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Background: Treatment for metastatic nasopharyngeal carcinoma (NPC) is challenging. Till now, a truly effective chemotherapy regimen for NPC has not yet been identified. These clinical observations prompted us to investigate a potential drug as alternative option for treating., Purpose: This study evaluated the inhibitory effects of Ovatodiolide (Ova), on tumorigenic and cancer stem cell characteristics of NPC cells., Methods: Two NPC cell lines (NPC-BM1 and NPC-BM2) were used to examine the anticancer effects of Ova and the molecular mechanism underlying these activities by using sulforhodamine B cytotoxicity assay, western blot, immunofluorescence, migration, colony and tumorsphere formation assays., Results: Ova significantly inhibited the viability of BM1 and BM2 cells, downregulated Bcl-xL and Puma, and upregulated Bax/Bad expression levels. Ova dose-dependent suppressed migratory/invasive potential of NPC cells, and reduced ability to form colonies. Ova-induced apoptosis correlated with increased Bax/Bcl-xL ratio while NPC motility and colony formation inhibition were associated with reduced expression of p-FAK, p-PXN, F-actin, and Slug proteins and increased E-cadherin. Furthermore, ova inhibited NPC tumorsphere formation, associated with decreased SOX2, OCT4 and JAK-STAT signaling pathway. Ova also attenuated NPC stem cell tumorigenicity, inhibited tumor growth, and enhanced the sensitivity of NPC cells to cisplatin treatment, in vivo., Conclusions: Our results demonstrated the anticancer efficacy of Ova in NPC and its potential as a putative inhibitor of JAK2 and STAT3, which are essential in tumorigenesis of NPC. Further development of Ova is encouraged., (Copyright © 2018. Published by Elsevier GmbH.)

Aim: Ovarian cancer is the fifth common cancer in females. The aim of our study was to determine function of Zeylenone on cell viability and apoptosis of ovarian carcinoma SKOV3 cells., Methods: Cell viability was measured by Cell counting kit-8 (CCK8) assay; Mitochondrial membrane potential (MMP) and apoptosis were detected by flow cytometry. The mRNA and protein levels of related factors were determined by Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively., Results: Cell viability was decreased by Zeylenone in a dose-dependent manner. Zeylenone with concentrations of 2.5, 5 and 10 μmol/L was used to treat ovarian carcinoma SKOV3 cells for 24 h in the following study. The loss of MMP and apoptosis were both significantly increased by Zeylenone. The mRNA and protein levels of cytochrome c (cyto c) and apoptosis inducing factor (AIF) in cytosol were increased by Zeylenone. The mRNA and protein levels of Caspase-3, Fas, Fasl and Bax were increased; while the expression of Bcl-2 was decreased by Zeylenone. The expression of (Janus family of tyrosine kinase) p-JAK and signal transducer and activator of transcription (p-STAT) was decreased significantly by Zeylenone., Conclusion: Zeylenone inhibited cell proliferation and promoted apoptosis in ovarian carcinoma cells. The JAK-STAT pathway was involved in this progress., (© 2018 Japan Society of Obstetrics and Gynecology.)

Objective: To investigate if Dishevelled 2 (DVL2) regulates the apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) via the JAK-STAT pathway. Methods: DVL2 overexpressed lentivirus was transfected into RA-FLS and the apoptosis rate was detected by flow cytometry. The effect of DVL2 on RA-FLS signaling pathway was detected by RNA-seq, and then the key genes were verified by RT-PCR. Results: Compared with the control group, DVL2 significantly increased the apoptosis rate of MH7A (3.2%±2.2% vs 25.7%±4.5%). RNA-seq results showed that DVL2 down-regulated the JAK-STAT pathway.The results of RT-PCR showed that DVL2 inhibited the gene expression of JAK2, Stat1, and Stat2; DVL2 still inhibited the gene expression of JAK2 and Stat2 but not Stat1 after TNF-α stimulation.DVL2 inhibited the gene expression of Bcl-xL, and the gene expression of Bcl-2 and Bcl-xL after TNF-α stimulation. Conclusion: DVL2 can increase the apoptosis rate of RA-FLS through inhibiting the JAK-STAT pathway and its downstream anti-apoptotic gene.

Simple Summary: Liver cancer remains a serious health issue worldwide, necessitating the development of novel treatments. Yadanziolide A (Y-A) has shown potential in treating liver cancer. Our research evaluated Y-A's effects on liver cancer cells and in a mouse model. We discovered that Y-A not only kills liver cancer cells but also prevents their spread and induces programmed cell death at effective doses. In animal models, Y-A reduced tumor growth and improved health markers. Our study also identified that Y-A targets specific pathways related to cancer cell survival and growth, offering insights into its mechanism. These findings support Y-A as a promising candidate for liver cancer therapy, highlighting its effectiveness and potential clinical application. Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. Yadanziolide A (Y-A), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver cancer remain incompletely understood. In this study, we conducted a comprehensive evaluation of Y-A's effects on liver cancer cells using a range of in vitro assays and an orthotopic liver cancer mouse model. Our findings reveal that Y-A exerts dose-dependent cytotoxic effects on liver cancer cells, significantly inhibiting proliferation, migration, and invasion at concentrations ≥ 0.1 μM. Furthermore, Y-A induces apoptosis, as evidenced by increased apoptotic cell populations and apoptosome formation. In vivo studies confirm that Y-A inhibits tumor growth and reduces liver damage in mouse models. Mechanistically, Y-A targets the TNF-α/STAT3 pathway, inhibiting STAT3 and JAK2 phosphorylation, thereby activating apoptotic pathways and suppressing tumor cell growth. These results suggest that Y-A has promising anticancer activity and potential utility in liver cancer therapy. [ABSTRACT FROM AUTHOR]

Background: L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of L-theanine in myocardial ischemia-reperfusion injury (MIRI). Methods: The cardioprotective effects and mechanisms of L-theanine and the role of Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling were investigated in MIRI mice using measures of cardiac function, oxidative stress, and apoptosis. Results: Administration of L-theanine (10 mg/kg, once daily) suppressed the MIRI-induced increase in infarct size and serum creatine kinase and lactate dehydrogenase levels, as well as MIRI-induced cardiac apoptosis, as evidenced by an increase in Bcl-2 expression and a decrease in Bax/caspase-3 expression. Administration of L-theanine also decreased the levels of parameters reflecting oxidative stress, such as dihydroethidium, malondialdehyde, and nitric oxide, and increased the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC), glutathione (GSH), and superoxide dismutase (SOD) in ischemic heart tissue. Further analysis showed that L-theanine administration suppressed the MIRI-induced decrease of phospho-JAK2 and phospho-STAT3 in ischemic heart tissue. Inhibition of JAK2 by AG490 (5 mg/kg, once daily) abolished the cardioprotective effect of L-theanine, suggesting that the JAK2/STAT3 signaling pathway may play an essential role in mediating the anti-I/R effect of L-theanine. Conclusions: L-theanine administration suppresses cellular apoptosis and oxidative stress in part via the JAK2/STAT3 signaling pathway, thereby attenuating MIRI-induced cardiac injury. L-theanine could be developed as a potential drug to alleviate cardiac damage in MIRI. [ABSTRACT FROM AUTHOR]

Previous studies have shown that scutellarin inhibits the excessive activation of microglia, reduces neuronal apoptosis, and exerts neuroprotective effects. However, whether scutellarin regulates activated microglia-mediated neuronal apoptosis and its mechanisms remains unclear. This study aimed to investigate whether scutellarin can attenuate PC12 cell apoptosis induced by activated microglia via the JAK2/STAT3 signalling pathway. Microglia were cultured in oxygen–glucose deprivation (OGD) medium, which acted as a conditioning medium (CM) to activate PC12 cells, to investigate the expression of apoptosis and JAK2/STAT3 signalling-related proteins. We observed that PC12 cells apoptosis in CM was significantly increased, the expression and fluorescence intensity of the pro-apoptotic protein Bax and apoptosis-related protein cleaved caspase-3 were increased, and expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) was decreased. Phosphorylation levels and fluorescence intensity of the JAK2/STAT3 signalling pathway-related proteins JAK2 and STAT3 decreased. After treatment with scutellarin, PC12 cells apoptosis as well as cleaved caspase-3 and Bax protein expression and fluorescence intensity decreased. The expression and fluorescence intensity of Bcl-2, phosphorylated JAK2, and STAT3 increased. AG490, a specific inhibitor of the JAK2/STAT3 signalling pathway, was used. Our findings suggest that AG490 attenuates the effects of scutellarin. Our study revealed that scutellarin inhibited OGD-activated microglia-mediated PC12 cells apoptosis which was regulated via the JAK2/STAT3 signalling pathway. [ABSTRACT FROM AUTHOR]

