Frontiers in Genetics
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2022
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IF 4.772
Tang Han,Du Han,Kuang Xielan,Huang Hao,Zeng Jingshu,Long Chongde,Zhu Binbin,Fu Licheng,Wang Hua,Zhang Qingjiong,Lin Shuibin,Yan Jianhua,Shen Huangxuan
Age-related macular degeneration (AMD), which is the leading cause of blindness among the elderly in western societies, is majorly accompanied by retinal pigment epithelium (RPE) degeneration. Because of the irreversible RPE cell loss among oxidative stress, it is crucial to search for available drugs for atrophic (dry) AMD. RNA-Seq analysis revealed that genes related to aging and mitochondrial health were differentially expressed under Arbutin treatment, whereas compared to oxidative injury, our study demonstrated that Arbutin substantially abrogated oxidative stress-induced cell senescence and apoptosis linked to intracellular antioxidant enzyme system homeostasis maintenance, restored mitochondrial membrane potential (MMP), and reduced the SA-β-GAL accumulation in RPE. Furthermore, Arbutin alleviated oxidative stress-mediated cell apoptosis and senescence via activation of SIRT1, as evidenced by the increase of the downstream FoxO3a and PGC-1α/β that are related to mitochondrial biogenesis, and the suppression of NF-κB p65 inflammasome, whereas rehabilitation of oxidative stress by SIRT1 inhibitor attenuated the protective effect of Arbutin. In conclusion, we validated the results in an in vivo model constructed by NAIO3-injured mice. OCT and HE staining showed that Arbutin sustained retinal integrity in the case of oxidative damage in vivo, and the disorder of RPE cytochrome was alleviated through fundus observation. In summary, our findings identified that oxidative stress-induced mitochondrial malfunction and the subsequent senescence acceleration in RPE cells, whereas Arbutin inhibited TBHP-induced RPE degeneration via regulating the SIRT1/Foxo3a/PGC-1α/β signaling pathway. These findings suggested that Arbutin is a new agent with potential applications in the development of AMD diseases.
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高影响因子
MEDIATORS OF INFLAMMATION
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2022
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IF 4.529
Jieru Han,Wenhao Li,Guangyu Shi,Yunlei Huang,Xutao Sun,Na Sun,Deyou Jiang
Ulcerative colitis (UC) is a complex inflammatory bowel disease (IBD) associated with mitochondrial function. Atractylenolide III (AT III) is a natural product with anti-inflammatory effects. The aim of this work is to investigate the protective effect of AT III on UC and its underlying mechanisms. Herein, dextran sulfate sodium- (DSS-) induced mice and lipopolysaccharide- (LPS-) stimulated intestinal epithelial cells (IEC-6) were employed to mimic UC pathologies in vivo and in vitro. The results showed that in DSS-induced mice, AT III significantly reversed the body weight loss, colon length reduction, disease activity index (DAI) increase, and histological damage. The production of proinflammatory factors and reduction of antioxidants in colitis were suppressed by AT III. In addition, we demonstrated that AT III attenuated the intestinal epithelial barrier destruction and mitochondrial dysfunction induced by DSS, which was similar to the in vitro results in LPS-treated IEC-6 cells. The protein levels of p-AMPK, SIRT1, and PGC-1α along with acetylated PGC-1α were also upregulated by AT III in vivo and in vitro. In conclusion, these findings support that AT III may protect against mitochondrial dysfunction by the activation of the AMPK/SIRT1/PGC-1α signaling pathway during UC development.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Hongxuan Yang,Yun Liang,Yue’e Chen,Lin Liu,Yingfang Wang,Qiting Dou,Jinmei Gong,Zijing Liao,Junqiu Dong,Xuguang Hu
