查找使用阿拉丁产品的科研文献

Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway

Lina Gu,Xufeng Tao,Youwei Xu,Xu Han,Yan Qi,Lina Xu,Lianhong Yin,Jinyong Peng

Oxidative stress is involved in hepatic stellate cells (HSCs) activation and extracellular matrix overproduction. We previously reported the promising effects of dioscin against CCl 4 -induced liver fibrosis, but its effects and mechanisms on BDL- and DMN-induced liver fibrosis remain unknown. The results in the present study indicated that dioscin significantly inhibited HSCs activation and attenuated hepatic fibrosis in rats. Furthermore, dioscin markedly up-regulated the levels of sirtuin 1 (Sirt1), HO-1, GST , GCLC and GCLM via increasing the nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2), which in turn inhibited mitogen-activated protein kinase 14 (p38 MAPK) phosphorylation and reduced the levels of COL1A1, COL3A1, α-SMA and fibronectin . These results were further validated by knockdown of Sirt1 and Nrf2 using siRNAs silencing, and abrogation of p38 MAPK using SB-203580 (a p38 MAPK inhibitor) in HSC-T6 and LX-2 cells. Collectively, our findings confirmed the potent effects of dioscin against liver fibrosis and also provided novel insights into the mechanisms of this compound as a candidate for the prevention of liver fibrosis in the future.

Interfering with Dusp2 alleviates high glucose-induced vascular endothelial cell dysfunction by promoting p38 MAPK pathway activation

Xinmiao Jiang,Qiong Yan,Jiaqi He,Zeqi Zheng,Xiaoping Peng,Xiaoyan Cao,Fangbin Zhou,Jungang Nie,Ting Kang

Background Hyperglycemia-induced vascular endothelial cell dysfunction is a major factor contributing to diabetic lower extremity ischemia. We intend to investigate the role of Dusp2 in hyperglycemia-induced vascular endothelial cell dysfunction and related mechanisms. Methods The human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG) as the cell model. Streptozotocin injection was performed to induce diabetes and femoral artery ligation was to induce hind limb ischemia in mice. The levels of Dusp2, p-p38 MAPK, E2F4, and p38 MAPK were evaluated by Western blot or quantitative real-time PCR. The laser Doppler perfusion imaging was conducted to measure blood flow recovery. The cell counting kit-8, transwell, and tube formation assay were performed to evaluate cell proliferation, migration, and angiogenesis, respectively. CD31 immunohistochemical staining was carried out to detect the capillary density of gastrocnemius. The dual-luciferase reporter gene assay and Chromatin immunoprecipitation assay were executed to explore the interaction between E2F4 and Dusp2. Results Dusp2 was highly expressed in HG-induced HUVECs and diabetic lower extremity ischemia model mice. Interference with Dusp2 promoted cell proliferation, migration, and angiogenesis, as well as alleviated mouse diabetic hindlimb ischemia. Dusp2 knockdown up-regulated p-p38 MAPK levels. We verified the binding between E2F4 and Dusp2. Overexpressing E2F4 suppressed Dusp2 levels and promoted cell proliferation, migration, and angiogenesis, co-overexpression of Dusp2 reversed the results. Conclusions Overexpressing E2F4 promotes endothelial cell proliferation, migration, and angiogenesis by inhibiting Dusp2 expression and activating p38 MAPK to alleviate vascular endothelial cell dysfunction under HG stimulation.

PP2A protects podocytes against Adriamycin-induced injury and epithelial-to-mesenchymal transition via suppressing JIP4/p38-MAPK pathway

