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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Background: Nuclear receptor subfamily 1 group D member 1 (NR1D1), a nuclear receptor associated with a variety of physiological processes, has a low level in ovarian cancer tissues compared with adjacent normal tissues. However, its role in ovarian cancer remains unclear. Methods: The level of NR1D1 in ovarian cancer cells was determined by quantitative real-time PCR. Its role in ovarian cancer was explored through gain-of-function and lose-of-function. Cell growth was evaluated by CCK8 assay, immunofluorescence and flow cytometry. Western blot was conducted to assess the activation of JAK/STAT3 signaling pathway. A xenograft model of ovarian cancer was established to explore the role of NR1D1 in vivo. Results: Up-regulation of NR1D1 repressed the ovarian cancer cell proliferation and induced cell cycle arrest and apoptosis, while silencing NR1D1 promoted their proliferation and G1/S transition. In addition, the JAK/STAT3 signaling pathway, an intracellular signal transduction closely associated with cancer progression, was inhibited by NR1D1. Consistently, xenografts with NR1D1 over-expression grew more slowly in vivo than the controls. Furthermore, NR1D1 up-regulated the expression of suppressor of cytokine signaling 3 (SOCS3), an inhibitor of the JAK/STAT3 signaling pathway. Whereas, SOCS3 silencing abolished the function of NR1D1 over-expression on ovarian cancer growth and JAK/STAT3 signaling pathway. Conclusions: NR1D1 up-regulated the expression of SOCS3, resulting in suppression of the JAK/STAT3 signaling pathway, thus retarding the growth of ovarian cancer cells. This study highlights a profound role of NR1D1 in the treatment of ovarian cancer. [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]

Background: Tongue squamous cell carcinoma (TSCC) is a major subtype of head and neck squamous cell carcinoma (HNSCC), which is an intractable cancer with a poor prognosis. Studies have shown that microRNAs (miRNAs) play an important role in TSCC biology. However, the expression and functions of miRNAs in TSCC remain unclear. Methods: The non-coding RNA profiles of TSCC were downloaded from the GEO database. WGCNA (Weighted gene co-expression network analysis) and differential expression miRNA (DE-miRNA) analyses were employed to identify key candidate miRNAs. miRNA expression was detected using RT-qPCR analysis. The target genes of key miRNAs were predicted. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to explore the potential functions and pathways of key miRNA. miRNA inhibitor was transfected to detect the function of miRNA. The effect of miRNA deregulation on TSCC cell proliferation and apoptosis was investigated using MTS, Annexin V-FITC/PI double staining, and flow cytometry assays. Results: miR-27a was a key miRNA in TSCC, which was significantly up-regulated in both Cal-27 cells and malignant tissues from the TSCC patients. In addition, functional analysis showed that miR-27a was involved in the regulation of the MAPK, ERBB, and Jak-STAT signaling pathways. Moreover, RHOA and PRKACA were potential target genes of miR-27a, suggesting them as possible mediators of the tumor-promoting effect of miR-27a. Moreover, downregulation of miR-27a inhibited cell proliferation and facilitated cell apoptosis in Cal-27 cells. Conclusion: Our findings strongly suggest that miR-27a could promote the tumorigenesis and development of TSCC, which makes it a potential new diagnostic marker and therapeutic target for TSCC. [ABSTRACT FROM AUTHOR]

Background: Nuclear receptor subfamily 1 group D member 1 (NR1D1), a nuclear receptor associated with a variety of physiological processes, has a low level in ovarian cancer tissues compared with adjacent normal tissues. However, its role in ovarian cancer remains unclear.Methods: The level of NR1D1 in ovarian cancer cells was determined by quantitative real-time PCR. Its role in ovarian cancer was explored through gain-of-function and lose-of-function. Cell growth was evaluated by CCK8 assay, immunofluorescence and flow cytometry. Western blot was conducted to assess the activation of JAK/STAT3 signaling pathway. A xenograft model of ovarian cancer was established to explore the role of NR1D1 in vivo.Results: Up-regulation of NR1D1 repressed the ovarian cancer cell proliferation and induced cell cycle arrest and apoptosis, while silencing NR1D1 promoted their proliferation and G1/S transition. In addition, the JAK/STAT3 signaling pathway, an intracellular signal transduction closely associated with cancer progression, was inhibited by NR1D1. Consistently, xenografts with NR1D1 over-expression grew more slowly in vivo than the controls. Furthermore, NR1D1 up-regulated the expression of suppressor of cytokine signaling 3 (SOCS3), an inhibitor of the JAK/STAT3 signaling pathway. Whereas, SOCS3 