Apoptosis-related Signaling Pathways Research Articles

Investigating the effects of quercetin fatty acid esters on apoptosis, mechanical properties, and expression of ERK in melanoma cell line (A375)

AimsMalignant melanoma (MM) is the most fatal skin cancer with a critical increase in the number of cases in the last decades. Recent studies have shown the antitumor potential of active biological phytochemical structures of flavonoids for the prevention and treatment of cancerous cells. In this study, two quercetin fatty acid esters (α-linolenic acid (ALA) and linoleic acid (LA)) compounds were evaluated in terms of inducing apoptotic human melanoma cells (A375) death in vitro. Main methodsThe MTT assay was utilized for comparing the effects of quercetin, ALA, and LA on A375 cell viability concentrations of 5, 25, 35, 50, and 100μg/mL for 24 and 48 h to obtain IC50. To detect the effects on apoptosis and to determine p-ERK/ERK apoptosis-related signaling pathway proteins level, flow-cytometry and western blot were used. Finally, the nano-mechanical properties of the melanoma A375 membrane structure containing elastic modulus value and cell-cell adhesion forces were investigated using Atomic Force Microscopy (AFM). Statistical data was analyzed in GraphPad v.8.0.0. Key findingsThe most significant A375 cell viability amplified effect of Q-LA was observed with a half-maximal inhibitory concentration (IC50 = 35 μg/mL, 48 h), proportional to dose. Ester compounds, especially Q-LA, showed the highest cell proliferation inhibition with improved elastic modulus, cell-cell adhesion forces (253 ± 11.2), and elevated apoptosis-inducing effect (p < 0.01**). Moreover, Q-LA significantly decreased the mean levels of p-ERK phosphorylation (0.1439) and, subsequently, apoptosis in A375 cells. SignificanceThe data presented in this study confirmed the antitumor activity of ester compounds against A375 cells, high-lighting the ability of the tested compounds to induce apoptosis.

Myricetin inhibits pseudorabies virus infection through direct inactivation and activating host antiviral defense.

Myricetin, a polyhydroxyflavone compound, is one of the main ingredients of various human foods and therefore also known as dietary flavonoids. Due to the continuous emergence of resistant strains of herpesviruses, novel control measures are required. In the present study, myricetin exhibited potent antiviral activity against pseudorabies virus (PRV), a model organism of herpesvirus. The suppression rate could reach up to 96.4% at a concentration of 500 μM in cells, and the 50% inhibitory concentration (IC50) was 42.69 μM. Moreover, the inhibitory activity was not attenuated by the increased amount of infective dose, and a significant reduction of intracellular PRV virions was observed by indirect immunofluorescence. A mode of action study indicated that myricetin could directly inactivate the virus in vitro, leading to inhibition of viral adsorption, penetration and replication in cells. In addition to direct killing effect, myricetin could also activate host antiviral defense through regulation of apoptosis-related gene expressions (Bcl-2, Bcl-xl, Bax), NF-κB and MAPK signaling pathways and cytokine gene expressions (IL-1α, IL-1β, IL-6, c-Jun, STAT1, c-Fos, and c-Myc). In PRV-infected mouse model, myricetin could enhance the survival rate by 40% at 5 days post infection, and viral loads in kidney, liver, lung, spleen, and brain were significantly decreased. The pathological changes caused by PRV infection were improved by myricetin treatment. The gene expressions of inflammatory factors (MCP-1, G-CSF, IL-1α, IL-1β, and IL-6) and apoptotic factors (Bcl-xl, Bcl-2, and Bax) were regulated by myricetin in PRV-infected mice. The present findings suggest that myricetin can effectively inhibit PRV infection and become a candidate for development of new anti-herpesvirus drugs.

Ononin alleviates endoplasmic reticulum stress in doxorubicin-induced cardiotoxicity by activating SIRT3

