CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
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2026
·Vol. 53
·期 9
·e70153
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IF 2.5
Renchuang Cao,Qingying Meng,Gengyuan Li,Shumei Yuan,Chunmei Li,Xin Zhao,Dongmei Zhang
Heat shock factor 2 (HSF2) and hypoxia‐inducible factor 1α are activated by angiotensin II (ANGII) in cardiomyocytes. The endoplasmic reticulum (ER) stress plays a critical role in cardiac hypertrophy. Moreover, HIF‐1α is known to be regulated by HSF2 in tumour cells. In this study, we hypothesised and clarified whether HSF2 trans‐activated HIF‐1α through initiation of ER stress in hypertrophic cardiomyocytes. Myocardial hypertrophy was induced by the treatment of ANGII. Expression of the gene or protein was assessed by applying RT‐PCR, WB, ICC and IHC. Luciferase and CHIP were applied to detect the transcription of HIF‐1α by HSF2. Both in vitro and in vivo, the expression of HIF‐1α, ER stress markers and HSF2 was increased in ANGII‐treated hypertrophic cardiomyocytes. Blocking ER stress suppressed the expression of HSF2 and HIF‐1α in ANGII‐treated cardiomyocytes. Silencing HSF2 inhibited HIF‐1α, thereby reducing hypertrophy but had no effect on ER stress. Similarly, silencing HIF‐1α reduced hypertrophy without affecting ER stress or HSF2 expression. HSF2 transcriptionally activated HIF‐1α. We concluded that ER stress induced by ANGII activates HSF2, which then trans‐activates HIF‐1α, promoting cardiac hypertrophy.
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Chinese Medicine
·
2026
·Vol. 21
·期 1
·146
·
IF 7.4
Yang Junfa,Shu Min,Fang Hui,Yang Fan,Li Jiahe,Sun Yuansong,Li He,Xu Tao
Background Liver fibrosis is a representative scarring response that can ultimately lead to liver cancer. However, relevant antifibrotic drugs for the effective treatment of liver fibrosis in humans have not yet been identified. 6-Shogaol is derived from natural products and exhibits multiple biological activities, including anti-inflammatory and antioxidant properties; however, its efficacy and potential mechanism of action against liver fibrosis remains unclear. This study aimed to examine the anti-fibrotic properties and potential mechanisms of action of 6-Shogaol. Methods Two liver fibrosis mouse models (carbon tetrachloride (CCl 4 ) and bile duct ligation (BDL)) were constructed to evaluate the anti-fibrotic properties of 6-Shogaol in vivo . Transforming growth factor-β1 (TGF-β1)-induced human hepatic stellate cells (HSCs) LX-2 cells were used as in vitro models. Network pharmacology analysis was introduced to explore the key targets of 6-Shogaol regarding the mechanisms on liver fibrosis. Molecular docking, molecular dynamics simulations, drug affinity reactivity target stability (DARTS) and isothermal titration calorimetry (ITC) were used to detect the affinity and binding between 6-Shogaol and its target. Additionally, we invested the mechanism of 6-Shogaol through RNA sequencing combined with Western blotting, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), immunofluorescence co-localization, histopathology, immunohistochemical staining and RT-qPCR. Results The results showed that 6-Shogaol remarkably alleviated CCl 4 - and BDL-induced liver fibrosis in mice, including observations of improved liver function, decreased activity of HSCs, and decreased extracellular matrix (ECM) deposition. In an in vitro model, 6-Shogaol suppressed TGF-β1-induced LX-2 activation. Mechanistically, RNA sequence analysis revealed that the effect of 6-Shogaol on liver fibrosis is linked to glycolytic reprogramming. 6-Shogaol suppressed HSCs glycolysis by decreasing glycolytic enzymes (HK2, PKM2, and GLUT1) and glycolytic metabolite levels (lactic acid and pyruvic acid). Furthermore, network pharmacology suggested HIF-1α as a potential 6-Shogaol target. Molecular docking, molecular dynamics simulations, DARTS, and ITC confirmed that 6-Shogaol could directly bind to HIF-1α. Interestingly, we demonstrated that HIF-1α knockout significantly inhibited HSCs glycolysis and activation, whereas the overexpression of HIF-1α increased HSCs glycolysis and activation. Moreover, specific knockout of HIF-1α did not enhance the suppressive effect of 6-Shogaol on HSCs activation or fibrosis-associated protein expression in vivo . Conclusion These findings showed that 6-Shogaol ameliorated liver fibrosis by modulating the expression of HIF-1α associated with glycolysis reprogramming and validate 6-Shogaol as a promising therapeutic strategy for liver fibrosis. Graphical
The alternative text for this image may have been generated using AI.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·Vol. 24
·期 1
·391
·
IF 15
Chen Ying,Peng De-Wei,Jiang Sheng-Rui,Shao Qian-Chun,Zhang Yi-Cong,Chi Zai-Long
