MOLECULAR AND CELLULAR ENDOCRINOLOGY
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2023
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IF 4.1
Huimin Chen,Yue Liu,Tingwei Zhang,Tongtong Huang,Yating Lang,Qinghao Sheng,Yingxiao Liu,Zhijuan Kong,Ying Gao,Shangwei Lu,Meilin Yang,Xia Li,Rong Wang,Zhimei Lv
Podocyte dysfunction has been identified as a crucial pathological characteristic of diabetic nephropathy (DN). However, the regulatory effects of long non-coding RNAs (lncRNAs) in this process have not been fully elucidated. Here, we performed an unbiased RNA-sequencing (RNA-seq) analysis of renal tissues and identified a significantly upregulated long non-coding RNA, ENST00000585189.1 (lncRNA 585189), in patients with DN. Furthermore, lncRNA 585189 was positively correlated with renal insufficiency and was upregulated in both DN patients and high-glucose-induced human podocytes. Gain- and loss-of-function experiments revealed that silencing lncRNA 585189 decreased the production of ROS, rescued aberrant mitochondrial morphology and membrane potential, and alleviated podocyte damage caused by high glucose. Mechanistically, bioinformatics analysis predicted an interaction between lncRNA 585189 and hnRNP A1, which was subsequently confirmed by RIP, pull-down, and EMSA assays. Further investigation revealed that lncRNA 585189 destabilizes the hnRNP A1 protein, leading to the downregulation of its expression. Conversely, hnRNP A1 promoted the expression of lncRNA 585189. Moreover, both RIP and pull-down assays demonstrated a direct interaction between hnRNP A1 and SIRT1, which enhanced SIRT1 mRNA stability. Our findings suggest that lncRNA 585189 suppresses SIRT1 through hnRNP A1, thereby hindering the recovery from mitochondrial abnormalities and podocyte damage. In summary, targeting lncRNA 585189 is a promising strategy for reversing mitochondrial dysfunction and treating DN.
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PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Man Hu,Wen Jiang,Chen Ye,Ting Hu,Qingqing Yu,Moran Meng,Lijuan Sun,Jichao Liang,Yong Chen
Schwann cells injury induced by high glucose (HG) contributes to the development of diabetic peripheral neuropathy (DPN). Honokiol has been reported to regulate glucose metabolism, however, its effect on DPN and the precise molecular mechanisms remain unclear. This study aimed to investigate the role of AMPK/SIRT1/PGC-1α axis in the protective effects of honokiol on DPN. The biochemical assay and JC-1 staining results demonstrated that honokiol reduced HG-induced oxidative stress and ferroptosis as well as mitochondrial dysfunction in Schwann cells. RT-qPCR and western blotting were utilized to investigate the mechanism of action of honokiol, and the results showed that HG-induced inhibition of AMPK/SIRT1/PGC-1α axis and changes of downstream gene expression profile were restored by honokiol. Moreover, silencing of Sirt1 by siRNA delivery markedly diminished the changes of gene expression profile induced by honokiol in HG-induced Schwann cells. More importantly, we found that administration of honokiol remarkably attenuated DPN via improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity in streptozotocin-induced diabetic rats. Collectively, these results demonstrate that honokiol can attenuate HG-induced Schwann cells injury and peripheral nerve dysfunction, suggesting a novel potential strategy for treatment of DPN.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2019
·
IF 3.585
Wu Luo,Yiyi Jin,Gaojun Wu,Weiwei Zhu,Yuanyuan Qian,Yali Zhang,Jieli Li,Aisong Zhu,Guang Liang
