查找使用阿拉丁产品的科研文献

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.

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.

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

LINC00938 alleviates hypoxia ischemia encephalopathy induced neonatal brain injury by regulating oxidative stress and inhibiting JNK/p38 MAPK signaling pathway

Jing Zhao,Meini Le,Jie Li,Qiong Huang,Haocong Chen,Wenyi Zhang,Huiwen Mao,Qing Sun,Aiguo Li,Yingmin Zhao,Lingling Yu,Mingjiang Yi,Jie Wang,Xinyuan Li,Guangming Zhang,Jun Ma,Xiaohua Dong

Hypoxic-ischemic encephalopathy (HIE) is an important factor leading to permanent damage of central nervous system (CNS) and even neonatal death . Long non-coding RNAs (lncRNAs) has been shown to get involved in the pathogenesis of nervous system diseases . LINC00938 is an intergenic lncRNA which is reported to be involved in neurodegenerative disease . However, the potential role of LINC00938 in nerve injury of neonatal HIE is undetermined. Here, we found that the expression of LINC00938 in the whole blood of neonates with HIE was downregulated compared with the non-HIE group. Functional study revealed that the expression of LINC00938 was significantly decreased in oxygen-glucose deprivation (OGD)-induced SH-SY5Y. Knockdown of LINC00938 induced the neural cell apoptosis by increased the protein level of Bax, Cleaved-Caspase3 and decreased the expression of Bcl-2. In addition, overexpression of LINC00938 prevented the apoptosis of SH-SY5Y from OGD injury. RNA-seq analysis showed that MAPK signaling was involved in the anti-apoptosis function of LINC00938. LINC00938 knockdown induced the activation of c-Jun-N-terminal kinase (JNK), p38 mitogen-activated protein kinase, and inhibited the activation of ERK signaling. However, LINC00938 play neuroprotective role in OGD-induced SH-SY5Y by suppression the phosphorylation of JNK and p38 MAPK rather than regulation of ERK signaling pathway . Further analyses illustrated that the cell apoptosis of neuronal cell was dependent on the elevation of reactive oxygen species (ROS) and result in mitochondria dysfunction in LINC00938 knockdown SH-SY5Y. Pretreated with ROS inhibitor N -acetylcysteine amide (NACA) dramatically suppressed LINC00938 knockdown induced oxidative stress and mitochondria dysfunction which induced cell apoptosis. In addition, NACA treatment significantly reduced the expression of p-JNK and p-p38 in OGD-induced SH-SY5Y. Furthermore, overexpression of LINC00938 displayed a notably neuroprotective effect by suppress central nervous system cell apoptosis via alleviating oxidative stress in CoCl 2 -induced hypoxic HIE model of zebrafish. Taken together, these results suggested that LINC00938 can act as a neuroprotective factor to inhibit oxidative stress and apoptosis of CNS under HIE conditions.

7-hydroxycoumarin-β-D-glucuronide protects against cisplatin-induced acute kidney injury via inhibiting p38 MAPK-mediated apoptosis in mice

Haijie Wu,Xiaohu Shi,Yingda Zang,Xiaodi Zhao,Xikun Liu,Weida Wang,Wenying Shi,Clarence T.T. Wong,Li Sheng,Xiaoguang Chen,Sen Zhang

Aims Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-β-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. Materials and methods Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. Key findings 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t 1/2β of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. Significance Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.

A Novel Peptide Derived from Arca inflata Induces Apoptosis in Colorectal Cancer Cells through Mitochondria and the p38 MAPK Pathway

Chunlei Li,Sirui Zhang,Jianhua Zhu,Weijuan Huang,Yuanyuan Luo,Hui Shi,Dongbo Yu,Liguo Chen,Liyan Song,Rongmin Yu

Colorectal carcinoma (CRC) is one of the major causes of cancer-related incidence and deaths. Here, we identified a novel antitumor peptide, P6, with a molecular weight of 2794.8 Da from a marine Chinese medicine,Arca inflataReeve. The full amino acid sequence and secondary structure of P6 were determined by tandem mass de novo sequencing and circular dichroism spectroscopy, respectively. P6 markedly inhibited cell proliferation and colony formation, and induced apoptosis in CRC cells. Mechanistically, transcriptomics analysis and a serial functional evaluation showed that P6 induced colon cancer cell apoptosis through the activation of the p38-MAPK signaling pathway. Moreover, it was demonstrated that P6 exhibited antitumor effects in a tumor xenograft model, and induced cell cycle arrest in CRC cells in a concentration-dependent mode. These findings provide the first line of indication that P6 could be a potential therapeutic agent for CRC treatment.Keywords:Arca inflata;antitumor peptide;apoptosis;MAPK signaling;calmodulin;colorectal cancer

Selenium nanoparticles improve nickel-induced testosterone synthesis disturbance by down-regulating miR-708-5p/p38 MAPK pathway in Leydig cells

Shuang Wang,Xueyan Gu,Jianhua Ma,Zhangyu Gu,Rui Zhang,Ruifen Li,Jun Bai,Peng Li,Linyu Wei,Yixing Ye,Yan Wang,Li Zhang,Li Su,Changhao Liang