Adenomyosis (ADS) is a common benign gynecological disease. Abnormal proliferation at the endometrial-myometrial interface (EMI) plays a crucial role in the occurrence and progression of ADS. miR-141-3p is associated with cell proliferation and apoptosis. However, the specific mechanism of miR-141-3p in the etiology of ADS is still unknown. In this study, we explored the effects of miR-141-3p on the proliferation and apoptosis of ADS EMI smooth muscle cells (SMCs). We collected EMI tissues for the primary culture of SMCs from 25 patients diagnosed with ADS and 20 without ADS. Real-time quantitative polymerase chain reaction and western blot were used to measure the mRNA and protein expression levels of miR-141-3p, JAK2, STAT3, phospho-JAK2, and phospho-STAT3 in ADS EMI SMCs. The cell counting kit 8 assay and flow cytometry analysis were used to evaluate the proliferation and apoptosis of EMI SMCs. The miR-141-3p mimic/inhibitor was used to increase or decrease the expression level of miR-141-3p. We added WP1066 to block the phosphorylation of JAK2/STAT3 pathway components. The miR-141-3p levels were decreased, while JAK2 and STAT3 levels were increased in ADS EMI SMCs. miR-141-3p overexpression significantly inhibited the proliferation and enhanced the apoptosis of EMI SMCs, whereas a decrease in miR-141-3p expression level was connected to the opposite results. Meanwhile, inactivated JAK2/STAT3 pathway decreased proliferation and enhanced apoptosis of EMI SMCs after WP1066 treatment. Furthermore, rescue experiments confirmed that the JAK2/STAT3 pathway was the downstream pathway of miR-141-3p and reduced the effect of miR-141-3p on the proliferation and apoptosis of EMI SMCs. These results demonstrate that miR-141-3p regulates the proliferation and apoptosis of ADS EMI SMCs by modulating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Cryptotanshinone (CPT), which is an important active ingredient of herbs, has shown great value for research. In particular, CPT exerts antitumor effects on various types of cancer; however, there are relatively few studies of CPT on gastric cancer cells. The objectives of this study were to investigate how CPT affects apoptosis in 5-fluorouracil-resistant SGC-7901 gastric cancer cells (SGC-7901/5-FU cells) and the molecular mechanism underlying its action. In this study, SGC-7901/5-FU cells were treated with 5-fluorouracil (5-FU) and CPT and the viability of the cells was assessed by CCK8 assay. Additionally, cellular apoptosis rates were evaluated using immunofluorescence and flow cytometry. Related gene expression was evaluated using Quantitative Real-time PCR methods and Western Blot, respectively. CPT inhibited SGC-7901/5-FU cell growth. The immunofluorescence results showed that CPT caused nuclear shrinkage in the cells. Quantitative Real-time PCR and Western Blot results also showed CPT decreased the expression of Mcl-1, Bcl-xl and Bcl-2 levels, and increased the expression of Bax. We demonstrated that CPT can inhibit the growth of SGC-7901/5-FU cells, and the mechanism may be related to the inhibition of the JAK2/STAT3 pathway. Additionally, CPT increased the inhibitory effect of 5-fluorouracil on SGC-7901/5-FU cells, an effect that correlated with changes in cellular resistance. [ABSTRACT FROM AUTHOR]

To investigate the effects of ginkgolide B on the proliferation and apoptosis of esophageal cancer cells and the related mechanisms. Human esophageal cancer OE19 cells were cultured in vitro. They were divided into control group (no intervention), low/medium/high dose test group (adding 6.25, 12.50 and 25.00 μmol/L ginkgolide B, respectively), ginkgolide B group (12.50 μmol/L ginkgolide B), positive drug group (4 mg/L cisplatin) and inhibitor group [12.50 μmol/L ginkgolide B+10.00 μmol/L janus kinase 2/transcriptional activator 3 (JAK2/STAT3) pathway inhibitor AG490] and activator group (12.50 μmol/L ginkgolide B+0.50 μmol/L JAK2/STAT3 pathway activator Colivelin), 24 h after intervention, cell count kit 8 (CCK-8), 5-acetyl-2' deoxyuridine (EdU) method, Hoechst 33258 staining, real-time fluorescence quantitative PCR (RT-qPCR) and protein immunoblot (WB) were used to detect cell viability, proliferation rate, apoptosis rate and expression levels of related factors. The results show that: compared with the control group, the cell viability of the medium/high dose test group and positive drug group was decreased (P<0.05), therefore, in this study, 12.50 μmol/L ginkgolide B group with significant difference and lower concentration was selected as ginkgolide B group for follow-up tests. Compared with the control group, the cell proliferation rate, Cyclin D1 mRNA and protein expression levels, p-JAK2 and p-STAT3 protein expression levels of ginkgolide B group and positive drug group were decreased, while the apoptosis rate and Caspase-3 mRNA and protein expression levels were increased (P<0.05). Compared with the ginkgolide B group, the changes of all indexes in inhibitor group were further enhanced (P<0.05). while those in activator group were significantly reversed (P<0.05). Ginkgolide B can inhibit the proliferation of OE19 cells and promote apoptosis of esophageal cancer cells by down-regulating JAK2/STAT3 signaling pathway. This study revealed a new anticancer mechanism of ginkgolide B and provided a theoretical basis for the study of esophageal cancer. [ABSTRACT FROM AUTHOR]

Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous lipids that act as agonists of the peroxisome proliferator-activated receptor α (PPARα). Recently, an interest in the role of these lipids in malignant tumors has emerged. Nevertheless, the effects of OEA and PEA on human neuroblastoma cells are still not documented. Type I interferons (IFNs) are immunomodulatory cytokines endowed with antiviral and anti-proliferative actions and are used in the treatment of various pathologies such as different cancer forms (i.e., non-Hodgkin's lymphoma, melanoma, leukemia), hepatitis B, hepatitis C, multiple sclerosis, and many others. In this study, we investigated the effect of OEA and PEA on human neuroblastoma SH-SY5Y cells treated with IFNβ. We focused on evaluating cell viability, cell proliferation, and cell signaling. Co-exposure to either OEA or PEA along with IFNβ leads to increased apoptotic cell death marked by the cleavage of caspase 3 and poly-(ADP ribose) polymerase (PARP) alongside a decrease in survivin and IKBα levels. Moreover, we found that OEA and PEA did not affect IFNβ signaling through the JAK-STAT pathway and the STAT1-inducible protein kinase R (PKR). OEA and PEA also increased the phosphorylation of p38 MAP kinase and programmed death-ligand 1 (PD-L1) expression both in full cell lysate and surface membranes. Furthermore, GW6471, a PPARα inhibitor, and the genetic silencing of the receptor were shown to lower PD-L1 and cleaved PARP levels. These results reveal the presence of a novel mechanism, independent of the IFNβ-prompted pathway, by which OEA and PEA can directly impair cell survival, proliferation, and clonogenicity through modulating and potentiating the intrinsic apoptotic pathway in human SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

This study delved at how the natural substance dieckol (DCL) prevents prostate cancerous cells from proliferating and migrating by blocking the JAK/STAT3 signaling pathway in PC‐3 cells. For numerous tests, the cells were treated to DCL at a range of concentrations (0–20 μM) for 24 h. DCL mediated cytotoxicity was analyzed by MTT assay. To evaluate ROS, DCFH‐DA staining was employed. Dual (AO/EtBr) staining was utilized to examine apoptotic changes, and MMP levels in PC‐3 cells were examined using the appropriate fluorescent staining assays. By using flow cytometry and western blotting, the protein expressions of cell survival, cell cycle, proliferation, and apoptosis were assessed. The results showed that DCL significantly cytotoxically affects PC‐3, and the IC50 was discovered to be 12 μM for 24 h exposure. Furthermore, after DCL treatment in PC‐3, considerable ROS generation and increased apoptotic signals were detected. STAT3, JAK1, PCNA, and cyclins D1 and E1 are all suppressed by DCL in PC‐3. In addition, DCL therapy in PC‐3 dramatically increased pro‐apoptotic proteins such Bax, caspase‐3, and cytochrome C. Therefore, DCL has been regarded as a chemotherapeutic agent because to its ability to decrease the expression of proteins that control cell proliferation, including STAT3, JAK1, PCNA, and cyclins D1 and E1. [ABSTRACT FROM AUTHOR]

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. Here, we show that K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway. Collectively, this study may provide a preliminary basis for further cancer treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