Diabetic cardiomyopathy (DCM) is a common and severe complication of diabetes. A multitude of factors are involved in the pathogenesis of DCM including chronic inflammation and oxidative stress . We have recently shown that compound LF10 prevents inflammatory responses in an animal model of lung injury. In the present study, we explored the protective effects and mechanism of LF10 against DCM using a mouse model of streptozotocin-induced diabetes and high glucose (HG)-challenged cultured cardiomyocytes. We show that LF10 suppressed diabetes-induced cardiomyocyte hypertrophy and fibrosis , which was accompanied by preservation of cardiac function in mice. Mechanistically, LF10 prevented increases in the levels of pro-inflammatory molecules and oxidative stress under in vitro and in vivo diabetic conditions. Moreover, LF10 restored HG-downregulated sirtuin 1 (SIRT1) in cardiomyocytes and prevented HG-induced activation of MAPKs. Using specific small-molecule regulators, we found that SIRT1 was an upstream signal of MAPKs. In conclusion, LF10 inhibited ROS and MAPKs-mediated inflammation by restoring SIRT1, and prevented development of DCM. LF10 targeted both oxidative stress and inflammation, two tightly interconnected pathogenic pathways, which makes LF10 a highly advantageous therapeutic drug potential.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Jiajun Yang,Siyu Hou,Yuhui Zhao,Zhaoyang Sun,Lilin Zhang,Yan Deng,Xiaoli Shang,Hanjie Yu,Zheng Li,Hongmei Li
The antidiabetic activity of the novel Buckwheat protein-derived peptide (Ala-Phe-Tyr-Arg-Trp, AFYRW) and its associated protein glycosylation have been verified. Our preliminary study demonstrates the potential of AFYRW as a therapeutic agent for diabetes, but the mechanism needs further investigation. Given the vital role of O-linked N -acetylglucosamine transferase (OGT) in diabetes mellitus and insulin resistance (IR), we focused on the underlying molecular mechanisms of them in ameliorating IR. We found AFYRW protects against hyperglycemia in diabetic mice and improves glucose metabolism in an IR cell model. Mechanistically, we demonstrated that AFYRW decreases glutamine-fructose-6-phosphate amidotransferase (GFAT) expression via X-box binding protein 1 (XBP1) in the hexosamine biosynthesis pathway (HBP), consequently decreasing OGT and stimulating the SIRT1/PGC1α pathway. Of note, the overlapping roles of increased SIRT1 and decreased OGT caused by AFYRW ameliorated IR. The data presented here show that AFYRW contributes to metabolism by directly controlling glucose homeostasis. Taken together, our study unveils that AFYRW protects against both insulin resistance and diabetes mellitus-induced hyperglycemia through OGT to regulate the SIRT1/PGC1α pathway, which provides a mechanistic basis for novel AFYRW to be a potential therapeutic agent.
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ACTA PHARMACOLOGICA SINICA
·
2024
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IF 6.9
Han Yan-lu,Yan Teng-teng,Li Hua-xin,Chen Sha-sha,Zhang Zhen-zhen,Wang Meng-yao,Chen Mei-jie,Chen Yuan-li,Yang Xiao-xiao,Wei Ling-ling,Duan Ya-jun,Zhang Shuang
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L -NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3β, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 μM) significantly alleviated H 2 O 2 -induced oxidative stress through the MMP2/SIRT1/GSK3β pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3β, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3β signaling pathway.
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CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 2
·257-263
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IF 1.5
Qingzhi Wan,Lisha Tang,Kaili Jin,Xuanyi Chen,Yinghuan Li,Xiaofeng Xu
Granulosa cells are somatic cells located inside follicles that play a crucial role in the growth and development of follicles. Quercetin and tanshinone are two key monomers in traditional Chinese medicine that have antioxidant and anti-aging properties. The KGN cell apoptosis model caused by triptolide (TP) was employed in this work to investigate granulosa cell death and medication rescue. Quercetin and tanshinone therapy suppressed KGN cell death and oxidation while also regulating the expression of critical apoptosis and oxidation-related markers such as B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). Further research revealed that the effects of Quercetin and Tanshinone were accomplished via deacetylation of FOXO3A in the cytoplasm and mitochondria via the SIRT1/SIRT3-FOXO3a axis. In summary, Quercetin and tanshinone protect KGN cells from apoptosis by reducing mitochondrial apoptosis and oxidation via the SIRT1/SIRT3-FOXO3a axis.