silencing abolished the function of NR1D1 over-expression on ovarian cancer growth and JAK/STAT3 signaling pathway.Conclusions: NR1D1 up-regulated the expression of SOCS3, resulting in suppression of the JAK/STAT3 signaling pathway, thus retarding the growth of ovarian cancer cells. This study highlights a profound role of NR1D1 in the treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the protective effects of nicotinamide riboside (NR) on oxidative damage in hydrogen peroxide (H2O2)-exposed human lens epithelial cell lines (SRA01/04) and the possible mechanisms underlying its protective effects. Materials and methods: SRA01/04 cells were divided into three groups: the control (CON) group, model (H2O2) group and treatment (NR+H2O2) group. Superoxide dismutase (SOD), catalase (CAT) and total glutathione (GSH) levels were detected to evaluate oxidative damage induced by different concentrations of H2O2 in SRA01/04 cells. After SRA01/04 cells were treated with NR and/or H2O2, cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst staining, cell apoptosis was analysed using flow cytometry, reactive oxygen species (ROS) were measured with the DCFH-DA probe, and mitochondria were stained with MitoTracker to measure the mitochondrial membrane potential (MMP). In addition, western blotting was performed to detect the levels of proteins associated with apoptosis and related signalling pathways. Results: H2O2 induced oxidative damage in SRA01/04 cells by inhibiting the activity of SOD and CAT and reducing total GSH levels. Treatment of SRA01/04 cells with NR significantly increased cell viability and reduced cell apoptosis and ROS generation, whereas SOD and CAT activities and total GSH and MMP levels were improved by the NR treatment in an H2O2-exposed cell model. Furthermore, NR significantly inhibited the activation of the MAPK pathway but promoted activation of the JAK2/Stat3 pathway compared with the model group. Conclusions: NR may alleviate oxidative damage by targeting the MAPK and JAK2/Stat3 pathways in H2O2-treated SRA01/04 cells. NR may represent anovel drug for preventing or treating cataracts. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive and common intracranial malignant tumor, and the prognosis is still poor after various treatments. Based on the poor prognosis of glioma, new drugs that suppress the rapid progression and aggressive growth of glioma are urgently needed. It has been reported that nitidine chloride (NC) can inhibit tumor growth and epithelial‐mesenchymal transition (EMT), and EMT is associated with cancer stem cell properties. The present study aimed to investigate the inhibitory effect of NC on the EMT process and stem cell‐like properties in glioma cells. The results showed that the migration and invasion abilities in U87 and LN18 glioma cells were significantly increased after the induction of EMT and these effects were inhibited by NC in a concentration‐dependent manner. NC treatment decreased the expression of EMT markers in glioma cells and self‐renewal capacity of glioma stem‐like cells. We demonstrated that these effects of NC were achieved via JAK2/STAT3 signaling. Taken together, these results indicate that NC inhibits the EMT process and glioma stem‐like properties via JAK2/STAT3 signaling pathway, suggesting that NC may be a potential anti‐glioma drug. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a serious neurological disease. Long non-coding RNA (lncRNA) small nucleolar RNA host gene (SNHG1) and microRNA-362-3p (miR-362-3p) were confirmed to be related to neurological disorders. However, it is unclear whether SNHG1 was involved in the development of SCI via regulating miR-362-3p. PC12 cells were treated with lipopolysaccharide (LPS) to imitate the in vitro cell model of SCI. Cell ciability and apoptosis rate were detected by cell counting kit-8 (CCK-8) assay and flow cytometry assay. The levels of SNHG1, miR-362-3p, and Janus kinase-2 (Jak2) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay were performed to verify the interaction between miR-362-3p and SNHG1 or Jak2. Besides, the levels of apoptosis- and autophagy- related proteins were detected by western blot assay. In present research, LPS suppressed cell viability, and induced apoptosis and autophagy in PC12 cells. SNHG1 knockdown could affect cell viability, and suppress cell apoptosis and autophagy in LPS-treated PC12 cells. Moreover, miR-362-3p was a target of SNHG1, miR-362-3p targeted Jak2 and negatively regulated Jak2/stat3 pathway. Our data also demonstrated that SNHG1 depletion inactivated Jak2/stat3 pathway to affect cell viability and confine apoptosis, autophagy in LPS-treated PC12 cells. Taken together, SNHG1 regulated cell viability, apoptosis and autophagy in LPS-treated PC12 cells by activating Jak2/stat3 pathway via sponging miR-362-3p. