Toxicology Research
·
2025
·Vol. 14
·期 5
·
IF 2.1
Wang Yanchen,Yu Leguang,Cui Yong,Guo Xiaoyan
Propofol is a widely used intravenous anesthetic for the induction and maintenance of general anesthesia. Although clinical observations have suggested potential nephrotoxic effects of propofol, experimental evidence remains limited. In this study, we investigated the renal effects of propofol in vitro using human renal proximal tubular epithelial (HK-2) cells. Our results demonstrate that propofol induces persistent oxidative stress and mitochondrial dysfunction, leading to apoptosis. Notably, propofol activates the JNK/c-JUN signaling pathway, which in turn promotes epithelial-to-mesenchymal transition (EMT), as evidenced by morphological changes and increased expression of mesenchymal markers such as vimentin and Snail. These findings suggest a mechanistic link between prolonged propofol exposure and renal fibrotic responses. Our work highlights the need for greater awareness of propofol-associated renal risks and provides a basis for future research into its underlying molecular mechanisms.
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高影响因子
Cancer Cell International
·
2021
·Vol. 21
·期 1
·1-9
·
IF 5.722
Li Li,Zhao Weidong
Background Non-coding RNAs (ncRNAs) have been identified as key regulators during the pathogenesis and development of cancers. However, most of ncRNAs have never been explored in acute myeloid leukemia (AML).Methods Gene expression was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Functional assays were performed to assess the cellular processes in AML cells. The relationship between genes was verified by means of a series of mechanism assays.Results Transmembrane phosphatase with tensin homology pseudogene 1 (TPTEP1) was notably downregulated in AML cells, and functionally acted as a proliferation-inhibitor. Additionally, TPTEP1 suppressed AML cell growth by inactivating c-Jun N-terminal kinase (JNK)/c-JUN signaling pathway. MicroRNA (MiR)-1303, as an oncogene, was predicted and validated as a target of c-JUN in AML cells. Also, TPTEP1 interacted with miR-1303 and they were mutually silenced by each other in AML cells. Furthermore, the effect of TPTEP1 overexpression on AML cell proliferation was counteracted under miR-1303 upregulation.Conclusion Our findings unmasked a feedback loop of TPTEP1/JNK/c-JUN/miR-1303 axis in AML cells, suggesting TPTEP1 and miR-1303 as potential targets for developing therapeutic strategies for AML patients.
研究领域:
分子生物学
·
癌症研究
·
血液学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2025
·Vol. 55
·期 3
·1-14
·
IF 5.8
Qiumin Xie,Qin Yi,Jing Zhu,Bin Tan,Han Xiang,Rui Wang,Huiwen Liu,Tangtian Chen,Hao Xu
Sepsis is often a cause of mortality in patients admitted to the intensive care unit. Notably, the heart is the organ most susceptible to the impact of sepsis and this condition is referred to as sepsis‑induced cardiomyopathy (SIC). Low triiodothyronine (T3) syndrome frequently occurs in patients with sepsis, and the heart is one of the most important target organs for the action of T3. Phospholamban (PLN) is a key protein associated with Ca2+‑pump‑mediated cardiac diastolic function in the myocardium of mice with SIC, and PLN is negatively regulated by T3. The present study aimed to explore whether T3 can protect cardiac function during sepsis and to investigate the specific molecular mechanism underlying the regulation of PLN by T3. C57BL/6J mice and H9C2 cells were used to establish in vivo and in vitro models, respectively. Myocardial damage was detected via pathological tissue sections, a Cell Counting Kit-8 assay, an apoptosis assay and crystal violet staining. Intracellular calcium levels and reactive oxygen species were detected by Fluo‑4AM and DHE fluorescence. The protein and mRNA expression levels of JNK and c‑Jun were measured by western blotting and reverse transcription‑quantitative PCR to investigate the molecular mechanisms involved. Subsequently, 100 clinical patients were recruited to verify the clinical application value of PLN in SIC. The results revealed a significant negative correlation between PLN and T3 in the animal disease model. Furthermore, the expression levels of genes and proteins in the JNK/c‑Jun signaling pathway and PLN expression levels were decreased, whereas the expression levels of sarcoplasmic reticulum calcium ATPase were increased after T3 treatment. These results indicated that T3 alleviated myocardial injury in SIC by inhibiting PLN expression and its phosphorylation, which may be related to the JNK/c‑Jun signaling pathway. Accordingly, PLN may have clinical diagnostic value in patients with SIC.