The present study aimed to increase the content of minor ginsenosides and enhance the anti-colorectal cancer activity of ginsenosides via biotransformation by Lactiplantibacillus plantarum MB11 screened from fermented foods. A subcutaneous transplantation tumor model of murine colorectal cancer CT26 cells was established in mice to study the anticarcinogenic activities and mechanism of fermented total ginsenosides (FTGs). The results showed that L. plantarum MB11 fermentation increased the content of minor ginsenosides and decreased that of major ginsenosides. FTGs reduced the tumor weight and size compared with the model group. Immunofluorescence and TdT-mediated dUTP nick end labeling (TUNEL) analysis showed that FTGs significantly increase the number of caspase-3 cells in tumor tissue and induce cell apoptosis. Mechanically, FTGs activate AMPK/mTOR autophagy pathway and regulate JAK2/STAT3 and Bax/Bcl-2/caspase-3 apoptosis pathway. Overall, fermentation with L. plantarum MB11 enhanced minor ginsenosides in total ginsenosides, and FTGs induced subcutaneous transplantation tumor autophagy and apoptosis in mice. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic ischemic post-conditioning (IPOC) is shown to protect the liver from injury induced by ischemia/reperfusion (IR). However, the mechanism underlying this protection has remained elusive. The present study aimed to investigate the role of the interleukin 6-Janus kinase-signal transducers and activators of transcription (IL-6-JAK-STAT) pathway in the protective effect of hepatic IPOC against the IR-induced injury in the liver. Methods: Twenty-five rats were randomly divided into 5 groups of (1) sham-operated, (2) IR, (3) IR+hepatic IPOC, (4) IR+tofacitinib (TOFA), and (5) IR+TOFA+hepatic IPOC. The changes induced by IR and the effects of different treatments were assessed by enzyme release, histopathological observations, the serum level of IL-6, and the occurrence of apoptosis detected via the expression of the Bax/Bcl-2 ratio. Results: The hepatic IPOC improved the liver injury induced by IR as shown by histological changes, reduction of IL-6 level, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) compared to the IR group (P <0.001,> P <0.05,> P P<0.05).> Conclusion: It suggests that the protective effect of hepatic IPOC against IR-induced injury may be mediated by activating the IL-6-JAK-STAT pathway. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) and STAT5 are the transcription factors that have been studied extensively in relevance to the development of cancers in humans. Suppression of either STAT3 or STAT5‐mediated signaling events has been demonstrated to be effective in inducing cytotoxicity in cancer cells. Herein, new hybrids of triazolyl‐indolo‐quinoxaline are synthesized and examined for their effect on the activation of STAT3 and STAT5 pathways in gastric cancer (GC) cells. Among the newly synthesized compounds, 2,3‐difluoro‐6‐((1‐(3‐fluorophenyl)‐1H‐1,2,3‐triazol‐5‐yl)methyl)‐6H‐indolo[2,3‐b]quinoxaline (DTI) displayed selective cytotoxicity against GC cells over their normal counterpart. Flow cytometric analysis, annexin‐V‐fluorescein isothiocyanate staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, live and dead assay, and caspase activation experiments suggested DTI as a potent inducer of apoptosis. The mechanistic approach revealed that DTI imparts cytotoxicity via downregulating the phosphorylation of STAT3Y705 and STAT5Y694/699. DTI significantly reduced the nuclear pool of STAT3/STAT5 and reduced the DNA interaction ability of STAT3/STAT5 as evidenced by immunofluorescence and electrophoretic mobility shift assay. Further investigation revealed that inhibitory effects towards STAT proteins were mediated through the suppression of upstream kinases such as JAK1, JAK2, and Src. Treatment of GC cells with pervanadate counteracted the DTI‐driven STAT3/STAT5 inhibition suggesting the involvement of tyrosine phosphatase. Upon DTI exposure, there was a significant upregulation in the mRNA and protein expression of PTPεC, which is a negative regulator of the JAK‐STAT pathway. Knockdown of PTPεC suppressed the DTI‐induced STATs inhibition in GC cells. Taken together, triazolyl‐indolo‐quinoxaline is presented as a new inhibitor of the STAT3/STAT5 pathway in GC cells. [ABSTRACT FROM AUTHOR]

Renal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity. [ABSTRACT FROM AUTHOR]

This study was designed to explore cryptanshinone (CPT) extract of Salvia miltiorrhiza stimulating pediatric acute myeloid leukemia (AML) stem cell (LSC) apoptosis and anti-inflammatory mechanism via accelerating microRNA (miR)-211-5p to restrain Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway activation. Obtaining blood samples from pediatric acute myeloid leukemia patients and healthy volunteers and detecting miR-211-5p and JAK2 were performed. Purchase of the human AML cell line KG1a was conducted, and sorting of KG1a cells was to gain LSC. Test of miR-211-5p and JAK2, the phosphorylation of JAK2/STAT3 was implemented. Pretreatment of LSCs was with CPT. Variation of miR-211-5p and JAK2 in LSCs was via plasmid transfection to explore their actions in cell advancement with apoptosis and inflammation. Identification of the targeting of miR-211-5p with JAK2 was implemented. In results: MiR-211-5p was declined in endometrial cancer, while JAK2 was elevated; CPT was available to boost LSC apoptosis and restrain the inflammation; elevated miR-211-5p or repressive JAK2 was available to strengthen the acceleration of CPT on LSCs apoptosis and the repression of inflammation; MiR-211-5p targeted JAK2; augmented JAK2 was available to turn around the action of elevated miR-211-5p. We conclude that CPT extract of Salvia miltiorrhiza stimulated pediatric LSC apoptosis and restrained the inflammation via accelerating microRNA (miR)-211-5p to suppress JAK2/STAT3 pathway activation. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) implicates oxidative stress, apoptosis, and inflammation, all of which may contribute liver injury. Aerobic exercise is assured to positively regulate metabolism in the liver. This project was designed to investigate whether and how aerobic exercise improves DM-induced liver injury.Methods: Seven-week-old male db/db mice and age-matched m/m mice were randomly divided into a rest control group or a group that received 12 weeks of aerobic exercise by treadmill training (10 m/min). Haematoxylin and eosin (HE) staining, electron microscopy, Oil Red O staining and TUNEL assays were used to evaluate the histopathological changes in mouse liver. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TRIG), cholesterol (CHOL) were analyzed by serum biochemical analysis. Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), and tissue levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were analyzed via ELISA. Nuclear factor E2-associated factor-2 (Nrf2), nuclear factor κB (NF-κB) and JAK2/STAT3 pathway-related proteins were measured by immunofluorescence, Western blotting and q-PCR. F4/80 expression in liver tissues was assessed by immunohistochemistry.Results: In diabetic mice, exercise training significantly decreased the levels of serum TRIG, CHOL, IL-6, TNF-α, ALT and AST; prevented weight gain, hyperglycaemia, and impaired glucose and insulin tolerance. Morphologically, exercise mitigated the diabetes-induced increase in liver tissue microvesicles, inflammatory cells, F4/80 (macrophage marker) levels, and TUNEL-positive cells. In addition, exercise reduced the apoptosis index, which is consistent with the results for caspase-3 and Bax. Additionally, exercise significantly increased SOD activity, decreased MDA levels, activated Nrf2 and decreased the expression of NF-kB, phosphorylated JAK2 and STAT3 proteins in the livers of diabetic mice.Conclusion: This study demonstrated that aerobic exercise reversed liver dysfunction in db/db mice with T2DM by reducing oxidative stress, apoptosis and inflammation, possibly by enhancing Nrf2 expression and inhibiting the JAK2/STAT3 cascade response. [ABSTRACT FROM AUTHOR]

This study aims to explore the function of circRIMS in cerebral ischemia/reperfusion (CIR) and its regulatory mechanism. The expression of the circRIMS was examined in GEO chip data and validated by qRT-PCR analysis. A middle cerebral artery occlusion/repression (MCAO/R) model was developed using C57BL/6J mice. Starbase and circinteractome were employed to identify the target miRNA and mRNA. The result was confirmed by dual-luciferase reporter assay, and biotinylated RNA-pulldown assay. The cell viability and apoptosis were confirmed through CCK-8 and flow cytometry assay. This study revealed that circRIMS expression was upregulated in MCAO mice model and OGD/RX-simulated cell model. Knockdown circRIMS demonstrated the functional of circRIMS in increasing cell viability, reducing apoptosis, LDH activity and inflammatory factors secretion in OGD/RX-simulated CIR injury in vitro. Additionally, miR-96-5p was identified as a target of circRIMS, while the STAT1 gene is a downstream gene of miR-96-5p, and JAK was also considered to be a downstream gene of the JAK-STAT pathway. Furthermore, inhibition of miR-96-5p or overexpression of STAT1 promoted the progression of CIR injury by elevating apoptosis, reducing cell viability, and increasing the secretion of inflammatory cytokines. CircRIMS contributes to the progression of CIR injury via regulating miR-96-5p/JAK/STAT1 axis. [ABSTRACT FROM AUTHOR]

