Genes & Diseases
·
2025
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IF 9.4
Yan Fu,Xu Huang,Siyuan Wang,Qitong Guo,Yuhao Wu,Xiangqin Zheng,Junke Wang,Shengde Wu,Lianju Shen,Guanghui Wei
Chlorpyrifos (CPF), a widely used organophosphate pesticide, accumulates in the environment and affects human health. Its neurotoxicity has been extensively studied, and recent research has revealed that it can also lead to abnormal spermatogenesis. However, the factors and molecular mechanisms involved remain unclear. In this study, male Sprague-Dawley rats were gavaged with different concentrations of CPF for 30 days, resulting in a disrupted blood-testis barrier (BTB) and abnormal spermatogenesis. RNA sequencing analysis of Sertoli cells, the primary components of the BTB and key targets of environmental toxins, revealed that ferroptosis-related genes were predominantly among the differentially expressed genes. The expression of ferroptosis-related markers was up-regulated, malondialdehyde and Fe 2+ levels were elevated, and glutathione levels were reduced in CPF-exposed testicular tissue and its metabolite TCP-exposed Sertoli cells, confirming that CPF exposure triggered ferroptosis in testes and Sertoli cells. Moreover, treatment with ferrostatin-1, a ferroptosis inhibitor, restored Sertoli cell junctional function. Given the important roles of clockophagy and the HIF-1α pathway in ferroptosis, we investigated the activity of clockophagy in testes and Sertoli cells. Unexpectedly, clockophagy activity was found to be enhanced by the significantly reduced expression levels of ARNTL and HIF-1α following CPF and TCP exposure. Notably, Arntl knockdown impaired Sertoli cell junctional function. Collectively, these findings strongly indicate that CPF induces ferroptosis in Sertoli cells through activating clockophagy, resulting in the decreased expression of HIF-1α and BTB-associated proteins; this ultimately leads to the disruption of BTB integrity and spermatogenesis dysfunction.
研究领域:
毒理学
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生殖生物学
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分子生物学
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DOI
PubMed
高影响因子
RESEARCH IN VETERINARY SCIENCE
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2020
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IF 1.892
Jing Dong,Yuelei Chen,Wenhui Yang,Xi Zhang,Lin Li
Breast cancer is a high incidence disease in humans. Artemisinin is an important extract that is widely used as an antimalarial drug which also serve as effective treatments for cancer. 32 nude mice were injected with 0.2 ml of MDA-MB-231 cell suspension of 2 × 10 7 cells/ml respectively. The nude mice models were randomly divided into four groups of 8 in each group. Each group was given daily gavage, high dose group: 200 mg/kg/0.1 ml, middle dose group 100 mg/kg/0.1 ml, low dose group 50 mg/kg/0.1 ml, control group: 0.1 ml vegetable oil was fed continuously for 21 days. ELISA was used to detect serum vascular endothelial growth the content of factor VEGF and hypoxia-inducible factor HIF-1α were detected. The expression of Notch pathway-related factors in tumor tissue was detected by fluorescence quantitative assay. ELISA results showed that the serum VEGF decreased significantly in the high dose group compared with the control group ( p < .01), while the other dose groups did not have significant ( p > .05). The serum HIF-1α in the high dose group compared with the control group, the decrease in HIF-1α was significant ( p < .05), and the other groups were not significant ( p > .05). The result of fluorescence quantitative section showed that artemisinin could down-regulate the expression of notch signaling related factors notch1, Dll4 and Jagged1, and 200 mg/kg dose group had the most significant effect. It may inhibit the development of tumors by reducing serum angiogenesis-related factors VEGF, HIF-1ɑ and inhibiting the activity of notch1 signaling pathway related factors.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
DISEASE MARKERS
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2022
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IF 3.464
Zhiwen Wang,Changfeng Wang,Jieping Fu,Ruen Liu,Xinhui Zhou
