PHYTOMEDICINE
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2026
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IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
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Biology-Basel
·
2026
·Vol. 15
·期 13
·999
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IF 4.3
Xiang Li,Bo Tian,Yuxin Chen,Huili Tong,Xiaoming Chen,Zhifeng Cheng
Simple SummaryType 2 diabetes (T2DM) often leads to skeletal muscle loss and weakness, a condition called sarcopenia, which worsens human health. This study explored whether carnosine, a natural dipeptide found in meat and present in human muscle, can help protect against muscle wasting. Using a T2DM sarcopenia mouse model and a high-glucose-treated C2C12 myotube in vitro model, the researchers found that carnosine levels were reduced in T2DM sarcopenia muscles. Oral carnosine supplementation in the mice helped alleviate skeletal muscle atrophy. Carnosine works by activating a cellular signaling pathway that boosts the number of mitochondria (the energy powerhouses of cells) and shifts muscle fibers toward a more oxidative type, leading to stronger and healthier muscles in T2DM sarcopenia mice. These findings suggest that carnosine supplementation could be a simple and promising nutritional strategy to help manage skeletal muscle loss in people with type 2 diabetes, though further studies in humans are needed to confirm its effectiveness.Type 2 diabetes mellitus (T2DM) accounts for over 90% of diabetes cases, and T2DM-related sarcopenia is a growing concern. Carnosine, abundant in human skeletal muscle, helps maintain muscle quality and function. This study investigated whether carnosine deficiency contributes to T2DM-related sarcopenia and whether exogenous carnosine supplementation alleviates muscle atrophy. A mouse model of T2DM sarcopenia was established using streptozotocin combined with a high-fat diet. LC-MS metabolomics revealed a significant reduction in carnosine content in the gastrocnemius muscle of model mice. A C2C12 myotube atrophy model was induced by high-glucose (HG), and qRT-PCR showed altered expression of carnosine metabolism-related enzymes, suggesting disrupted carnosine homeostasis under T2DM conditions. Mechanistic investigations using immunofluorescence, Western blotting, transcriptome sequencing, mitochondrial staining, and molecular docking indicated that carnosine may alleviate high-glucose-induced myotube atrophy through the PI3K/AMPK/PGC-1α signaling pathway. In vivo, carnosine supplementation increased the number of mitochondria and the proportion of slow muscle fibers in gastrocnemius muscle, ameliorating the atrophic phenotype. These findings suggest that carnosine has potential as a candidate for intervention in T2DM-related sarcopenia, though further validation of its direct molecular targets is required.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Yangwei Xiang,Qin Wang,Ke Zhou,Weili Han
Phthalate esters (PAEs), widely used as plastic additives in consumer products such as food packaging, can be metabolized to phthalic acid (PTA) in vivo . However, the potential contribution of PTA to respiratory fibrotic processes remains poorly understood. In this study, we investigated the effects and underlying mechanisms of PTA on pulmonary fibrogenesis using human lung fibroblast IMR-90 cells chronically exposed to environmentally relevant concentrations of PTA (0–60 μg/L) for 14 days. PTA exposure promoted pro-fibrotic responses and cellular senescence, as evidenced by increased expression of fibrosis-associated markers, enhanced senescence-associated β-galactosidase activity, and upregulation of CDKN2A . Proteomic profiling and functional perturbation experiments further implicated the IL-1α/NF-κB/SASP signaling axis in these responses. PTA-induced senescence and pro-fibrotic effects were attenuated by inhibition of NF-κB signaling and IL-1 signaling, supporting the functional involvement of this pathway. In a bleomycin-induced progressive pulmonary fibrosis model, subsequent PTA exposure further aggravated collagen deposition and increased the pulmonary expression of fibrosis-, senescence-, and Il-1a/Nf-κb -associated genes, providing in vivo support for the biological relevance of the pathway identified in vitro . Molecular docking additionally predicted a potential interaction between PTA and IL-1α. Therefore, these findings offer novel mechanistic insights into environmental pollutant-induced fibrogenesis. Download: Download high-res image (131KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Lv Nanning,Dong He,Sun Haifu,Shi Jing,Wu Xinhui,Chen Xiaofan,Li Hongye,Feng Xiaoxiao,Guo Xuran,Dong Xieping,Hu Ying,Zheng Longpo,Liu Mingming
