BIOCHEMICAL PHARMACOLOGY
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2026
·
IF 6.5
Wupei Pan,Xiaoyi Zou,Wenxin Tang,Xin Zheng,Minjuan Xie,Jie Zhou
Sodium aescinate (SA), derived from seeds of the Chinese herb Suoluozi ( Aesculus wilsonii Rehd.), has been linked to severe kidney injury during clinical use. We previously found that SA induces nephrocyte ferroptosis, and upregulation of glutathione peroxidase 4 (GPX4) or ferroptosis suppressor protein 1 (FSP1) expression only partially attenuates this toxic effect. In this study, we demonstrated that SA reduced cellular levels of hydrogen sulfide (H 2 S) and reduced coenzyme Q10 (CoQ10H 2 ), leading to impaired antioxidant defense and lipid peroxidation (LPO) in renal cells. Mechanistically, SA suppressed the expression of activating transcription factor 4 (ATF4), cystathionine γ-lyase (CTH) and sulfide: quinone oxidoreductase (SQOR). The SA-induced downregulation of CTH expression was attributed to the decreased recruitment of ATF4 to the cis -regulatory element (CRE) of the CTH promoter. ATF4 overexpression in SA-treated cells upregulated CTH expression, which elevated H 2 S and CoQ10H 2 levels, improved antioxidant defense, and reduced ferroptosis. Critically, CTH silencing completely abrogated these protective effects. Conversely, CTH or SQOR overexpression, or H 2 S supplementation restored CoQ10H 2 levels and protected against SA-induced ferroptosis. However, in SQOR-deficient cells, neither intervention rescued CoQ10H 2 nor alleviated nephrotoxicity despite increased H 2 S levels. Additionally, alternative oxidase (AOX) overexpression abolished the protective effect of the ATF4/CTH/SQOR axis by oxidizing CoQ10H 2 back to its inactive form. In conclusion, SA induced ferroptosis-mediated kidney injury by disrupting the ATF4/CTH/SQOR axis, leading to reduced CoQ10H 2 levels and impaired redox homeostasis. This study introduces this pathway as a novel therapeutic target for SA-induced nephrotoxicity.
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CANCER SCIENCE
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2026
·
IF 4.9
Xinyu Xu,Jiayuan Wang,Meng Jiang,Ling Ouyang
Ovarian cancer is one of the most prevalent gynecologic malignancies worldwide. Dysregulated cell proliferation and angiogenesis are well-recognized to be involved in the pathogenesis of ovarian cancer. Nucleolar Protein 7 (NOL7), a novel RNA-binding protein, has been identified as a tumor suppressor and a key anti-angiogenetic factor. However, the function of NOL7 and its underlying molecular mechanisms in ovarian cancer remain unclear. In this study, we demonstrated that NOL7 expression was down-regulated in ovarian cancer tissues, and low NOL7 expression was associated with poorer prognosis in patients with ovarian cancer. Overexpression of NOL7 decreased cell viability, inhibited cell cycle entry and proliferation, and promoted apoptosis in OVCAR-3 and SKOV-3 cells. Additionally, NOL7 overexpression decreased VEGF-A level, increased TSP-1, and suppressed angiogenesis of human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of NOL7 in ovarian cancer cells enhanced cell proliferation and angiogenesis, while reducing apoptosis. In vivo experiments further confirmed that NOL7 overexpression inhibited tumor growth and angiogenesis. Mechanistic studies revealed that NOL7 could bind to the 3′UTR of growth arrest and DNA damage inducible alpha (GADD45A), and overexpression of NOL7 up-regulated GADD45A expression by stabilizing GADD45A mRNA in ovarian cancer cells. The anti-cancer effects of the NOL7/GADD45A were mediated by inhibiting the phosphorylation of STAT3 at Ser727. Collectively, our findings indicate that NOL7 functions as a tumor suppressor in ovarian cancer and provide a novel therapeutic target for the treatment of ovarian cancer.