Doxorubicin (DOX) is a potent anthracycline antineoplastic drug. However, its dose-dependent cardiotoxicity limits its clinical application. Ononin is a natural isoflavone glycoside that is crucial in modulating apoptosis-related signaling pathways. In this study, we assessed the possible cardioprotective effects of ononin in DOX-induced cardiotoxicity and elucidated the underlying molecular mechanisms. In vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats, respectively. First, DOX was injected into the tail veins of Wistar rats to induce cardiomyopathy. Next, rats in the DOX + Ononin30 and DOX + Ononin60 groups were intragastrically administered ononin two weeks before DOX treatment. H9C2 cells were treated with vehicle or DOX with or without ononin. Next, 3-TYP was used to determine the relationship between endoplasmic reticulum (ER) stress and sirtuin 3 (SIRT3) expression. Ononin treatment ameliorated DOX-induced myocardial injury as determined by echocardiography. Furthermore, ononin partially restored DOX-induced cardiac dysfunction; the left ventricular ejection fraction (LVEF) and left ventricular systolic fractional shortening (LVFS) increased after pre-treatment with ononin. Further, ononin suppressed DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. The Bax/Bcl-2 ratio and 78-kD glucose-regulated protein (GRP78) and CCAAT enhancer-binding protein (CHOP) expression levels were higher in the DOX-treated group than in the control group but ononin treatment improved these parameters. These effects are associated with SIRT3 activity. Moreover, 3-TYP blocked the ononin-mediated protective effects. Hence, ononin positively affected DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, possibly mediated by stimulation of the SIRT3 pathway.

Amelioration of systemic antitumor immune responses in cocktail therapy by immunomodulatory nanozymes.

Nanozymes that mimic natural enzyme–like activities have gradually emerged in cancer therapy. To overcome the bottlenecks of single-mode nanozymes, including “off-target” toxicity and ineffectiveness toward metastatic cancers, we designed magnetic nanoparticle–based multifunctional visualized immunomodulatory nanozymes. Besides the partial initiation of the prime immune response by intrinsic immunogenicity, as a smart drug delivery system with a temperature- and pH-sensitive dual response to the tumor microenvironment, these nanozymes released immune agonists to boost enhanced systemic immune response, eventually ameliorating the cancer immune microenvironment through many aspects: activating dendritic cells, improving the function of CD8+ T cells, and decreasing the population of myeloid-derived suppressor cells, which inhibited both primary and metastatic cancers. Mechanistically, these nanozymes regulated the reactive oxygen species–related Akt signaling pathway and consequently activated cell apoptosis–related signaling pathways, which provided a deeper understanding of the synergistic mechanism of multifunctional nanozymes. Our findings offer a promising imaging-guided cocktail therapy strategy through immunomodulatory nanozymes.

Knockout of circRNA single stranded interacting protein 1 (circRBMS1) played a protective role in myocardial ischemia-reperfusion injury though inhibition of miR-2355-3p/Mammalian Sterile20-like kinase 1 (MST1) axis

ABSTRACT Evidence suggests circRBMS1 regulates mRNA to mediate cell apoptosis, inflammation, and oxidative stress in different diseases. MST1 is reported to be the target and activator of apoptosis-related molecules and signaling pathways. Hence, the present study aims to investigate the role of circ-RBMS1/miR-2355-3p/MST1 in the development of I/R injury. In vitro experiments showed increased circ-RBMS1 and decreased miR-2355-3p in H/R-induced HCMs. CircRBMS1 served as a sponge for miR-2355-3p and miR-2355-3p targeted MST1. Furthermore, knockout of circRBMS1 attenuated cell apoptosis, oxidized stress, and inflammation in H/R-induced HCMs. In vivo experiments indicated circRBMS1 knockdown attenuated cardiac function damage, cell apoptosis, oxidative stress injury and inflammatory response through miR-2355-3p/MST1 axis in mice. In summary, these results demonstrated circRBMS1 played a protective role in myocardial I/R injury though inhibition of miR-2355-3p/MST1 axis. It might provide a new therapeutic target for cardiac I/R injury.

Molecular mechanism of microRNAs regulating apoptosis in osteosarcoma.

Osteosarcoma is a primary malignant bone tumor with no effective treatment. Apoptosis, one of the programmed cell death, is any pathological form of cell death mediated by intracellular processes. Under the pathological state, the de-regulated regulation of apoptosis can disrupt the balance between cell proliferation and death, causing osteosarcoma proliferation and metastasis. As carcinogenic or tumor suppressor factors, microRNAs (miRNAs) regulate apoptosis of osteosarcoma cells by regulating apoptosis-related genes and apoptosis-related signaling pathways, such as mitochondrial apoptosis pathway, death receptor pathway, and endoplasmic reticulum pathway. Meanwhile as these abnormal miRNAs can be stored and transported by exosomes, detecting exosomes can be seen an effective method to diagnose osteosarcoma in the early stage. This review provides the current knowledge of miRNAs and their target genes related to the apoptosis of osteosarcoma, summarizes abnormal expression and regulation of miRNAs and signaling pathways in osteosarcoma and prospects the detection of exosome as a method for early diagnosis of osteosarcoma.