Purpose. Cinnamaldehyde (CA) is the main ingredient in cinnamon, and it has been proven to have an inhibitory effect on many different tumor types. However, it lacks effect on glioma. This paper explores the effect CA has on glioma cells U87 and U251 at the cellular and molecular levels. Methods. The relationship between Hif-1α and Sept9 was found by CGGA. Cell Viability Assay (CCK8) was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. Annexin V-FITC/PI were used to detect the cell apoptosis. Western blotting was used to determine the specified protein level. Results. Cell proliferation assay results revealed CA to inhibit the proliferation of glioma cells in a dose-dependent manner. It promoted apoptosis for upregulating the expression of Bax and downregulating the expression of Bcl-2. Wound Healing Assay and transwell test found CA to have anti-invasion ability and that it upregulated the expression of E-cadherin and downregulated the expressions of MMP-2 and MMP-9. The molecular mechanism was studied from a tumor microenvironment (TME) perspective. Pi3k inhibitor (LY294002) was used for interfering with cells, and the results found CA to demonstrate a similar effect. Hif-1α and Sept9 expressions were inhibited, and Akt and p-Akt were also inhibited. By using CoCl2 to make hypoxia, CA was discovered to inhibit the high expression of Hif-1α and Sept9, demonstrating a correlation with the Pi3k/Akt pathway. It is suggested that the mechanism of Sept9 under hypoxia regulation can be realized through the Pi3k/Akt pathway. Conclusions. This study proves for the first time that CA is an effective drug for inhibiting the proliferation of glioma through Sept9 and reveals Sept9 to be related to the Pi3k/Akt pathway in terms of tumor microenvironment, providing a molecular basis for the further study of CA in glioma treatment.
研究领域:
肿瘤学
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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
BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Nan Yang,Xiang Li
Epigallocatechin gallate (EGCG) is an active catechin in green tea and has multiple biological functions, such as anti-inflammation, anti-cancer, and immune regulation. This work aimed to study the protective function of EGCG against asthma and the mechanism. Asthma in mice was induced by house dust mite (HDM) challenge. EGCG treatment alleviated tissue injury, inflammation, mucus production and collagen deposition, and it reduced M2 macrophage infiltration in mouse lung tissues induced by HDM. The bioinformatics analyses in this study suggested that target genes of EGCG were enriched in the hypoxia inducible factor-1 (HIF-1) pathway, EGCG treatment targeted HIF-1α and thereby suppressed vascular endothelial growth factor A (VEGFA) activation. Adenovirus (AAV) overexpression vectors of HIF-1α and VEGFA were administrated into mice after EGCG treatment. Either restoration of HIF-1α or VEGFA significantly blocked the protective functions of EGCG treatment against HDM-induced allergic asthma . In conclusion, this study demonstrates that EGCG treatment relieves asthmatic symptoms in mice by suppressing HIF-1α/VEGFA-mediated M2 skewing of macrophages.
研究领域:
免疫学
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药理学
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呼吸医学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Xin Guo,Bao-Nian Huang,Yu-Han Liu,Yan-Qiu Wang,Huan-Yu Che,Xue-Kun Liu
Ethnopharmacological relevance Crataegus pinnatifida Bunge, a plant used traditionally in herbal medicine for digestive health, is known for its gut-protective properties. Orientin, a natural flavonoid compound abundant in this species, exhibits anti-inflammatory and gut-protective activities. Aim of the study This study examined the therapeutic potential of orientin against ulcerative colitis (UC) and aimed to elucidate its underlying molecular mechanisms. Methods This study established a DSS-triggered UC mouse model. RNA sequencing was carried out to identify key signaling pathways implicated in orientin's therapeutic effects. Disease activity, intestinal barrier integrity, inflammatory responses, ferroptosis, were systematically evaluated. To validate the role of GLUT1 in the pathogenesis of UC, GLUT1-knockdown mice were utilized. Additionally, LPS-stimulated primary intestinal epithelial cells (IECs) were employed to further confirm the protective effects of orientin in vitro. Results RNA sequencing revealed that orientin significantly modulated genes associated with inflammation, ferroptosis, and metabolic pathways. Orientin alleviated DSS-triggered colitis by boosting body weight, preserving colon length, reducing histological damage. GLUT1 deficiency exacerbated intestinal injury, whereas orientin treatment attenuated these effects by regulating the ROS/HIF-1α/GLUT1 signaling axis. Orientin also repressed pro-inflammatory cytokines, neutrophil infiltration, and oxidative stress, while inhibiting the ferroptosis pathway. Moreover, it normalized glycolytic reprogramming by targeting the ROS/HIF-1α/GLUT1 pathway. In vitro studies further confirmed orientin's protective effects on IECs by enhancing barrier function, reducing inflammation, and restoring metabolic homeostasis. Conclusions This study underscores the pivotal role of the ROS/HIF-1α/GLUT1 axis and demonstrates the therapeutic potential of orientin in UC.