Diabetic bone defects are difficult to repair because chronic hyperglycemia disrupts local immunometabolic and vascular homeostasis, leading to persistent inflammation, poor angiogenesis, and impaired osteogenesis. Here we report a piezoelectrically driven hierarchical biomimetic architecture that promotes diabetic bone defect repair through spatially bidirectional regulation of HIF-1α. The system comprises an ultrasound-responsive PLLA/ZnO/DFO biomimetic periosteum and a conductive GelMA/MXene/Ce-MOF@Arg defect-filling hydrogel. Under ultrasound stimulation, the upper layer generates piezoelectric microcurrents and releases deferoxamine, which is associated with activation of endothelial HIF-1α/VEGF signaling and angiogenic responses, whereas the lower layer relays electrical cues into the defect core and is associated with reduced macrophage HIF-1α expression and glycolytic activity in parallel with arginine delivery and Ce-MOF nanozyme-mediated redox regulation. This design promotes recovery toward a more favorable immunometabolic-vascular state by coupling superficial pro-angiogenic activation with deep anti-inflammatory metabolic remodeling. The scaffold shows favorable piezoelectric, conductive, mechanical, degradation, and release properties, promotes endothelial migration, drives macrophage polarization toward a reparative phenotype, enhances osteogenic-angiogenic coupling, and substantially accelerates critical-sized calvarial defect healing in diabetic rats. Our findings provide an electroactive and spatially coordinated strategy for diabetic bone regeneration.
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Journal of Advanced Research
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2026
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IF 17.1
Jiaxin Su,Lingcheng Wu,Huiru Zhu,Haoru Wang,Xiaoya He,Bing Liang,Jinhua Cai
Introduction Acute kidney injury (AKI) is a devastating global health burden. Its pathogenesis, particularly in ischemia/reperfusion (I/R) injury, centers on a vicious cycle between a reactive oxygen species (ROS)-driven inflammatory storm and severe mitochondrial dysfunction in renal tubular cells. While activation of the SIRT1/PGC-1α pathway is a promising therapeutic target for mitochondrial recovery, its potent agonist resveratrol (Rsv) suffers from poor bioavailability, and monotherapy fails to address the concomitant inflammatory pathology. Objective This study aimed to develop a kidney-targeted theranostic nanoplatform that synergistically breaks this pathological cycle. We hypothesized that a nanoplatform co-delivering Rsv and a ROS-scavenging component could concurrently suppress inflammation via direct ROS elimination and restore mitochondrial homeostasis via SIRT1/PGC-1α activation, with integrated magnetic resonance imaging (MRI) capability for monitoring. Methods We engineered a theranostic nanoplatform designated Rsv@HMnO 2 -HA (HMRH NPs). The platform was constructed by loading Rsv into hollow mesoporous manganese dioxide (HMnO 2 ) nanozymes, followed by surface coating with hyaluronic acid (HA) for active targeting to CD44 receptors over expressed on injured renal tubules. The system’s physicochemical properties were thoroughly characterized. Its therapeutic efficacy and theranostic performance were systematically evaluated in a well-established murine model of renal I/R-induced AKI, using a combination of biochemical assays, histological analysis, molecular biology techniques, and in vivo MRI. Results HMRH NPs successfully accumulated in injured kidneys and disassembled in situ. The HMnO 2 shell effectively scavenged excess ROS, attenuating the inflammatory response. The co-released Rsv activated the SIRT1/PGC-1α pathway, restored mitochondrial biogenesis, and improved cellular energy homeostasis. The released Mn 2+ ions enabled clear T 1 -weighted MRI contrast, allowing real-time visualization of renal targeting and therapeutic progression. Conclusion The results conclusively demonstrate that the HMRH NPs successfully implements a synergistic two-pronged therapeutic strategy. By co-delivering a ROS-scavenger and a mitochondrial-regenerative agent directly to the site of injury, the platform effectively disrupts the critical pathological crosstalk between inflammation and mitochondrial damage in AKI. This work presents a holistic, targeted, and image-guided nanomedicine strategy, offering a promising approach for the effective treatment and monitoring of AKI.