Acacetin is a natural flavonoid compound found in diverse plants, which has strong anti‐inflammatory and anti‐cancer activities. This work aimed at investigating how acacetin functions on esophageal squamous carcinoma cells. In this work, esophageal squamous carcinoma cell lines were subjected to increasing doses of acacetin, and the proliferative, migrative, invasive and apoptotic phenotypes were evaluated by a series of in vitro experiments. Genes related to acacetin and esophageal cancer were predicted by bioinformatics analysis. The levels of apoptosis‐relevant proteins and JAK2/STAT3 pathway‐relevant proteins in esophageal squamous carcinoma cells were probed by Western blot. It was revealed that acacetin could block the growth and aggressiveness of TE‐1 and TE‐10 cells and promote the apoptosis. Acacetin treatment induced bax's expression and repressed bcl‐2's expression. Notably, acacetin inhibits JAK2/STAT3 pathway in esophageal squamous carcinoma cells. In summary, acacetin inhibits the malignant progression of esophageal squamous carcinoma via restraining JAK2/STAT3 signaling. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effect of down-regulation of miR-320a expression on the myocardial hypoxia/reoxygenation (H/R)injury model, and to clarify its related mechanism. Methods: Real-time fluorescence quantitative PCR (RT-qPCR)method was used to detect the expression levels of miR-320a in serum of the patients with actue myocardial infarction (AMI)and the myocardial H9C2 cells induced by H/R. The miR-320a inhibitor, inhibitor NC, small interference Janus kinase 2 (si-JAK2), and si-NC plasmids were transfected into the H9C2 cells respectively, and blank control group was set up. After successful transfection, the H/R treatment was performed. The H9C2 cells were divided into control group, H/R group, H/R + inhibitor NC group, H/R + miR-320a inhibitor group, H/R + miR-320a inhibitor + si-NC group and H/R + miR-320a inhibitor + si-JAK2 group. The targeting relationship between miR-320a and Janus kinase 2 (JAK2)was detected by double luciferase reporter gene; the proliferation rate of cells in various groups were detected by CCK-8 assay; the activities of superoxide dismutase (SOD)and levels of malonaldehyde (MDA)in cells and the levels of lactate dehydrogenase (LDH)in cell culture supernanant in various groups were detected by biochemical method; the apoptotic rates of cells in various groups were detected by flow cytometry; the expression levels of miR-320a and JAK2 mRNA in cells in various groups were detected by RT-qPCR method; the expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), cleaved-cysteinyl aspartate specific proteinase-3 (cleaved-caspase-3), JAK2, signal transducers and activator of transcription 3 (STAT3), and phosphorylated STAT3 (p-STAT3)proteins in cells in various groups were detected by Western blotting method. Results: The expression levels of miR-320a in serum of the patients with AMI and the myocardial H9C2 cells in H/R group were significantly higher than those in control group (P<0. 05). The results of double Luciferase reporter gene detection suggested that miR-320a could targetedly bind with JAK2. Compared with control group, the proliferation rate of the cells and SOD activity in the cells in H/R group were decreased significantly (P<0. 05), the apoptotic rate of the cells, MDA level and LDH activity in the cells were significantly increased (P<0. 05), the expression levels of Bcl-2 and JAK2 proteins and ratio of p-STAT3/STAT3 in the cells were significantly decreased (P<0. 05), and the expression levels of Bax and cleaved caspase-3 proteins in the cells were significantly increased (P<0. 05). Compared with H/R group, the proliferation rate of the cells and SOD activity in the cells in H/R+miR-320a inhibitor group were increased (P<0. 05), while the apoptotic rate of the cells, MDA level in the cells, LDH activity in the cell culture supernanant were decreased (P<0. 05), the expression levels of Bcl-2 and JAK2 proteins and ratio of p-STAT3/STAT3 in the cells were significantly increased (P<0. 05), the expression levels of Bax and cleaved- caspase-3 proteins in the cells were significantly decreased (P<0. 05). Compared with H/R+miR-320a inhibitor+ si-NC group, the proliferation rate of the cells and SOD activity in the cells in H/R+miR-320a inhibitor+ si-JAK2 group were decreased (P<0. 05), and the apoptotic rate of the cells, MDA level in the cells, and LDH activity in the cell culture supernanant were increased (P<0. 05). Conclusion: Down-regulation of miR-320a expression can inhibit the apoptosis of the cardiomyocytes induced by H/R and increase the proliferation activity of cells, and its mechanism is related to the targeted regulation of JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Exercise preconditioning (EP) is essential for preventing ischemic stroke. Recent studies have shown that EP exerts neuroprotective effects in the cerebral ischemia‐reperfusion injury model. Nonetheless, there have been few reports on the relationship between EP and the Th17/Treg balance. Moreover, it is unclear whether the JAK2/STAT3 pathway is responsible for the neuroprotective effect of EP. Therefore, we aimed to explore the impact of EP, other than the anti‐inflammatory and antiapoptotic functions, on the Th17/Treg balance via the JAK2/STAT3 pathway in a middle cerebral artery occlusion (MCAO)‐induced model. Results: Fifty rats were randomly allocated into five groups, including the sham group (n = 10), EP+sham group (n = 10), MCAO group (n = 10), EP+MCAO group (n = 10), and EP+MCAO+JAK2/STAT3 pathway agonist (coumermycin A1, CA1) group (n = 10). The results indicated that EP alleviated neurological deficits, reduced infarct volume, and ameliorated neuronal apoptosis induced by MCAO. Additionally, the MCAO‐induced Th17/Treg imbalance could be rectified by EP. The decreased levels of IL‐10 and Foxp3 and increased IL‐17 and RORα in the MCAO group were reversed by EP treatment. Regarding inflammation, EP reduced the concentrations of IL‐6 and IL‐17 and elevated those of IL‐10 and TGF‑β. The neuroprotective effects of EP were accompanied by decreased phosphorylation of JAK2 and STAT3. Furthermore, CA1 pretreatment diminished all the beneficial effects of EP partially. Conclusion: Our findings suggest that EP contributes to attenuating neuronal apoptosis, Th17/Treg imbalance, and inflammation induced by MCAO via inhibiting the JAK2/STAT3 pathway, indicating its therapeutic potential in ischemic stroke. [ABSTRACT FROM AUTHOR]

Background: A growing body of research shows that drug monomers from traditional Chinese herbal medicines have antineuroinflammatory and neuroprotective effects that can significantly improve the recovery of motor function after spinal cord injury (SCI). Here, we explore the role and molecular mechanisms of Alpinetin on activating microglia-mediated neuroinflammation and neuronal apoptosis after SCI. Methods: Stimulation of microglia with lipopolysaccharide (LPS) to simulate neuroinflammation models in vitro, the effect of Alpinetin on the release of pro-inflammatory mediators in LPS-induced microglia and its mechanism were detected. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of Alpinetin on activating microglia-mediated neuronal apoptosis. Finally, rat spinal cord injury models were used to study the effects on inflammation, neuronal apoptosis, axonal regeneration, and motor function recovery in Alpinetin. Results: Alpinetin inhibits microglia-mediated neuroinflammation and activity of the JAK2/STAT3 pathway. Alpinetin can also reverse activated microglia-mediated reactive oxygen species (ROS) production and decrease of mitochondrial membrane potential (MMP) in PC12 neuronal cells. In addition, in vivo Alpinetin significantly inhibits the inflammatory response and neuronal apoptosis, improves axonal regeneration, and recovery of motor function. Conclusion: Alpinetin can be used to treat neurodegenerative diseases and is a novel drug candidate for the treatment of microglia-mediated neuroinflammation. [ABSTRACT FROM AUTHOR]