Lu Zhihong,Zhu Xiujuan,Ye Yuhong,Fu Haidong,Mao Jianhua

Protein phosphatase 2A (PP2A) is one of the major protein serine/threonine phosphatases (PPPs) with regulatory effects on several cellular processes, but its role and function in Adriamycin (ADR)-treated podocytes injury needs to be further explored. Mice podocytes were treated with ADR and PP2A inhibitor (okadaic acid, OA). After transfection, cell apoptosis was detected by flow cytometry. Expressions of podocytes injury-, apoptosis- and epithelial-to-mesenchymal transition (EMT)- and JNK-interacting protein 4/p38-Mitogen-Activated Protein Kinase (JIP4/p38-MAPK) pathway-related factors were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot as needed. Interaction between PP2A and JIP4/MAPK pathway was confirmed using co-immunoprecipitation (Co-Ip) assay. In podocytes, ADR inhibited PP2A, Nephrin and Wilms’ tumor (WT) 1 expressions yet upregulated apoptosis and Desmin expression, and suppressing PP2A expressionenhanced the effects. PP2A overexpression reversed the effects of ADR on PP2A and podocyte injury-related factors expressions and apoptosis of podocytes. JIP4 was the candidate gene interacting with both PP2A and p38-MAPK pathway, and PP2A overexpression alleviated the effects of ADR on p38-MAPK pathway-related factors expressions. Additionally, in ADR-treated podocytes, PP2A suppression enhanced the effects of ADR, yet silencing of JIP4 reversed the effects of PP2A suppression on regulating p38-MAPK pathway-, apoptosis- and EMT-related factors expressions and apoptosis, with upregulations of B-cell lymphoma-2 (Bcl-2) and E-cadherin and down-regulations of Bcl-2 associated protein X (Bax), cleaved (C)-casapse-3, N-cadherin, Vimentin and Snail. PP2A protects ADR-treated podocytes against injury and EMT by suppressing JIP4/p38-MAPK pathway, showing their interaction in podocytes.

Inhibition of p38 MAPK increases the sensitivity of 5‑fluorouracil‑resistant SW480 human colon cancer cells to noscapine

Zheng Han,Liu Meng,Xiaodong Huang,Jie Tan,Weijie Liu,Wei Chen,Yanli Zou,Yishan Cai,Shasha Huang,Aifang Chen,Ting Zhan,Min Huang,Xiaoli Chen,Xia Tian,Qingxi Zhu

A major cause of treatment failure in advanced colon cancer is resistance to chemotherapy. p38 mitogen‑activated protein kinase (MAPK) has been associated with cellular apoptosis and plays an important role in multidrug resistance (MDR) in cancer cells. In the present study the effect of p38 MAPK on the sensitivity of 5‑fluorouracil (5‑FU)‑resistant SW480 (SW480/5‑FU) human colon cancer cells to noscapine was investigated. Following p38 MAPK interference, the inhibitory effect of noscapine on cell viability and proliferation was increased in the SW480/5‑FU cells and there was also a decrease in the expression level of minichromosome maintenance proteins, recombinant Ki‑67 and proliferating cell nuclear antigen. Inhibition of p38 MAPK also enhanced noscapine‑induced G1‑phase cell cycle arrest in the SW480/5‑FU cells and there was also a decrease in the protein and mRNA expression level of cyclin D, cyclin E and cyclin‑dependent kinase 2, and an increase in the expression level of P57. Furthermore, p38 MAPK interference increased noscapine‑induced apoptosis of the SW480/5‑FU cells and there was an increase in the protein and mRNA expression level of caspases‑3 and 8 and Bax, and decreased Bcl‑2 expression level. The sensitivity of the SW480/5‑FU cells to noscapine was also increased following p38 MAPK interference, as demonstrated by MDR inhibition via decreased Akt activity and reduced protein expression level of the MDR proteins P‑glycoprotein, multidrug resistance protein 1 and ATP‑binding cassette G2. These observations indicated that inhibition of p38 MAPK increased the sensitivity of the SW480/5‑FU cells to noscapine by suppressing proliferation, induction of cell cycle arrest and apoptosis, and reversal of MDR in the SW480/5‑FU cells.