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ANTIOXIDANTS & REDOX SIGNALING
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2025
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IF 6.1
Xian-Dong Li,Yue-Xin Ning,Yi-Feng Pei,Jing-Yuan Niu,Jian Luo,Yi-Na Zhang,Zi-Ai Zhao,Xiao-Wen Hou,Qian-Kun Zhao,Tian-Ce Xu,Hui-Sheng Chen
Aims: Cathodal transcranial direct current stimulation (C-tDCS), a noninvasive physical therapy, has potential neuroprotective effects in acute ischemic stroke. However, the rational timing of its application and the underlying mechanisms remain inadequately understood. This study aims to investigate its neuroprotective effects and the involved mechanisms.Results: Our in vivo results indicated that C-tDCS applied during the reperfusion phase but not during the ischemic phase significantly improved neurological outcomes, reduced infarct volume, and mitigated histopathological damage in middle cerebral artery occlusion/reperfusion rats. C-tDCS during the reperfusion phase suppressed ferroptosis, activated nuclear factor erythroid 2-related factor 2 (Nrf2), and inhibited mitophagy. In vitro, the ferroptosis inducer RSL3 negated the protective effects of cathodal direct current stimulation on HT22 neuronal cells subjected to oxygen-glucose deprivation/reoxygenation injury. Furthermore, the Nrf2 inhibitor ML385 and the mitophagy activator FCCP reversed the inhibitory effects of C-tDCS on ferroptosis, with FCCP also affecting Nrf2 activation by C-tDCS.Innovation and Conclusions: These results demonstrate that C-tDCS during reperfusion attenuates cerebral ischemia-reperfusion injury by coordinating mitophagy inhibition and Nrf2 activation to counteract ferroptosis, which provides new evidence for its potential translational clinical applications. Antioxid. Redox Signal. 00, 000–000.
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DNA AND CELL BIOLOGY
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2025
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IF 2.6
Lijiang Zhao,Xueqing Wu,Qiang Li,Yan Shen,Sheng Zeng,Jinbao Wang,Qian Liu
Bisphenol A (BPA) is the most common endocrine disruptor that has toxicity to the reproductive system and male infertility. However, the underlying mechanisms of BPA’s toxicity to Sertoli cells remain poorly understood. Cellular communication network factor 5 (CCN5) is reported to regulate cell proliferation, apoptosis, and differentiation. Our study demonstrated a significant elevation of CCN5 expression in the testis of nonobstructive azoospermia patients and TM4 Sertoli cells exposed to BPA. Knockdown of CCN5 reduced apoptotic cells after BPA treatment, as determined by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Cells exposed to BPA showed increased expressions of Bax and cleaved poly(ADP-ribose) polymerase, decreased expression of Bcl-2, as well as elevated activities of caspase-3 and caspase-9 in BPA-induced TM4 cells, which were reversed by CCN5 inhibition. Loss of CCN5 declined phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eukaryotic translation initiation factor 2A and decreased activating transcription factor 4 and C/EBP-homologous protein in BPA-treated cells. Furthermore, silencing CCN5 blocked BPA-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Administration of anisomycin, a mitogen-activated protein kinase (MAPK) activator, reversed the effects of CCN5 knockdown on BPA-induced endoplasmic reticulum (ER) stress and apoptosis. Taken together, CCN5 promotes apoptosis and ER stress in Sertoli cells exposed to BPA by activating the p38/JNK MAPK signaling pathway.
研究领域:
生殖生物学
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毒理学
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分子生物学
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Journal of Translational Medicine
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2025
·Vol. 23
·期 1
·1-19
·
IF 7.5
Han Ning,Yu Na,Yu Li
Background Diabetic retinopathy (DR) is the common cause of diabetic vascular complications and it causes blindness. Until now, there are still some patients with DR who lack effective treatment. Tripartite motif containing 44 (TRIM44) has been shown to play a significant role in endothelial cells. However, the role of TRIM44 in DR remains unknown. Methods Diabetes was induced in rats through the administration of an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ). Rat retinal microvascular endothelial cells (RMECs) were subjected to stimulation under high glucose (HG) conditions. A thorough proteomic investigation and bioinformatic analysis were performed to identify the differentially expressed proteins (DEPs) in rat RMECs after blocking TRIM44. A dual luciferase reporter assay was employed to assess the luciferase activity of TRIM44. Results TRIM44 was highly expressed in the retinal tissues of rats with diabetes and HG-induced RMECs. In vivo assays suggested that TRIM44 silencing improved the pathological alterations of DR rats as demonstrated by the downregulated expression of isolectin-B4 and VEGFA, along with a decrease in acellular capillaries within the retinal tissues. Knockdown of TRIM44 markedly reduced cell viability, proliferation, migration, invasion, and angiogenesis in HG-evoked RMECs. Mechanistically, TRIM44 was demonstrated to be activated transcriptionally by KLF transcription factor 9 (KLF9), a known facilitator of angiogenesis in DR. In HG-induced cells, the loss of TRIM44 resulted in the reverse of the endothelial cell function caused by KLF9 overexpression. After the comprehensive analysis, 64 upregulated and 38 downregulated DEPs were screened out for a series of functional enrichment analyses. Conclusions Collectively, this study demonstrates that TRIM44 knockdown suppressed diabetes-induced retinal vascular dysfunction in DR.