Ethnopharmacological relevance Lonicera japonica Thunb (honeysuckle), a traditional Chinese medicine, has been historically used to clear heat, detoxify, and dispel wind-heat. Modern research has identified various bioactive constituents from honeysuckle, supporting its potential in managing inflammatory and metabolic disorders. However, the anti-hyperuricemic activity and mechanism of its peptide components remain unexplored. Aim of the study: This study aimed to investigate the anti-hyperuricemic effect of honeysuckle-derived peptides and the underlying mechanisms, with a focus on uric acid production, excretion, and gut microbiota modulation. Materials and methods Nine novel peptides were identified from honeysuckle by HPLC-MS/MS and screened through molecular docking against xanthine oxidase (XOD). In vitro XOD inhibition and antioxidant assays were performed. A hyperuricemic mouse model was induced by potassium oxonate and hypoxanthine. Mice were treated with honeysuckle peptides at low, medium, and high doses. Serum biomarkers, renal and ileal histopathology, protein and mRNA expression of PGC-1α/PPARγ/ABCG2 pathway components, and gut microbiota composition (16S rRNA sequencing) were analyzed. Results Molecular docking confirmed strong binding between the peptides and XOD. In vitro , honeysuckle peptides significantly inhibited XOD activity and exhibited potent antioxidant capacity. In vivo , peptide treatment effectively reduced serum uric acid, XOD, creatinine, and blood urea nitrogen levels, alleviated renal and intestinal tissue damage, and suppressed inflammatory cytokines. The treatment also significantly upregulated the renal PGC-1α/PPARγ/ABCG2 pathway at both protein and mRNA levels. Furthermore, the peptides restored gut microbial diversity and corrected the Firmicutes/Bacteroidota ratio. Conclusion Honeysuckle peptides ameliorate hyperuricemia through a dual mechanism: inhibiting uric acid production by suppressing XOD activity and promoting its renal excretion by activating the PGC-1α/PPARγ/ABCG2 pathway, coupled with restoring gut microbiota homeostasis. This study provides a pharmacological basis for the traditional use of honeysuckle and highlights its peptides as promising candidates for managing hyperuricemia.
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JOURNAL OF ETHNOPHARMACOLOGY
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2021
·
IF 4.36
Li-na Ji,Shan Wu,Dan-qing Fu,Si-jia Fang,Guan-qun Xie,Yong-sheng Fan,Jie Bao
Ethnopharmacological relevance Jieduquyuziyin prescription (JP) is a traditional Chinese medicine (TCM) formula. According to both TCM theory and more than a decade of clinical practice, JP has been testified to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription in China. Aim of the study To determine the effect of JP on the treatment of SLE by glucocorticoid (GC) and to further examine the molecular mechanisms. Materials and methods We conducted in vivo experiments to estimate the effect of JP on hepatic gluconeogenesis in MRL/lpr mice treated with GC. Additionally, isoproterenol (ISO) induced hepatic gluconeogenesis model and GC-treated MRL/lpr mouse hepatocytes were carried out in vitro experiments to verify the effect of JP on gluconeogenesis. Results The results showed that JP combined with GC could effectively alleviate the lupus symptoms in MRL/lpr mice and improve the pathological changes of the kidney and liver. And the combination of JP reduced the side effects caused by GC, which was related to the inhibition of GC-induced hepatic gluconeogenesis in MRL/lpr mice. Specifically, JP up-regulated the expression of glucocorticoid receptor (GR) α, phosphoinositide-3-kinase (PI3K) and Akt restrained by GC to reduce the production of forkhead box O1 (FoxO1), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In viv o, the use of JP either alone or with GC could reduce spleen enlargement , high levels of serum antibodies, aggravated urine protein and renal pathological damage in MRL/lpr mice. Furthermore, the glucose content was reduced in the liver of MRL/lpr mice treated with JP, and the liver damage and steatosis were also alleviated. In vitro , the expressions of PI3K and Akt increased and the expressions of FoxO1, PGC-1α, PEPCK and G6Pase decreased after JP treatment in ISO-treated hepatocytes. Compared with MRL/MP mice, we found that JP could significantly inhibit the expression of gluconeogenesis in the hepatocytes of MRL/lpr mice induced by GC to a greater extent. Conclusions The therapeutic effect of JP on GC-induced is likely related to hepatic gluconeogenesis, which provides a new perspective to reveal the positive role of JP in SLE.