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Journal of Functional Foods
·
2024
·
IF 3.8
Ya-wen Zhang,Yue-ru Shen,Hong-yu Zhang,Huai-tong Yao,Bing Hu
Sleep is essential to animals with circadian rhythms. Sleep deprivation causes serious pathophysiological consequences, such as DNA damage and oxidative stress. Pyrroloquinoline quinone (PQQ) is a bioactive food ingredient with antioxidant properties. Here, we used zebrafish continuous swimming paradigm sleep deprivation model to investigate the effect of PQQ on DNA damage. We found that DNA damage and neuronal activity increase following sleep deprivation. PQQ pretreatment reduced DNA damage in the zebrafish dorsal pallium. As an antioxidant, PQQ effectively inhibited reactive oxygen species (ROS) production induced by 2,2′-azobis-2-methyl-propanimidamide dihydrochloride (AAPH) and sleep deprivation, and upregulated the expression of antioxidant genes sod1 and gpx4b . Also, PQQ ameliorated the decreased silent information regulator 1 (SIRT1) expression level, suggesting that PQQ may remove excessive ROS by activating SIRT1, thereby reducing DNA damage within neurons. This study indicates that PQQ has strong antioxidant function, provides ideas for further development of ingredients for sleep recovery.
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PHYTOTHERAPY RESEARCH
·
2024
·
IF 6.1
Gang Kuang,Yisi Zhao,Liuyang Wang,Tingyu Wen,Panting Liu,Bei Ma,Qiaozhi Peng,Fang Xu,Lin Ye,Jing Fan
Acute hepatic injury (AHI) is associated with poor prognosis in sepsis patient; however, to date, no specific therapeutic approach has been established for this disease. Therefore, we aimed to explore the effects and action mechanisms of Astragaloside IV (AS) on AHI. C57BL/6 mice, RAW264.7 cells, and bone marrow-derived macrophages were used in this study. Sepsis-associated AHI model mice were established using lipopolysaccharide + D-galactosamine. Pathological examination of liver tissues and serum alanine aminotransferase/aspartate aminotransferase was performed to evaluate the liver function. Moreover, inflammatory cytokine levels, proportion of M1/M2 macrophages and their marker levels, and cell pyroptosis-related indicator levels were determined in the liver of the AHI model mice with or without AS treatment. AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) expression was determined after AS treatment. Additionally, inflammatory cytokine levels, liver injury, and macrophage polarization were evaluated after inhibiting the AMPK/SIRT1 pathway. AS alleviated lipopolysaccharide + D-galactosamine-induced AHI and inhibited inflammatory reactions in the blood and liver of mice. AS also promoted the M1-to-M2 phenotypic transformation of macrophages in the liver of AHI model mice and in vitro, thereby decreasing the pro-inflammatory cytokine levels and increasing the anti-inflammatory cytokine levels. AS increased AMPK and SIRT1 levels in the liver and macrophages. Furthermore, AS improved liver injury by elevating the expression of the AMPK/SIRT1 signaling pathway and inhibiting pyroptosis in macrophages. Overall, AS alleviated AHI by promoting M1-to-M2 macrophage transformation and inhibiting macrophage pyroptosis via activation of the AMPK/SIRT1 signaling pathway.
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JOURNAL OF BIOTECHNOLOGY
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2026
·
IF 4
Mengjun Sun,Chunliu Mi,Tiantian Dong,Jingwen Xue,Yan Lin,Shaolei Geng,Qiuli Sun,Xinjian Chang,Tianyun Wang
7,8-DHF enhances recombinant protein expression 1.5-1.6 fold and reduces antibody aggregation by 6.0% in CHO cells. • 7,8-DHF elevates NAD+ to activate SIRT1-PGC-1β, improving mitochondrial energy synthesis and reducing lactate. • 7,8-DHF upregulates BCL-2 and downregulates BAX/cleaved caspase-3, inhibiting apoptosis in CHO cells. • 7,8-DHF acts as a metabolic modulator to overcome aerobic glycolysis limitations in biopharmaceutical production. Chinese hamster ovary (CHO) cells serve as a critical mammalian system for producing therapeutic proteins in biopharmaceuticals. However, these cells exhibit highly active aerobic glycolysis during culture, which leads to reduced energy conversion efficiency and excessive lactic acid accumulation. This metabolic dysregulation can further impair cell growth and recombinant protein expression. Enhancing the endogenous NAD⁺ level is critical for improving cellular metabolism; however, current technical approaches face significant challenges. In the present study, we found that 7,8-dihydroxyflavone increased the expression of recombinant proteins in CHO cells by 1.6- and 1.5-fold, respectively, while reducing antibody aggregation by approximately 6.0%. Transcriptome and metabolic pathway analyses revealed that the elevated intracellular NAD⁺ content activated the SIRT1-PGC-1β pathway, which modulates mitochondrial energy synthesis and enhances antioxidant capacity while mitigating lactate accumulation in the glycolytic pathway. Furthermore, 7,8-dihydroxyflavone significantly inhibited apoptosis by upregulating BCL-2 expression and downregulating BAX and cleaved caspase-3 expression. Taken together, these findings indicate that 7,8-dihydroxyflavone may serve as a promising metabolic modulator for recombinant protein production.
