indeed, provide promising potential for use in combination therapy in the treatment of PF.