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors targeting the programmed cell death‐1 (PD‐1)/PD‐1 ligand 1 (PD‐L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD‐L1 inducer is IFNγ, which is secreted by T cells and NK cells. Importantly, IFNγ‐induced PD‐L1 is one of the major mechanisms by which cancer cells escape host immunity. Methods: Here, we found that the NSCLC cell line, LC‐2/ad, has a unique character; the PD‐L1 expression in these cells is up‐regulated by both IFNγ and epidermal growth factor (EGF). Results: Comparative analysis of the cell signaling pathway showed that IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC‐2/ad cells. IFNγ‐induced PD‐L1, but not EGF‐induced PD‐L1, was clearly blocked by the JAK‐STAT inhibitor tofacitinib. Interestingly, IFNγ decreased the expression of NK cell‐activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFNγ stimuli attenuated NK cell‐mediated cytotoxicity in LC‐2/ad cells, which was, however, blocked by tofacitinib. Conclusions: Taken together, our study shows that tofacitinib blocks the IFNγ‐induced transformation from an NK cell‐sensitive phenotype to an NK cell‐resistant one in IFNγ‐reacted LC‐2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFNγ‐induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients. [ABSTRACT FROM AUTHOR]

Infectious bursal disease virus (IBDV), the best-characterized member of the Birnaviridae family, is a highly relevant avian pathogen causing both acute and persistent infections in different avian hosts. Here, we describe the establishment of clonal, long-term, productive persistent IBDV infections in DF-1 chicken embryonic fibroblasts. Although virus yields in persistently infected cells are exceedingly lower than those detected in acutely infected cells, the replication fitness of viruses isolated from persistently infected cells is higher than that of the parental virus. Persistently infected DF-1 and IBDV-cured cell lines derived from them do not respond to type I interferon (IFN). High-throughput genome sequencing revealed that this defect is due to mutations affecting the IFN-α/β receptor subunit 2 (IFNAR2) gene, resulting in the expression of IFNAR2 polypeptides harboring large C-terminal deletions that abolish the signaling capacity of IFN-α/β receptor complex. Ectopic expression of a recombinant chicken IFNAR2 gene efficiently rescues IFN-α responsiveness. IBDV-cured cell lines derived from persistently infected cells exhibit a drastically enhanced susceptibility to establishing new persistent IBDV infections. Additionally, experiments carried out with human HeLa cells lacking the IFNAR2 gene fully recapitulate results obtained with DF-1 cells, exhibiting a highly enhanced capacity to both survive the acute IBDV infection phase and to support the establishment of persistent IBDV infections. Results presented here show that the inactivation of the JAK-STAT signaling pathway significantly reduces the apoptotic response induced by the infection, facilitating the establishment and maintenance of IBDV persistent infections. IMPORTANCE Members of the Birnaviridae family, including infectious bursal disease virus (IBDV), exhibit a dual behavior, causing acute infections that are often followed by the establishment of lifelong persistent asymptomatic infections. Indeed, persistently infected specimens might act as efficient virus reservoirs, potentially contributing to virus dissemination. Despite the key importance of this biological trait, information about mechanisms triggering IBDV persistency is negligible. Our report evidences the capacity of IBDV, a highly relevant avian pathogen, to establish longterm, productive, persistent infections in both avian and human cell lines. Data presented here provide novel and direct evidence about the crucial role of type I IFNs on the fate of IBDV-infected cells and their contribution to controlling the establishment of IBDV persistent infections. The use of cell lines unable to respond to type I IFNs opens a promising venue to unveiling additional factors contributing to IBDV persistency. [ABSTRACT FROM AUTHOR]

Tetrabromobisphenol A (TBBPA) and lead (Pb) are widely used in industrial field, which poses a serious threat to human and animal health. In particular, a large volume of wastewater containing TBBPA and Pb was discharged into the aquatic environment, causing a seriously negative impact on fish. Currently, whether TBBPA and Pb have a synergistic toxicity on fish remains unclear. In this study, we used the grass carp hepatocytes (L8824 cell line) exposed to either TBBPA or Pb, or both to determine their potential impacts on fish. The results showed that Pb or TBBPA induced oxidative stress and the loss of mitochondrial membrane potential in grass carp hepatocytes. In contrast to the control cells, the levels of JAK2, p -JAK2, STAT3 and p-STAT3 were significantly upregulated after exposure to TBBPA and Pb. Furthermore, the levels of Caspase3, Caspase9 and Bax