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CARBOHYDRATE POLYMERS
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2025
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IF 12.5
Wuyan Xu,Kun Liu,Jiaqing Chen,Junliang Liu,Siming Li,Hua Wang,Binghong Luo,Qingqi Meng
Bone regeneration is clinically challenging because vascularization, osteo-induction, and immune modulation are difficult to synchronize. Inspired by the native periosteum's bilayer architecture and multifunctional roles, we developed a wood-engineered Janus periosteum (EW-P-D@HACA-T) that integrates deferoxamine (DFO)-functionalized elastic wood (EW-P-D) with a bio-adhesive catechol-modified hyaluronic acid/tricalcium phosphate hydrogel (HACA-T). This construct mimics the anisotropic structure and compartmentalized functions of natural periosteum, providing dual support for angiogenesis and osteo-immunomodulation. EW-P-D maintains mechanical integrity and guides cell orientation, while sustained release activates the HIF-1α/VEGF pathway to enhance endothelial maturation and bone formation. Concurrently, the HACA-T composite hydrogel promotes osteogenic differentiation and polarizes macrophages toward an M2 phenotype, creating a pro-regenerative immune microenvironment. Furthermore, transcriptomic profiling revealed coordinated activation of p53, TGF-β, and ECM remodeling pathways, highlighting the scaffold's capacity to orchestrate tissue regeneration at the molecular level. In vivo evaluation using a rat skull defect model confirmed superior bone bridging, collagen deposition, neovascularization, and systemic biosafety. This study presents a structurally and functionally integrated wood-engineered periosteum substitute, demonstrating a paradigm shift toward engineered solutions that synchronize mechanical, angiogenic, and immunomodulatory cues for bone defect repair.
研究领域:
生物材料学
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组织工程
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免疫调控
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骨科学
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分子生物学
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转化医学
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2024
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IF 4.6
Jiazhen Huang,Ying Tang,Yibing Li,Wei Wei,Fuli Kang,Shuang Tan,Lin Lin,Xiaohang Lu,Heng Wei,Ning Wang
High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer that causes great threats to women's health. Therefore, we performed RNA-sequencing technology in clinical samples to explore the molecular mechanisms underlying the progression of HGSOC. We then noticed BBOX1, a kind of 2-oxoglutarate-dependent enzyme that is highly expressed in HGSOC tumor tissues. Functional studies showed that BBOX1 promotes cell survival and growth of HGSOC cells in vitro and in vivo. Overexpression of the wild-type BBOX1 promoted cell proliferation, but the Asn191 and Asn292 mutation (key amino acid for the enzymatic activity of BBOX1) counteracted this effect ( P < 0.05), which indicated that the promotion effect of BBOX1 on HGSOC cell proliferation was related to its catalytic activity. Downregulation of BBOX1 reduced the activity of the mTORC1 pathway, and decreased protein expression of IP3R3 and phosphorylation level of S6K Thr389 . Metabolomics analysis revealed that BBOX1 is implicated in the glucose metabolism, amino acid metabolism, and nucleotide metabolism of HGSOC cells. In addition, inhibition of BBOX1 suppressed HGSOC cell glycolysis and decreased glucose consumption, lactate production, and the expression of key factors in glycolysis. Finally, we found hypoxia induced the expression of BBOX1 in HGSOC cells and confirmed that BBOX1 could be transcriptionally activated by hypoxia-inducible factor-1α, which could directly bind to the BBOX1 promoter. In summary, BBOX1 mediated the metabolic reprogramming driven by hypoxia, and affected cell metabolism through the mTORC1 pathway, thus acting as an oncogene during HGSOC development.