The altered expression of microRNA (miRNA) has been implicated in glioma. Here, the current study aimed to clarify the oncogenic effects of miR-19b-3p on cellular processes of glioma and to elucidate the underlying mechanism associated with SOCS3 and the JAK-STAT signaling pathway. Differentially expressed genes related to glioma were initially identified via microarray analysis. Twenty-five glioma patients were selected for clinical data collection, while additional 12 patients with traumatic brain injuries were selected as controls. Cell senescence was assessed by β-galactosidase staining, proliferation by MTT assay and apoptosis by flow cytometry following gain- and/or loss-of-function of miR-19b-3p or SOCS3. Glioma xenograft mouse model was developed through subcutaneous injection to nude mice to provide evidence in vivo. The glioma patients exhibited overexpressed miR-19b-3p and poorly-expressed SOCS3. SOCS3 was identified as a target gene of miR-19b-3p through dual-luciferase reporter gene assay. miR-19b-3p repressed SOCS3 expression and activated the JAK-STAT signaling pathway. Furthermore, miR-19b-3p inhibition promoted apoptosis and senescence, and suppressed cell proliferation through inactivation of the JAK-STAT signaling pathway and up-regulation of SOCS3. The reported regulatory axis was validated in nude mice as evidenced by suppressed tumor growth. Taken together, this study demonstrates that miR-19b-3p facilitates glioma progression via activation of the JAK-STAT signaling pathway by targeting SOCS3, highlighting a novel therapeutic target for glioma treatment. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs), as key regulators, are closely associated with the development of a variety of disease. However, the mechanisms by which lncRNAs regulate Clostridium perfringens type C induced piglet diarrhea are unclear. Methods: In the present study, we explored the expression and characterization of lncRNAs in a C. perfringens beta2 (CPB2) toxin-treated intestinal porcine epithelial cell line-J2 (IPEC-J2) using RNA-sequencing (RNA-seq). Results: A total of 6,558 lncRNAs were identified, of which 49 lncRNAs were significantly differentially expressed between the control and CPB2 groups. Functional enrichment analysis showed that the target genes of differentially expressed lncRNA EN-90756 were mainly associated with defense response to virus, and negative regulation of apoptotic process. LncRNA EN-90756 was significantly up-regulated in IPEC-J2 cells at different time points after CPB2 treatment. Functionally, knockdown of lncRNA EN-90756 might regulate the proliferation and apoptosis of IPEC-J2 cells by affecting the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway. LncRNA EN-90756 may be involved in CPB2 toxin-induced piglet diarrhea by regulating the expression of its target gene MX1 (encoding MX dynamin like GTPase 1). Conclusion: Long non-coding RNA EN-90756 affected the antiviral ability of IPEC-J2 cells by regulating the expression of MX1. Meanwhile, lncRNA EN-90756 might regulate cell proliferation and apoptosis by affecting JAK-STAT signaling pathway activation. These findings provide novel perspectives and directions for further exploration of the regulatory mechanisms of lncRNAs on CPB2 toxin-induced diarrhea in piglets. [ABSTRACT FROM AUTHOR]

An increasing number of studies have focus upon β-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation β-AR blocker, has not been explored for use against T-ALL. In this study, the level of β-ARs was explored in pediatric T-ALL patients. Moreover, the antitumor effects of CVD against T-ALL were assessed in vitro and in vivo , and the underlying mechanisms were investigated. The viability of T-ALL cells following CVD treatment was detected using a CCK-8 assay, and the apoptotic and cell cycle effects were measured using flow cytometry. The protein levels of β-ARs, cAMP, Epac, JAK2, STAT3, p-STAT3, PI3K, p-PI3K, AKT, p -AKT, mTOR, cyclin D1, PCNA, and cleaved caspase-3 were assessed by Western blotting. In vivo experiments were used to investigate the effect of CVD on T-ALL growth in mice. The results indicated that β-ARs were highly expressed in the newly diagnosed T-ALL cells when compared to those in the control group (P < 0.05). In vitro , CVD significantly inhibited T-ALL cell viability, promoted apoptosis and blocked the G0/G1 phase of cell cycle. After CVD treatment, the protein levels of β-ARs, cAMP, Epac, PI3K, p-PI3K, AKT, p -AKT, mTOR, JAK2, STAT3, p-STAT3, cyclin D1 and PCNA were significantly downregulated (P < 0.05); whereas cleaved caspase-3 was significantly upregulated (P < 0.05). In vivo , the volume and weight of the xenograft tumors were significantly decreased in the CVD group (P < 0.05). CVD promoted xenograft tumor apoptosis and reduced the proportion of CEM-C1 cells in murine peripheral blood and bone marrow (P < 0.05). Our results demonstrate that β-ARs are expressed in T-ALL. CVD has a strong antitumor effect against T-ALL and inhibits β-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL. • The expression of β-ARs in patients with T-ALL and T-ALL cells was first discovered. • β-adrenergic receptors are positive regulators of T-ALL viability. • We find for the first time that carvedilol has a strong anti T-ALL effect. • Carvedilol can inhibit T-ALL cells proliferation and promotes apoptosis. • Carvedilol can inhibit cAMP/Epac, PI3K/AKT/mTOR and JAK2/STAT3 signaling pathways. [ABSTRACT FROM AUTHOR]

Objectives: Esculetin is a coumarin derivative, which is extracted from the dried barks of fraxinus chinensis Roxb. Although it is reported esculetin possesses multiple pharmacological activities, its associated regulatory mechanism on ovarian cancer isn't well investigated. Methods: Cytotoxicity is evaluated by MTT, clonogenic and living/dead cells staining assays. Migration and invasion effects are investigated by wound healing, and transwell assays. The effect of cell cycle and apoptosis are analyzed by flow cytometry and western blotting. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) is assessed by fluorescence microscope. Analysis of animal experiments are carried out by various pathological section assays. Key findings: Esculetin exerts an anti- ovarian cancer effect. It is found that apoptosis induction is promoted by the accumulation of excessive ROS and inhibition of JAK2/STAT3 signalling pathway. In addition, exposure to esculetin leads to the cell viability reduction, migration and invasion capability decrease and G0/G1 phase cell cycle arrest induced by down-regulating downstream targets of STAT3. In vivo experimental results also indicate esculetin can inhibit tumour growth of mice. Conclusions: Our study provides some strong evidences to support esculetin as a potential anti-cancer agent in ovarian cancer. [ABSTRACT FROM AUTHOR]

Theasaponin derivatives, which are reported to exert antitumor activity, have been widely reported to exist in edible plants, including in the seed cake of Camellia oleifera (C.), which is extensively grown in south of China. The purpose of this study was to isolate new theasaponin derivatives from C. seed cake and explore their potential antitumor activity and their underlying molecular mechanism. In the present study, we first isolated and identified four theasaponin derivatives (compounds 1, 2, 3, and 4) from the total aglycone extract of the seed cake of Camellia oleifera by utilizing a combination of pre-acid-hydrolysis treatment and activity-guided isolation. Among them, compound 1 (C1) and compound 4 (C4) are newly discovered theasaponins that have not been reported before. The structures of these two new compounds were characterized based on comprehensive 1D and 2D NMR spectroscopy and high-resolution mass spectrometry, as well as data reported in the literature. Secondly, the cytotoxicity and antitumor property of the above four purified compounds were evaluated in selected typical tumor cell lines, Huh-7, HepG2, Hela, A549, and SGC7901, and the results showed that the ED50 value of C4 ranges from 1.5 to 11.3 µM, which is comparable to that of cisplatinum (CDDP) in these five cell lines, indicating that C4 has the most powerful antitumor activity among them. Finally, a preliminary mechanistic investigation was performed to uncover the molecular mechanism underlying the antitumor property of C4, and the results suggested that C4 may trigger apoptosis through the Bcl-2/Caspase-3 and JAK2/STAT3 pathways, and stimulate cell proliferation via the NF-κB/iNOS/COX-2 pathway. Moreover, it was surprising to find that C4 can inhibit the Nrf2/HO-1 pathway, which indicates that C4 has the potency to overcome the resistance to cancer drugs. Therefore, C1 and C4 are two newly identified theasaponin derivatives with antitumor activity from the seed cake of Camellia oleifera, and C4 is a promising antitumor candidate not only for its powerful antitumor activity, but also for its ability to function as an Nrf2 inhibitor to enhance the anticancer drug sensitivity. [ABSTRACT FROM AUTHOR]