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FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Dongxiao Meng,Minghui Chang,Xianling Dai,Qin Kuang,Guangchuan Wang
Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of liver transplantation and hepatocellular carcinoma (HCC). Regrettably, its pathological mechanisms are still not fully comprehended. GTP-binding protein 8 (GTPBP8), belonging to the GTP-binding protein superfamily, assumes a crucial role in RNA metabolism, cell proliferation, differentiation, and signal transduction. Its aberrant expression is associated with oxidative stress and mitochondrial dysfunctions. Nevertheless, its specific functions and mechanisms of action, particularly in NASH, remain elusive. In our current study, we initially discovered that human hepatocytes L02 displayed evident mitochondrial respiratory anomaly, mitochondrial damage, and dysfunction upon treatment with palmitic acids and oleic acids (PO), accompanied by significantly reduced GTPBP8 expression levels through RNA-Seq, RT-qPCR, western blotting, and immunofluorescence assays. We then demonstrated that GTPBP8 overexpression mediated by adenovirus vector (Ad-GTPBP8) markedly attenuate lipid accumulation, inflammatory response, and mitochondrial impair and dysfunction in hepatocytes stimulated by PO. Conversely, adenovirus vector-mediated GTPBP8 knockdown (Ad-shGTPBP8) significantly accelerated lipid deposition, inflammation and mitochondrial damage in PO-treated hepatocytes in vitro . Furthermore, we constructed an in vivo NASH murine model by giving a 16-week high fat high cholesterol diet (HFHC) diet to hepatocyte specific GTPBP8-knockout (GTPBP8 HKO ) mice. We firstly found that HFHC feeding led to metabolic disorder in mice, including high body weight, blood glucose and insulin levels, and liver dysfunctions, which were accelerated in these NASH mice with GTPBP8 deficiency in hepatocytes. Consistently, GTPBP8 HKO remarkably exacerbated the progression of NASH phenotypes induced by HFHC, as proved by the anabatic lipid accumulation, inflammation, fibrosis and reactive oxygen species (ROS) production in liver tissues, which could be largely attributed to the severe mitochondrial damage and dysfunction. Mechanistically, we further identified that GTPBP8 interacted with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in hepatocytes. Importantly, the hepaprotective effects of GTPBP8 against mitochondrial dysfunction, oxidative stress and inflammation was largely dependent on PGC-1α expression. Collectively, GTPBP8 may exert a protective role in the progression of NASH, and targeting the GTPBP8/PGC-1α axis may represent a potential strategy for NASH treatment by improving mitochondrial functions.
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Journal of Functional Foods
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2024
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IF 3.8
Dan Song,Yuan Liu,Kehui Wu,Manting Lyu,Yongshu Wu,Yanan Zhang,Panling Wang,Xiangchen Li
The present study sought to investigate the protective effect of Lycopene (LYC) on Bisphenol A (BPA)-induced lipid accumulation and elucidate the potential molecular mechanism. In vitro, the PK15 cells with or without LYC were exposed to BPA for 6 h to detect the lipid accumulation using Nile red’s and Oil Red O’ staining. Meanwhile, redox status, mitochondrial function, gene expression and protein levels relating to lipid accumulation were evaluated by cellular biochemical assays, immunofluorescence staining, quantitative real-time PCR (qRT-PCR) and Western blot, respectively. In addition, ROS scavenger N-acetylcysteine (NAC), SIRT1 inhibitor EX527, SIRT1 siRNA and PGC-1α siRNA were used to verify the target signaling pathways responsible for the protective effect of LYC against BPA-indcued lipid accumulation. In vivo, the twenty four male Wistar rats were randomly divided into three groups, received either BPA (50 mg/kg/day BW) or LYC (10 mg/kg/day BW) orally for 60 days. The kidney tissues were evaluated by HE’s and Oil Red O’s staining, lipid-associated genes and proteins expression were detected through qRT-PCR and Western blot. The results showed that BPA-exposed PK15 cells and rats had increased lipid droplets with elevated transcription of lipogenic factors SREBP1 and PPARγ, and down-regulated PPARα expression, and which is accompanied by redox imbalance and abnormal mitochondrial function. Conversely, LYC prevented BPA-induced lipid metabolism disorder and lipid accumulation through impeding ROS overproduction. Moreover, PK15 cells and rats exposed to BPA showed decrease in SIRT1 and PGC-1α levels, whereas LYC blocked the decrease of SIRT1 and PGC-1α protein levels. Furthermore, inhibition or silence of SIRT1 and PGC-1α abrogated the improvements of LYC on ROS generation, mitochondrial mass impairement and lipid accumulation in BPA-treated PK15 cells. Collectively, these findings indicate that SIRT1/PGC-1α signaling pathway is involved in the protective effect of LYC on BPA-induced lipid accumulation. These results also provide a potential promising therapeutic of LYC against BPA-induced lipid accumulation in kidney cells and organs.