研究领域:
分子生物学
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糖尿病学
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眼科学
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Oncology Letters
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2025
·Vol. 29
·期 6
·1-14
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IF 2.2
Fangfei Li,Xuan Du,Mei Han,Xiaoying Feng,Chunmeng Jiang
Gastric adenocarcinoma (GAC) is a prevalent form of cancer that frequently displays abnormal metabolism characterized by increased aerobic glycolysis. Therefore, inhibition of glycolysis may exhibit therapeutic potential for the management of advanced or recurrent gastric cancer. Analysis of ethylmalonic encephalopathy protein 1 (ETHE1) expression levels in 30 pairs of cancerous and paracancerous tissues, and 50 tumor tissue sections collected from patients with GAC revealed that ETHE1 expression was upregulated in cancerous tissues compared with in paracancerous tissues. Advanced tumor stage, lymph node metastasis and Tumor‑Node‑Metastasis stage were associated with high ETHE1 expression. Knockdown of ETHE1 expression in GAC cells resulted in a significant inhibition of cell proliferation and in cell cycle arrest, accompanied by downregulated levels of cyclin D1 and cyclin‑dependent kinase 4. ETHE1 knockdown also resulted in increased apoptosis of GAC cells, and increased caspase‑3 and caspase‑9 activity. Additionally, the expression levels of proteins associated with aerobic glycolysis were downregulated following ETHE1 knockdown, which may reduce glucose consumption, lactic acid production and ATP levels. In the in vivo experiments, suppressed tumor growth and increased tumor cell apoptosis were observed in the xenograft tumor model in animals injected with ETHE1‑knockdown GAC cells. In summary, knockdown of ETHE1 inhibited aerobic glycolysis, promoted apoptosis and inhibited tumor cell proliferation in GAC cells. These results highlight ETHE1 as a promising molecular target for the treatment of GAC potentially using an adjuvant to target it, offering a novel approach in the exploration of targeted therapeutic drugs for GAC.
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Biology Direct
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2025
·Vol. 20
·期 1
·1-18
·
IF 4.9
Liang Ruopeng,Zhang Xiaoxue,Wu Shitao,Liu Jing,Zhai Yunpeng,Lin Chaojie,Wang Zhenya,Zhang Yi,Chen Hao,Zhu Rongtao
Background Patients diagnosed with gallbladder carcinoma (GBC) accompanied by hepatic metastasis exhibit unfavorable prognoses generally. Mitochondrial dysfunction promotes cellular transformation and cancer cell survival implicating its importance in cancer development. Previous studies have indicated that dynamin 1 like (DNM1L) is a key mediator of mitochondrial fission. However, whether DNM1L regulates mitochondrial homeostasis in GBC remains unknown. Methods The morphological changes of mitochondria were investigated by transmission electron microscopy and mitoTracker red staining. Co-immunoprecipitation assay was performed to detect the interaction of ubiquitin-specific protease-3 (USP3) and DNM1L. The cell-derived xenograft and liver metastasis tumor models were established to validate the function of DNM1L in vivo . The metabolomics data from transcriptomics/metabolomics were analyzed to identify the differentially expressed genes/metabolites of DNM1L in GBC. Results DNM1L exhibited a marked upregulation in clinical GBC tissues compared to the adjacent tissues, and it promoted proliferation, invasiveness, and migration capability of GBC cells by inducing mitochondrial dysfunction. Mice subcutaneously injected with DNM1L overexpression cells exhibited elevated intrahepatic metastatic nodules within their livers. USP3, a deubiquitinating enzyme, was demonstrated to directly interact with DNM1L and it specifically cleaved the K48-linked polyubiquitin chains to deubiquitinate and stabilize DNM1L. By integrating two omics, we found several altered pathways and speculated that DNM1L disturbed DNA synthesis and glycine, serine, threonine, and pyrimidine metabolism pathways. Conclusion Our findings suggest that DNM1L is a promising clinical target for GBC treatment and that focusing on DNM1L may provide new insights into GBC strategy.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Zimin Cai,Fangqin Fu,Sifeng Zhu,Jibin Wu,Xu Han,Shuai Jiang,Zhiyong Qian,Cheng Wang
The pharmacokinetic behavior of nanocarrier in vivo has been confirmed to be greatly influenced by the dynamic protein corona covered its surface, which also affects the ultimate clinical efficacy. Herein, we explored one novel polymersomes based on Poly(2-methyl-2-oxazoline) polymers (PMOXA 5 -PDBH 13 -PMOXA 5 ) with excellent drug-carrying capacity and specific protein corona manipulation. Compared to PEGylated nanoparticle (NP), the polymersomes (PC-SOM) provided a considerable advancement in therapeutic efficiency, which can selectively accumulate in tumor tissues, enhancing cellular internalization via specific proteins covering its surface such as fibronectin and moesin. Notably, in vivo antitumor effect showed that doxorubicin-loaded PC-SOM exhibited superior inhibitory rate 75.5% than 48.24% of PEGylated NP. Furthermore, through protein corona analysis we found that PC-SOM enhanced the adsorption of apolipoprotein A-I while suppressed the adsorption of complement C3 and immunoglobulin in serum from healthy volunteers and human breast cancer volunteers. These elaborated the reasons of longer circulation times and superior tumor-targeting capabilities of PC-SOM. Our work provided a promising nanoagent with novel surface-design by the dynamic protein corona for excellent pharmacokinetic behavior and antitumor effect.