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PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2026
·
IF 12.2
Ning Yang,Yuan Qiao,Jing Wu,Chao Niu,Jianpeng Wang,Shiming Sun,Chunyan Liu,Jingtao Chen,Shan Zhu
SLMO2 is upregulated by chemotherapeutics and reduces GBM chemosensitivity. • SLMO2 mediates TMZ- and H 2 O 2 -induced mitophagy in GBM cells. • SLMO2 transcriptionally upregulates the mitophagy receptor BNIP3. • SLMO2 promotes BNIP3 via the ROS–NF-κB–HIF-1α signaling axis. Glioblastoma (GBM) is a highly aggressive malignancy, with chemoresistance acting as a major hurdle that severely limits clinical efficacy and long-term prognosis. Mitophagy, a core mechanism of mitochondrial quality control, enables tumor cells to adapt to chemotherapy-induced stress and maintain survival. However, its regulatory mechanism in GBM chemoresistance remains poorly understood. Here, we identify SLMO2 as a key factor mediating chemoresistance in GBM. Low-dose TMZ induces protective mitophagy, whereas SLMO2 knockdown abrogates this autophagic defense, thereby sensitizing GBM cells to TMZ-induced apoptosis. Mechanistically, TMZ treatment upregulates SLMO2, which potently activates HIF-1α signaling to transcriptionally drive BNIP3-mediated mitophagy, a process dependent on ROS-NF-κB signaling. Notably, this SLMO2-mediated cascade is also engaged under cisplatin-induced stress, indicating a broader role in chemoresistance. Collectively, our findings reveal that SLMO2 promotes chemoresistance in GBM by regulating BNIP3-mediated mitophagy. Targeting SLMO2 disrupts mitochondrial homeostasis by this process, offering a novel therapeutic strategy for enhancing chemosensitivity in GBM. Download: Download high-res image (228KB) Download: Download full-size image
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高影响因子
JOURNAL OF IMMUNOLOGY
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2026
·Vol. 215
·期 4
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IF 4
Xu Shujuan,Jiang Yixiang,Wang Shengtao,Chen Beili,Lin Wenyuan,Jiang Fang,Wu Xianyi,Tang Rongfang,Nie Yuwei,Chen Tongtong,Wang Xiaotao
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid neoplasms characterized by treatment difficulties and a propensity to progress to acute myeloid leukemia. Impaired natural killer (NK) cell surveillance is a hallmark of MDS, yet the underlying molecular mechanisms remain poorly understood. This study aims to elucidate the mechanism by which HIF-1α regulates NK cell differentiation disorders and its impact on NK cell cytotoxicity in MDS. Flow cytometry was employed to compare HIF-1α expression and NK cell differentiation between wild-type and NUP98/HOXD13 (NHD13) mice. Our results demonstrated a significant increase in HIF-1α expression in the bone marrow and peripheral blood of MDS mice, accompanied by a notable decrease in immature NK cell subsets and activating receptors (NKG2D, NKp44, and DNAM-1). Overexpression of HIF-1α in human NK cells or pharmacological stabilization with CoCl2 inhibits the differentiation into mature NK cells, suppresses the expression of degranulation molecules such as Granzyme B, and impairs NK cell cytotoxicity. Western blot analysis indicated that HIF-1α regulates NK cell differentiation and function via the JAK1/STAT5/SOCS2 signaling pathway. Collectively, these findings suggest that the hypoxic microenvironment in MDS enhances HIF-1α expression, which subsequently impairs NK cell maturation and inhibits their cytotoxicity. Targeting HIF-1α may delay MDS progression by enhancing NK cell function via the JAK1/STAT5/SOCS2 signaling pathway.