were all increased while the level of Bcl2 was decreased in hepatocytes exposed to TBBPA or Pb. Results of flow cytometry and AO/EB staining reveled significant increases in the number of apoptotic cells in the TBBPA and Pb group compared to the controls. Notably, cells exposed to both TBBPA and Pb exhibited more severe damage than the single exposure, manifested by a higher number of apoptotic cells in the co-exposure group than the single exposure groups. Nevertheless, N-acetyl- l -cysteine (NAC) treatment could remarkably alleviate oxidative damage and loss of membrane potential in grass carp hepatocytes induced by TBBPA and Pb. Altogether, our study showed that combined exposure of TBBPA and Pb has a synergistic toxicity due to, inducing oxidative stress to activate JAK2/STAT3 signaling pathway, resulting in apoptosis of carp hepatocytes. This study shed a new light on the toxicological mechanism of exposure of TBBPA and Pb and provided a potential treatment of toxicity induced by TBBPA and Pb. [Display omitted] • TBBPA and Pb had synergistic effects. • TBBPA and Pb exposure induced oxidative stress. • TBBPA and Pb exposure activated JAK2/STAT3 signaling pathway. • TBBPA and Pb exposure caused apoptosis. [ABSTRACT FROM AUTHOR]

Background: Ischemia-reperfusion injury (IRI) is an important factor limiting the success of cardiac reperfusion therapy. Curcumin has a significant cardioprotective effect against IRI, can inhibit ventricular remodeling induced by pressure load or MI, and improve cardiac function. However, the poor water solubility and low bioavailability of curcumin restrict its clinical application. Methods: In this study, we prepared and evaluated a curcumin-hydrogel (cur-hydrogel) to reduce cardiomyocyte apoptosis and reactive oxygen species formation induced by hypoxia-reoxygenation injury, promote autophagy, and reduce mitochondrial damage by maintaining the phosphorylation of Cx43. Results: Meanwhile, cur-hydrogel can restore cardiac function, inhibit myocardial collagen deposition and apoptosis, and activate JAK2/STAT3 pathway to alleviate myocardial ischemia-reperfusion injury in rats. Conclusions: The purpose of this study is to elucidate the protective effects of cur-hydrogel on myocardial ischemia-reperfusion injury by regulating apoptosis, autophagy, and mitochondrial injury in vitro and in vivo, which lays a new theoretical and experimental foundation for the prevention and reduction of IRI. [ABSTRACT FROM AUTHOR]

Background: Cerebral ischemia/reperfusion injury is a severe problem in patients with brain ischemia. Brain injury caused by the immune response is important in the pathogenesis of cerebral ischemia/reperfusion injury and immune pathways. It is important to investigate potential targets for the treatment of cerebral ischemia/reperfusion injury. Methods: In this experiment, we evaluated the effect of an exogenous JAK antagonist AG490 in the cerebral ischemia/reperfusion injury model, which was established by middle cerebral artery occlusion (MCAO). Histology study, TUNEL staining, Western blot, and RT‐PCR were employed to examine the effects of AG490 in cerebral ischemia/reperfusion injury. Results: In the brain tissue of MCAO mice, JAK2 was highly expressed. AG490 is an inhibitor of JAK2, which reduced the phosphorylation level of JAK2. AG490 downregulated the phosphorylated activation of JAK3 and their downstream STAT3. The antiapoptotic activity of AG490 on cerebral ischemia/reperfusion injury mice was consistent with in vitro data. It reduced the phosphorylation of JAK2/JAK3/STAT3 and the apoptosis rate in cultured neurons upon apoptosis induction. Besides, we also observed the neuroprotective effects of AG490 on cerebral ischemia/reperfusion injury. Administration of AG490 could further enhance the expression of neurotrophins including BNDF, NT3, and the neurotrophin receptor TrkB. Conclusion: Therefore, AG490 is pluripotent for cerebral ischemia/reperfusion injury through both antiapoptosis and neuroprotective activities. The antiapoptosis effect is dependent on its regulation of the JAK‐STAT pathway. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a malignant tumor derived from the skeletal system, often occurring in bone tissues, and it is the most common malignant tumor in the skeletal system, with more than 90% of cases being highly malignant. The present study was designed to explore the regulatory effects of microRNA (miR)-19a on the proliferation and apoptosis of osteosarcoma cells, and its influence on the activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The expression of miR-19a in adult SaOS-2 osteosarcoma cells was downregulated via lentiviral transfection, and the cells were divided into a control group, NC-inhibitor group and miR-19a-inhibitor group. The expression of miR-19a in each group was detected via quantitative polymerase Chain reaction (qPCR). Next, the cell