Toxics
·
2025
·Vol. 13
·期 2
·129
·
IF 4.1
Liuxin Wang,Weiwei Cao,Ting Wu
Cadmium (Cd) is an important environmental pollutant that can enter the body and inflict kidney damage. Quercetin (Que) is a natural flavonoid compound that can alleviate kidney damage in Cd-treated rats, but the specific mechanism is unclear. Herein, 24 male Sprague–Dawley rats were divided into four groups, namely the control, Cd, Cd + Que, and Que groups. Four weeks later, the rats were anesthetized with ether and were euthanized; then, their blood was collected and their kidneys were removed. Renal function markers were measured. Kidney tissue structure was observed by HE staining, cell apoptosis was detected by the TUNEL method, and mRNA and protein expression levels in the IRE1α-XBP1 apoptosis signaling pathway were analyzed by RT-PCR and Western blotting. Results showed that the Cd treatment group exhibited decreased renal dysfunction and pathologic injury. Cd-induced tissue damage and cell apoptosis and significantly increased the mRNA and protein expression levels (p< 0.01) related to the IRE1α-XBP1 signaling pathway. Compared with the Cd group, the Cd + Que group exhibited increased renal dysfunction. Conversely, kidney tissue damage and renal cell apoptosis decreased, and the mRNA and protein expression levels of IRE1α and XBP1 significantly decreased (p< 0.01). Cd treatment inflicted renal damage. Therefore, Que can restore the kidney tissue damage and alleviate the cell apoptosis caused by Cd through the inhibition of the IRE1α-XBP1 signaling pathway.
研究领域:
环境毒理学
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药理学
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分子生物学
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PubMed
高影响因子
ENVIRONMENT INTERNATIONAL
·
2024
·
IF 10.3
Haining Du,Jiaxin Li,Xiangjuan Wei,Daqian Yang,Boya Zhang,Xingpei Fan,Meimei Zhao,Ruijiao Zhu,Ziyi Zhang,Yuxia Zhang,Xiaoyan Li,Ning Gu
Methylparaben (MP), a preservative widely used in daily supplies, exists in both the environment and the human body. However, the potential health risks posed by MP remain unclear. This study aimed to unravel the mechanisms by which MP disrupts glucose and lipid homeostasis. For this, we administered MP to mice and observed changes in glucose and lipid metabolism. MP exposure led to hyperglycemia, hyperlipidemia, visceral organ injury, and hepatic lipid accumulation. RNA sequencing results from mice livers indicated a close association between MP exposure and endoplasmic reticulum (ER) stress, inflammatory response, and glucose and lipid homeostasis. Western blotting and quantitative reverse transcription–polymerase chain reaction revealed that MP activated ER stress, particularly the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway, which further promoted the activation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways phosphorylated insulin receptor substrate-1 (IRS1) (ser 307), resulting in decreased phosphorylation of protein kinase B (Akt) (ser 473), leading to insulin resistance. Additionally, MP exposure promoted lipogenesis through ER stress. To explore potential remedies, we administered the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the IRE1α-XBP1 pathway inhibitor toyocamycin to mice, both of which protected against metabolic disorders and organ injury caused by MP. These findings suggest that MP induces disruptions in glucose and lipid metabolism through ER stress, primarily through the IRE1α-XBP1 pathway.
研究领域:
毒理学
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代谢
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内分泌学
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分子生物学
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DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2018
·
IF 1.173
Lei Liu,Lu Xu,Shaoqing Zhang,Dong Wang,Guoxia Dong,Hanwen Chen,Xinjian Li,Chi Shu,Rong Wang
Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damages in IR-induced ARF. Rats were administrated with STF-083010 and were subjected to induction of ARF using a ligation method. Then the effect of STF-083010 administration on the renal structure and function, oxidative stress, and inflammation in model rats was assessed. Furthermore, the levels of expression of UPR members and downstream effectors regulating apoptosis were detected as well. The results showed that establishment of the ARF model induced ER stress and impaired the renal structure and function. Administration of STF-083010 ameliorated impairments in the structure and function of the kidneys and the effect was associated with the suppressed oxidative stress and inflammation. At the molecular level, STF-083010 inhibited the prolonged UPR by downregulating the expressions of GRP78, p-IRE1, XBP1s, CHOP, and caspase 3, partially explaining the decreased apoptotic rate. The current study evaluated the potential of STF-083010 in treating ER stress-induced symptoms in ARF for the first time, and the findings demonstrated that STF-083010 resulted in effective treatment outcomes of ARF.