Maslinic Acid Attenuates Ischemia/Reperfusion-Induced Acute Kidney Injury by Suppressing Inflammation and Apoptosis Through Inhibiting NF-κB and MAPK Signaling Pathway.

Inflammation and apoptosis are the major contributors to the mechanisms of acute kidney injury (AKI) due to renal ischemia-reperfusion injury (IRI). Maslinic acid (MA), a pentacyclic triterpene acid mostly found in dietary plants, the current study was to demonstrate the renoprotective effect of MA on IRI-induced AKI, and to investigate the role of inflammation and apoptosis-related signaling pathways as a molecular mechanism. C57BL/6J mice were subjected to IRI for 72 h, and MA was daily administered by intraperitoneal injection during this period. In parallel, rat renal proximal tubule cells (NRK52E) were prophylactically treated with MA and then exposed to hydrogen peroxide (H2O2). MA treatment significantly inhibited the mRNA expression of interleukin (IL-1β), tumor necrosis factor-α (TGF-α), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1(ICAM-1). Also, MA reduced the expression of Bax/Bcl2 ratio and cleaved caspase-3. In NRK52 cells, MA inhibited the IκBα degradation, blocked NF-κB/p65 phosphorylation, and nuclear translocation. The phosphorylation of ERK, JNK, and p38 was attenuated by MA in IRI-induced kidney injury and H2O2-stimulated NRK52 cells. The expression levels of IL-1β, MCP-1, and ICAM-1 were upregulated in H2O2-stimulated NRK52E cells, which was attenuated by NF-κB inhibitor. H2O2 treatment increased the Bax/Bcl2 ratio and cleaved caspase-3 in NRK52E cells, which was counteracted by MAPK inhibitors. Together, our data demonstrate that MA suppresses IR-induced AKI injury through NF-κB and MAPK signaling pathways and that MA is a promising agent in the treatment of kidney diseases.

ITGB1 promotes apoptosis in H9C2 cells

Myocardial infarction is a heart disease with high mortality rate. The research on the cardiomyocyte apoptosis is helpful to the prevention and treatment of myocardial infarction. As a cell surface receptor, the function of ITGB1 gene in cardiomyocytes is not clear. This study aimed to analyze the function and molecular mechanism of cardiomyocyte derived ITGB1 in myocardial apoptosis. To analyze cardiomyocyte apoptosis, TUNEL staining was performed with ITGB1 overexpression and knockdown in H9C2 cells. Apoptosis-related markers were also detected using Western blot. In addition, apoptosis-related signaling pathways were detected to elucidate the molecular mechanism regulated by ITGB1. Our results indicated that ITGB1 promoted cardiomyocyte apoptosis by inhibiting the Notch1 and Smad2/3 signal pathways. These data highlight the potential usefulness of ITGB1 as a potential target for preventing myocardial infarction.

Abstract 12423: Normoxic Therapy Attenuated Oxidative Stress Related mRNA Gene Expressions in a Post-Cardiac Arrest Rat Model

Objective: We recently reported that post-resuscitation normoxic therapy attenuates oxidative stress in multiple organs and improves post-cardiac arrest (CA) organ injury, oxygen metabolism, and survival. Yet, detailed mechanisms of gene expression patterns and signaling pathways mitigated by normoxic therapy have not been elucidated. Therefore, we assessed post-resuscitation normoxic therapy-modified gene expression of oxidative stress-related signaling molecules. Methods: Rats were resuscitated from 10 minutes of asphyxial CA and divided into 2 groups: those that inhaled 100% supplemental O 2 (CA-FIO2 1.0) and those that inhaled 30% supplemental O 2 (CA-FIO2 0.3). Control groups were also prepared for comparison (control-FIO2 1.0, control-FIO2 0.3). At 2 hours after resuscitation, brain and heart tissues were collected, and mRNA purifications followed by real-time PCR measurements were performed to compare gene expression of hyperoxia-induced inflammatory and apoptosis-related signaling pathways amongst these groups. Results: In the brain, relative IL-1 beta mRNA gene expression levels, which represent inflammatory signaling pathways, increased post-CA (8.1±2.3 in CA-FIO2 1.0 and 1.0±0.4 in control-FIO2 0.3, p&lt;0.05), but were significantly attenuated by normoxic therapy (2.3±0.2 in CA-FIO2 0.3, p&lt;0.05). Likewise, normoxic therapy significantly reduced oxidative stress-induced inflammatory (NFKB1, TGFB1, MAPK14, TRAF6) and apoptosis-related (BAX, EGF) mRNA gene expression levels in the brain, whereas no statistical differences were detected in the heart. Conclusions: Post-CA normoxic therapy significantly attenuated the gene expression of oxidative stress-induced inflammation and apoptosis in the brain, while there were no remarkable changes in the heart. Therefore, it is inferred that the heart is more tolerant to hyperoxic injury compared to the brain.