proliferation and apoptosis levels in each group were detected via methyl thiazolyl tetrazolium (MTT) assay and flow cytometry, respectively, and the level of reactive oxygen species (ROS) in cells was further determined. Moreover, the expression levels of apoptosis-related proteins and JAK2/STAT3 signaling pathway-related proteins were detected through western blotting. The expression level of miR-19a in the miR-19a-inhibitor group was significantly lower than that in the control group and NC-inhibitor group (P<0.01). Downregulation of miR-19a significantly reduced the proliferation ability (P<0.01), increased the apoptosis level of SaOS-2 cells (P<0.01), and significantly increased the ROS level in cells (P<0.01). Downregulation of miR-19a also promote cleaved caspase-3/caspase-3 expression in the OS cells (P<0.01) and inhibited Bcl-2/Bax expression (P<0.01). Additionally, downregulation of miR-19a markedly lowered the protein expression levels of phosphorylated (p-)JAK2, p-STAT3 and myeloid cell leukemia-1 (Mcl-1) in the cells (P<0.01). To conclude, downregulation of miR-19a can inhibit the JAK2/STAT3 signaling pathway in SaOS-2 cells, promote the expression of apoptosis-related proteins, and increase the ROS level in cells, thereby promoting apoptosis and inhibiting cell proliferation. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to explore the potential molecular signaling pathway mediated by the statin rosuvastatin in cultured human coronary artery endothelial cells (HCAECs) induced by CoCl2. CoCl2 was used to induce the apoptosis of HCAECs. Myocardial infarction rats were established and received statin or PBS treatment. Reverse transcription-quantitative PCR, western blotting, ELISA, TUNEL assay and immunohistochemistry were used to analyze the role of statin treatment. The results showed that rosuvastatin treatment decreased apoptosis of HCAECs induced by CoCl2 by increasing anti-apoptosis Bcl-xl and Bcl-2 expression, and decreasing pro-apoptosis Bax, Bad, caspase-3 and caspase-9 expression. The myocardial ischemia rat model demonstrated that rosuvastatin treatment decreased the mitochondrial reactive oxygen species, inflammation, mitochondrial damage, lipid catabolism, heart failure and the myocardial infarction areas, but improved the cardiac function indicators, right and left ventricular ejection fraction and increased expression levels of Janus kinase (JAK) and signal transducer and activator of transcription (STAT)3 in myocardial tissue. In conclusion, the results of the current study revealed that the statin rosuvastatin presents cardioprotective effects by activation of the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

The tripartite motif (TRIM) protein family are implicated in a wide array of cellular processes, including cell growth, differentiation, apoptosis and inflammation. This study aimed to investigate the specific function of TRIM59 in chondrocytes and its association with the pathophysiology of osteoarthritis (OA). We observed the downregulated TRIM59 expression in OA cartilage compared to normal tissues. Overexpression of TRIM59 suppressed interleukin 1 beta (IL-1β)-induced extracellular matrix (ECM) metabolic imbalance, proinflammatory cytokine production, apoptosis and decrease in cell viability. Mechanistic analyses further revealed that IL-1β-induced activation of the NF-κB and JAK2/STAT3 pathway is suppressed upon TRIM59 overexpression. TRIM59 expression was consistently decreased in a rat OA model in vivo , and its overexpression led to inhibition of matrix metallopeptidase-13 (MMP-13) production, proinflammatory cytokine levels and increased collagen type II (collagen II) and aggrecan synthesis. Our data collectively suggest that TRIM59 plays a critical in OA development through regulation of NF-κB and JAK2/STAT3 signaling pathway. Pharmacological upregulation of TRIM59 may therefore present an effective novel therapeutic approach for OA. • TRIM59 expression is downregulated in human OA cartilage and IL-1β-induced chondrocytes. • TRIM59 attenuates IL-1β-induced chondrocyte apoptosis, inflammatory response and matrix degradation. • TRIM59 counteracted cartilage matrix degradation in the rat OA model. • TRIM59 represses IL-1β activated NF-κB and JAK2/STAT3 signaling pathway activation in chondrocytes. [ABSTRACT FROM AUTHOR]