研究领域:
药理学
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肾病学
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分子生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Baoyuan Li,Fengying Cui,Jingyuan Suo,Xiangjun Chen,Jinrong Peng,Wei Hong,Wenting Li
Immunogenic cell death (ICD) plays a critical role in regulating the immunogenicity of cancer cells to activate the immune response, thus influencing the control of tumor growth. The continuous accumulation of ROS and activation of the endoplasmic reticulum stress (ERS) pathway are both vital for the amplification of ICD effects. Inhibition of the IRE1α-XBP1 signal is considered to facilitate the reduction of the adaptive response of the ER, which exacerbates ERS. Herein, a multifunctional nanoparticle (FE/IR780-NP) composed of XBP1 inhibitor-loaded mesoporous nanoparticles coated with photosensitizer-β-cyclodextrin complexes via GSH-responsive linkers was constructed and characterized. The results of in vitro cellular assays indicate that under intracellular conditions, after the shearing of GSH, the FE/IR780-NPs are divided into peptide-modified Toy-loaded mesoporous silica nanoparticles targeting the ER and IR780-β-cyclodextrin complexes targeting the mitochondrion. The combination of NIR irradiation and XBP1 inhibition significantly potentiates ER stress and amplifies the effects of ICD. Enhanced calreticulin (CRT) exposure, the main indicator of ICD effects, was almost double that of the groups without NIR irradiation (approximately 4 times higher than that of the single toy-treated groups). By establishing a 4T1 triple-negative breast cancer model in mice, the enhanced suppression of tumor growth by FE/IR780-NP-mediated photoimmunotherapy was also supported by in vivo results. FE/IR780-NPs can serve as promising candidates for the amplification of ICD effects to control the progression of aggressive cancers.
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2026
·
IF 4.8
Li Ma,Jing Wang,Jin Zhao,Jingrong Wang,Xiaolian Wen,Meijing Zheng,Liping Su
Background Current understanding of B cell heterogeneity in diffuse large B cell lymphoma (DLBCL) and its functional impact on disease progression remains incomplete. This study applies single-cell RNA sequencing to identify and characterize a distinct proliferation-related B cell subpopulation in DLBCL, aiming to address this knowledge gap. Methods We utilized dataset GSE182434 from the Gene Expression Omnibus (GEO) database for the analysis, with the aim of identifying genes that are specifically highly expressed in different cell clusters. The copy number variation analysis was performed using B cells of normal samples as the control. Thereafter, the cell–cell communication analysis was implemented to reveal the potential ligand–receptor pairs, and the functional enrichment analysis was performed to uncover the enriched pathways. Further, the potential transcription factors–target genes networks were plotted via SCENIC analysis, and a series of validation assays were implemented using DLBCL cells. Results The single-cell landscape of DLBCL revealed a reduced proportion of B cells, CD8 + T cells, and naïve T cells. Malignant B cells exhibited chr1q amplification and chr6 deletion, with genes in these regions linked to immune suppression and impaired antigen presentation, respectively. Further subclustering identified a proliferative B cell subcluster (subcluster 2) enriched in nucleotide metabolism and cell cycle pathways. This subcluster was characterized by elevated XBP1 activity, regulating ER stress response, and downregulation of SPIB, RELB, and IRF factors involved in lymphocyte activation and interferon signaling. Functionally, XBP1 silencing suppressed DLBCL cells proliferation and invasion. Cell communication analysis revealed crosstalk between this B cell subpopulation and CD8+ T/NK cells via MIF-(CD74+CXCR4) and LTA-TNFRSF pathways. Conclusion This analysis has identified and characterized the proliferation-related B cells in DLBCL, which may provide some ideas for the treatment strategies in immune-oncology and cellular therapies. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-025-03673-2.