TGF-β1 impairs IgA class switch recombination and production in porcine Peyer's patches B cells

Caiying Wang,Yue Zhang,Yabin Lu,Xin Huang,Huazheng Jiang,Guohui Chen,Yongheng Shao,Huub F.J. Savelkoul,Christine A. Jansen,Guangliang Liu

Secretory IgA is crucial for preventing the invasion of entero-pathogens via intestinal mucosa. While it is well-established that Transforming growth factor β1 (TGF-β1) regulates IgA production in human and mouse B cells, our previous investigation revealed different functions of TGF-β1 in IgA generation in pigs compared with humans and mice, with the underlying mechanism remaining elusive. In this study, IgM + B cells from porcine Peyer's patches (PPs) were isolated and stimulated with recombinant porcine TGF-β1 to evaluate the effect of TGF-β1 on pigs. The results showed that antibody production from B cells of PPs was impaired by TGF-β1 ex vivo. Furthermore, TGF-β1 treatment led to a decrease in the expression of germ-line transcript αand postswitch transcript α. Moreover, we observed that TGF-β1 predominantly inhibited the phosphorylation of p38-mitogen-activated protein kinases (MAPK), confirming the involvement of the p38-MAPK pathway in porcine IgA generation and IgA class switch recombination. The application of p38-MAPK inhibitor resulted in decreased B-cell differentiation levels. Collectively, this study demonstrates that exogenous TGF-β1 restrains the production and class switch recombination of IgA antibodies by inhibiting p38-MAPK signaling in porcine PPs B cells, which may constitute a component of TGF-β1-mediated inhibition of B-cell activation.

Propofol Protects against Cerebral Ischemia/Reperfusion Injury by Down-Regulating Long Noncoding RNA SNHG14

Bei Sun,Hao Ou,Fei Ren,Yujiao Guan,Ye Huan,Hongwei Cai

Cerebral ischemia-reperfusion (CI/R) injury is a serious central nervous system disease. Propofol (PPF) exerts a neuroprotective effect in CI/R injury; the underlying cause is still unclear. Here, we cultured mouse hippocampal neuron (HT22 cells) in oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to mimic CI/R injury in vitro. PPF treatment promoted cell viability and reduced apoptotic cells in the OGD/R-treated HT22 cells, which was effectively abrogated by SNHG14 overexpression. Moreover, we constructed a CI/R injury mouse model on C57BL/6J mice by middle cerebral artery occlusion/reperfusion (MCAO/R), followed by administration of PPF. PPF reduced neuronal damage and loss, enhanced glial cell hyperplasia, and ameliorated cerebral cortex tissue damage and brain infarct in MCAO/R-induced mice. SNHG14 overexpression aggravated MCAO/R-induced CI/R injury in mice. Furthermore, SNHG14 promoted the expression of Atg5 and Beclin 1 via competitively binding miR-30b-5p, which contributed to activate autophagy and apoptosis in HT22 cells. In addition, the levels of p-p38 and p-SP1 were reduced in the OGD/R-treated HT22 cells in the presence of PPF. SP1 interacted with the promoter of SNHG14 and elevated the expression of SNHG14. PPF treatment inhibited the SP1-mediated up-regulation of SNHG14. In conclusion, this work demonstrates that PPF inhibits SNHG14 expression though the p38 MAPK signaling pathway. SNHG14 promotes Atg5 and Beclin 1 expression by sponging miR-30b-5p and thus activates autophagy and aggravates CI/R injury.

Integrated Identification of Macrophage NF-κB, p38 MAPK and AKT1 Signalling as Candidate Targets of Zerumbone in Experimental Periodontitis