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 10.6
Jiawen Lu,Yangchun Shen,Xingtao Zhou,Yuting Wang,Hui Ye,Qiang Yu,Jianhua Xie,Yi Chen
Acrylamide (AA) and 5-hydroxymethylfurfural (HMF) are processing-derived contaminants that frequently co-occur in environmental and dietary exposure, yet the health effects of their co-exposure remain poorly understood. Here, we show that co-exposure to AA and HMF induces duodenal injury in mice, whereas neither toxin alone causes significant damage. Macrophage depletion using clodronate liposomes significantly attenuates this pathology, identifying macrophages as important mediators of the intestinal injury. Co-exposure promotes macrophage polarization toward a pro-inflammatory phenotype. Notably, direct exposure of intestinal epithelial cells to AA and HMF produces limited cytotoxicity. In contrast, conditioned medium from AA+HMF-treated macrophages compromises epithelial viability and barrier integrity in both intestinal epithelial cells and mouse intestinal organoids. These findings indicate that macrophage-mediated inflammatory responses, rather than direct epithelial toxicity, contribute substantially to AA+HMF-induced intestinal injury. Mechanistically, AA and HMF co-exposure triggers mitochondrial dysfunction and elevated mitochondrial reactive oxygen species (mtROS) production in macrophages, accompanied by enhanced glycolysis and hypoxia-inducible factor-1α (HIF-1α) activation. Pharmacological inhibition or genetic silencing of HIF-1α attenuates metabolic and inflammatory responses, while scavenging mtROS or iNOS inhibition reduces macrophage activation. Collectively, these findings reveal an immune-mediated mechanism underlying AA and HMF co-exposure-induced intestinal injury and highlight macrophage responses as a determinant of contaminant mixture toxicity.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Wenwei Li,Yang Liu,Ming Wei,Zhichao Yang,Hao Tang,Wei Huang
α-Solanine, a glycoalkaloid (GA) extracted from the stems of the potato plant, exhibits bioactivity and medicinal potential that necessitate further investigation. The impact and underlying mechanisms of α-Solanine on osteoarthritis (OA) remain to be elucidated. To achieve enhanced therapeutic outcomes, we have designed and synthesized a UIO-66-NH 2 @α-Solanine@PEI charged particle (USP) that amplifies the therapeutic effects of α-Solanine, demonstrating superior efficacy. Our approach involved the synthesis of a novel drug delivery system, the USP, to augment the therapeutic potential of α-Solanine in the treatment of OA. An OA rat model was established, and USP treatment was administered. The therapeutic effects were verified through histochemical staining and micro-CT. In vitro, α-Solanine significantly suppressed the expression of proteins related to glycolysis and notably inhibited ferroptosis. RNA sequencing revealed hypoxia-inducible factor-1α (HIF-1α) as a potential pathway mediating the effects of α-Solanine, and it was found that the co-addition of cycloheximide (CHX) led to a shortened decay time of HIF-1α. In vivo, rats with OA demonstrated significant inhibition of glycolysis and ferroptosis following treatment with USP, along with improvements in OA characteristics. These findings suggest that α-Solanine can inhibit the intense glycolysis associated with OA via the HIF-1α pathway and alleviate ferroptosis in chondrocytes. Treatment with USP demonstrated superior efficacy in the management of OA, providing a new therapeutic strategy for the disease.
研究领域:
医学
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药理学
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生物化学
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DOI
PubMed
高影响因子
MICROVASCULAR RESEARCH
·
2025
·
IF 2.7
Xiao Xu,Xiaohu Ge,Hongbo Ci,Maitiseyiti Abulaihaiti,JianPing Yang,YangYang Li,Feng Zhu
Background Thromboangiitis obliterans (TAO, Buerger's disease) is a chronic inflammatory disorder that affects small and medium-sized vessels in the limbs. Although the pathogenesis of TAO remains incompletely understood, elevated levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with cardiovascular diseases. This study investigates the mechanism by which PAI-1 activates the NF-κB/NLRP3 inflammatory pathway in vascular endothelial cells through hypoxia-inducible factor-1α (HIF-1α), contributing to the progression of TAO. Methods Proteomic analysis was performed on plasma samples from 5 TAO patients and 5 healthy controls to identify differentially expressed proteins (DEPs). In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to 1 % hypoxia to mimic TAO conditions. Interventions included PAI-1 knockdown using lentiviral vectors and treatment with the HIF-1α agonist dimethyloxalylglycine (DMOG). Cell viability was assessed using the CCK-8 assay, apoptosis was measured by flow cytometry, and inflammatory factor levels were detected by enzyme-linked immunosorbent assay (ELISA). Protein expression was analyzed by Western blotting. In vivo, a TAO rat model was established by sodium laurate injection. The severity of limb ischemia was evaluated using gross lesion grading and infrared thermography, while pathological changes were assessed by hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Results Elevated levels of PAI-1, HIF-1α, and key molecules in the NLRP3/NF-κB pathway were observed in both TAO rats and hypoxic HUVECs. PAI-1 knockdown significantly improved limb ischemia and suppressed the NLRP3/NF-κB pathway in TAO rats. Compared with the DMOG intervention group, combined treatment with PAI-1 knockdown and DMOG effectively alleviated ischemic symptoms, increased body weight, and reduced the expression of HIF-1α and inflammatory pathway molecules in TAO rats. Conclusion PAI-1 promotes the progression of TAO by activating the NF-κB pathway via HIF-1α. Targeted inhibition of PAI-1 represents a potential therapeutic strategy for TAO.