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高影响因子
Nature Communications
·
2025
·
IF 15.7
Qianqian Ying,Yongchen Chen,Luochen Shen,Yang Xu,Ruilin Tian
RNA splicing is fundamental to cellular function, yet systematic investigation of its complex regulation has been limited by existing methods. Here, we present SPLiCR-seq ( SPL icing regulator i dentification through CR ISPR screening), a high-throughput CRISPR screening platform that enables direct measurement of RNA splicing outcomes for pooled genetic perturbations, overcoming limitations of traditional fluorescence-based approaches. Applying SPLiCR-seq to investigate XBP1 splicing during the unfolded protein response (UPR), we conduct targeted and genome-wide screens across diverse cellular contexts, revealing both common and cell-type specific regulators. Notably, we identify GADD34 ( PPP1R15A ) as a novel modulator of IRE1α-XBP1 signaling, demonstrating that it directly interacts with IRE1α and functions independently of its canonical role in eIF2α dephosphorylation. Pharmacological inhibition of GADD34 using Sephin1 effectively suppressed XBP1 splicing and alleviated CAR-T cell exhaustion in an ex vivo model, leading to enhanced tumor-killing capacity across multiple cancer models. This work not only establishes a powerful new tool for systematically studying RNA splicing regulation but also uncovers a promising therapeutic strategy for improving CAR-T cell immunotherapy through modulation of the IRE1α-XBP1 pathway. Systematic investigation of RNA splicing regulation remains challenging. Here, authors present SPLiCR-seq, a CRISPR platform enabling direct measurement of splicing outcomes for pooled perturbations. They identify GADD34 as a novel IRE1α-XBP1 regulator, with inhibition enhancing CAR-T cell activity.
研究领域:
分子生物学
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遗传学
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RNA生物学
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免疫治疗
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细胞信号转导
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CRISPR技术
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癌症研究
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Dake Huang,Ke Shen,Li Gui,Qiongqiong Cao,Fangmei Yu,Yunxia Lu
Given resveratrol's (RES) potential as an anti-aging agent, this study explored its ability to inhibit the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome through the miR-217/SIRT1 axis in senescent endothelial cells. Male C57BL/6 mice were administered a customized regular diet supplemented with 0.04 % RES for 64 consecutive weeks. Subsequently, the effects of RES on senescent human umbilical vein endothelial cells (HUVECs) induced by H 2 O 2 were evaluated. Gene expression analyses were conducted following SIRT1 knockdown in HUVECs treated with H 2 O 2 and RES, or transfected with miR-217 mimics and inhibitors. The study found that RES reduced body weight, improved endothelial function, enhanced SIRT1 expression, and suppressed the expression of miR-217, NADPH oxidase 4 (NOX4), and NLRP3 in the senescent thoracic aorta. Additionally, RES significantly reduced the expression of NOX4, X-box binding protein 1 spliced (XBP1s), and reactive oxygen species (ROS) production in a dose-dependent manner in senescent HUVECs. SIRT1 knockdown resulted in the activation of the NLRP3 inflammasome by upregulating NOX4 and XBP1s expression, an effect that was partially attenuated by RES pretreatment. RES also suppressed the expression of miR-217 induced by H 2 O 2 . The miR-217 mimic facilitated cellular senescence; however, RES mitigated this effect, which was further amplified by the miR-217 inhibitor.
研究领域:
分子生物学
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老年医学
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心血管病学
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细胞衰老
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信号转导
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氧化应激
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RNA干扰
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药理学
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DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-15
·
IF 3.8
Chen Linli,Guo Xiaojing,Lin Wen,Huang Yingying,Zhuang Suling,Li Qianfeng,Xu Jianhua,Ye Shengnan
Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.