研究领域:
心脏病学
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内分泌学
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重症医学
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分子生物学
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2022
·
IF 4.271
Yishuang Luo,Jinyu Kang,Jia Luo,Zheng Yan,Shengtao Li,Zhuoheng Lu,Yufei Song,Xie Zhang,Julin Yang,Aiming Liu
The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188–9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl 3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid . The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis . The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl 3 , there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI.
研究领域:
肝病学
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免疫学
·
分子生物学
·
药理学
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PubMed
高影响因子
Frontiers in Pharmacology
·
2019
·
IF 3.845
Shi Chenxi,Hao Beili,Yang Yang,Muhammad Ishfaq,Zhang Yuanyuan,Chang Yicong,Li Ying,Li Changwen,Li Rui,Liu Fangping
Acetaminophen (APAP) is an analgesic–antipyretic drug and widely used in clinics. Its overdose may cause serious liver damage. Here, we examined the mechanistic role of c-Jun N-terminal kinase (JNK) signaling pathway in liver injury induced by different doses of APAP. Male mice were treated with APAP (150 and 175 mg·kg−1), and meanwhile JNK inhibitor SP600125 was used to interfere APAP-induced liver damage. The results showed that JNK signaling pathway was activated by APAP in a dose-dependent manner. C-Jun N-terminal kinase inhibitor decreased JNK and c-Jun activation significantly (P < 0.01) at 175 mg·kg−1 APAP dose, and phosphorylation levels of upstream proteins of JNK were also decreased markedly (P < 0.05). In addition, serum aminotransferases activities and hepatic oxidative stress increased in a dose-dependent manner with APAP treatment, but the levels of aminotransferases and oxidative stress decreased in mice treated with JNK inhibitor, which implied that JNK inhibition ameliorated APAP-induced liver damage. It was observed that apoptosis was increased in APAP-induced liver injury, and SP600125 can attenuate apoptosis through the inhibition of JNK phosphorylation. Meanwhile, glutathione S-transferases A1 (GSTA1) content in serum was enhanced, while GSTA1 content and expression in liver reduced significantly with administration of APAP (150 and 175 mg·kg−1). After inhibiting JNK, GSTA1 content in serum decreased significantly (P < 0.01); meanwhile, GSTA1 content and expression in liver enhanced. These findings suggested that JNK signaling pathway mediated APAP-induced hepatic injury, which was accompanied by varying GSTA1 content and expression in liver and serum.
研究领域:
药理学
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毒理学
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分子生物学
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肝病学
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PubMed
高影响因子
Foods
·
2024
·Vol. 13
·期 23
·3810
·
IF 4.7
Song Yu,Lianpeng Zou,Jiawei Zhao,Yiping Zhu
Fumonisin B1 is a common food contaminant that has been found to adversely affect the reproductive system, especially Sertoli cells. However, the potential mitigation of FB1-induced cytotoxicity in Sertoli cells has not been fully elaborated. Resveratrol is a natural substance with anti-inflammatory, antioxidant, and anti-tumor properties. Herein, the protective effects of resveratrol against FB1-induced cytotoxicity in Sertoli cells were examined in this work. The mouse Sertoli cell line (TM4) was used as a research model. These results indicated that FB1 (40 μM and 80 μM) significantly reduces cell viability, disrupts the cell barrier, and induces an inflammatory response in TM4 cells. To our surprise, resveratrol (15 μM) showed an ability to reverse adverse effects induced by FB1 (40 μM). Furthermore, resveratrol could alleviate the FB1-induced apoptosis, decrease ROS level, and promote the antioxidant enzymes (CAT and SOD2) expression in FB1-treated TM4 cells. The addition of resveratrol could mitigate FB1-induced promoted phosphorylation of JNK and upregulation of c-jun expression. Interestingly, resveratrol was also able to mitigate the cytotoxicity of FB2 (40 μM), FB3 (40 μM), and an FB1-FB2-FB3 (40 μM-40 μM-40 μM) combination group on TM4 cells. In summary, this research displayed that resveratrol may alleviate fumonisin B1-induced cytotoxicity in Sertoli cells via inhibiting oxidative stress-mediated JNK/c-jun signaling pathway-induced apoptosis. This study provides new insights into the prevention and treatment of FB1-induced testicular toxicity and highlights the potential application value of resveratrol.