Cardiac developmental toxicity and transcriptome analyses of zebrafish (Danio rerio) embryos exposed to Mancozeb

Mancozeb (MZ), an antibacterial pesticide, has been linked to reproductive toxicity, neurotoxicity, and endocrine disruption. However, whether MZ has cardiactoxicity is unclear. In this study, the cardiotoxic effects of exposure to environment-related MZ concentrations ranging from 1.88 μM to 7.52 μM were evaluated at the larval stage of zebrafish. Transcriptome sequencing predicted the mechanism of MZ-induced cardiac developmental toxicity in zebrafish by enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). Consistent with morphological changes, the osm, pfkfb3, foxh1, stc1, and nrarpb genes may effect normal development of zebrafish heart by activating NOTCH signaling pathways, resulting in pericardial edema, myocardial fibrosis, and congestion in the heart area. Moreover, differential gene expression analysis indicated that cyp-related genes (cyp1c2 and cyp3c3) were significantly upregulated after MZ treatment, which may be related to apoptosis of myocardial cells. These results were verified by real-time quantitative RT-qPCR and acridine orange staining. Our findings suggest that MZ-mediated cardiotoxic development of zebrafish larvae may be related to the activation of Notch and apoptosis-related signaling pathways.

Ethyl Acetate Fraction of Abelmoschus manihot (L.) Medic Flowers Exerts Inhibitory Effects Against Oxidative Stress in H2O2-Induced HepG2 Cells and D-Galactose-Induced Aging Mice.

Oxidative stress has been demonstrated to be associated with numerous aging-related diseases. Ethyl acetate fraction of Abelmoschus manihot (L.) Medic (EA) had been reported to possess strong radical-scavenging activity due to its rich content of flavonoids. This work aimed to determine the protective effects of EA against oxidative injuries in vivo and in vitro, as well as to explore the relevant mechanisms behind these effects. Pretreatment with EA significantly elevated cell viability of H2O2-induced HepG2 cells, reduced the reactive oxygen species level, decreased apoptotic cells, and inhibited activities of caspase 3/9. Meanwhile, EA pretreatment elevated the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while reduced malondialdehyde (MDA) generation and lactate dehydrogenase (LDH) release dose-dependently. In addition, EA modulated key marker genes expression of antioxidation and apoptosis-related signaling pathways at the messenger RNA (mRNA) and protein levels. In the animal studies, EA also significantly enhanced the antioxidant activity and reduced MDA generation in serum, liver, and brain of the D-galactose (D-gal)-induced mice. Furthermore, the histological analysis indicated that EA effectively alleviated liver and brain injury of mice induced by D-gal, dose-dependently. EA as a potential antioxidant agent promoted health and reduced the risk of aging-associated diseases.

Potential Roles of Iridoid Glycosides and Their Underlying Mechanisms against Diverse Cancer Growth and Metastasis: Do They Have an Inhibitory Effect on Cancer Progression?

Iridoids are glycosides found in plants, having inherent roles in defending them against infection by viruses and microorganisms, and in the rapid repair of damaged areas. The emerging roles of iridoid glycosides on pharmacological properties have aroused the curiosity of many researchers, and studies undertaken indicate that iridoid glycosides exert inhibitory effects in numerous cancers. This review focuses on the roles and the potential mechanism of iridoid glycosides at each stage of cancer development such as proliferation, epithelial mesenchymal transition (EMT), migration, invasion and angiogenesis. Overall, the reviewed literature indicates that iridoid glycosides inhibit cancer growth by inducing cell cycle arrest or by regulating apoptosis-related signaling pathways. In addition, iridoid glycosides suppress the expression and activity of matrix metalloproteinases (MMPs), resulting in reduced cancer cell migration and invasiveness. The antiangiogenic mechanism of iridoid glycosides was found to be closely related to the transcriptional regulation of pro-angiogenic factors, i.e., vascular endothelial growth factors (VEGFs) and cluster of differentiation 31 (CD31). Taken together, these results indicate the therapeutic potential of iridoid glycosides to alleviate or prevent rapid cancer progression and metastasis.