Accumulating evidence demonstrates that Macleaya cordata extract exerts antiviral and anti-inflammatory effects in various diseases. The present study aimed to investigate the potential effects of M. cordata on rotavirus SA11-induced diarrhea in mice. Diarrhea severity, levels of inflammatory cytokines, histological changes in the small intestine and the underlying mechanisms were evaluated in rotavirus-stimulated mice treated with 1, 2 and 4 mg/kg/day M. cordata or 4 mg/kg/day ribavirin (positive control). M. cordata treatment effectively ameliorated rotavirus-induced diarrhea in a dose-dependent manner by decreasing viral RNA levels. In addition, M. cordata reduced the release of pro-inflammatory cytokines including migration inhibitory factor, interleukin (IL)-8, IL-β, interferon-γ and tumor necrosis factor-α, and elevated the secretion of the anti-inflammatory cytokine IL-10 following rotavirus infection. M. cordata inhibited intestinal epithelial cell apoptosis and improved intestinal inflammation after rotavirus infection. The study also revealed that M. cordata exerted antiviral and anti-inflammatory effects on rotavirus-induced diarrhea by suppressing the Janus kinase 2 (JAK2)/STAT3 pathway, as reflected by decreased protein expression of phosphorylated (p)-JAK2 and p-STAT3. Overall, M. cordata effectively inhibited the inflammation caused by rotavirus, which was closely associated with the suppression of JAK2/STAT3 phosphorylation. These data suggested that M. cordata may be applied as a treatment for rotavirus-induced diarrhea. [ABSTRACT FROM AUTHOR]

MicroRNA plays an integral role in the development of atherosclerosis. Our study aimed to investigate the roles of miR‐599 in lipopolysaccharide (LPS)‐induced endothelial damage in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with a miR‐599 mimic and negative control, and then exposed to LPS. The expression of miR‐599 was detected by quantitative real time‐polymerase chain reaction (RT‐qPCR). Cell viability was analyzed by CCK‐8 assay and trypan blue exclusion assay; the formation of DNA fragments was tested by Cell Death Detection ELISA Plus kit; the incidence of apoptosis was detected by flow cytometry; the expression of p53 and cleaved‐caspase 3 (c‐caspase 3) was evaluated by western blot. Moreover, the mRNA levels and concentrations of tumour necrosis factor (TNF)‐α, interleukin (IL)‐6, ICAM‐1 and VCAM‐1 were assayed by RT‐qPCR and ELISA. The results showed that overexpression of miR‐599 increased cell viability, reduced DNA fragments, the incidence of apoptosis, as well as the protein levels of p53 and c‐caspase 3 in the presence of LPS. TNF‐α, IL‐6, ICAM‐1 and VCAM‐1 mRNA levels and concentrations were also decreased upon miR‐599 upregulation. In addition, the dual luciferase reporter assay demonstrated that ROCK1 is a direct target of miR‐599. MiR‐599 overexpression inhibited ROCK1 expression. Induced expression of ROCK1 reversed the roles of miR‐599 in apoptosis and inflammation. The gain function of miR‐599 function inhibited activation of the JAK2/STAT3 signalling pathway, which was abrogated by overexpression of ROCK1. Taken together, our results indicate that miR‐599 attenuates LPS‐caused cell apoptosis and inflammatory responses through the JAK2/STAT3 signalling pathway via targeting ROCK1. [ABSTRACT FROM AUTHOR]

Effect of CXCL8 gene silencing-mediated JAK-STAT signaling pathway on epithelial-mesenchymal transition (EMT) of human cutaneous melanoma cells was explored. Eighty patients with cutaneous melanoma were enrolled in the study. Cells were transfected accordingly and divided into five groups: The blank group (human cutaneous melanoma cells), NC group (human cutaneous melanoma cells + blank vector plasmid transfection), CXCL8 siRNA group (human cutaneous melanoma cells + CXCL8 silent expression vector plasmid transfection), AG490 group (human cutaneous melanoma cells + JAK-STAT signal pathway inhibitor transfection), CXCL8 siRNA + AG490 group (human cutaneous melanoma cells + JAK-STAT signaling pathway inhibitor + CXCL8 silent expression vector plasmid transfection). The expression levels of CXCL8, JAK2, STAT3, epithelial cadherin (E-cadherin), neurotrophic cadherin (N-cadherin) and vimentin in tissues and cells were detected by RT-qPCR and western blot analysis. CCK-8 and flow cytometry were used to detect cell proliferation and apoptosis. Compared with adjacent normal tissues, the expression of E-cadherin in human cutaneous melanoma tissues was significantly decreased, whereas the expression of CXCL8, JAK2, STAT3, vimentin and N-cadherin was significantly increased (P<0.05). Compared with the blank group, CXCL8 siRNA group and CXCL8 siRNA + AG490 group had significantly lower expression of CXCL8 (P<0.05). Compared with the blank group, the expression levels of JAK2, STAT3, vimentin and N-cadherin in CXCL8 siRNA group, AG490 group and CXCL8 siRNA + AG490 group were decreased, the expression of E-cadherin was increased, the cell proliferation ability was decreased and apoptosis was increased (P<0.05). Compared with CXCL8 siRNA group, the expression of JAK2, STAT3, vimentin and N-cadherin in CXCL8 siRNA + AG490 group were significantly decreased, the expression of E-cadherin was significantly increased, cell proliferation ability was decreased and apoptosis was increased (P<0.05). In conclusion, CXCL8 gene expression silencing may inhibit EMT and cell proliferation while promoting cell apoptosis of human cutaneous melanoma cells