MECHANISMS OF AGEING AND DEVELOPMENT
·
2024
·
IF 5.3
Zhen-Zhen Yu,Jia-Jun Tu,Mei-Ling Ou,Jin-Xiong Cen,Kun Xue,Shao-Jun Li,Jing Zhou,Guo-Dong Lu
Aging, a complex biological process influenced by genetic, environmental, and pharmacological factors, presents a significant challenge in understanding its underlying mechanisms. In this study, we explored the divergent impacts of metformin treatment on the lifespan and healthspan of young and old C. elegans , demonstrating a intriguing “elixir in youth, poison in elder” phenomenon. By scrutinizing the gene expression changes in response to metformin in young (day 1 of adulthood) and old (days 8) groups, we identified nhr-57 and C46G7.1 as potential modulators of age-specific responses. Notably, nhr-57 and C46G7.1 exhibit contrasting regulation patterns, being up-regulated in young worms but down-regulated in old counterparts following metformin treatment. Functional studies employing knockdown approaches targeting nhr-57 , a gene under the control of hif-1 with a documented protective function against pore-forming toxins in C. elegans , and C46G7.1 , unveiled their critical roles in modulating lifespan and healthspan, as well as in mediating the biphasic effects of metformin. Furthermore, deletion of hif-1 retarded the influence of metformin, implicating the involvement of hif-1 / nhr-57 in age-specific drug responses. These findings underscored the necessity of deciphering the mechanisms governing age-related susceptibility to pharmacological agents to tailor interventions for promoting successful aging.
研究领域:
药理学
·
老年学
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分子生物学
·
遗传学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Yutong Kang,Abudureyimu Alimujiang,Fan Zhou,Liangmian Chen,Hongzhi Wang,Wenjing Wei,Jingcheng Zhao,Ziqi Zhu,Wancheng Sun,Xuejiao Xie,Shixia Huo,Dengqiu Xu,Zhijian Li
Objective Psoriasis is a chronic, immune-mediated dermatological disorder characterized by pathological epidermal hyperplasia, aberrant keratinocyte differentiation, and dermal infiltration of inflammatory cells. Sihe Tufuling (SHTFL), a clinically established traditional Chinese medicine formula, has demonstrated therapeutic efficacy in psoriasis management. This study aimed to investigate the anti-psoriatic activity of SHTFL and its principal herb, Smilax glabra Roxb. (SGR), and to elucidate their underlying mechanisms of action. Methods Ultra-performance liquid chromatography-mass spectrometry was used to identify the major chemical constituents of SHTFL and SGR. An imiquimod (IMQ)-induced psoriasis-like mouse model was employed to assess therapeutic efficacy using the psoriasis area and severity index, spleen index, hematoxylin and eosin staining, immunohistochemistry, immunofluorescence. Transcriptomic sequencing, single-cell RNA sequencing, gene knockdown, immunofluorescence, and quantitative reverse-transcription PCR analyses were performed to investigate the molecular mechanisms involved. Results The results of the chemical component identification indicated that flavonoids constitute essential components in both the SHTFL formula and SGR. Treatment with SHTFL and SGR resulted in a significant reduction of the PASI score, skin thickness, splenic index and serum levels of inflammatory cytokines in IMQ-induced mice psoriasis mice. Moreover, both SHTFL and SGR alleviated psoriasis by inhibiting keratinocyte hyperproliferation and the inflammatory response in IMQ-induced mice. Transcriptomic analysis revealed that SHTFL and SGR mitigates keratinocyte hyperproliferation and the inflammatory response by modulating the HIF-1 signaling pathway. Furthermore, HIF-1α knockdown abolished the protective effects of SHTFL in these models. Conclusion Our results indicate that both SHTFL and SGR hinder the excessive growth of keratinocytes and reduce inflammation in psoriasis by inhibiting the HIF-1 signaling pathway. This evidence backs SHTFL as a promising therapeutic approach for psoriasis.
