MOLECULAR NEUROBIOLOGY
·
2021
·Vol. 59
·期 1
·429-444
·
IF 5.59
Zou Ying,Zhang Jiaqi,Liu Jingmin,Xu Jiawei,Fu Lanya,Ma Xinrui,Xu Yizhou,Xu Shuyi,Wang Xianghai,Guo Jiasong
Silent information regulator 6 (SIRT6) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Previous studies have been reported a pro-regenerative role of SIRT6 in central nervous system injury. However, the role of SIRT6 in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of SIRT6 steering Schwann cell dedifferentiation during Wallerian degeneration in injured peripheral nerve. Herein, we first examined the expression pattern of SIRT6 after peripheral nerve injury. Using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that SIRT6 inhibitor accelerates Schwann cell dedifferentiation as well as axonal and myelin degeneration, while SIRT6 activator attenuates this process. Moreover, in an in vitro Schwann cell dedifferentiation model, we found SIRT6 inhibitor promotes Schwann cell dedifferentiation through upregulating the expression of c-Jun. In addition, downregulation of c-Jun reverse the effects of SIRT6 inhibition on the Schwann cells dedifferentiation and axonal and myelin degeneration. In summary, we first described SIRT6 acts as a negative regulator for Schwann cells dedifferentiation during Wallerian degeneration and c-Jun worked as a direct downstream partner of SIRT6 in injured peripheral nerve.
研究领域:
神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CANCER LETTERS
·
2026
·
IF 11.8
Shuangshuang Ma,Minxin Chen,Xiaozheng Sun,Baochao Wei,Fengxin Sun,Xueqi Xie,Yiheng Huang,Zhaoyun Liu,Rong Xiao,Ling Wei,Fei Wang,Ying Xu,Jinming Yu,Dawei Chen,Meng Wu
Tamoxifen has been commonly used in endocrinotherapy for estrogen receptor (ER)-positive breast cancer. In recent years, the immunomodulatory effects of high-dose tamoxifen have been discovered. The immunosuppressive tumor microenvironment (TME), however, remains a major obstacle to the efficacy of radiotherapy. Whether high-dose tamoxifen can reprogram TME to synergistically enhance radiation efficacy is still ambiguous. Here, we have found high-dose tamoxifen could dramatically enhance radiation-induced antitumor effects without significant side effects in immunocompetent mice. Flow cytometry and multiplex immunofluorescence experiments revealed that radiation combined with tamoxifen resulted in significant enrichment of effector CD8 + T cells and M1 tumor associated macrophages (TAMs). While depletion of TAMs and CD8 + T cells impaired the synergistic antitumor effects mediated by combination treatment of radiation and tamoxifen. Furthermore, spatial proximity analysis demonstrated a dramatically reduced nearest-neighbor distance between CD8 + T cells and M1-like TAMs in the combination group, indicating enhanced cellular interaction within the TME. In vitro experiments demonstrated that tamoxifen directly acted on TAMs, rather than CD8 + T cells, to promote M1 polarization and subsequently enhanced the activation and effector function of CD8 + T cells, regardless of ER expression in tumor cells and macrophages. Mechanistically, RNA-sequencing and experimental validation uncovered that tamoxifen and tumor cell-derived TNF-α and IL-1β after irradiation synergistically activated the JNK/c-JUN pathway and promoted M1 polarization of TAMs. In conclusion, our study revealed the immunomodulatory effects of high-dose tamoxifen in the context of radiation and provided preclinical evidence for combination therapy of high-dose tamoxifen and radiotherapy in both ER-positive and ER-negative cancers.
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2025
·
IF 8.3
Chunyu Wang,Kunjing Liu,Jing Ji,Wenyuan Ma,Haojia Zhang,Kai Wang,Yukun Lin,Chongyang Ma,Xueqian Wang,Fafeng Cheng
Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major global chronic liver disorder, with metabolic dysfunction-associated steatohepatitis (MASH) representing its severe subtype. Liu-Jun-Zi Decoction (LJZD), a classical traditional Chinese medicine (TCM) formula, has shown clinical efficacy against MASH, however, its underlying mechanisms remain unclear. Purpose To investigate the molecular mechanism through which LJZD alleviates hepatic steatosis in MASH mice by restoring irisin secretion in skeletal muscle. Methods A MASH mouse model was established using a methionine and choline deficient (MCD) diet, followed by LJZD treatment. First, major chemical components of LJZD were identified via UHPLC-QE-MS. Subsequently, histopathological and biochemical analyses were performed to evaluate the effects of LJZD on MASH and skeletal muscle atrophy. Finally, the secretion of irisin in skeletal muscle was assessed, and bioinformatics analysis was used to screen downstream targets of irisin. Results LJZD significantly alleviated hepatic steatosis, injury, inflammation, and fibrosis in MASH mice while improving concomitant skeletal muscle atrophy. Furthermore, LJZD enhanced irisin secretion from skeletal muscle. Integrated transcriptomic analysis identified carboxylesterase 2A (CES2A) as a key hepatic downstream effector of irisin. Conclusion LJZD ameliorates MASH by promoting skeletal muscle irisin secretion, which upregulates hepatic CES2A to enhance lipid catabolism. In summary, current data extend the research scope on LJZD's pharmacological effects and suggest new approaches for clinical MASH treatment. LJZD alleviates hepatic steatosis by targeting skeletal muscle, indicating its potential as a therapeutic candidate for MASH.