by inhibiting the activation of JAK-STAT signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Quercetin belongs to the flavonoids family, which has been proven to have extensive pharmacological effects. Nevertheless, the function of quercetin in peripheral arterial disease (PAD) has not yet been reported. In the research, we purposed to disclose the effectiveness of quercetin in the pathogenesis of PAD. Methods: HMEC-1 cells were cultivated in Matrigel for 24 h to observe the tube-formation. Detections of cell viability, migration and apoptosis were through implementing CCK-8, Transwell and flow cytometry methods. Western blot was utilised for measuring angiogenesis-, migration- and apoptosis-correlative factors. MiR-216a expression was examined via qRT-PCR, and its functions in HMEC-1 cells were uncovered after miR-216a mimic transfection. Assessment of JAK2/STAT3 and PI3K/AKT pathways was via implementing western blot. Results: HMEC-1 cells were spontaneously vascularised under Matrigel condition. Quercetin predominantly repressed cell viability, migration, VEGF expression and facilitated apoptosis in HMEC-1 cells. Additionally, suppression of miR-216a was discovered in HMEC-1 cells after quercetin stimulation, meanwhile miR-216a overexpression annulled the functions of quercetin in HMEC-1 cells. Besides, quercetin deactivated PI3K/AKT and JAK/STAT pathways through adjusting miR-216a. Conclusion: The above-mentioned consequences exhibited that quercetin suppressed HMEC-1 cell viability, migration and tube-formation through hindering JAK2/STAT3 and PI3K/AKT pathway via declination of miR-216a. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is a common form of malignant cancer in worldwide which has a poor prognosis. Despite recent improvements in the treatment of GC, the prognosis is not yet satisfactory for GC patients. CYT997, a novel microtubule-targeting agent, recently has been identified to be a promising anticancer candidate for the treatment of cancers; however, the effects of CYT997 in GC remain largely unknown. Methods: Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry. The mitochondrial ROS were detected by confocal microscope and flow cytometry. Gastric cancer patient-derived xenograft (PDX) model was used to evaluate its antitumor activity of CYT997 in vivo. Results: CYT997 inhibited gastric cancer cell proliferation and induced cell apoptosis and triggered autophagy. CYT997 induced apoptosis through triggering intracellular mitochondrial ROS generation in GC cells. ROS scavengers N-acetylcysteine (NAC) and Mitoquinone (MitoQ) distinctly weakened CYT997-induced cell cycle G2/M arrest and apoptosis in GC cells. Pretreatment with autophagy inhibitor 3-MA promoted the effect of CYT997 on cells apoptosis. Mechanistically, CYT997 performed its function through regulation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in GC cells. In addition, CYT997 inhibited growth of gastric cancer patient-derived xenograft (PDX) tumors. Conclusions: CYT997 induces autophagy and apoptosis in gastric cancer by triggering mitochondrial ROS accumulation to silence JAK2/STAT3 pathway. CYT997 might be a potential antitumor drug candidate to treat GC. [ABSTRACT FROM AUTHOR]

Naringenin is a natural compound with potential anti-cancer effects against several cancer types. Also, its precise molecular mechanisms regarding tumor growth suppression has not been completely elucidated. In the current study the apoptosis-inducing and anti-proliferative effects of Naringenin together with cyclophosphamide were studied in breast cancer cells and the participation of JAK2/STAT3 pathway was investigated. In this regard, MDA-MB-231 breast cancer cells were cultured and hence, treated with different concentrations of Naringenin. Apoptosis was measured via flowcytometric analysis of annexin V binding and cell viability was assessed via MTT assay. Protein and gene expression were investigated via Western blotting and real-time PCR, respectively. The function of caspase enzymes were also assessed. The results exhibited that Naringenin triggered apoptosis and markedly decreased cell viability. Furthermore its coadministration with cyclophosphamide improved its anti-tumor properties. Moreover, Naringenin up-regulated the expression of BAX while decreased the expression of Bcl-2. Caspases 3 and 9 were activated by Naringenin, an influence, which was augmented via cyclophosphamide. Docking studies revealed an interaction between Naringenin and STAT3 that was confirmed via attenuation of STAT3 phosphorylation subsequent to treating the cells with Naringenin. Furthermore, Naringenin exhibited the capacity to suppress the function of IL-6 in modulating apoptosis-associated genes expression. Overall, these results indicated that a Naringenincyclophosphamide combination impairs proliferation signaling and induces apoptosis to a greater extent than either