研究领域:
心血管医学
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分子生物学
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炎症研究
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血管生物学
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DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
·
2024
·
IF 2.3
Hu-Ri Piao,Xin-Yu Ma,Ming-Yue Li,Kai-Han Jin,Zhen-Yuan Han,Yuan-Liang Gao,Yu-Qing Zhao,Xue-jun Jin
The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for cancer. Here, three series of panaxadiol derivatives containing a thiazole moiety (5a-l, 7a-i, and 9a-i) were synthesized and evaluated for HIF-1α inhibitory activity using a Hep3B cell-based luciferase reporter assay. Compounds 5d and 7b showed the strongest inhibitory activity with IC50 values of 17.37 and 6.42 μM, respectively, and did not show any significant cytotoxicity. Western blot assay results indicated that these two compounds exhibited more potent inhibition, compared with panaxadiol, of the expression of HIF-1α protein in Hep3B cells at a concentration of 50 µM. Molecular docking experiments were also performed to investigate the structure–activity relationship.
研究领域:
药理学
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肿瘤学
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药物化学
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DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2026
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IF 6.5
Caiyu Lian,Mingcheng Sun,Yue Li,Lin Wang
Cadmium (Cd) exposure triggers ferroptosis in renal tubular cells. • TFRC upregulation drives Cd‑induced ferroptosis by promoting iron influx. • HIF‑1α directly binds the TFRC promoter to transactivate its expression. • mPTP‑mediated calcium efflux activates CaMKII/HIF‑1α/TFRC axis. Cadmium (Cd) is a ubiquitous environmental pollutant and well-established nephrotoxicant primarily targeting renal proximal tubular cells. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a key mechanism in Cd‑induced kidney injury. Despite the central role of mitochondria in ferroptosis, the precise organellar events linking Cd exposure to ferroptotic execution remain obscure. Using Sprague‑Dawley rats and renal proximal tubular cells, we found that Cd exposure instigated ferroptosis, evidenced by iron overload, altered ferroptosis markers, lipid peroxidation, and typical mitochondrial morphology under transmission electron microscopy. Pharmacological inhibition of ferroptosis significantly attenuated Cd‑induced cellular damage, identifying ferroptosis as a critical driver. Mechanistically, Cd triggered opening of the mitochondrial permeability transition pore (mPTP), leading to mitochondrial calcium efflux and activation of calcium/calmodulin‑dependent protein kinase II (CaMKII). Activated CaMKII in turn increased hypoxia-inducible factor-1α (HIF-1α) transcription and promoted its nuclear accumulation. Notably, upregulated HIF‑1α directly bound to the promoter of transferrin receptor (TFRC) to stimulate expression of this key iron transport mediator, as confirmed by chromatin immunoprecipitation assay. Moreover, genetic knockdown of TFRC markedly attenuated Cd‑triggered ferroptosis and consequent cytotoxicity, establishing TFRC as a critical executioner of Cd‑evoked renal injury. Taken together, these findings delineate a novel signaling axis from mPTP‑mediated calcium efflux to HIF‑1α‑dependent TFRC transactivation that drives ferroptosis in Cd‑induced nephrotoxicity, offering a mechanistic basis for understanding and mitigating the renal health risks posed by environmental Cd exposure. Download: Download high-res image (405KB) Download: Download full-size image
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高影响因子
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