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JOURNAL OF MOLECULAR HISTOLOGY
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2025
·Vol. 56
·期 6
·1-14
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IF 2.2
Wang Pu,Sun Congcong,Shi Chao,Gao Yong,Luan Chunyu,Yan Chao
Osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes such as articular cartilage degeneration and bone hyperplasia. Mitochondrial dysfunction in chondrocytes has been identified as a critical factor contributing to the progression of OA. Although Evodiamine (Evo) has been demonstrated effeicacy in inhibiting inflammatory responses and matrix degradation in OA chondrocytes, its effects and underlying mechanisms regarding mitochondrial dysfunction in these cells remain to be elucidated. IL-1β was utilized to stimulate chondrocytes in order to establish an in vitro OA model. Subsequently, the proliferation, lactate dehydrogenase (LDH) release, and apoptosis of chondrocytes were systematically evaluated. Mitochondrial function in chondrocytes was evaluated by quantifying of ATP content, ROS level, mitochondrial DNA (mtDNA) copy number, activities of mitochondrial respiratory chain Complexes I and III, as well as mitochondrial membrane potential change. Furthermore, the protein expression levels of the SIRT1/PGC-1α signaling pathway were examined, and an intervention involving the SIRT1 inhibitor EX527 was conducted to elucidate the potential mechanisms underlying the effects of Evo on chondrocytes. Evo treatment significantly elevated the proliferation activity of IL-1β-stimulated chondrocytes, inhibited LDH release and apoptosis, increased mtDNA copy number and ATP content, enhanced the enzymatic activities of Complexes I and III, and suppressed ROS production as well as mitochondrial membrane potential loss. Furthermore, Evo treatment activated the SIRT1/PGC-1α signaling pathway. However, the addition of the SIRT1 inhibitor EX-527 partially attenuated the protective effects of Evo against IL-1β-induced chondrocyte injury by exacerbating mitochondrial dysfunction. Evo promotes mitochondrial biosynthesis, reduces ROS production and improves mitochondrial function by activating SIRT1/PGC-1α pathway, thereby inhibiting IL-1β-induced chondrocyte injury.