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高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2026
·
IF 4.3
Liu Bai Han,Zhang Jin Ge,Peng Dong Qiao,Jin Yong Cheng
Copper is an essential trace element for beef cattle, yet its muscle developmental regulatory mechanism remains unclear. This study investigated the effects of copper sulfate (CuSO₄) on myogenic differentiation of bovine skeletal muscle-derived cells (BSMC) and the underlying molecular mechanisms. BSMC were isolated from the longissimus thoracis muscle of three 30-month-old crossbred steers, with each steer defined as an independent experimental unit corresponding to a separate biological replicate ( n = 3). Based on cell viability, CuSO₄ was used at 0, 0.1, 1, and 10 µM. All cell samples were harvested at differentiation day 6 (D6). The 0.1 µM CuSO₄ treatment during cell growth significantly promoted D6 myotube formation ( P = 0.049), and upregulated mRNA and protein expression of myogenic differentiation 1 (MyoD) ( P = 0.044, P = 0.030), as well as protein expression of hypoxia-inducible factor-1α (HIF-1α) ( P = 0.037) and β-catenin ( P = 0.050). During differentiation, 1 µM CuSO₄ significantly facilitated D6 myotube formation ( P = 0.0004), increased myogenic factor 5(Myf5) mRNA and protein expression ( P = 0.030, P = 0.006), and elevated HIF-1α ( P = 0.025) and β-catenin ( P = 0.004) protein levels, whereas Wnt10b protein expression remained unaltered ( P = 0.930). Single or combined pharmacological inhibition of HIF-1α and β-catenin markedly reversed copper’s pro-myogenic effect on BSMC. In conclusion, copper modulates BSMC myogenic differentiation via the HIF-1α/β-catenin axis by enhancing β-catenin protein stability independent of Wnt10b transcription. HIF-1α acts upstream to drive β-catenin, and a reciprocal regulatory relationship may exist in which β-catenin in turn helps sustain HIF-1α abundance, thereby supporting cascade signaling and downstream myogenic transcription. This study elucidates copper’s molecular mechanism governing muscle development and provides theoretical support for precise copper supplementation to improve beef production performance.
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DOI
高影响因子
Biomedical Materials
·
2026
·Vol. 21
·期 3
·035012
·
IF 3.9
Xuefei Xiang,Yufang Yang,Heyou Gao,ZhiYun Chen,JingYi Xie,QingChuan Hu,Yu Wang
Composite scaffolds composed of porous polyurethane (PU) block copolymer and nano-hydroxyapatite (n-HA) have demonstrated significant potential in bone defect repair. However, the co-effect of osteogenesis and angiogenesis during the process of large bone defect repair is still not yet fully understood. Recent research has found that erythropoietin (EPO) is essential for both osteogenesis and angiogenesis, offering a new research direction for bone regeneration strategies. In this study, a polydopamine (pDA)-modified, EPO-functionalized HA/PU scaffold was fabricated, and its physicochemical properties, release kinetics, and effects on bone repair were systematically investigated. In vitro, a co-culture system of human umbilical vein endothelial cells and rat bone marrow mesenchymal stem cells was used to evaluate the scaffold’s effects on cell proliferation, osteogenic, angiogenic, and HIF-1α/ vascular endothelial growth factor (VEGF) pathway. In vivo, the modified composite scaffold was implanted onto the cranial bone defects of Sprague-Dawley rats to assess its efficacy in promoting bone repair and HIF-1α/VEGF pathway. In vitro, the EPO/pDA/HA/PU group showed more three-dimensional cell morphology with prominent pseudopodia, facilitating cell adhesion, and significantly increased mRNA expression of ALP, Runx2, CD31, CD34, HIF-1α and VEGF. In vivo, the EPO/pDA/HA/PU group exhibited the most significant bone regeneration, with micro- computed tomography analysis confirming a significantly higher the ratio of bone tissue volume to total tissue volume (BV/TV) compared to the blank and HA/PU control groups. These results indicated that the modified composite scaffold enabled sustained release of EPO, which upregulated the expression of HIF-1α and VEGF, thereby enhancing osteogenic and angiogenic capabilities both in vitro and in vivo. Our research demonstrated that loading of EPO onto the HA/PU composite scaffold could effectively promote osteogenesis and angiogenesis. HIF-1α/VEGF signaling plays a crucial role in this process. This discovery provides novel insights and methods for using HIF-1α/VEGF as a regulatory target to advance the clinical translation of large bone defects repair.