compound alone and can serve as a potent chemotherapeutic regimen for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Basic and clinical studies have demonstrated that the free radical scavenger edaravone has cytoprotective effects on acute myocardial infarction (AMI) but the underlying mechanism is not fully understood. The aim of this research is to explore the effect of edaravone on the apoptotic process involving the JAK2/STAT3 signaling pathway. AMI in rats was established by left anterior descending coronary artery ligation. Two hours after AMI model established rats were treated with edaravone, edaravone plus AG490, physiological saline, respectively. We detected antioxidant effects by reduced glutathione (GSH), glutathione S-transferase (GST), and Glutathione Peroxidase (GSHPx) Activity. The expressions of t-JAK2, p-JAK2, t-STAT3, p-STAT3 and cleaved caspase-3 were examined by western blot. The mRNA levels for Bcl-2, Bax, Fas, and FasL were measured by RT-PCR and apoptosis was assessed by TUNEL. Edaravone significantly improved hemodynamics after AMI (p < 0.05) and reduced the total infarct volumes (p < 0.05). Compared with Sham rats, the mRNA of Bax, Fas, and FasL increased in different degrees in the AMI group, however, the mRNA of Bcl-2 and the ratio of Bcl-2/Bax decreased, especially the myocardial apoptosis index significantly increased in AMI hearts (all p < 0.05). After treatment with edaravone, the mRNA levels of Bcl-2 and the ratio of Bcl-2/Bax significantly upregulated whereas Bax, Fas, FasL apparently decreased, and the protein expressions of p-JAK2 and p-STAT3 dramatically increased (p < 0.05). In addition, cotreatment with JAK2 inhibitor AG490 abolished the effects of edaravone. We conclude that edaravone attenuated myocardial apoptosis induced by AMI via JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs have been documented to be protective against ischemia/reperfusion (I/R) injury. However, few research works have focused on the protective effects of PRR34‐AS1 on I/R injury after total knee arthroplasty (TKA). The objective of the present study was to investigate the possible effect of PRR34‐AS1 on I/R injury after TKA. A mouse model with I/R injury after TKA was established. The interaction between PRR34‐AS1 and Janus kinase 1 (JAK1) was examined and thoroughly investigated. Next, the effects of PRR34‐AS1 on the expression of apoptosis‐related proteins, JAS‐signal transducer and activator of transcription (STAT) signaling pathways, and inflammation‐related genes, chondrocyte proliferation, and apoptosis were analyzed after gain‐ and loss‐of‐function experiments. Attenuated symptoms were observed in mice pretreated with propofol, which was evidenced by decreased positive expression rate of JAK1 protein and superoxide dismutase content along with increased malondialdehyde content and IL‐10 levels. PRR34‐AS1 was poorly expressed in mice with I/R injury after TKA. JAK1 was a target of PRR34‐AS1. Upregulated PRR34‐AS1 diminished expression of JAK1, STAT1, JAK2, and STAT3 as well as cell apoptosis, while enhancing cell proliferation in vitro. Furthermore, JAK1 silencing could reverse the suppressed cell proliferation and enhanced cell apoptosis of chondrocytes imposed by silencing PRR34‐AS1. Upregulation of PRR34‐AS1 can potentially relieve I/R injury after TKA in mice pretreated with propofol through inhibition of the JAS‐STAT signaling pathway by targeting JAK1. [ABSTRACT FROM AUTHOR]

Thyroid cancer is the most important malignant tumor reported in human populations where, its treatment remains undeveloped. Fisetin, a plant flavonoid exhibits several pharmacological properties like antioxidant, anti-inflammatory, and anticancer function. In the existing study, we assessed fisetin mediated cytotoxic effects and action potential of fisetin on cell proliferation in TPC-1 human cancer cells. Also, examined the apoptosis in TPC-1 cells by reactive oxygen species (ROS) generation, the mitochondrial membrane potential (MMP) and apoptotic morphological changes through AO/EtBr staining. Additionally, we analyzed the effects of fisetin through ELISA analysis to evaluate the caspases expression and studied JAK 1 and STAT3 signaling molecule in TPC1 cells. Our results demonstrated that fisetin stimulated apoptosis, which confirmed through reduced cell viability, improved ROS generation, altered MMP and cell cycle phases in TPC-1 cells. Further, the fisetin up-regulated the expression of caspase (3, 8, and 9) expressions in TPC-1 cells. Also, we observed the fisetin down-regulated the JAK 1 and STAT3 expression in TPC1 cells. Thus, the fisetin induced apoptosis in TPC-1 cells by the induction of oxidative damage and enhanced caspases expression by down-regulating JAK 1 and STAT3 signaling molecules. Hence, the fisetin would be considered as a beneficial therapeutic agent for the thyroid cancer treatment. [ABSTRACT FROM AUTHOR]