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CELLULAR SIGNALLING
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2026
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IF 4.7
Yuan Wang,Li Zhu,Xinyi Huang,Zijun Zhou,Yinli Xu,Boxuan Sun,Jiahui Li,Liming Yu,Huishan Wang
Muscle-specific histone methyltransferase 1 (Smyd1) is required for skeletal and cardiac muscle development, yet its roles and mechanisms in diabetes-associated atrial fibrillation (AF) remain poorly defined. This study aims to elucidate the role of the Smyd1-PGC-1α pathway in the pathogenesis of AF and to investigate the underlying mechanisms. In this study, employing bioinformatic data and in vivo/in vitro experiment, we demonstrated that Smyd1 is significantly down-regulated in the atrium of diabetic mice and in HL-1 cardiomyocytes treated with high-glucose/palmitic acid (HG/PA). This detrimental effect was coincided with diminished PGC-1α transcription and impaired mitochondrial biogenesis, contributing to pathological atrial enlargement, structural and electrical remodeling, fibrosis, lipid droplet accumulation, and increased AF susceptibility. Crucially, Smyd1 overexpression reversed the aforementioned damage. Mechanistically, cardiac-specific overexpression of Smyd1 enhanced mitochondrial biogenesis and respiration by activating PGC-1α transcription and ameliorated HG/PA-induced dysfunction in mitochondrial dynamics and membrane potential. This pathway attenuates high-fat-diet/streptozotocin (HFD/STZ) -induced myocardial injury and reduces susceptibility to diabetes-associated AF. These findings indicate that the Smyd1-PGC-1α axis represents a promising preclinical target that warrants further investigation in human tissues and clinical settings.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Linxin Zhang,Mengyang Wang,Wei Liu,Xiaoli Cui,Chang Liu,Hui Yu,Jiangning Hu,Di Yang,Haiming Sun
Ethnopharmacological relevance Shenfu Decoction (SFD) is a traditional famous prescription for replenishing qi and restoring yang . Pharmacological research has confirmed that SFD can warm and tonify yang qi and exerts good therapeutic effects on cardiovascular-related diseases. However, there are no reports on kidney diseases caused by hypertension, and its molecular mechanism needs further exploration. Aim of the study This study aimed to investigate whether SFD ameliorates hypertensive renal disease (HRD) and to clarify whether such protection is achieved through alleviate mitochondrial dysfunction and subsequent inhibition of apoptosis via the AMPK/SIRT1/PGC 1α signaling pathway. Methods and materials Combining network pharmacology, an Ang II-induced hypertensive kidney injury model in C57BL/6 mice, and the NRK-52E cell model, renal function, mitochondrial function, oxidative stress, inflammatory factors, and apoptosis were assessed. Co-immunoprecipitation was used to verify the interaction between SIRT1 and PGC-1α. Results SFD treatment improved AngII-induced renal dysfunction without altering blood pressure. Network pharmacology combined with experiments identified stigmasterol (STI) as the active component, which alleviates mitochondrial dysfunction, reduces oxidative stress/inflammation, and decreases apoptosis by activating the AMPK/SIRT1/PGC-1α pathway. Mechanistically, the N-terminus of SIRT1 can directly interact with the PGC-1α D2 domain. Conclusions This study provides evidence that SFD and its active STI alleviate HRD by activating the AMPK/SIRT1/PGC-1α pathway to alleviate mitochondrial dysfunction and oxidative stress in renal epithelial cells.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Linfang Wu,Jing Wang,Yonghuan Yan,Lu Wang,Qi Huang,Jinyong Peng,Lili Li
Endometritis is a prevalent condition of the reproductive system that leads to significant tissue damage in the uterus, thereby seriously impacting the health and quality of life of these patients. Hesperidin (HES), a natural flavonoid glycoside, displays various biological activities. Nonetheless, the protective effect of HES treatment against endometritis remains uncertain. In this study, we examined the protective effects of HES on endometritis induced by lipopolysaccharide (LPS) both in vivo and in vitro . In vitro experimental results showed that HES reduced the levels of inflammatory factors, improved mitochondrial morphology, increased mitochondrial activity and inhibited ROS levels; moreover, it activated the AMPK/PGC-1 α signalling pathway in LPS-induced human endometrial endothelial cells (HEECs). AMPK served as a potential target of HES, which was further validated using molecular docking, molecular dynamic simulation, CETSA and SPR. Moreover, in vivo experimental results indicated that HES significantly mitigated the histopathological alterations in the uterus caused by LPS, as well as reduced the levels of inflammatory factors, MPO activity, the expression levels of CD38, and CD138 and activated the AMPK/PGC-1α signalling pathway. Overall, HES mitigated mitochondrial oxidative stress and inflammatory response primarily through activation of the AMPK/PGC-1α signalling pathway, thereby exerting protective effects against endometritis.