研究领域:
肿瘤学
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病毒学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2021
·Vol. 46
·期 5
·1-14
·
IF 3.906
Zhiwei Wang,Mingxing Li,Yuanfeng Liu,Zhentao Qiao,Tao Bai,Ling Yang,Bo Liu
Dihydroartemisinin (DHA), an artemisinin derivate, has been investigated as a potential antitumor drug in primary liver cancer (PLC). Ferroptosis is a form of iron‑dependent cell death that can be driven by lipid peroxidation inducers. The present study aimed to determine whether and how DHA could promote the death of PLC cells by inducing ferroptosis. In total, four PLC cell lines with different p53 statuses, including Hep3B (p53 null), Huh7 (p53 mutant), PLC/PRF/5 (p53 mutant) and HepG2 (p53 wild‑type), were treated with various concentrations of DHA. The effects of DHA on all three branches of the unfolded protein response (UPR) were evaluated. To deactivate the UPRs, small interfering RNA was used to knockdown the expression of activating transcription factor (ATF)4, X‑box binding protein 1 (XBP1) or ATF6 in PLC cells. The effect of DHA on the promoter activity of Chac glutathione specific γ‑glutamylcyclotransferase 1 (CHAC1) was evaluated using a dual luciferase reporter assay. The results revealed that DHA‑induced death in PLC cells was irrelevant of the p53 status. PLC cells exposed to DHA displayed classic features of ferroptosis, such as increased lipid reactive oxygen species and malondialdehyde levels, an iron overload, and decreased activity or expression of glutathione (GSH), glutathione peroxidase 4, solute carrier family (SLC) 7 member 11 and SLC family 3 member 2. The antitumor effects of DHA in PLC cells were significantly weakened by two typical ferroptosis inhibitors, ferrostatin‑1 and deferoxamine mesylate salt, whereas the antitumor effects were augmented following iron overload. Furthermore, DHA activated all three branches of the UPR (eukaryotic translation initiation factor 2 α kinase 3/eukaryotic translation initiation factor 2A/ATF4, inositol‑requiring transmembrane kinase/endoribonuclease 1α/XBP1 and ATF6 branches) in vitro. Notably, DHA‑induced ferroptosis was significantly attenuated following the knockdown of ATF4, XBP1 or ATF6 expression. In addition, the promoter activity of CHAC1, a gene capable of degrading GSH, was enhanced by DHA, but weakened when the aforementioned three UPR transcription factors were knocked down. In conclusion, the findings of the present study suggested that DHA may effectively induce ferroptosis in PLC cells through the activation of anti‑survival UPRs and the upregulation of CHAC1 expression.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Food & Function
·
2023
·Vol. 14
·期 4
·2200-2211
·
IF 6.1
Dongbao Cai,Xusheng Li,Qingjie Xu,Haiwei Li,Ruijing Liu,Jiali Chen,Xinwei Jiang,Jianxia Sun,Caiyong Lai,Weibin Bai
Testicular hyperthermia induced by unhealthy living habits and pathological or occupational factors can cause spermatogenic dysfunction with an outcome of sub-fertility or even infertility. Cyanidin-3-O-glucoside (C3G) is the most typical anthocyanin in foods that has been recognized as an antioxidant with promising protection for male reproduction. However, its specific effect against testicular hyperthermia and the mechanisms involving its primary gastrointestinal metabolite protocatechuic acid (PCA) are still unexplored. In the present study, testicular hyperthermia in mice was established by employing a single hot water bath at 43 °C for 30 min. C3G and PCA were intragastrically given to investigate their prevention ability against heat stress-induced testicular damage. It was found that C3G and PCA restored the external diameter and thickness, and alleviated atrophy and vacuolation of seminiferous tubules. Simultaneously, C3G and PCA enhanced testicular heat stress tolerance through reducing superfluous eIF2α phosphorylation and stress granule formation. C3G and PCA effectively improved the testicular antioxidant system and regulated the IRE1α-XBP1 pathway, contributing to mitigatory spermatogenesis dysfunction and testicular damage. This finding revealed that anthocyanins were the novel compounds for alleviating testicular damage, and provided a reliable theoretical basis for improving male fertility disturbed by heat stress.