研究领域:
生物医学工程
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药理学
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纳米医学
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FOLIA HISTOCHEMICA ET CYTOBIOLOGICA
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2025
·
IF 2.2
Jianuo Li,Yuhuai Guo,Xiangxin Zeng,Hongzhao Tian,Yapeng Han,Shuo Cai,Min Sun
Introduction. The aberrant activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway is involved in spinal cord injury (SCI) progression. Electroacupuncture (EA) stimulation is effective in alleviating SCI, but the mechanism is poorly understood. Material and methods. An SCI model was constructed by cord contusion at T10, and AG490 (a JAK2 inhibitor) served as a positive control in this study. We evaluated the effects of EA on locomotor activity and spinal damage in SCI rats. The effects of EA on astrocytes and microglia and on the JAK2/STAT3 signalling pathway in the cells were investigated. Results. Behavioural tests showed that hind limb motor function of rats was improved after EA stimulation. The therapeutic effects of EA stimulation in restoring motor function, alleviating injured spinal cords, and inhibiting spinal cord neuronal apoptosis in SCI rats, were similar to those of AG490. Increased STAT3 activation was observed in astrocytes and microglia in the spinal cord of SCI rats, and this was reversed by EA stimulation. EA alleviated astrogliosis and inhibited microglia M1 polarisation in SCI rat spinal cords. In addition, RNA expression levels of pro-inflammatory factors IL-6, CXCL1, and TNF-α in rat spinal cords were suppressed by EA stimulation, while the expression level of the anti-inflammatory factor heme oxygenase 1 was increased. Meanwhile, the expression of p-JAK2, p-STAT3, and JAK2/STAT3 downstream targets SOCS3 and COX-2 in the spinal cord of SCI rats was inhibited by EA stimulation. Interestingly, the observed effects were comparable to those treated with EA. Conclusions. Our findings demonstrate that EA stimulation ameliorates SCI in rats and exerts an inhibitory effect on the JAK2/STAT3 signalling pathway.
研究领域:
神经科学
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医学
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FASEB JOURNAL
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2025
·Vol. 39
·期 9
·e70561
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IF 4.2
Haocong Zhang,Xianyun Qin,Hong Yuan,Liangbi Xiang,Hailong Yu
Neuronal inflammation and apoptosis aggravate the secondary injury after spinal cord injury (SCI). Cathepsin L (CTSL) is a lysosomal cysteine protease with effects on the regulation of inflammation, but its role in SCI remains unclear. The in vivo T10 mouse spinal cord contusion model was established. The results showed that CTSL expression was increased following SCI and then gradually decreased. Moreover, CTSL was mainly expressed in microglia. To detect the function of CTSL, after contusive injury, the mice were immediately injected with lentiviruses carrying CTSL shRNA. The results showed that CTSL depletion promoted functional recovery, accompanied by increased locomotor ability. CTSL deficiency reduced lesion cavity areas by inhibiting neuronal apoptosis and neuroinflammation. Indeed, CTSL deficiency decreased the secretion of TNF-α, IL-6, and MCP-1 and M1 microglia polarization in the spinal cord. CTSL depletion inhibited the expression and assembly of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. In vitro, CTSL expression was increased in LPS-treated BV2 cells. CTSL silencing repressed LPS-induced M1 polarization, as evidenced by the reduction in TNF-α, IL-6, and MCP-1 expression in the supernatant of BV2 cells. CTSL knockdown induced the downregulation of NLRP3 expression and activation. The inhibition role of CTSL knockdown in microglial inflammation and M1 polarization was reversed by NLRP3 agonist. Collectively, the study suggests that CTSL induces the microglia M1 polarization-mediated inflammation via promoting NLRP3 activation and thereby inhibits functional recovery after SCI. Graphical The inhibition of CTSL improves functional recovery and alleviates neuroinflammation through microglial polarization after spinal cord injury. Mechanically, CTSL knockdown inhibited NLRP3 expression and activation, which repressed the production of pro-inflammatory cytokines in M1 microglia, thereby inhibiting spinal cord injury-induced neuroinflammation.