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DOI
PubMed
高影响因子
Journal of Functional Foods
·
2026
·
IF 3.9
Zexuan Wu,Yonghong Long,Fugang Huang,Ze Yang,Yanzuo Wu,Yihong Gan,Xiufang Chen,Guanqun Xie
Capsaicin (CAP), the pungent compound in chili peppers, is well-known for its anti-inflammatory properties, yet its role in autoimmune immunometabolism remains unexplored. In a murine model of Collagen-Induced Arthritis,CAP markedly attenuated joint swelling, cartilage damage, and bone erosion. Mechanistically, CAP targeted HIF-1α, leading to a coordinated suppression of both BNIP3-mediated mitophagy and the characteristic glycolytic shift in M1 macrophages. This dual metabolic suppression was recapitulated in human THP-1-derived M1-like macrophages, where it inhibited M1 polarization and reduced pro-inflammatory cytokine secretion. Collectively, these data identify CAP as a food-derived immunometabolic modulator that alleviates rheumatoid arthritis (RA) by concurrently disrupting mitophagy and glycolysis in M1 macrophages via HIF-1α.
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DOI
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Shouchun Xiao,Jingna Cui,Yue Cao,Yaru Zhang,Jiaxing Yang,Li Zheng,Fanrong Zhao,Xueke Liu,Zhiqiang Zhou,Donghui Liu,Peng Wang
Chemical-caused reproductive dysfunction has emerged as a global public health concern. This study investigated the adverse effects of the organophosphorus pesticide malathion on reproductive function in adolescent male mice at environmentally relevant concentrations. The results indicated that eight-week malathion exposure reduced testis weight, caused sex and thyroid hormone disorders, and induced testicular spermatogenic epithelium damage and oxidative stress. Testicular RNA sequencing indicated that malathion significantly affected testicular energy metabolism, hypoxia-inducible factor 1 (HIF-1) signaling, and steroid hormone biosynthesis pathways. Malathion significantly increased the gene and protein expression of HIF-1α by upregulating key genes in the mitogen-activated protein kinase (MAPK) pathway ( Map2k2 , Mapk3 , and Eif4e2 ) and the phosphatidylinositol 3-kinase (PI3K) pathway ( Pik3r2 and Akt1 ). Furthermore, malathion downregulated HIF-1α degradation-regulating genes while upregulating anaerobic metabolism and inflammation-related genes, thereby inhibiting normoxia and promoting hypoxia processes. Testicular hypoxia subsequently induced steroid hormone biosynthesis disorders and spermatogenesis dysfunction. Molecular docking verified that malathion interfered with HIF-1α and steroid hormone synthases (CYP11A1, CYP17A1 and CYP19A1) by forming hydrogen bonds and hydrophobic interactions with these proteins. This study presents the first evidence that malathion triggers spermatogenesis dysfunction in mice through activating the HIF-1/MAPK/PI3K pathway, providing a comprehensive understanding of the reproductive toxicity risks associated with organophosphorus pesticides.