Quantitative proteomics and bioinformatics analyses reveal the protective effects of cyanidin-3-O-glucoside and its metabolite protocatechuic acid against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced cytotoxicity in HepG2 cells via apoptosis-related pathways

The aim of this study was to investigate the mechanism of action of cyanidin-3-O-glucoside (C3G) and its metabolite protocatechuic acid (PCA) mediated protection against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced cytotoxicity in HepG2 cells. The effects of C3G and PCA on cell viability, LDH release and apoptosis in IQ-induced HepG2 cells were evaluated using CCK-8, LDH release and flow cytometry assays, respectively. TMT-based proteomics was utilized to characterize the proteins and pathways associated with the improvement after C3G and PCA treatment. Results showed that exposure to IQ significantly increased cytotoxicity and apoptosis in HepG2 cells, which were alleviated by C3G and PCA. C3G was more effective than PCA in protecting HepG2 cells against IQ-induced cytotoxicity and regulating the related signaling pathways. Proteomics and bioinformatics analyses and Western blot validation revealed that apoptosis-related signaling pathways played pivotal roles in protecting against the cytotoxicity of IQ by C3G, and XIAP was identified as the target protein. Molecular docking proved that C3G had strong binding affinity to XIAP and hindered the binding of IQ to the BIR3 domain of XIAP, resulting in the inhibition of apoptosis. Our findings suggested that C3G has potential as a preventive food ingredient to prevent carcinogenic risk of heterocyclic aromatic amines.

Curcumin Regulates Cancer Progression: Focus on ncRNAs and Molecular Signaling Pathways.

Curcumin [(1E,6E) ‑1,7‑bis(4‑hydroxy‑3‑methoxyphenyl) hepta‑1,6‑diene‑3,5‑ dione] is a natural polyphenol derived from the rhizome of the turmeric plant Curcuma longa. Accumulated evidences have presented curcumin’s function in terms of anti-inflammatory, antioxidant properties, and especially anti-tumor activities. Studies demonstrated that curcumin could exert anti-tumor activity via multiple biological signaling pathways, such as PI3K/Akt, JAK/STAT, MAPK, Wnt/β-catenin, p53, NF-ĸB and apoptosis related signaling pathways. Moreover, Curcumin can inhibit tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis by regulating tumor related non-coding RNA (ncRNA) expression. In this review, we summarized the roles of curcumin in regulating signaling pathways and ncRNAs in different kinds of cancers. We also discussed the regulatory effect of curcumin through inhibiting carcinogenic miRNA and up regulating tumor suppressive miRNA. Furthermore, we aim to illustrate the cross regulatory relationship between ncRNA and signaling pathways, further to get a better understanding of the anti-tumor mechanism of curcumin, thus lay a theoretical foundation for the clinical application of curcumin in the future.

Apoptosis of Endothelial Cells Induced by Anti-Platelet Integrin β3 Antibody

To investigate the damaging of human umbilical vein endothelial cells (HUVEC) induced by antiplatelet integrin β3 antibodies in vitro. The serum from 36 chronic ITP patients were collected, flow cytometry and monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay were used to collect antiplatelet integrin β3 antibodies from the serum of the patients. After HUVEC were treated by ITP patient serum (PS) containing anti-integrin β3 antibodies, the cell damage was detected by Lactate dehydrogenase (LDH) assay, cell apoptosis was detected by flow cytometry, the expression of apoptosis-related gene Bax was detected by Reverse transcription-Quantitative real-time PCR (RT-qPCR), and expression of Apoptosis-related signaling pathway protein Akt and related protein Bax were detected by Western blot. HUVEC were treated by PS combined with Akt activator SC79, the cells damage were detected by LDH assay, apoptosis of the cells were detected by flow cytometry, the expression of apoptosis-related gene Bax was detected by RT-qPCR. Among 36 cases of serum from the chronic ITP patients, 5 patients' serum containing anti-integrin β3 antibodies were collected. After HUVEC was treated by PS, the viability of LDH was significant increased（P<0.05）, so as for the apoptosis of the cells（P<0.05）, the expression of gene and protein of Bax was increased up-regulated（P<0.05）, the protein expression of pAkt was down-regulated（P<0.05）. Comparing with HUVEC cultured with PS alone, the viability of LDH of HUVEC treated by PS combined with SC79 was significantly reduced（P<0.05）, so as for the apoptosis of the cells（P<0.05）, and gene expression of Bax was significantly decreased（P<0.05）. Anti-integrin β3 serum can cause the damage and apoptosis of HUVEC through Akt signaling pathway，the apoptotic effects of anti-integrin β3 antibodies to HUVEC was effectively reversed by SC79.