Characterised by progressive alveolar bone loss, periodontitis arises from immune dysregulation and is classified as a chronic inflammatory condition. Zerumbone (Zer) has anti-inflammatory properties; however, its mechanism within the periodontal context remains unclear. We investigated the therapeutic effects and potential molecular targets of Zer by integratingin vivoefficacy assessment (using male C57BL/6 mice), network pharmacology, molecular docking, and molecular dynamics simulations, together with analysis of public single-cell transcriptomic data, with mechanistic validation using RAW 264.7 macrophages stimulated with LPS. In vivo, Zer attenuated bone resorption, preserved collagen integrity, reduced the number of TRAP-positive osteoclasts, and mitigated inflammation without hepatorenal toxicity. Network pharmacology predictedNFKB1,MAPK14, andAKT1as potential core targets, while IL-17 pathway enrichment suggested the involvement ofIL17A; single-cell data localisedNFKB1/MAPK14/AKT1to macrophages and showed thatIL17Ais predominantly expressed in T cells. In vitro, Zer dose-dependently suppressed LPS-driven phosphorylation of NF-κB p65, p38 MAPK and AKT1, correlating with reduced pro-inflammatory cytokine release and an M1-to-M2 phenotypic shift. In vivo, Zer also reduced gingival IL-17A expression. However, as IL-17A is primarily produced by T cells and our in vitro experiments were conducted exclusively in macrophages, this observation remains correlative and does not establish a direct T-cell-mediated effect. Collectively, these findings suggest that Zer ameliorates periodontitis partly through suppression of macrophage NF-κB and p38 MAPK signalling, with reduced AKT1 phosphorylation observed alongside these effects; however, whether AKT1 causally contributes to these effects remains to be determined. In addition, the potential impact on T-cell-associated IL-17A responses warrants further investigation.

Silibinin A decreases statin‑induced PCSK9 expression in human hepatoblastoma HepG2 cells

Zhewen Dong,Wenxiang Zhang,Siyu Chen,Chang Liu

Hypercholesterolemia is one of the major risk factors for the occurrence and development of atherosclerosis. The most common drugs used to treat hypercholesterolemia are 3‑hydroxy‑3‑methyl‑glutaryl‑CoA reductase inhibitors, known as statins. Statins induce a beneficial increase in the levels of the low density lipoprotein receptor (LDLR) and additionally upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to LDLR degradation. This process causes a negative feedback response that attenuates the lipid lowering effects of statins. Therefore, the development of PCSK9 inhibitors may increase the lipid‑lowering functions of statins. In the present study, a drug‑screening assay was developed using the human PCSK9 promoter, based on data from a dual‑luciferase reporter assay, and the efficacies of various compounds from Traditional Chinese Medicine were examined. Among the compounds examined, SIL was demonstrated to function by targeting PCSK9. It was identified that SIL treatment decreased the expression levels of PCSK9 in HepG2 cells by decreasing the activity of the PCSK9 promoter in a dose‑and time‑dependent manner. Notably, SIL antagonized the statin‑induced phosphorylation of the p38 MAPK signaling pathway. The present study suggested that SIL may be developed as a novel PCSK9 inhibitor that may increase the efficiency of statin treatment.

Inhibition of angiotensin II type 1 receptor partially prevents acute elevation of pulmonary arterial pressure induced by endovascular ethanol injection

Shen Yuchen,Wang Zhenfeng,Su Lixin,Zheng Lianzhou,Han Yifeng,Jiao Xiaohui,Fan Xindong,Wang Deming

This study aimed to examine whether the administration of losartan can prevent acute elevation of pulmonary arterial pressure (AEPAP) induced by endovascular ethanol injection and to assess its related mechanisms. Male swine were selected and performed with absolute ethanol endovascular injection. Saline was used as the negative control. Losartan was administered preoperatively. Pulmonary arterial pressure (PAP), femoral arterial pressure (FAP) and heart rate (HR) were monitored during operations. Venous plasma and pulmonary artery (PA) tissue were harvested for analyses. Protein level was detected by Western blotting and ELISA, whereas qRT-PCR was used in mRNA detection. H & E staining and immunohistochemistry were conducted to evaluate histopathology. Ethanol injection elevated PAP in swine. The concentration of RAS ligands was elevated in plasma (all P  < 0.0001) but not in PA. The level of oxidative stress increased in both plasma and PA. MRNA level of AT1R ( P  < 0.01, 95% CI: 0.251–1.006), not AT2R increased in PA. Losartan failed to inhibit AEPAP after all sessions of ethanol injection, and partially reversed the ethanol-induced PA remodeling. The P38 MAPK was activated after ethanol injection and could be inhibited by losartan ( P  < 0.01, 95% CI: −0.391 to −0.164). Ethanol also promoted the translocation of the P40-PHOX/P47-PHOX/P67-PHOX complex and the activation of NOX, which was independent from RAS. Endovascular ethanol injection can induce AEPAP mainly by activating RAS and P38 MAPK signaling. Losartan can partially prevent AEPAP and vascular remodeling owing to the promotion of NOX activity by ethanol. Mechanism diagram of endovascular ethanol injection-induced acute elevation of pulmonary arterial pressure (AEPAP) partially prevented by losartan. RAS: Renin–angiotensin system; AGT: angiotensinogen; Ang I: angiotensin I; ACE: angiotensin I converting enzyme; Ang II: angiotensin II. AT1R: angiotensin II type 1 receptor. NOX2: NADPH oxidase 2. PA: pulmonary artery.