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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代谢学
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Cell Death & Disease
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2024
·Vol. 15
·期 10
·1-15
·
IF 8.1
Chen Zi-Xiong,Mu Mao-Yuan,Yang Guang,Qi Han,Fu Xiao-Bo,Wang Gui-Song,Jiang Wei-Wei,Huang Bi-Jun,Gao Fei
Denticleless E3 ubiquitin protein ligase homolog (DTL), the substrate receptor of the CRL4A complex, plays a central role in genome stability. Even though the oncogenic function of DTL has been investigated in several cancers, its specific role in hepatocellular carcinoma (HCC) still needs further elucidation. Data from a clinical cohort ( n = 209), RNA-sequencing, and public database (TCGA and GEO) were analyzed, indicating that DTL is closely related to patient prognosis and could serve as a promising prognostic indicator in HCC. Functionally, DTL promoted the proliferation, metastasis, and sorafenib resistance of HCC in vitro. In the orthotopic tumor transplantation and tail vein injection model, DTL promoted the growth and metastasis of HCC in vivo. Mechanically, we revealed for the first time that DTL was transcriptionally activated by hypoxia-inducible factor 1α (HIF-1α) under hypoxia and functioned as a downstream effector molecule of HIF-1α. DTL promotes the ubiquitination of SAFB-like transcription modulator (SLTM) and subsequently relieves the transcriptional repression of Notch1. These results suggested that DTL may be a potential biomarker and therapeutic target for HCC.
研究领域:
肿瘤学
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分子生物学
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癌症遗传学
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JOURNAL OF MOLECULAR MEDICINE-JMM
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2024
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IF 4.8
Su Qi,Chen Kun,Ren Jiayan,Zhang Yu,Han Xu,Leong Sze Wei,Wang Jingjing,Wu Qing,Tu Kaihui,Sarwar Ammar,Zhang Yanmin
Abstract Non-small cell lung cancer (NSCLC) is a highly malignant tumor with a poor prognosis. Hypoxia conditions affect multiple cellular processes promoting the adaptation and progression of cancer cells via the activation of hypoxia-inducible factors (HIF) and subsequent transcription activation of their target genes. Preliminary studies have suggested that estrogen receptor β (ERβ) might play a promoting role in the progression of NSCLC. However, the precise mechanisms, particularly its connection to HIF-1α-mediated modulation under hypoxia, remain unclear. Our findings demonstrated that the overexpression of ERβ, not ERα, increased cell proliferation and inhibition of apoptosis in NSCLC cells and xenografts. Tissue microarray staining revealed a strong correlation between the protein expression of HIF-1α and ERβ. HIF-1α induced ERβ gene transcription and protein expression in CoCl 2 -induced hypoxia, 1% O 2 incubation, or HIF-1α overexpressing cells. ChIP identified HIF-1α binding to a hypoxia response element in the ESR2 promoter. The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the tumor growth, thus emphasizing the promising prospects of targeting HIF-1α and ERβ as a therapeutic approach for the treatment of NSCLC. Key messages
ERβ, not ERα, increases cell proliferation and inhibition of apoptosis in NSCLC cells and xenografts.
A strong correlation exists between the protein expression of HIF-1α and ERβ.
HIF-1α induced ERβ gene transcription and protein expression in hypoxic cells via binding to HRE in the ESR2 promoter.
The suppression of HIF-1α and ERβ both in vitro and in vivo effectively reduced the NSCLC tumor growth.