研究领域:
神经科学
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免疫学
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CLINICAL SCIENCE
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2025
·
IF 7.7
Renzi Zhang,Yuhua Zhong,Qiudie Liu,Mengqi Zhang,Daoxin Wang,Sheng Li,Di Qi
Acute respiratory distress syndrome (ARDS) is an acute and severe disease with a high mortality rate. The outbreak of immune inflammation in the lung is an important pathogenic mechanism of ARDS. Notably, an imbalance in macrophage polarization is an important link in the occurrence and development of this inflammatory response. Recently, neuropeptides have been shown to regulate inflammation, but the role of neuropeptides in ARDS remains unclear. The aim of this study was to investigate the regulatory effect of calcitonin gene-related peptide (CGRP) on the inflammatory response in ARDS. We found that CGRP expression was increased in the serum of ARDS patients and in both in vitro and in vivo models of ARDS. CGRP can regulate the polarization of macrophages by targeting its receptor (receptor activity-modifying protein 1); reduce the proportion of M1 macrophages; increase the proportion of M2 macrophages; and reduce pathological injury, inflammation, oxidative stress, and apoptosis in lung tissue in LPS-induced ARDS both in vitro and in vivo . Additionally, we performed transcriptome sequencing and found that hypoxia-inducible factor-1α (HIF-1α) is involved in the above process and that CGRP can alleviate ARDS-related pathological damage, inflammation, and oxidative stress by inhibiting the HIF-1α pathway to regulate macrophage polarization balance. These results indicate that CGRP has good potential for clinical translation in the treatment of pulmonary infection in ARDS. Furthermore, this study provides new ideas for the treatment of inflammatory bursts in ARDS.
研究领域:
免疫学
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分子生物学
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病理学
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高影响因子
COMPUTERS IN BIOLOGY AND MEDICINE
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2025
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IF 6.3
Zhe Wang,Hao-tian Zhang,Si-yue Li,Xiu-ping Song,Chong-zhen Shi,Ye-wen Zhang,Fei Han
Objective To explore the active components and mechanisms of Lingguizhugan decoction (LGZGD) in the treatment of Alzheimer's disease (AD) through an integrated approach. Methods The active components of LGZGD in rat serum were identified using HPLC-FTICR MS. Network pharmacology and molecular docking analyses were conducted, and their findings were validated using an Aβ 1-42 -induced AD rat model. Results Twenty-four active components and 324 common targets were identified and used to construct the networks. KEGG pathway enrichment analysis linked key target genes with MAPK, Rap1, and NF-κB signaling pathways. Molecular docking results indicated that three key targets (IL-6, TNF, and EGFR) and 10 core components are closely associated with LGZGD in the treatment of AD. LGZGD improved the spatial learning and memory abilities of AD rats. LGZGD reduced neuronal damage and increased the number of neurons in the cortex and hippocampal CA1 region of AD rats. LGZGD decreased Aβ 1-42 expression in the rat hippocampus, alleviated oxidative stress in AD rats, and decreased TNF-α, IL-6, IL-1β, and HMGB1 levels in the cerebral cortical tissue. LGZGD markedly decreased Iba-1 and iNOS expression and increased CD206 levels to inhibit M1 activation and promote M2 activation. LGZGD increased the expression of p-GSK-3β, ERK, and p-ERK, while decreasing the expression of p-Tau, IKKβ, p-IκBα, p-p65, p-p38, and p-JNK in the hippocampus of AD rats. Conclusion LGZGD treats AD by modulating targets like IL-6, TNF, MAPK3, and BCL2, thereby alleviating cognitive impairments in rats. Its neuroprotective effects in treating AD are mediated through the NF-κB/MAPK signaling pathways.
研究领域:
神经科学
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中药学
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分子生物学
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