Context: Shenlian extract (SL) is a combination of Salvia miltiorrhiza Bge. (Labiatae) and Andrographis paniculata (Burm. F.) Wall. Ex Nees (Acanthaceae) extracts, which promote blood circulation and clear endogenous heat toxins. Myocardial ischaemia-reperfusion injury (MI/RI) is aggravated myocardial tissue damage induced by reperfusion therapy after myocardial infarction. Objectives: This study explores the effect of SL on MI/RI and the underlying mechanism. Materials and methods: Primary peritoneal macrophages (pMACs) were treated with LPS and SL (5, 10 or 20 lg/mL) for 24 h. The myocardial ischaemia-reperfusion (MI/R) model was established after administration of different doses of SL (90, 180 or 360mg/kg). Myocardial tissue injury was assessed by methylthiazolyl tetrazolium (TTC) staining and levels of creatine kinase (CK), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) in mice. The double immunofluorescence staining of iNOS/F4/80 and CD86/F4/80 was used to detect macrophage M1 polarization. The levels of miR-155, inflammatory factors and chemokines were detected by qRT-PCR or ELISA. CD86, iNOS, SOCS3, JAK2, p-JAK2, STAT3 and p-STAT3 proteins expressions in macrophages were analyzed by western blotting. Conditioned medium transfer systems were designed to unite M1 macrophages with H/R cardiomyocytes, and cell apoptosis was detected by TUNEL staining, western blotting or immunohistochemistry. Results: SL reduced apoptosis, diminished CK and LDH levels, raised SOD concentration and decreased infarct size in the MI/R model. Meanwhile, SL decreased miR-155 level, inhibited M1 macrophage polarization and inflammation. Furthermore, SL promoted SOCS3 expression and blocked JAK2/STAT3 pathway in vitro. Conclusions: SL may be a promising TCM candidate for MI/RI. The underlying mechanisms could be associated with inhibition of M1 macrophage polarization via down-regulating miR-155. [ABSTRACT FROM AUTHOR]

Context: Cyanidin has been shown to have therapeutic potential in osteoarthritis. However, it is unclear whether cyanidin prevents the progression of intervertebral disc degeneration (IVDD). Objective: This study evaluates the effects of cyanidin on IVDD in vitro and in vivo. Materials and methods: Nucleus pulposus cells (NPCs) isolated from lumbar IVD of 4-week-old male Sprague-Dawley (SD) rats were exposed to 20 ng/mL IL-1b, and then treated with different doses (0-120 mM) of cyanidin for 24 h. SD rats were classified into three groups (n=8) and treated as follows: control (normal saline), IVDD (vehicle), IVDDþcyanidin (50mg/kg). Cyanidin was administered intraperitoneally for 8 weeks. Results: The IC50 of cyanidin for NPCs was 94.78 mM, and cyanidin had no toxicity at concentrations up to 500 mg/kg in SD rats. Cyanidin inhibited the apoptosis of NPCs induced by IL-1b (12.73 ± 0.61% vs. 18.54 ± 0.60%), promoted collagen II (0.82-fold) and aggrecan (0.81-fold) expression, while reducing MMP-13 (1.02-fold) and ADAMTS-5 (1.40-fold) expression. Cyanidin increased the formation of autophagosomes in IL-1b-induced NPCs, and promoted LC3II/LC3I (0.83-fold) and beclin-1 (0.85-fold) expression, which could be reversed by chloroquine. Cyanidin inhibited the phosphorylation of JAK2 (0.47-fold) and STAT3 (0.53-fold) in IL-1b-induced NPCs. The effects of cyanidin could be enhanced by AG490. Furthermore, cyanidin mitigated disc degeneration in IVDD rats in vivo. Discussion and conclusions: Cyanidin improved the function of NPCs in IVDD by regulating the JAK2/STAT3 pathway, which may provide a novel alternative strategy for IVDD. The mechanism of cyanidin improving IVDD still needs further work for in-depth investigation. [ABSTRACT FROM AUTHOR]

Liza haematocheila is exposed to various chemical contaminants from anthropogenic sources, including tributyltin chloride (TBTC). Yet the toxicity mechanism of TBTC on haarder remains unclear. The haarder was exposed to different doses (0, 10%, 20%, and 50% of LC 50 -96 h) of TBTC. In this study, the results revealed its high bioaccumulation in the livers and significant alteration for development. The activities of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase decreased after 96-h exposure to TBTC, this accompanied by an increased malondialdehyde level. TBTC exposure caused the intense production of reactive oxygen species, a reduction in total blood cell count in serum, and apoptosis-related alterations in livers, indicating that enhanced oxidative stress occurred in the process of TBTC exposure. Histological results revealed angiorrhexis and infiltration of inflammatory cells, vacuolar degeneration of hepatocytes in the livers, and swelling, fusion, and disintegration of gill organs. Interestingly, the obtained transcriptional profiles indicated that high doses of TBTC caused energy disorder, apoptosis, and adipogenesis restriction mediated by cytokines and adipokines in Jak-STAT and adipocytokine signaling pathways. In summary, acute exposure to high doses of TBTC could impair the antioxidant system and pathways related to energy, apoptosis and adipogenesis, eventually posing a serious challenge to the fitness of haarder individuals and its fish populations as marine resources. [Display omitted] • Tributyltin chloride (TBTC) bioaccumulated highly in haarder livers. • Apoptosis was induced by TBTC in haarder livers. • TBTC caused transcriptome changes in haarder livers. • TBTC caused energy disorder and adipogenesis restriction in haarder. [ABSTRACT FROM AUTHOR]

Purpose: To determine the potential effect of Chikusetsu saponin IVA (CS-IVA) on benign prostatic hyperplasia (BPH), as well as the mechanism of action. Methods: Benign prostatic hyperplasia epithelial cell response to treatment by CS-IVA was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation assay, and cell cycle analysis. Flow cytometry and immunoblot assay were used to assess the effect of CS-IVA on cell apoptosis. Mitochondrial damage was examined by JC-1 staining and immunoblot, while immunoblot assay was also performed to determine the effect of CS-IVA on JAK/STAT3 pathway. Results: CS-IVA inhibited the growth and cycle progression of BPH-1 cell but promoted cell apoptosis (p < 0.01). It also exacerbated mitochondrial damage in BPH-1 cell lines (p < 0.01). With regard to the mechanism of action, CS-IVA inhibited JAK/STAT3 pathway in BPH-1 cells (p < 0.01). Conclusion: CS-IVA induces apoptosis and mitochondrial dysfunction of BPH-1 cells by inhibiting JAK/STAT3 pathway, and thus it is a potential drug for the treatment of BPH. However, in vivo studies on the effect of CS-IVA are are required to validate these results. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a multisystemic and placental inflammatory disease that causes maternal and infant health issues. As one of the active components in peony root extract, paeonol (Pae) exerts anti‐apoptosis and anti‐inflammatory effects. Nonetheless, the protective role of Pae in PE has not yet been characterized. A mouse model of PE was constructed through tail vein injection of 1 mg/d phosphatidylserine/dioleoyl‐phosphatidycholine suspension. The levels of inflammatory cytokines in the placenta were examined via enzyme‐linked immunosorbent assay (ELISA). The mRNA levels of inflammatory cytokines (TNF‐α, IL‐6, IFN‐γ, and IL‐4) and apoptosis markers (Bax, Bcl‐2, and caspase‐3) were tested using quantitative reverse transcription‐polymerase chain reaction (qRT–PCR). Western blot analysis was performed to detect the protein levels of apoptosis markers and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway‐related molecules. Here, Pae repressed the inflammatory response in the placenta of PE‐like mouse models, as demonstrated by the decreased concentrations and mRNA levels of TNF‐α, IL‐6, and IFN‐γ and the increased concentrations and mRNA levels of IL‐4. Apoptosis in the placentas of PE‐like mouse models was attenuated by Pae, as manifested by the downregulated mRNA and protein levels of Bax and cleaved‐caspase‐3 and the upregulated Bcl‐2. Administration of Pae inhibited the phosphorylation of JAK2 and STAT3 in the placental tissues of PE mice. The JAK2/STAT3 pathway agonist (SC‐39100) reversed Pae treatment‐mediated suppression of placental inflammation and apoptosis in PE mice. Overall, Pae inhibits the JAK2/STAT3 signaling pathway to attenuate placental inflammation and apoptosis in PE mice. [ABSTRACT FROM AUTHOR]