研究领域:
中医药学
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药理学
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肝病学
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分子生物学
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代谢疾病
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生物信息学
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产品关联
DOI
PubMed
高影响因子
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
Cell Death & Disease
·
2017
·Vol. 8
·期 7
·e2935
·
IF 5.965
Zhou Wei,Yao Jihong,Wang Guangzhi,Chen Zhao,Li Zhenlu,Feng Dongcheng,Li Yang,Qasim Wasim,Tan Wenzhi,Ning Shili,Tian Xiaofeng
Intestinal ischemia–reperfusion (I/R) is a common clinical problem that occurs during various clinical pathological processes. Excessive apoptosis has an indispensable role in intestinal I/R injury. Tumor necrosis factor receptor-associated factor 2 (TRAF2) and PKC ζ have an essential role in apoptosis. Here, we aimed to investigate the effects of PKC ζ and TRAF2 and to explore the correlation between PKC ζ and TRAF2 in intestinal I/R injury. Mice were subjected to intestinal I/R injury in vivo . In vitro experiments were conducted by treating Caco-2 cells with hypoxia/reoxygenation (H/R) stimulation to simulate intestinal I/R. Intestinal tissue samples and Caco-2 cells were examined using various approaches. Intestinal I/R induced the membrane translocation and phosphorylation of PKC ζ . Pretreatment with the PKC ζ activator phosphatidylcholine remarkably attenuated gut injury by suppressing apoptosis. H/R induced PKC ζ to combine with TRAF2, which was phosphorylated by PKC ζ at Ser 55 , but not at Ser 11 , under intestinal I/R or H/R conditions. In addition, TRAF2 Ser 55 phosphorylation increased cell survival by inhibiting cell apoptosis in the H/R model. Mechanistically, TRAF2 Ser 55 phosphorylation promoted NF- κ B activation but suppressed c-Jun activation in Caco-2 cells under H/R conditions. The results of this study demonstrate that the PKC ζ /TRAF2 pathway represents a novel protective mechanism against intestinal I/R injury. Therefore, the PKC ζ /TRAF2 pathway is a novel target for potential treatments of intestinal I/R injury-related diseases.
研究领域:
分子生物学
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细胞生物学
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病理学
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DOI
PubMed
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
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血液学
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Deying Men,Jiahe Dai,Yuxue Yuan,Haifen Jiang,Xinyu Wang,Yifan Wang,Liang Tao,Jun Sheng,Yang Tian
Moringa oleifera leaf peptide, which is a plant-derived bioactive peptide, exhibits several advantages, including safety, high efficiency and nontoxic side effects. The goal of this study was to identify representative antiosteoporotic peptides from Moringa oleifera leaf proteins and determine their regulatory mechanisms using network pharmacology, molecular docking and molecular dynamics. The following core targets of Moringa oleifera leaf antiosteoporotic peptides were screened by network pharmacology: SRC, MAPK1, JUN and STAT3. Through molecular docking, DPYLGK was identified as a representative active peptide from the Moringa oleifera leaf protein, and SRC was determined to be a potential primary target. Molecular dynamics revealed the intermolecular mechanism of DPYLGK and SRC. Cellular assays showed that DPYLGK promotes bone formation and inhibits bone resorption. These findings demonstrated that DPYLGK is an anti-osteoporotic peptide with dual regulatory effects and will aid in the development of functional foods to prevent osteoporosis.
研究领域:
药理学
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分子生物学
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生物信息学
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营养科学
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DOI
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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产品关联
DOI
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
·
免疫学
·
分子生物学
·
药理学
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产品关联
DOI
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
·
毒理学
·
分子生物学
·
肝病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2022
·
IF 3.571
Hui Liu,Si-Yu Wang,Jin-Hao Zhu,Jin-Di Xu,Shan-Shan Zhou,Ming Kong,Qian Mao,Song-Lin Li,He Zhu
Si-Jun-Zi decoction (SJZD) with ginseng as the principal medicinal herb is a traditional Chinese Medicine multi-herb prescription that commonly employed to treat colorectal cancer etc. Previous studies showed that nearly half of the commercial ginseng was sulfur-fumigated, one of the postharvest processing methods that commonly causes sulfur-dioxide (SO 2 ) residue and chemical composition transformation in medical herbs. In this study, the effect of sulfur-fumigated ginseng on global quality of SJZD was evaluated by UPLC-QTOF-MS/MS based metabolomics and multiple chromatographic techniques based glycomics strategies. For non-saccharides components, sulfur-fumigated ginseng led to the emergence of sulfur-containing derivatives and alteration of saponins and flavonoids in SJZD. For saccharide components, sulfur-fumigated ginseng decreased the total contents and molecular weights of polysaccharides , changed the monosaccharide composition of polysaccharides, and increased the contents of oligosaccharides and free monosaccharides of SJZD. The alterations of SJZD were aggravated with the sulfur-fumigated content of ginseng. Those phenomena might be attributed to 1) sulfur-fumigation caused the generation of sulfur-containing derivatives in ginseng, which further transferred to SJZD, and 2) sulfur-fumigation caused the residue of SO 2 in ginseng, which reduced the pH value and further changed the dissolution of saponins and flavonoids and accelerated the degradation of the polysaccharides to oligosaccharides and/or monosaccharides in SJZD. Furthermore, although storage reduced the SO 2 residue in sulfur-fumigated ginseng, it couldn’t recover the alterations of chemical profiles in SJZD. In conclusion, sulfur-fumigated ginseng altered the global quality of SJZD, which promoted that extra attention must be paid during the application of herbal formulas that containing sulfur-fumigated herbs.
研究领域:
中医
·
药理学
·
代谢组学
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糖组学
·
草药
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DOI
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
·
药理学
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细胞与分子生物学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）