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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JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-18
·
IF 10.435
Zhao Bonan,Dong Zhipeng,Liu Weixing,Lou Fangning,Wang Qiyan,Hong Hao,Wang Yue
Background According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC. Results In this study, the use of poly( l -Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects—enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models. Conclusions We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment. Graphic abstract
研究领域:
肿瘤学
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药学
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免疫疗法
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PHYTOMEDICINE
·
2026
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IF 8.3
Chong Gao,Wei Liu,Sai-Hu Liu,Shuang Zheng,Chen-Yu Wang,Xu Dai,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Background Reprogramming of aerobic glycolysis occurs with HSCs activation and is associated with regression of liver fibrosis. Trigonelline (TRG), a plant alkaloid extracted from Trigonella foenum-graecum L seeds, has a variety of pharmacological effect. Purpose The current study investigated the hepatoprotective effect and mechanism of TRG against hepatic fibrosis by regulating glycolysis. Methods Anti-hepatic fibrosis effects of TRG were detected in thioacetamide (TAA)-induced hepatic fibrosis mice. HSCs or LX-2 were stimulated with TGF-β or conditioned medium (CM) from LPS-stimulated THP-1, then incubated with TRG, phloretin (PHL), rosiglitazone (RGZ), siRNA Glut-1 or plasmid with Glut-1. Results TRG significantly reduced serum transaminase levels, liver histopathological changes, excessive collagen deposition, inflammatory response, and neutrophil recruitment in TAA-induced mice. TAA increased hepatic Glut-1, HIF-1α and key enzymes of glycolysis expressions, while TRG completely reversed this effect. TRG also obviously regulated the combination of Glut-1 and HIF-1α to affect glycolysis in activated HSCs. TRG could inhibit α-SMA, IL-6, IL1R1, and HIF-1α expressions accompanying inhibition of Glut-1, function as PHL (Glut-1 inhibitor). Glut-1 silencing weakened α-SMA, IL-6, IL1R1, and HIF-1α expressions and enhanced the effect of TRG in activated LX-2. TRG inhibited LX-2 activation caused by Glut-1 overexpression, even demonstrated in interaction between LX-2 and macrophages. Further, TRG shown that improved fibrogenesis and inflammatory response by inhibiting Glut-1 compared with PHL in vivo . Conclusion TRG could ameliorate hepatic fibrosis through inhibiting ECM excessive deposition and inflammatory response. Inhibiting Glut-1-HIF-1α axis and glycolysis was a potential therapeutic strategy for TRG ameliorating liver microenvironment, further against hepatic fibrosis.
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Biomaterials Advances
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2024
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IF 5.5
Xianzhen Yin,Yihao Wei,Haotian Qin,Jin Zhao,Yixiao Chen,Sen Yao,Nan Li,Ao Xiong,Deli Wang,Peng Zhang,Peng Liu,Hui Zeng,Yingqi Chen
Angiogenesis plays a crucial role in bone regeneration. Hypoxia is a driving force of angiogenesis at the initial stage of tissue repair. The hypoxic microenvironment could activate the hypoxia-inducible factor (HIF)-1α signaling pathway in cells, thereby enhancing the proliferation, migration and pro-angiogenic functions of stem cells. However, long-term chronic hypoxia could inhibit osteogenic differentiation and even lead to apoptosis. Therefore, shutdown of the HIF-1α signaling pathway and providing oxygen at later stage probably facilitate osteogenic differentiation and bone regeneration. Herein, an oxygen tension regulating hydrogel that sequentially activate and deactivate the HIF-1α signaling pathway were prepared in this study. Its effect and mechanism on stem cell differentiation were investigated both in vitro and in vivo . We proposed a gelatin-based hydrogel capable of sequentially delivering a hypoxic inducer (copper ions) and oxygen generator (calcium peroxide). The copper ions released from the hydrogels significantly enhanced cell viability and VEGF secretion of BMSCs via upregulating HIF-1α expression and facilitating its translocation into the nucleus. Additionally, calcium peroxide promoted alkaline phosphatase activity, osteopontin secretion, and calcium deposition through the activation of ERK1/2. Both Cu 2+ and calcium peroxide demonstrated osteogenic promotion individually, while their synergistic effect within the hydrogels led to a superior osteogenic effect by potentially activating the HIF-1α and ERK1/2 signaling pathways.
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