• It was the first time to evaluate the possible molecular mechanism of Corbrin capsules for treatment of AKI-COVID-19. • TP53, JAK2, PIK3CA, PTGS2, KEAP1, and MCL1 as the top six core protein targets. • Immune infiltration analysis revealed a notable disparity in the expression of quiescent memory CD4 T cells. • This study provided new understanding of the molecular mechanisms based on network pharmacology. of the study: This study used network pharmacology and the Gene Expression Omnibus (GEO) database to investigate the therapeutic effects of Corbrin capsules on acute kidney injury (AKI)-COVID-19 (coronavirus disease 2019). The active constituents and specific molecular targets of Corbrin capsules were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. The targets related to AKI and COVID-19 disease were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, and GEO databases. A protein–protein interaction (PPI) network was constructed by utilizing Cytoscape. To enhance the analysis of pathways associated with the pathogenesis of AKI-COVID-19, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Furthermore, immune infiltration analysis was performed by using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. Molecular docking was used to assess interactions between differentially expressed genes and active ingredients. Verification was performed by utilizing GEO databases and in vivo assays. This study revealed an overlap of 18 significantly differentially expressed genes between the Corbrin capsules group and the AKI-COVID-19 target group. Analysis of the PPI network identified TP53, JAK2, PIK3CA, PTGS2, KEAP1, and MCL1 as the top six core protein targets with the highest degrees. The results obtained from GO and KEGG analyses demonstrated that the target genes were primarily enriched in the apoptosis and JAK-STAT signaling pathways. Moreover, the analysis of immune infiltration revealed a notable disparity in the percentage of quiescent memory CD4 + T cells. Western blot analyses provided compelling evidence suggesting that the dysregulation of 6 core protein targets could be effectively reversed by Corbrin capsules. This study revealed the key components, targets, and pathways involved in treating AKI-related COVID-19 using Corbrin capsules. This study also provided a new understanding of the molecular mechanisms underlying this treatment. [ABSTRACT FROM AUTHOR]

Protein neddylation inactivation is a novel topic in cancer research. However, there are few studies on the mechanism of neddylation underlying the development of sheep follicular granulosa cells (GCs). In this study, the development of follicular GCs in sheep was inactivated by MLN4924, a neddylation‐specific inhibitor, which significantly attenuated the proliferation and cell index of sheep follicular GCs. Further, the inactivation of neddylation by MLN4924 caused the accumulation of the cullin ring ligase (CRLs) substrates Wee1 and c‐Myc, which could upregulate NOXA protein expression. Meanwhile, the B‐cell lymphoma/leukemia 2 (BCL2) family members Bcl‐2 and MCL‐1 were downregulated, subsequently inducing apoptosis in follicular GCs of sheep. Increasing Wee1 levels caused G2/M‐phase arrest. The effects of neddylation inactivation on Akt, the JAK2/STAT3 signaling pathway, and Forkhead box class O(FOXO) family members were evaluated. Neddylation inactivation by MLN4924 increased the levels of phospho‐Akt, JAK2, phospho‐STAT3, and FOXO1 (p < 0.05) and decreased the levels of phospho‐FOXO3a and STAT3 (p < 0.05). In addition, MLN4924 could alter the mitochondrial morphology of GCs, increase cellular glucose utilization and lactate production, increase reactive oxygen species (ROS) generation, and promote sheep follicular GCs glycolysis, thus causing changes in mitochondrial functions. Together, these findings point to an unrecognized role of neddylation in regulating follicular GCs proliferation in sheep. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of β-Elemene (β-Ele) on the cisplatin sensitivity of OSCC cells and its mechanism in vitro and in vivo. Methods: The human OSCC cell lines Tca-8113 and the cisplatin-resistant cell line Tca-8113-CDDP were cultured with β-Ele or/and cisplatin. The cytotoxicity of cisplatin or β-Ele, cell viability, cell cycles and apoptosis were detected. And the expression of JAK2/STAT3 related protein were detected. The xenograft tumor model of OSCC was established in nude mice and treated with cisplatin and/or β-Ele. The volume and weight of the transplanted tumor was measured, and the expression of p-JAK2 and p-STAT3 and cell apoptosis in the xenograft tumor tissues were detected. Results: The combination of β-Ele and cisplatin significantly suppressed the cell proliferation, induced cell cycle arrest, promoted the apoptosis of Tca-8113-CDDP cells, and suppressed the activation of JAK2/STAT3 signaling pathway. The rescue experiments suggested that β-Ele enhanced cisplatin sensitivity via down-regulating JAK2/STAT3 signaling pathway. In vivo, β-Ele and cisplatin synergistically suppressed the tumor growth and induced apoptosis, and down-regulated the expression of p-JAK2 and p-STAT3. Conclusions: β-Ele inhibits the cell viability and enhances the cisplatin sensitivity of OSCC by blocking the activation of JAK/STAT3 signaling pathway in vitro and in vivo, and the combination of β-Ele and cisplatin maybe a novel treatment for OSCC. [ABSTRACT FROM AUTHOR]

Poultry is a major source of human foodborne illness caused by broad host range Salmonella serovars (paratyphoid), and developing cost-effective, pre-harvest interventions to reduce these pathogens would be valuable to the industry and consumer. Host responses to infectious agents are often regulated through phosphorylation. However, proteomic mechanisms of Salmonella acute infection biology and host responses to the bacteria have been limited concentrating predominately on the genomic responses of the host to infection. Our recent development of chicken-specific peptide arrays for kinome analysis of host phosphorylation-based cellular signaling responses provided us with the opportunity to develop a more detailed understanding of the early (4-24 h post-infection) host-pathogen interactions during the initial colonization of the cecum by Salmonella. Using the chickenspecific kinomic immune peptide array, biological pathway analysis showed infection with S. Enteritidis increased signaling related to the innate immune response, relative to the non-infected control ceca. Notably, the acute innate immune signaling pathways were characterized by increased peptide phosphorylation (activation) of the Toll-like receptor and NOD-like receptor signaling pathways, the activation of the chemokine signaling pathway, and the activation of the apoptosis signaling pathways. In addition, Salmonella infection induced a dramatic alteration in the phosphorylation events of the JAK-STAT signaling pathway. Lastly, there is also significant activation of the T cell receptor signaling pathway demonstrating the initiation of the acquired immune response to Salmonella infection. Based on the individual phosphorylation events altered by the early Salmonella infection of the cecum, certain conclusions can be drawn: (1) Salmonella was recognized by both TLR and NOD receptors that initiated the innate immune response; (2) activation of the PPRs induced the production of chemokines CXCLi2 (IL-8) and cytokines IL-2, IL-6, IFN-a, and IFN-g; (3) Salmonella infection targeted the JAK-STAT pathway as a means of evading the host response by targeting the dephosphorylation of JAK1 and TYK2 and STAT1,2,3,4, and 6; (4) apoptosis appears to be a host defense mechanism where the infection with Salmonella induced both the intrinsic and extrinsic apoptotic pathways; and (5) the T cell receptor signaling pathway activates the AP-1 and NF-kB transcription factor cascades, but not NFAT. [ABSTRACT FROM AUTHOR]

Network pharmacology, as a novel way using bioinformatics to explore drug targets and interactions in cancer, broadens our understanding of drug action, thereby facilitating drug discovery. Here, we utilized network pharmacology to explore the role and mechanism by which cinobufotalin functions in colon adenocarcinoma (COAD). We found that cinobufotalin represses the growth and proliferation of colon cancer cells, and integrated public databases for targets reported to be associated with COAD, together with those predicted to be targets of cinobufotalin. Targets overlapped between COAD-associated proteins and cinobufotalin target proteins were used to filter candidate targets of cinobufotalin in COAD. The following proteins were thought to occupy a key position in COAD-cinobufotalin target networks: SRC, PIK3R1, MAPK1, PIK3CA, HSP90AA1, CTNNB1, GRB2, RHO1, PTPN11, and EGFR. The networks regulated by cinobufotalin were involved mainly in extracellular signal stimulation and transduction, including MAPK signaling pathway, PI3K-AKT signaling pathway, and JAK-STAT signaling pathway. Besides, transcriptome sequencing results also indicated that cinobufotalin inhibits the response of colon cancer cells to extracellular stimulation and promotes cell apoptosis. Molecular docking results showed that cinobufotalin matches in the pocket of the top candidate cinobufotalin target proteins (SRC, PIK3R1, MAPK1 and PIK3CA). These findings demonstrate cinobufotalin can be developed as potential anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced thrombocytopenia (CIT) is a common complication when treating malignancies with cytotoxic agents wherein carboplatin is one of the most typical agents causing CIT. Janus kinase 2 (JAK2) is one of the critical enzymes to megakaryocyte proliferation and differentiation. However, the role of the JAK2 in CIT remains unclear. In this study, we used both carboplatin-induced CIT mice and MEG-01 cell line to examine the expression of JAK2 and signal transducer and activator of transcription 3 (STAT3) pathway. Under CIT, the expression of JAK2 was significantly reduced in vivo and in vitro. More surprisingly, the JAK2/STAT3 pathway remained inactivated even when thrombopoietin (TPO) was administered. On the other hand, carboplatin could cause prominent S phase cell cycle arrest and markedly increased apoptosis in MEG-01 cells. These results showed that the thrombopoiesis might be interfered through the downregulation of JAK2/STAT3 pathway by carboplatin in CIT, and the fact that exogenous TPO supplement cannot reactivate this pathway. [ABSTRACT FROM AUTHOR]