Eucalrobusone C suppresses cell proliferation and induces ROS-dependent mitochondrial apoptosis via the p38 MAPK pathway in hepatocellular carcinoma cells

Kai-Li Jian,Chao Zhang,Zhi-Chun Shang,Lei Yang,Ling-Yi Kong

ABSTRACT Background Eucalyptus extracts have anti-cancer activity against various cancer cells . Formyl-phloroglucinol meroterpenoids (FPMs), which are typical secondary metabolites of the genera Eucalyptus, have many important pharmacological activities . Purpose Eucalrobusone C (EC), a new bioactive phytochemical , was first isolated from the leaves of Eucalyptus robusta in our laboratory. EC is a FPM, and our previous research revealed that EC showed strongest cytotoxicity in three cancer models than other compounds isolated from the leaves of E. robusta . This study investigated its anti-tumor effects on human hepatocellular carcinoma (HCC) and its underlying mechanisms. Methods Cell viability was measured by MTT assay . Cell cycle, apoptosis and mitochondrial transmembrane potential were determined by flow cytometry. Immunofluorescence was determined by a laser scanning confocal microscope . Protein levels were analyzed by Western blotting . Results Our results showed that EC exerted strong anti-proliferative activity against HCC cells in a concentration- and time-dependent manner. EC markedly induced apoptosis through the caspase-dependent mitochondrial pathway, and the cell cycle was arrested at S phase. SB203580 , a p38 MAPK inhibitor, effectively decreased cell death caused by EC. Moreover, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by EC and reversed EC-induced p38 MAPK activation. Conclusion Our findings indicate that EC induces mitochondrial-dependent apoptosis in HCC cells through ROS generation and p38 MAPK activation, making EC a promising candidate for further development as an anticancer agent for HCC cells.

NAA50-mediated SLU7 stabilization promotes cisplatin resistance in bladder cancer via regulating MAP3K3 mRNA nuclear export and p38 MAPK activation