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LABORATORY INVESTIGATION
·
2020
·Vol. 100
·期 9
·1223-1237
·
IF 4.197
Kong Huimin,Wang Huaili,Zhuo Zhihong,Li Zhenbiao,Tian Peichao,Wu Jing,Liu Jian,Chen Zheng,Zhang Jiyao,Luo Qiang
MicroRNAs regulate gene expression at the posttranscriptional level, and this process has been shown to be implicated in the pathological processes of temporal lobe epilepsy. At present, studies about the impact of microRNA-181a (miR-181a) on epilepsy have focused on hippocampal neurons, and the effect of miR-181a on other cells in the hippocampus remains poorly understood. Herein, we explored the role of miR-181a-5p in a lithium-pilocarpine model of epilepticus in immature rats. We found that the hippocampal expression level of miR-181a-5p was increased. Inhibition of miR-181a-5p protected the hippocampus against epilepsy, including hippocampal insults, neuronal apoptosis, astrocyte and microglia activation, neuroinflammation, oxidative stress, mitochondrial function, and cognitive dysfunction. Moreover, miR-181a-5p inhibition exerted a seizure-suppressing effect via SIRT1 upregulation. Overall, our findings reveal the potential role of the miR-181a-5p/SIRT1 pathway in the development of temporal lobe epilepsy, and this pathway may represent a novel target for ameliorating epilepsy and its sequelae.
研究领域:
神经科学
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分子生物学
·
药理学
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Journal of Advanced Research
·
2026
·
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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APOPTOSIS
·
2023
·Vol. 28
·期 3
·607-626
·
IF 7.2
Yu Li-Ming,Dong Xue,Huang Tao,Zhao Ji-Kai,Zhou Zi-Jun,Huang Yu-Ting,Xu Yin-Li,Zhao Qiu-Sheng,Wang Zhi-Shang,Jiang Hui,Yin Zong-Tao,Wang Hui-Shan
Ferroptosis contributes to the pathogenesis of atrial fibrillation (AF), although the mechanisms are still largely uncovered. The current study was designed to explore the pharmacological effects of icariin against ethanol-induced atrial remodeling, if any, and the mechanisms involved with a focus on SIRT1 signaling. Excessive ethanol-treated animals were administered with Ferrostatin-1, Erastin or icariin to evaluate the potential effects of icariin or ferroptosis. Then, the underling mechanisms was further explored in the in vitro experiments using HL-1 atrial myocytes. Excessive ethanol administration caused significant atrial damage as evidenced by increased susceptibility to AF, altered atrial conduction pattern, atrial enlargement, and enhanced fibrotic markers. These detrimental effects were reversed by Ferrostatin-1 or icariin treatment, while Erastin co-administration markedly abolished the beneficial actions conferred by icariin. Mechanistically, ethanol-treated atria exhibited markedly up-regulated pro-ferroptotic protein (PTGS2, ACSL4, P53) and suppressed anti-ferroptotic molecules (GPX4, FTH1). Icariin treatment inhibited ethanol-induced atrial ferroptosis by reducing atrial mitochondrial damage, ROS accumulation and iron overload. Interestingly, the in vivo and in vitro data showed that icariin activated atrial SIRT1-Nrf-2-HO-1 signaling pathway, while EX527 not only reversed these effects, but also abolished the therapeutic effects of icariin. Moreover, the stimulatory effects on GPX4, SLC7A11 and the suppressive effects on ACSL4, P53 conferred by icariin were blunted by EX527 treatment. These data demonstrate that ferroptosis plays a causative role in the pathogenesis of ethanol-induced atrial remodeling and susceptibility to AF. Icariin protects against atrial damage by inhibiting ferroptosis via SIRT1 signaling. Its role as a prophylactic/therapeutic drug deserves further clinical study.
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