研究领域:
毒理学
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生殖生物学
·
分子生物学
·
内分泌学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2021
·
IF 10.588
Yuhao Wu,Junke Wang,Tianxin Zhao,Jiadong Chen,Lian Kang,Yuexin Wei,Lindong Han,Lianju Shen,Chunlan Long,Shengde Wu,Guanghui Wei
Di-(2-ethylhexyl) phthalate (DEHP) is an extensively used plasticizer and has been shown to cause reproductive dysfunction in humans and model animals. However, the exact mechanisms of testicular injury induced by DEHP exposure have not been fully clarified. Using gas chromatography-mass spectrometry, we found that mono-2-ethylhexyl ester (MEHP, a major biometabolite of DEHP) and DEHP concentrations were elevated in mouse serum after DEHP exposure. Using RNA-seq, we found that ferroptosis and HIF-1 signaling pathways might be involved in testicular injury due to prepubertal DEHP exposure. Subsequent Western blotting, ferrous iron and MDA measurements, and immunofluorescence of testicular sections verified the RNA-seq findings. Consistently, based on the RNA-seq findings, we found that ferroptosis and HIF-1 signaling pathways might play crucial roles in Leydig and Sertoli cell injury due to MEHP exposure in vitro. Further experiments also confirmed ferroptosis in Leydig and Sertoli cells. Using Western blotting, cellular immunofluorescence and ChIP-qPCR, we found that MEHP exposure caused HIF-1α accumulation and stabilization, resulted in HIF-1α translocation into the nucleus, and induced HIF-1α/ Hmox1 binding in Leydig and Sertoli cells. To clarify whether HIF-1α plays a pivotal role in MEHP-induced ferroptosis, we knocked out Hif-1α using the CRISPR/Cas9 technique. We found that Hif-1α knockout rescued MEHP-induced ferroptosis. In summary, our findings certified that prepubertal DEHP exposure led to ferroptosis in mouse testes via the HIF-1α/HO-1 signaling pathway.
研究领域:
毒理学
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生殖生物学
·
分子生物学
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DOI
PubMed
高影响因子
Frontiers in Physiology
·
2021
·
IF 4.566
Lin Jinyan,Fan Lele,Han Yuming,Guo Juanjuan,Hao Zhiqiang,Cao Lingna,Kang Jiamin,Wang Xiaoqin,He Jianping,Li Jingang
The Gansu zokor (Eospalax cansus) is a subterranean rodent species that is unique to China. These creatures inhabit underground burrows with a hypoxia environment. Metabolic energy patterns in subterranean rodents have become a recent focus of research; however, little is known about brain energy metabolism under conditions of hypoxia in this species. The mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) coordinates eukaryotic cell growth and metabolism, and its downstream targets regulate hypoxia inducible factor-1α (HIF-1α) under conditions of hypoxia to induce glycolysis. In this study, we compared the metabolic characteristics of hypoxia-tolerant subterranean Gansu zokors under hypoxic conditions with those of hypoxia-intolerant Sprague-Dawley rats with a similar-sized surface area. We exposed Gansu zokors and rats to hypoxia I (44 h at 10.5% O2) or hypoxia II (6 h at 6.5% O2) and then measured the transcriptional levels of mTORC1 downstream targets, the transcriptional and translational levels of glycolysis-related genes, glucose and fructose levels in plasma and brain, and the activity of key glycolysis-associated enzymes. Under hypoxia, we found that hif-1α transcription was upregulated via the mTORC1/eIF4E pathway to drive glycolysis. Furthermore, Gansu zokor brain exhibited enhanced fructose-driven glycolysis under hypoxia through increased expression of the GLUT5 fructose transporter and ketohexokinase (KHK), in addition to increased KHK enzymatic activity, and utilization of fructose; these changes did not occur in rat. However, glucose-driven glycolysis was enhanced in both Gansu zokor and rat under hypoxia II of 6.5% O2 for 6 h. Overall, our results indicate that on the basis of glucose as the main metabolic substrate, fructose is used to accelerate the supply of energy in Gansu zokor, which mirrors the metabolic responses to hypoxia in this species.