Wang Benlin,Zheng Xianchong,Hua Qingsheng,Zou Feng,Huang Tao,Chen Jiawei

Background Cisplatin-based chemotherapy is first-line for muscle-invasive bladder cancer (BLCA), but chemoresistance remains the primary barrier to clinical efficacy. RNA-binding proteins (RBPs) orchestrate post-transcriptional gene regulation and are increasingly implicated in cancer chemoresistance; however, the role and regulatory mechanism of the splicing factor RBP SLU7 in BLCA cisplatin resistance remain completely unknown. Methods We analyzed SLU7 expression and clinical prognosis in two independent cisplatin-treated BLCA cohorts (GSE87304, GSE169455). Cisplatin-resistant BLCA cell lines (T24-CIS, UMUC3-CIS) were established for functional assays (CCK-8, qRT-PCR, western blotting). Molecular interactions were validated by RIP-qPCR, immunofluorescence(IF), RNA-FISH, nucleocytoplasmic fractionation, co-immunoprecipitation (co-IP), and mass spectrometry (MS). In vivo therapeutic efficacy was assessed in BLCA xenograft models. Results SLU7 was significantly upregulated in cisplatin-resistant BLCA cells, and high SLU7 expression independently predicted poor cancer-specific survival (CSS) and recurrence-free survival (RFS) in cisplatin-treated patients. SLU7 knockdown suppressed MAP3K3 expression, inhibited p38 MAPK pathway, and restored cisplatin sensitivity. Mechanistically, SLU7 directly bound MAP3K3 mRNA and promoted its nuclear export—a non-canonical function independent of its canonical splicing activity. MS and Co-IP identified NAA50 as the upstream regulator that catalyzes N-terminal acetylation of SLU7 to prevent its ubiquitin-proteasomal degradation, thereby sustaining SLU7 stability. Pharmacological inhibition of NAA50 with Naa50-IN-1 destabilized SLU7, blocked the MAP3K3-p38 axis, and reversed cisplatin resistance in vitro and in vivo. Conclusions We uncover a novel NAA50–SLU7–MAP3K3-p38 MAPK regulatory axis that drives cisplatin resistance in BLCA. NAA50-mediated N-terminal acetylation stabilizes SLU7, which in turn facilitates MAP3K3 mRNA nuclear export to activate p38 MAPK signaling. Targeting NAA50 represents a promising therapeutic strategy to overcome cisplatin resistance in BLCA, and SLU7 serves as a predictive biomarker for cisplatin response.

Sodium butyrate alleviates neuronal ferroptosis after gas explosion-induced traumatic brain injury via regulation of JNK/P38 MAPK signaling pathway

Xinwen Dong,Zheng Luo,Cuiying Li,Jie Gao,Yue Ma,Xiaoran Ma,Jiahang Yang,Sanqiao Yao,Weidong Wu,Yichun Bai,Qunwei Zhang,Wenjie Ren

Gas explosion (GE) exposure led to significant neuropathology in rats. • GE induced JNK/p38 MAPK pathway activation, ferroptosis, and inflammation. • Sodium butyrate mitigated these effects by inhibiting JNK/p38 MAPK activation. This study investigated the neuroprotective effects of sodium butyrate (NaB) against gas explosion (GE)-induced traumatic brain injury (TBI), with particular emphasis on its modulation of ferroptosis. GE exposure was simulated using a shock tube in vivo and a shockwave therapy instrument in vitro . A comprehensive assessment was performed, including behavioral tests, histopathological examination, molecular analyses (c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4), and interleukin-6 (IL-6)/interleukin-10 (IL-10)/tumor necrosis factor-α (TNF-α)), and in vitro validation using a CTX TNA2 rat astrocyte/H19-7 rat hippocampal neuron/GMI-R1 rat microglia (CTX/H19-7/GMI-R) tri-culture system. Pharmacological inhibition with SP600125 (a JNK inhibitor), SB203580 (a p38 MAPK inhibitor), and ferrostatin-1 (Fer-1, a ferroptosis inhibitor) was employed to confirm pathway involvement. GE exposure induced profound neuropathological changes, characterized by mitochondrial cristae disruption, inflammatory cell infiltration, and locomotor deficits. At the molecular level, GE exposure activated the JNK/p38 MAPK pathway (as evidenced by increased JNK and p38 phosphorylation), triggered ferroptosis (elevated Fe 2+ and malondialdehyde levels, with reduced GPX4 and SLC7A11 expression), and elicited a pro-inflammatory response (increased IL-6 and TNF-α, decreased IL-10). NaB administration effectively counteracted these deleterious effects by restoring redox homeostasis, suppressing JNK/p38 activation, and rebalancing inflammatory cytokine profiles. Notably, co-administration of pathway inhibitors potentiated the protective effects of NaB, further corroborating the involvement of JNK/p38 MAPK-mediated ferroptosis in GE-induced TBI. Collectively, these findings indicate that NaB attenuates GE-induced TBI and ferroptosis, likely through inhibition of the JNK/p38 MAPK signaling pathway. Download: Download high-res image (288KB) Download: Download full-size image