Transcriptome analysis reveals possible antitumor mechanism of Chlorella exopolysaccharide.

Microalgae, one of the most important classes of biomass producers, can produce exopolysaccharides similar to bacteria. The exopolysaccharide from Chlorella (CEPS) displays remarkable anticancer activity the mechanism of which remains to be elucidated. In this study, we analyzed the inhibitory effect of CEPS on the growth of HeLa cells. The results showed that CEPS inhibited the proliferation, decreased the viability, and changed the morphology of HeLa cells. Transcriptome analysis showed that 1894 genes were differentially expressed in the CEPS-treated group compared with the control group, including 1076 genes that were upregulated and 818 genes that were downregulated. The results of gene function enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in apoptosis and tumor-related biological processes and participated in several cancer and apoptosisrelated signaling pathways, including the MAPK signaling pathway, TNF signaling pathway, and the PI3K-Akt signaling pathway. The protein-protein interaction network identified 13 DEGs including PTPN11, RSAD2, ISG15, IFIT1, MX2, IFIT2, OASL, OAS1, JUN, OAS2, XAF1, ISG20, and IRF9 as hub genes. Our results suggest that CEPS is a promising therapeutic drug for the follow-up interventional therapy of cancer.

Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study.

Kidneys are one of the targets for SARS-CoV-2, it is reported that up to 36% of patients with SARS-CoV-2 infection would develop into acute kidney injury (AKI). AKI is associated with high mortality in the clinical setting and contributes to the transition of AKI to chronic kidney disease (CKD). Up to date, the underlying mechanisms are obscure and there is no effective and specific treatment for COVID-19-induced AKI. In the present study, we investigated the mechanisms and interactions between Quercetin and SARS-CoV-2 targets proteins by using network pharmacology and molecular docking. The renal protective effects of Quercetin on COVID-19-induced AKI may be associated with the blockade of the activation of inflammatory, cell apoptosis-related signaling pathways. Quercetin may also serve as SARS-CoV-2 inhibitor by binding with the active sites of SARS-CoV-2 main protease 3CL and ACE2, therefore suppressing the functions of the proteins to cut the viral life cycle. In conclusion, Quercetin may be a novel therapeutic agent for COVID-19-induced AKI. Inhibition of inflammatory, cell apoptosis-related signaling pathways may be the critical mechanisms by which Quercetin protects kidney from SARS-CoV-2 injury.

Metapristone (RU486-derivative) inhibits endometrial cancer cell progress through regulating miR-492/Klf5/Nrf1 axis

BackgroundEndometrial cancer is an invasive gynecological cancer prevalent in the world. The pathogenesis of endometrial cancer is related to multiple levels of regulation, referring to oestrogen, tumor-suppressor gene (e.g. PTEN) or microRNAs (e.g. miR-23a and miR-29b). Metapristone is a hormone-related drug, which is widely used in clinical treatment of endometrial cancer. However, the underlying regulatory mechanism of metapristone on endometrial cancer is still unclear, especially the regulatory effect on microRNAs. The aim of this study is to investigate the specific molecular mechanism of metapristone regulating microRNAs in the treatment of endometrial cancer.MethodsRL95-2 cells and Ishikawa cells were used as the endometrial cancer models. MiR-492 or si-miR-492 was transfected into RL95-2 cells and Ishikawa cells to explore the role of miR-492 in endometrial cancer. The cell cancer model and mice cancer model were used to confirm the function and mechanism of metapristone affected on endometrial cancer in vitro and in vivo. Mechanically, cell proliferation was monitored using MTT assay, cell colony formation assay and EdU assay. Luciferase reporter assay was used to identify the downstream target gene of miR-492. The protein expression and RNA expression were respectively measured by western blot and qRT-PCR for cell signaling pathway research, subsequently, were verified in the mice tumor model via immunohistochemistry.ResultsMetapristone as a kind of hormone-related drug significantly inhibited the endometrial cancer cell growth through regulating cell apoptosis-related gene expression. Mechanically, miR-492 and its target genes Klf5 and Nrf1 were highly expressed in the endometrial cancer cell lines, which promoted cell proliferation and inhibited cell apoptosis. Metapristone decreased the expression of miR-492 and its target genes Klf5 and Nrf1, leading to endometrial cancer cell growth inhibition in vitro and in vivo.ConclusionMetapristone inhibited the endometrial cancer cell growth through regulating the cell apoptosis-related signaling pathway and decreasing the expression of miR-492 and its downstream target genes (Klf5 and Nrf1), which provided the theoretical basis in clinical treatment of endometrial cancer.