研究领域:
毒理学
·
生殖生物学
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药理学
·
细胞与分子生物学
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PubMed
高影响因子
AGING CELL
·
2021
·Vol. 20
·期 3
·e13319
·
IF 9.304
Gang Du,Zhiming Liu,Zihua Yu,Zhangpeng Zhuo,Yuedan Zhu,Juanyu Zhou,Yang Li,Haiyang Chen
As they age, adult stem cells become more prone to functional decline, which is responsible for aging-associated tissue degeneration and diseases. One goal of aging research is to identify drugs that can repair age-associated tissue degeneration. Multiple organ development-related signaling pathways have recently been demonstrated to have functions in tissue homeostasis and aging process. Therefore, in this study, we tested several chemicals that are essential for organ development to assess their ability to delay intestinal stem cell (ISC) aging and promote gut function in adult Drosophila . We found that taurine, a free amino acid that supports neurological development and tissue metabolism in humans, represses ISC hyperproliferation and restrains the intestinal functional decline seen in aged animals. We found that taurine represses age-associated ISC hyperproliferation through a mechanism that eliminated endoplasmic reticulum (ER) stress by upregulation of the target genes of unfolded protein response in the ER (UPR ER ) and inhibiting the c-Jun N-terminal kinase (JNK) signaling. Our findings show that taurine plays a critical role in delaying the aging process in stem cells and suggest that it may be used as a natural compound for the treatment of age-associated, or damage-induced intestinal dysfunction in humans.
研究领域:
衰老研究
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干细胞生物学
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分子遗传学
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PubMed
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
·
2025
·
IF 11.9
Long Xu,Xinyan Wu,Luosha Long,Suchun Li,Meiying Huang,Meng Li,Pinning Feng,Moshe Levi,Wei Chen,Lei Wang,Chunling Li,Weidong Wang
Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism. Lithocholic acid (LCA), a TGR5 agonist, markedly decreased systolic blood pressure induced by DOCA-salt in mice, which was associated with decreased ENaC expression in the kidney. DOCA-salt treatment increased renal expression of histone H3 lysine 4 trimethylation (H3K4me3) and decreased expression of lysine-specific demethylase 5A (KDM5A), a lysine demethylase, which was markedly reversed by LCA. TGR5 knockout caused further increased systolic blood pressure and ENaC expression in mice with DOCA-salt in association with increased H3K4me3 and decreased KDM5A. In immortalized mouse cortical collecting duct (mpkCCD) cells LCA markedly inhibited aldosterone-induced ENaC-mediated current. LCA treatment or TGR5 overexpression markedly inhibited ENaC and H3K4me3 protein expression in association with decreased KDM5A in mpkCCD cells treated with either aldosterone or angiotensin II. Inhibition or knockdown of KDM5A in mpkCCD cells prevented LCA-induced downregulation of ENaC expression by promoting H3K4me3 on the ENaC transcription start site. LCA upregulated KDM5A expression was likely through JNK/c-Jun signal pathway. In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through activating TGR5 and upregulating KDM5A-induced H3K4me3 demethylation in ENaC promoter region.
研究领域:
肾病学
·
分子生物学
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药理学
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PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Wei Xu,Sijia Fang,Yong Wang,Xiaoqing Chi,Xiaodan Ma,Tao Zhang,Songhua Hu
The present study was to investigate the molecular mechanism underlying lymphocyte activation by total polysaccharides from Atractylodis macrocephalae (RAMPtp). The results showed that RAMPtp significantly promoted the secretions of cytokines (IFN-γ, IL-1α, IL-21, IFN-α, CCL4, CXCL9 and CXCL10), increased the proportions of CD4 + and CD8 + subpopulations, and enhanced the expressions of c-JUN, NFAT4, STAT1 and STAT3. microRNA sequencing identified 67 differentially expressed miRNAs (DEMs) in RAMPtp-stimulated SMLN lymphocytes, including 55 up-regulated and 12 down-regulated. GO and KEGG enrichment analyses of the predicted DEMs-targeted genes indicated that they were associated with immune system pathways, including PI3K-Akt, MAPKs, Jak-STAT and Calcium signaling pathways, which were confirmed by western blot and pathway inhibition assays. RAMPtp was further observed to favor immunostimulatory effect on both T and B lymphocytes via binding to TCR and membrane Ig individually. These findings might explain the immunomodulatory mechanism of RAMPtp in ameliorating the bovine intramammary infection.