Objective Retinal neovascularization is a leading cause of irreversible blindness worldwide. Chinese herbal medicines have unique therapeutic properties, such as antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to investigate the therapeutic effects and underlying mechanisms of the Chinese medicinal herb Curcuma longa -derived extracellular vesicle-like particles (CL-EVLPs) in a mouse model of retinal neovascularization. Methods CL-EVLPs were extracted from fresh Curcuma longa rhizomes through differential centrifugation and sucrose density gradient centrifugation and characterized by transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA), and western blot analysis of EVLP-associated protein markers. CL-EVLPs were administered to oxygen-induced retinopathy (OIR) model mice via intravitreal injection. The therapeutic effects were evaluated using retinal flat mounts, fundus fluorescein angiography (FFA), and reactive oxygen species (ROS) staining. The underlying molecular mechanisms were explored through metabolomics, transcriptomics, and network pharmacology analyses, and the expression levels of relevant factors were quantified using real-time polymerase chain reaction (PCR) or western blotting. In vitro experiments were conducted using human retinal microvascular endothelial cells (hRMECs) and BV2 microglia. Results CL-EVLPs exhibited typical EV-like characteristics, including a saucer‑ or cup‑shaped morphology, a mean diameter of 140.7 nm, and enrichment of the EV‑related protein ARF1. CL-EVLPs effectively inhibited neovascularization in the OIR model, as evidenced by reduced pathological neovascular tufts and avascular zones and decreased vascular permeability and tortuosity. Furthermore, CL-EVLPs significantly decreased ROS production in the retinas of OIR mice. Mechanistically, CL-EVLPs inhibited HIF-1α/VEGF/ERK signaling and activated the NRF2/HO-1 antioxidant pathway. In vitro experiments confirmed that CL-EVLPs inhibited endothelial cell viability and alleviated oxidative stress in microglia. Integrated network pharmacology and metabolomics analyses proved that the cargo molecules of CL-EVLPs, such as curcumin and its derivatives, auraptene, and triptophenolide, exhibit regulatory antioxidant and anti-inflammatory effects and modulate multiple signaling pathways associated with retinal neovascular diseases. Conclusion CL-EVLPs effectively suppress retinal neovascularization by inhibiting the HIF-1α/VEGFA/ERK axis and activating the NRF2/HO-1 pathway. This study suggests that CL-EVLPs, as a multitarget therapeutic strategy, hold promising clinical translational potential for the treatment of retinal neovascular diseases. Graphical abstract The alternative text for this image may have been generated using AI.
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Stem Cell Research & Therapy
·
2020
·Vol. 11
·期 1
·1-13
·
IF 5.116
Chai Miaomiao,Gu Ce,Shen Qihua,Liu Jiaxing,Zhou Yi,Jin Ziyang,Xiong Wanli,Zhou Yan,Tan Wensong
Background and aim Inadequate vascularization is a challenge in bone tissue engineering because internal cells are prone to necrosis due to a lack of nutrient supply. Rat bone marrow-derived mesenchymal stem cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs) were cocultured to construct prevascularized bone tissue in osteogenic induction medium (OIM) in vitro. The angiogenic capacity of HUVECs was limited in the coculture system. In this study, the effects of the components in the medium on HUVEC angiogenesis were analyzed. Methods The coculture system was established in OIM. Alizarin red staining and alkaline phosphatase staining were used to assess the osteogenic ability of MSCs. A Matrigel tube assay was used to assess the angiogenic ability of HUVECs in vitro. The proliferation of HUVECs was evaluated by cell counting and CCK-8 assays, and migration was evaluated by the streaked plate assay. The expression levels of angiogenesis-associated genes and proteins in HUVECs were measured by qRT-PCR and Western blotting, respectively. Results Dexamethasone in the OIM suppressed the proliferation and migration of HUVECs, inhibiting the formation of capillary-like structures. Our research showed that dexamethasone stimulated HUVECs to secrete tissue inhibitor of metalloproteinase (TIMP-3), which competed with vascular endothelial growth factor (VEGF-A) to bind to vascular endothelial growth factor receptor 2 (VEGFR2, KDR). This effect was related to inhibiting the phosphorylation of ERK and AKT, which are two downstream targets of KDR. However, under hypoxia, the enhanced expression of hypoxia-inducible factor-1α (HIF-1α) decreased the expression of TIMP-3 and promoted the phosphorylation of KDR, improving HUVEC angiogenesis in the coculture system. Conclusion Coculture of hypoxia-preconditioned HUVECs and MSCs showed robust angiogenesis and osteogenesis in OIM, which has important implications for prevascularization in bone tissue engineering in the future.