Plants from the family Brassicaceae produce brassinin (BSN), which is an essential indole phytoalexin. BSN can kill certain types of cancer cells. Using hepatocarcinoma (HCC) cells, we examined the molecular mechanisms of BSN. We found that HCC cell growth was suppressed and apoptosis was induced by BSN via the downregulation of the JAK/STAT3 pathway. The cytoplasmic latent transcription factor STAT3, belonging to the STAT family, acted as both a signal transducer and an activator and was linked to tumor progression and decreased survival. BSN incubation caused HCC cells to produce reactive oxygen species (ROS). By activating caspase-9/-3 and PARP cleavage, Bcl-2 was reduced, and apoptosis was increased. BSN inhibited constitutive STAT3, JAK2, and Src phosphorylation. The JAK/STAT signaling cascade was confirmed by siRNA silencing STAT3 in HCC cells. BSN also suppressed apoptosis by Z-Val-Ala-Asp-Fluoromethylketone (Z-VAD-FMK), an apoptotic inhibitor. N-acetylcysteine (NAC) inhibited the production of ROS and diminished BSN-induced apoptosis. Our findings suggested that BSN has potential as a treatment for cancer. [ABSTRACT FROM AUTHOR]

Objective: To study the effect of resveratrol (RES) on the apoptosis, invasion and migration of human osteosarcoma cell line MG-63 through JAK2/STAT3 signaling pathway. Methods: MG-63 cells were cultured in vitro, and MG-63 cells were treated with different concentrations of RES. Annexin V-FITC/PI double staining was used to detect the effects of RES at different times and different concentrations on the apoptosis of MG-63 cells. Scratch test and Transwell invasion test were used to detect the effects of different time and different concentration of RES on the invasion and migration ability of MG-63 cells. Western blotting was used to detect the expression of phosphorylated protein tyrosine kinase 2 (p-JAK2), phosphorylated protein tyrosine kinase 3 (p-STAT3), apoptosis-associated protein B lymphocytoma-2(Bcl-2), Bcl-2 family of pro-apoptotic proteins(Bax), matrix metalloproteinase(MMP)-2 and MMP-9 in MG-63 cells after treated with RES at different times points and concentrations. Results: The higher the RES concentration, and the longer the time, the higher the apoptosis rate of MG-63 cells (P<0.05). The higher the RES concentration, the weaker the migration and invasion ability of MG-63 cells (P<0.05). After RES treatment of MG-63 cells, the expression of p-JAK2, p-STAT3, Bcl-2, MMP-2 and MMP-9 were significantly decreased, while the expression of Bax was significantly increased, and the expression levels of pp-JAK2, p-STAT3, Bax, Bcl-2, MMP-2 and MMP-9 were RES concentration-dependent (P<0.05). Conclusions: RES may promote the apoptosis of human osteosarcoma MG-63 cells by regulating the JAK2/STAT3 signaling pathway, and inhibit the invasion and migration ability of osteosarcoma cells. [ABSTRACT FROM AUTHOR]

[Display omitted] Non-small cell lung cancer (NSCLC) still lacks effective treatment because of its extensive mutation diversity and frequent drug resistance. Therefore, it is urgent to develop new therapeutic strategies for NSCLC. In this study, we evaluated the inhibitory effect of a new coumarin-furoxan hybrid compound 9 , a nitric oxide (NO) donor drug, on NSCLC proliferation and its mechanism. Our results show that compound 9 can inhibit the growth of four NSCLC cell lines and H1975 xenograft model in a dose-dependent manner. Compound 9 effectively releases high concentrations of NO within the mitochondria, leading to cellular oxidative stress, mitochondrial dysfunction, and apoptosis. Moreover, compound 9 inhibits JAK2/STAT3 protein phosphorylation and induces S-nitrosylation modification of STAT3, ultimately resulting in endogenous apoptosis in NSCLC. Additionally, compound 9 significantly induces NSCLC ferroptosis by depleting intracellular GSH, elevating MDA levels, inhibiting SLC7A11/GSH protein expression, and negatively regulating the JAK2/STAT3 pathway. In summary, this study elucidates the inhibitory effects of compound 9 on NSCLC proliferation and provides insights into the underlying mechanisms, offering new possibilities for NSCLC treatment strategies. [ABSTRACT FROM AUTHOR]

Pancreatic cancer, a poor prognosis and high morbidity and mortality cancer, is a malignant tumor occurring in pancreatic exocrine glands. Currently, surgery and gemcitabine (Gem) are commonly used to treat pancreatic cancers. However, the high recurrence rate and resistance makes the therapeutic effects still unsatisfied. Apoptosis is comprehensively recognized as one of the major ways of the programmed cell death, refers to the autonomous and orderly death process of cells in order to maintain the stability of the body's environment after receiving a certain signal or stimulation. Currently, it has also been proven to be a promising way for the treatment of pancreatic cancer. Nowadays, some active ingredients from herbal medicine have been reported to be effective for the treatment of pancreatic cancer via inducing cells apoptosis. Therefore, this article reviews the current references regarding anti pancreatic cancer effects of natural products derived from herbal medicines via triggering apoptosis, and summarizes the related potential signal pathways, including death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, MAPK mediated apoptotic pathway, ERS mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other pathways such as JAK-STAT signal pathway, which can lay a certain foundation for the research and development of new natural products against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Objective. At present, studies have confirmed that NDRG4 is specifically expressed in the heart, while its effect on the heart is still unclear. This study is to explore the effect of NDRG4 on cardiomyocyte apoptosis caused by acute myocardial infarction (AMI). Methods. Twenty SD rats were randomly divided into Sham (left anterior descent of heart without ligation) and AMI groups. In this study, coronary artery ligation was used to establish an AMI model, and the AMI model was verified by auxiliary examination and pathological examination. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) was used to detect the expression level of Bax and Bcl-2 in heart tissues, and NDRG mRNA levels in tissues were also detected. qRT-PCR technology was used to verify the transfection efficiency of NDRG4 in H9C2 cells, and the change of apoptosis level of H9C2 cells was detected by Cell Counting Kit-8 (CCK-8) assay and TUNEL staining; besides, the expression level of apoptosis-related factors was detected by WB and qRT-PCR technology. Simultaneously with the modeling of rats, we injected adenovirus (Ad) into the heart tissue and examined the structural and functional changes of the rat heart. Then, WB technology was used to detect the expression level of the JAK2/STAT3 signaling pathway. Results. The heart function and heart structure of rats in the MI group were dramatically worse, and the expression level of NDRG4 was also dramatically reduced. The overexpression of NDRG4 in H9C2 cells can effectively inhibit the ischemia/hypoxia- (I/H-) induced decrease in cell viability and increase in apoptosis rate and inhibit the increase in Bax/Bcl-2 ratio. Moreover, overexpression of NDRG4 in heart tissue can effectively improve the cardiac function and structural destruction caused by MI. In addition, NDRG4 can inhibit JAK2/STAT3 pathway activation. Conclusion. The expression of NDRG4 in the MI tissue of rats was suppressed, while overexpression of NDRG4 by injection of Ad can obviously protect the rat heart. Furthermore, overexpression of NDRG4 in H9C2 cells can effectively inhibit the I/H-induced decrease in cell viability and increase in apoptosis rate, and this may be related to the inhibition of the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Objective(s): Vitexin, a natural flavonoid, is commonly found in many foods and traditional herbal medicines and has clear health benefits. However, the role of vitexin in cholestasis is presently unclear. This study investigated whether vitexin mitigated glycochenodeoxycholate (GCDC)-induced hepatocyte injury and further elucidated the underlying mechanisms. Materials and Methods: A cell counting kit-8 (CCK-8) assay was conducted to evaluate cell viability. The mitochondrial membrane potential (MMP, Δm), reactive oxygen species (ROS) levels, and apoptosis rate of hepatocytes exposed to GCDC were detected by flow cytometry (FCM). We then measured the cytoprotective effects of vitexin against oxidative stress. The molecular signaling pathway was further investigated by using Western blotting and signaling pathway inhibitors. Results: Here, we showed that vitexin increased cell viability and reduced cell apoptosis, necroptosis, and oxidative stress in a dose-dependent manner in GCDC-treated hepatocytes. In addition, by using selective inhibitors, we further confirmed that inhibition of the JAK2/STAT3 pathway by vitexin was mediated by prolonged activation of Sirtuin 6 (SIRT6). Conclusion: Vitexin attenuated GCDC-induced hepatocyte injury via SIRT6 and the JAK2/STAT3 pathways. [ABSTRACT FROM AUTHOR]