研究领域:
免疫学
·
分子生物学
·
兽医学
·
药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
La Yan,Juanyu Zhou,Lu Yuan,Jinbao Ye,Xudong Zhao,Gang Ren,Haiyang Chen
Inflammatory bowel diseases (IBDs) are characterized by chronic relapsing intestinal inflammation that causes digestive system dysfunction. For years, researchers have been working to find more effective and safer therapeutic strategies to treat these diseases. Silibinin (SIL), a flavonoid compound extracted from the seeds of milk thistle plants, possesses multiple biological activities and is traditionally applied to treat liver diseases. SIL is also widely used in the treatment of a variety of inflammatory diseases attributed to its excellent antioxidant and anti-inflammatory effects. However, the efficacy of SIL against IBDs and its mechanisms remain unclear. In this study, using Drosophila melanogaster as a model organism, we found that SIL can effectively relieve intestinal inflammation caused by dextran sulfate sodium (DSS). Our results suggested that SIL supplementation can inhibit the overproliferation of intestinal stem cells (ISCs) induced by DSS, protect intestinal barrier function, acid-base balance, and intestinal excretion function, reduce intestinal reactive oxygen species (ROS) levels and inflammatory stress, and extend the lifespan of Drosophila . Furthermore, our study demonstrated that SIL ameliorates intestinal inflammation via modulating the c-Jun N-terminal kinase (JNK) signaling pathway in Drosophila . Our research aims to provide new insight into the treatment of IBDs.
研究领域:
药理学
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免疫学
·
分子生物学
·
胃肠病学
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PubMed
高影响因子
Frontiers in Immunology
·
2024
·
IF 5.7
Zhuwei Liang,Chao Zhang,Xiaoyu Liu,Kaiyue Yang,Zhile Xiong,Bingshao Liang,Jialiang Mai,Xiaojun Xiao,Jie Liu,Pingchang Yang,Damo Xu,Zhenwen Zhou
Background: Milk allergy commonly occurs in children, mainly caused by bovine-derived casein (CAS) protein. Neutrophil-activating protein (NAP) of Helicobacter pylori plays an immunomodulatory role with potential to suppress Th2-type immune responses. Bacillus subtilis (B. subtilis) spores are commonly used as oral vectors for drug delivery.Objective: To investigate whether recombinantly expressed NAP on B. subtilis spores could be an effective treatment for CAS allergy in mouse.Methods: After CAS sensitization, mice were orally administered B. subtilis spores expressing recombinant NAP for 6 weeks. Allergic symptoms and parameters were evaluated after CAS challenge oral gavage, including allergic inflammation, splenic cytokines, and serum-specific antibodies. Protein levels of Toll-like receptor 2 (TLR2) and c-JUN in the jejunum tissue were measured by western blot. Bone marrow-derived macrophages (BMDMs) were stimulated with inactivated NAP spores to measure the influence on cytokine profiles in vitro.Results: NAP recombinant spore treatment significantly reduced allergic symptoms and intestinal inflammation. Interleukin-12 and interferon-gamma levels increased, whereas serum CAS-specific IgG1 and IgE levels decreased. TLR2 and c-JUN expression levels were elevated in the jejunal tissue. Inactivated NAP spores polarized BMDMs to the M1 phenotype and enhanced cytokine expression, which were inhibited by a TLR2 neutralizing antibody.Conclusion: NAP offers a new strategy in the treatment of CAS allergy by inhibiting the Th2 response, while eliciting macrophages to promote Th1 immune responses.
研究领域:
免疫学
·
过敏
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·133-145
·
IF 6.15
Shen Dai-fei,Cheng He,Cai Bo-zhi,Cai Wen-feng,Wang Bin,Zhu Qing,Wu Yue-bin,Liu Man,Chen Run-ji,Gao Fen-fei,Zhang Yan-mei,Niu Yong-dong,Shi Gang-gang
N -n-Butyl haloperidol iodide (F 2 ) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F 2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl 4 ) or thioacetamide (TAA). The mice received F 2 (0.75, 1.5 or 3 mg·kg −1 ·d −1 , ip) for 4 weeks of fibrosis induction. We showed that F 2 administration dose-dependently ameliorated CCl 4 - or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-β receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F 2 (0.1, 1, 10 μM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F 2 inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-β signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-β1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-β signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F 2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-β signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F 2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1. F 2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.
研究领域:
药理学
·
肝病学
·
细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
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