研究领域:
生殖生物学
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药理学
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分子生物学
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PubMed
高影响因子
Italian Journal of Animal Science
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2021
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IF 2.217
Yi Ma,Mawda Elmhadi,Chao Wang,Hao Zhang,Hongrong Wang
Several studies have demonstrated that high-concentrate (HC) diet with thiamine supplementation can alleviate rumen epithelium inflammation and protecting the barrier function in goats. This study aimed to investigate the effects of dietary supply of thiamine on mitophagy and endoplasmic reticulum stress (ERS) during high-concentrate diet feeding. Twenty-four Boer goats (35.62 ± 2.4 kg) were used in this study, goats were subsequently assigned to 3 treatment groups (8 goats in each group) as follows: a low-concentrate diet (CON; concentrate: forage 30:70), a high-concentrate diet (HC; concentrate: forage 70:30) and high-concentrate diet with 200 mg thiamine/kg DMI (HCT; concentrate: forage 70:30) for 12 weeks. Compared with the HC group, the goats of HCT group had a markedly higher final weight, net weight gain, and average daily gain (ADG). The blood physiological and biochemical results showed that the HCT group expressed a lower the content of lymphocytes and leukocytes but a higher total protein and monocytes compared with that of HC group. The rumen epithelial mitochondrial membrane potential change (ΔΨm), relative mitochondrial DNA (mtDNA) content, adenosine triphosphate (ATP) level, together with the activities of the respiratory complexes I, III, and IV were markedly higher in the HCT group relative to HC ones. Relative to the HC group, the unc-51 like autophagy activating kinase 1 (ULK1), microtubule-associated protein 1 light chain 3 (LC3), autophagy-related 5 (ATG5), autophagy related 7 (ATG7), Beclin1, PTEN induced putative kinase 1 (PINK1), PERK (PKR-Endoplasmic Reticulum Kinase), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), X-box binding protein 1 (XBP1), heat shock 70 kDa protein 5 (HSPA5), DNA damage-inducible transcript 3 (DDIT3) and DNA damage-inducible transcript 4 (DDIT4) mRNA levels were decreased, but the breast cancer 1 (BRCA1), ataxia telangiectasia mutated (ATM), heat shock factor binding protein 1 (HSBP1) were increased in rumen epithelium of the HCT group. The results of transmission electron micrographs showed that the cell structure of the HCT group was higher integrity than that in the HC group, and the damage degree of mitochondria as well as endoplasmic reticulum being lower than the HC group. These results demonstrated that dietary thiamine could enhance rumen epithelial integrity by suppressing the responses of ERS and mitophagy during long-term HC diet feeding.HIGHLIGHTSThis study is the first to demonstrate that the reduction of inflammatory response is related to the down-regulation of autophagy and endoplasmic reticulum stress in goats.Thiamine has good anti-inflammatory and anti-oxidation properties, which can be applied in intensive industry to reduce the negative effects caused by long-term high-concentrate diet.
研究领域:
动物营养
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分子生物学
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兽医学
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营养基因组学
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Chunxia Shi,Maohua Pei,Yao Wang,Qian Chen,Pan Cao,Luyi Zhang,Jin Guo,Wei Deng,Luwen Wang,Xun Li,Zuojiong Gong
Evidence shows that trimethylamine (TMA)/trimethylamine-N-oxide (TMAO) is closely related to non-alcoholic fatty liver disease (NAFLD). The conversion of TMA to TMAO is mainly catalyzed by flavin-containing monooxygenases 3 (FMO3) and FMO1. In this study, we explored the role of TMA in the process of NAFLD. The human NAFLD liver puncture data set GSE89632 and rat TMAO gene chip GSE135856 was downloaded for gene differential expression analysis. Besides, oleic acid (OA) combined with palmitate were used to establish high-fat cell model. TMA, TMAO and FMO1-siRNA were used to stimulate L02 cells. Contents of free fatty acid (FFA), triglyceride (TG), TMAO, FMO1 and unfolded protein response (UPR) related proteins GRP78, XBP1 , Derlin-1 were detected. Our results showed that FMO1 and PEG10 were important in the progression of NAFLD. Immunohistochemistry showed that FMO1 in NAFLD liver was increased. In addition, the contents of FFA, TG, FMO1 expression, and TMAO were significantly increased after OA + palmitate and TMA stimulation. However, after silencing FMO1 with siRNA, the expressions of these molecules were decreased. Besides, the protein levels of GRP78, XBP1, Derlin-1 were increased after TMAO treatment (all P < 0.05). In Conclusion, high fat and TMA could induce the expression of FMO1 and its metabolite TMAO. When FMO1 is silenced, the effects of high fat and TMA on TMAO are blocked. And the role of TMAO in NAFLD may be through the activation of UPR.
研究领域:
肝病学
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分子生物学
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代谢组学
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胃肠病学
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DOI
PubMed
高影响因子
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