研究领域:
组织工程
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细胞生物学
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分子生物学
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生物医学工程
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2021
·
IF 6.514
Fan-Fan Shang,Jing Ying Wang,Qian Xu,Hao Deng,Hong-Yan Guo,Xuejun Jin,Xiaoting Li,Qing-Kun Shen,Zhe-Shan Quan
Four series of hypoxia-inducible factor-1 alpha (HIF-1α) functioning derivatives stemming from modifications to the C-29 carboxyl group of celastrol were designed and synthesized, and their anticancer activities were evaluated. To address the structure and activity relationship of each derivative, extensive structural changes were made. HRE luciferase reporter assay demonstrated that 12 modified compounds showed superior HIF-1α inhibitory activity. Among them, compound C6 exhibited the best features: firstly, the strongest HIF-1α inhibitory activity (IC 50 = 0.05 μM, 5-fold higher than that of celastrol); secondly, lower cytotoxicity (22-fold lower, C6-16.85 μM vs celastrol-0.76 μM). Thus, the safety factor of C6 was about 112 times higher than that of celastrol. Western blot assay indicated that C6 may inhibit the expression of HIF-1α protein in cells. Additionally, C6 hindered tumor cell cloning , migration and induced cell apoptosis . It is worth mentioning that in the mouse tumor xenograft model, C6 (10 mg/kg) displayed good antitumor activity in vivo , showing a better inhibition rate (74.03%) than the reference compound 5-fluorouracil (inhibition rate, 59.58%). However, the celastrol treatment group experienced collective death after four doses of the drug. Moreover, C6 minimally affected the mouse weight, indicating that its application in vivo has little toxic effect. H&E staining experiments show that it could also exacerbate the degree of tumor cell damage. The results of water solubility experiment show that the solubility of C6 is increased by 1.36 times than that of celastrol. In conclusion, C6 is a promising antitumor agent through HIF-1α pathway.
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International Journal of Ophthalmology
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2019
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IF 1.189
Li-Fei Wang,Zhong-Yang Yan,Ya-Lin Li,Yan-Hui Wang,Sheng-Juan Zhang,Xin Jia,Lu Lu,Yan-Xia Shang,Xin Wang,Yun-Huan Li,Shan-Yu Li
AIM To explore the effect of Obtusifolin on retinal pigment epithelial cell growth under hypoxia. METHODS In vitro chemical hypoxia model of ARPE-19 cells was established using cobalt chloride (CoCl 2 ). Cell viability was tested by cell counting kit-8 (CCK-8) assay. Western blot and real-time quantitative polymerase chain reaction were applied to detect proteins and mRNAs respectively. Flow cytometry was used to examine the cell cycle. Secretion of vascular endothelial growth factor (VEGF) was tested by using enzyme linked immunosorbent assay (ELISA). RESULTS Under the chemical hypoxia model established by CoCl 2 , hypoxia inducible factor-1α (HIF-1α) mRNA and protein levels was up-regulated. Cell viability was increased and the proportion of S phase was higher. Obtusifolin could reduce cell viability under hypoxic conditions and arrest cells in G1 phase. Obtusifolin reduced the expression of Cyclin D1 and proliferating cell nuclear antigen (PCNA) in the hypoxic environment and increased the expression of p53 and p21. The levels of VEGF, VEGFR2 and eNOS proteins and mRNA were significantly increased under hypoxia while Obtusifolin inhibited the increasing. CONCLUSION Obtusifolin can inhibit cell growth under hypoxic conditions and down-regulate HIF-1/VEGF/eNOS secretions in ARPE-19 cells.
研究领域:
眼科学
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细胞生物学
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分子生物学
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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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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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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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PHARMACOLOGICAL RESEARCH
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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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INTERNATIONAL IMMUNOPHARMACOLOGY
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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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MICROVASCULAR RESEARCH
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2025
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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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