The present study was designed to investigate the role of miR-708-5p/p38 mitogen-activated protein kinase (MAPK) pathway during the mechanism of selenium nanoparticles (Nano-Se) against nickel (Ni)-induced testosterone synthesis disorder in rat Leydig cells. We conducted all procedures based on in vitro culture of rat primary Leydig cells. After treating Leydig cells with Nano-Se and NiSO 4 alone or in combination for 24 h, we determined the cell viability, reactive oxygen species (ROS) levels, testosterone production, and the protein expression of key enzymes involved in testosterone biosynthesis: steroidogenic acute regulatory (StAR) and cytochrome P450 cholesterol side chain cleavage enzyme (CYP11A1). The results indicated that Nano-Se antagonized cytotoxicity and eliminated ROS generation induced by NiSO 4 , suppressed p38 MAPK protein phosphorylation and reduced miR-708-5p expression. Importantly, we found that Nano-Se upregulated the expression of testosterone synthase and increased testosterone production in Leydig cells. Furthermore, we investigated the effects of p38 MAPK and miR-708-5p using their specific inhibitor during Nano-Se against Ni-induced testosterone synthesis disorder. The results showed that Ni-inhibited testosterone secretion was alleviated by Nano-Se co-treatment with p38 MAPK specific inhibitor SB203580 and miR-708-5p inhibitor, respectively. In conclusion, these findings suggested Nano-Se could inhibit miR-708-5p/p38 MAPK pathway, and up-regulate the key enzymes protein expression for testosterone synthesis, thereby antagonizing Ni-induced disorder of testosterone synthesis in Leydig cells.

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.

Selenium deficiency sensitizes the skin for UVB-induced oxidative damage and inflammation which involved the activation of p38 MAPK signaling

Xiaokang Zhu,Mingdong Jiang,Erqun Song,Xiaoji Jiang,Yang Song

Ultraviolet B (UVB) radiation causes oxidative damage and inflammation, and ultimately increases the risk of skin carcinogenesis. Selenium is an essential trace element, previous studies indicated selenium deficiency impairs tissue antioxidant capacity in different experimental models. However, the synergistic effect of selenium deficiency and UVB radiation on skin damage is not clear. In the current study, our data revealed selenium deficiency resulted in further increases of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS) and phosphorylated H2AX levels, decreases of GSH level and antioxidant enzyme activities in UVB-irradiated mice. Selenium deficiency also exacerbated UVB-induced cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6 mRNA expressions. Mechanism studies indicated that UVB-induced p38 signaling was further elevated in the skin of mice maintained with selenium deficiency diet, compared with those maintained with selenium adequate diet. Our investigation suggested that selenium deficiency diet weakens the antioxidant capacity of UVB-irradiated mice skin, which sensitizes to UV radiation-induced oxidative damage and inflammation.

Bile Duct Ligation Impairs Function and Expression of Mrp1 at Rat Blood–Retinal Barrier via Bilirubin-Induced P38 MAPK Pathway Activations

Ping Li,Yiting Yang,Zijin Lin,Shijin Hong,Ling Jiang,Han Zhou,Lu Yang,Liang Zhu,Xiaodong Liu,Li Liu

Liver injury is often associated with hepatic retinopathy, resulting from accumulation of retinal toxins due to blood–retinal barrier (BRB) dysfunction. Retinal pigment epithelium highly expresses MRP1/Mrp1. We aimed to investigate whether liver injury affects the function and expression of retinal Mrp1 using bile duct ligation (BDL) rats. Retinal distributions of fluorescein and 2,4-dinitrophenyl-S-glutathione were used for assessing Mrp1 function. BDL significantly increased distributions of the two substrates and bilirubin, downregulated Mrp1 protein, and upregulated phosphorylation of p38 and MK2 in the retina. BDL neither affected the retinal distribution of FITC-dextran nor expressions of ZO-1 and claudin-5, demonstrating intact BRB integrity. In ARPE-19 cells, BDL rat serum or bilirubin decreased MRP1 expression and enhanced p38 and MK2 phosphorylation. Both inhibiting and silencing p38 significantly reversed the bilirubin- and anisomycin-induced decreases in MRP1 protein. Apparent permeability coefficients of fluorescein in the A-to-B direction (Papp, A-to-B) across the ARPE-19 monolayer were greater than Papp, B-to-A. MK571 or bilirubin significantly decreased Papp, A-to-Bof fluorescein. Bilirubin treatment significantly downregulated Mrp1 function and expression without affecting integrity of BRB and increased bilirubin levels and phosphorylation of p38 and MK2 in rat retina. In conclusion, BDL downregulates the expression and function of retina Mrp1 by activating the p38 MAPK pathway due to increased bilirubin levels.Keywords:bile duct ligation;blood–retinal barrier;multidrug resistance-associated protein 1;liver injury;p38 MAPK;bilirubin

Solid Lipid Nanoparticles Enhanced the Neuroprotective Role of Curcumin against Epilepsy through Activation of Bcl-2 Family and P38 MAPK Pathways

Ruiqi Huang,Yanjing Zhu,Lijuan Lin,Simin Song,Liming Cheng,Rongrong Zhu

Oxidative stress of neurons caused by a series of complex neuropathological processes will induce certain neurodegenerative disorders including epilepsy. Curcumin (Cur) is an effective natural antioxidant compound; however, the poor bioavailability obstructs its neural protective applications. In this study, Cur is encapsulated in solid lipid nanoparticles (SLNs) for better neuroprotective efficacy. In vitro study certified that Cur-SLNs functioned obviously better against neuronal apoptosis than Cur, by significantly decreasing the level of free radical and reversing mitochondrial function through the activation of the Bcl-2 family. In vivo experiments showed that SLNs transported Cur through the blood–brain barrier (BBB). The behavioral performance of epileptic mice was improved by Cur-SLNs, with more NeuN but less TUNEL positive cells observed in hippocampus. The in vivo mechanism was also explored. Cur-SLNs reduced neuronal apoptosis through Bcl2 family and P38 MAPK pathways. Overall, Cur-SLNs have better protective effects toward oxidative stress in neurons than free Cur both in vitro and in vivo, which suggests they may be a promising agent against neurodegenerative disorders including epilepsy.