研究领域:
生理学
·
分子生物学
·
代谢学
·
神经科学
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DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Niu Jiale,Liu Guangxia,He Guangyao,Zhang Xiaomeng,Bai Huihui,Lu Yamin
To investigate the role of IL-17 in macrophage M1 polarization within a type 2 diabetic (T2DM) milieu and to evaluate the therapeutic potential of its neutralizing antibody. PMA-differentiated THP-1 macrophages were polarized to M1 state. Under high glucose, cells were treated with IL-17 and an IL-17 neutralizing antibody. Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured; mRNA levels of TNF-α, HIF-1α, and NLRP3 were assessed by qPCR; and protein expression related to the NF-κB, mTOR/HIF-1α axis and pyroptosis (NLRP3, Caspase-1, GSDMD) was analyzed by Western Blot. High glucose and IL-17 synergistically promoted M1 polarization, enhancing proinflammatory cytokine secretion. This was associated with activation of the NF-κB, mTOR/HIF-1α signaling axis and induction of pyroptosis, evidenced by NLRP3 inflammasome assembly, Caspase-1 activation, and GSDMD cleavage. The IL-17 neutralizing antibody effectively suppressed these pathological processes. IL-17 acts as a key immunological amplifier in diabetes, driving M1 polarization, oxidative stress, and pyroptosis via the NF-κB, mTOR/HIF-1α axis and NLRP3 inflammasome. Treatment with an αIL-17 effectively reversed the aberrant activation of the aforementioned cellular phenotypes and signaling pathways, partially restoring macrophage functional balance. This finding provides preliminary experimental support for further exploration of IL-17-targeted immunomodulatory strategies to ameliorate diabetes-associated metabolic inflammation.
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产品关联
DOI
PubMed
高影响因子
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
·
2015
·Vol. 56
·期 13
·8166-8178
·
IF 3.404
Guoxu Xu,Daohuan Kang,Chaoyang Zhang,Hui Lou,Chen Sun,Qian Yang,Lixia Lu,Guo-Tong Xu,Jingfa Zhang,Fang Wang
Purpose:Zinc transporter 8 (ZnT8) was downregulated in hypoxic retina, which could be rescued by hypoxia-inducible factor-1α (HIF-1α) inhibition. Erythropoietin (EPO) protects retinal cells in diabetic rats through inhibiting HIF-1α as one of its mechanisms. We hence tried to explore the effect of EPO in regulating ZnT8 and protecting retinal cells in diabetic rats and possible mechanisms.Methods:Diabetes was induced in Sprague-Dawley rats. Intravitreal injection of EPO was performed 1 month after diabetes onset. The CoCl2-treated rat Müller cell line (rMC-1) was cotreated with EPO, soluble EPO receptor (sEPOR), digoxin, or U0126. Cell viability, cell death, and intracellular zinc level were examined. The expression of ZnT8, HIF-1α, AKT, and ERK was studied.Results:In diabetic rat retinas, EPO significantly decreased HIF-1α expression and increased ZnT8 expression. In CoCl2-treated rMC-1 cells, EPO increased cell viability and decreased intracellular zinc. Erythropoietin or digoxin could activate ERK pathway, downregulate HIF-1α, and upregulate ZnT8. The effect of EPO was abolished by sEPOR and U0126. Transient knockdown of ZnT8 increased intracellular zinc level, but not to a degree that would decrease cell viability or cause cell death.Conclusions:In diabetic retinas, EPO maintains zinc homeostasis through activating the ERK pathway and downregulating HIF-1α, and thus upregulating ZnT8 expression. This work proposed a possible new protective mechanism for EPO in, and indicated a potential target for, the treatment of diabetic retinopathy.