Transcriptional Profiling of Exosomes Derived from Staphylococcus aureus-Infected Bovine Mammary Epithelial Cell Line MAC-T by RNA-Seq Analysis.

Mastitis is a common disease in the dairy industry that causes huge economic losses worldwide. Exosomes (carrying proteins, miRNA, lncRNA, etc.) play a vital role in the regulation of immune response. lncRNA can play a variety of regulatory roles by combining with protein, RNA, and DNA. The expression of mRNA and lncRNA in exosomes derived from bovine mammary epithelial cells infected by S. aureus is rarely understood. To explore this issue, RNA sequencing analysis was performed on exosomes derived from S. aureus-infected and noninfected MAC-T cells. Analysis of the sequencing results showed that there were 186 differentially expressed genes, 431 differentially expressed mRNAs and 19 differentially expressed lncRNAs in the exosomes derived from S. aureus-infected and noninfected MAC-T cells. By predicting lncRNA target genes, it was found that 19 differentially expressed lncRNAs all acted on multiple mRNAs in cis and trans. GO analysis revealed that differentially expressed genes and lncRNA target genes played significant roles in such metabolism (reactive oxygen species metabolic processes), transmembrane transport, cellular response to DNA damage stimulus, and response to cytokines. KEGG enrichment indicated that lncRNA target genes gathered in the TNF pathway, Notch pathway, MAPK pathway, NF-kappa B pathway, Hippo pathway, p53 pathway, reactive oxygen species metabolic processes, and longevity regulating pathway. In summary, all data indicated that differentially expressed gene, mRNA, and lncRNA in transcriptional profiling of exosomes participated in bacterial invasion and adhesion, oxidative stress, inflammation, and apoptosis-related signaling pathway. The data obtained in this study would provide valuable resource for understanding the lncRNA information in exosomes derived from dairy cow mammary epithelial cells and conduced to the study of S. aureus infection in dairy cow mammary glands.

The Effect of Resistance Training and Berberine Chloride on the Apoptosis-related Unfolded Protein Response Signaling Pathway in the Hippocampus of Diazinon-poisoned Rats.

Introduction:Diazinon is one of the most widely-used organophosphate pesticides in the world. This toxin enters the body in various ways and induces oxidative stress in various tissues. It has been proved that activation of Unfolded Protein Response (UPR) under oxidative stress is a steady mechanism for maintaining cell function and survival. Therefore, the present study aimed to review the effect of Resistance Training (RT) and Berberine Chloride (BC) on the apoptosis-related UPR signaling pathway in the hippocampus of diazinon-poisoned rats.Methods:In this experimental study, 40 male Wistar rats weighing 250 ±50 g were randomly divided into eight groups of five rats of 1) diazinon + 2 mg/kg BC + RT, 2) diazinon + 15 mg/kg BC + RT, 3) diazinon, 4) diazinon + RT, 5) diazinon + 2 mg/kg BC, 6) diazinon + 15 mg/kg BC, 7) healthy control, and 8) sham. The groups were treated for 5 weeks. At the end of the fifth week, ATF-4, ATF-6, and CHOP gene expression in hippocampus tissue were measured by quantitative real-time RT-PCR.Results:Diazinon significantly increased the expression of ATF-4, ATF-6, and CHOP in the hippocampus tissue of rats. Administrating 15 mg/kg BC with RT significantly decreased these genes, indicating a decrease in the rate of apoptosis in the hippocampus.Conclusion:This study showed that RT and BC have a protective effect against diazinon-induced toxicity in the hippocampus.