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Frontiers in Nutrition
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2026
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IF 5.5
Binhong Hu,Ling Yao,Xin Deng,Wei Zhao,Kuo Chen,Jiacheng Zhang,Zhiqiang Li,Jin-ping Li,Wei Jiang,Huabao Liu
AimsThis study aims to explore the potential therapeutic effect of Dendrobium officinale polysaccharide (DOP) on non-alcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD), and to elucidate the underlying mechanism involving the SIRT6/PGC-1α signaling axis and the regulation of the gut microbiota.MethodsWe extracted and characterized DOP. We established a rat model of NAFLD induced by HFD and evaluated the efficacy of DOP by integrating multi-omics techniques (transcriptomics, metabolomics) and 16S rRNA sequencing. To verify the specific role of SIRT6, we introduced the SIRT6 inhibitor OSS_128167 in the primary hepatocyte model induced by oleic acid/palmitic acid (OA/PA).ResultsDOP significantly alleviated liver steatosis, oxidative stress, and lipid metabolism disorders induced by HFD. Multi-omics analysis indicated that DOP regulated liver glycerophospholipid metabolism and restored intestinal microbiota homeostasis, significantly increasing the abundance of beneficial bacteria such as Lactobacillus. Mechanistically, DOP activated the liver SIRT6/PGC-1α signaling axis, thereby enhancing antioxidant defense and inhibiting lipogenesis. Crucially, in vitro experiments confirmed that the SIRT6 inhibitor OSS_128167 eliminated the protective effect of DOP on lipid accumulation, confirming that the effect of DOP depends on SIRT6.ConclusionDOP improves NAFLD through dual mechanisms of regulating the gut-liver axis homeostasis and directly activating the liver SIRT6/PGC-1α signaling pathway. The results of this study provide a theoretical basis for developing DOP as a drug for the treatment of NAFLD.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
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IF 5.195
Xiaohui Jin,Leilei Zhu,Shuaifei Lu,Caiyin Li,Ming Bai,Erping Xu,Jiduo Shen,Yucheng Li
Mitochondrial dysfunction has been reported to be involved in the pathogenesis of depression, and mitophagy is a key pathway for mitochondrial quality control. This study aimed to investigate the effect of baicalin on mitophagy in the hippocampus of mice exposed to chronic unpredictable mild stress (CUMS) and explore its potential mechanism. After exposure to CUMS for 6 weeks, mice were given baicalin (20 mg/kg) or fluoxetine (20 mg/kg) by oral gavage for 4 weeks, and HT22 cells were injured by corticosterone (CORT) in vitro. Depression-like behaviors were assessed by sucrose preference test and tail suspension test . The mitochondrial structure was observed by transmission electron microscopy . Detection of mitophagy and mitophagy-related protein by mitophagy kit and Western blot . The results showed that baicalin improved depressive-like behaviors in CUMS mice, and ameliorated mitochondrial structural impairment in the hippocampus neuron. Baicalin significantly down-regulated light chain 3(LC3)II/I, protein sequestosome 1 (P62), and translocase of the outer membrane 20 (TOM20), and up-regulated Nip-like protein (NIX), Adenylate activated protein kinase (AMPK), and Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α. Furthermore, molecular docking showed that baicalin interacts with AMPK through hydrogen bonding. Baicalin increased NIX and AMPK, and improved mitophagy level and mitochondrial function in HT22 cells. Treatment with Phorbol 12-Myristate 13-acetate demonstrated that up-regulation of NIX ameliorated CORT-induced mitochondrial dysfunction in HT22 cells. In conclusion, the present study suggested that the antidepressant effect of baicalin may be related to the enhancement of NIX-mediated mitophagy through activating the AMPK/PGC-1α pathway by directly binding to AMPK.
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