研究领域:
眼科学
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内分泌学
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细胞生物学
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分子生物学
·
糖尿病研究
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DOI
PubMed
高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-13
·
IF 3.8
Zhu Dongsheng,Chen Feng,Qiang Hongjia,Qi Han
To clarify the impact of SETD2 on macrophage function in pediatric patients with acute suppurative osteomyelitis and to elucidate the precise underlying mechanism. To gain insights into the potential functions of SETD2, a comprehensive study was conducted utilizing a co-culture model of human bone mesenchymal stem cells (hBMSCs) and bone marrow-derived macrophages (THP-1). A range of techniques were employed, including quantitative polymerase chain reaction, western blotting, ELISA, alkaline phosphatase activity assays, alizarin red S staining, luciferase reporter gene assays, and chromatin immunoprecipitation, to unravel the intricate interactions and molecular mechanisms involving SETD2 in this system. It was observed that SETD2 expression was reduced in THP-1 cells stimulated by staphylococcal protein A (SPA). Furthermore, the downregulation of SETD2 resulted in elevated M1 macrophage polarization and glycolysis, effects that were mitigated by SPA stimulation. Notably, SPA-stimulated THP-1 cells exhibited an increase in HIF-1α expression, which exhibited an inverse correlation with SETD2 levels. Moreover, it was discovered that SETD2 functioned as a catalyst for H3K36me3 and bound to the HIF-1α gene, which, in turn, regulated HIF-1α expression. Furthermore, the suppression of HIF-1α abrogated the consequences of SETD2 downregulation on glycolysis and M1 macrophage polarization. Lastly, the study demonstrated that M1 macrophage polarization serves as a mediator for BMP4’s inhibitory effect on osteogenic differentiation of hBMSCs. This research has uncovered a previously unknown role of SETD2 in macrophages during osteomyelitis, revealing its significance in the pathogenesis of this condition. These findings suggest SETD2 as a novel target for the treatment of osteomyelitis.
研究领域:
免疫学
·
分子生物学
·
细胞生物学
·
骨科
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2019
·Vol. 19
·期 4
·2758-2766
·
IF 1.851
Ya Hou,Xiaobo Wang,Xiaorui Chen,Jing Zhang,Xiaopeng Ai,Yusheng Liang,Yangyang Yu,Yi Zhang,Xianli Meng,Tingting Kuang,Yao Hu
This study was conducted to establish a stable hypobaric hypoxia brain injury model. SD rats were randomly separated into control and model groups, and placed outside or inside of a hypobaric chamber, respectively. Subsequent to 24 h anoxic exposure, plasma superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG) and lactate dehydrogenase (LDH) were measured using commercial biochemical kits. Hematoxylin‑eosin (H&E), Nissl's and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to observe the morphology of neurons in the hippocampus. The protein expression levels of apoptotic protease activating factor‑1 (Apaf‑1), hypoxia inducible factor‑1α (HIF‑1α), caspase‑3, cleaved caspase‑3, Bcl‑2‑associated X protein (Bax) and cytochrome c (cyto‑c) were detected using western blot and immunohistochemistry analyses. Hypoxic substantially induced morphological lesions in the hippocampus concomitant with the physical behavioral performance deficit. Furthermore, hypoxia markedly exacerbated the levels of MDA, LDH and GSSG, and restrained GSH (P<0.01) and SOD (P<0.05) levels compared with the control group. In addition, hypoxia significantly induced the protein expression of Apaf‑1, HIF‑1α, caspase‑3, cleaved caspase‑3, Bax and Cyto‑c (P<0.01) compared with the control group. Finally, a lower number and volume of Nissl bodies were verified in the hypoxic group. TUNEL results demonstrated a greater number of apoptotic cells in the hypoxic group. The present study demonstrates a model of rat hypoxic brain injuries induced by a hypobaric chamber at 9,000 m for 24 h. Furthermore, the redox enzyme, HIF‑1α and mitochondrial apoptosis‑associated protein, along with H&E and Nissl's staining, may be applied to evaluate the degree of injury.
研究领域:
神经科学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
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