Advanced Science
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2024
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IF 14.3
Qiwen Yu,Jiakai Zhang,Jiye Li,Yaodong Song,Jie Pan,Chaopeng Mei,Mengwei Cui,Qianqian He,Haifeng Wang,Huihui Li,Bo Cheng,Yan Zhang,Wenzhi Guo,Changju Zhu,Sanyang Chen
Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP-induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5-ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention.
研究领域:
肝病学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
BMC Ophthalmology
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2020
·Vol. 20
·期 1
·1-10
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IF 1.413
Yan Weiming,Long Pan,Wei Dongyu,Yan Weihua,Zheng Xiangrong,Chen Guocang,Wang Jiancong,Zhang Zuoming,Chen Tao,Chen Meizhu
Background Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats.Methods Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted.Results Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.Conclusion sTogether, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.
研究领域:
眼科学
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药理学
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神经科学
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DOI
PubMed
高影响因子
TALANTA
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2020
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IF 5.339
Qidi He,Meng Chen,Xiangan Lin,Zuanguang Chen
Single nucleotide polymorphism (SNP) analysis based on allele-specific polymerase chain reaction (AS-PCR) is a relatively effective and economical method compared with other genotyping technologies such as DNA sequencing, DNA hybridization and isothermal amplification strategies. But AS-PCR is limited by its labor-intensive optimization of reaction parameters and time-consuming result assessment. In this study, we put forward a novel idea of data processing to address this problem. SNP analysis was accomplished by AS-PCR with endpoint electrochemical detection . For each sample, two separate reactions were run simultaneously with two sets of allele-specific primers (wild-type primers for W system and mutant primers for M system). We measured their redox current signals on screen-printed electrodes once AS-PCR finished and calculated the difference value of current signals between two systems to determine the genotyping result. Based on the difference value of fluorescent signals, real-time fluorescent PCR was used to study reaction parameters in AS-PCR. With screened parameters, we obtained the genotyping results within 50 min. 36 hair-root samples from volunteers were analyzed by our method and their genotypes of ALDH2 gene (encoding aldehyde dehydrogenase 2) were totally identical with data from commercialized sequencing. Our work first employed difference value between two reaction systems to differentiate allele and provided a novel idea of data processing in AS-PCR method. It is able to promote the quick analysis of SNP in the fields of health monitor, disease precaution, and personalized diagnosis and treatment.
研究领域:
分子生物学
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遗传学
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生物医学工程
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Guangyao Shan,Yunyi Bian,Guangyu Yao,Jiaqi Liang,Haochun Shi,Zhengyang Hu,Zhaolin Zheng,Guoshu Bi,Hong Fan,Cheng Zhan
Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and associated with drug resistance in lung adenocarcinoma (LUAD). It's found that aldehyde dehydrogenase 2 (ALDH2), which is highly mutated in East Asian populations, is correlated with response to chemotherapy in LUAD patients. The rs671 variant knock-in, downregulation, and pharmacological inhibition of ALDH2 render LUAD cells more vulnerable to ferroptosis inducers and platinum-based chemotherapy. ALDH2 inhibits ferroptosis through the detoxification of 4-hydroxynonenal and malondialdehyde, the product of lipid peroxidation, as well as the production of NADH at the same time. Besides, ALDH2 deficiency leads to elevated intracellular pH (pHi), thus inhibiting the ERK/CREB1/GPX4 axis. Interestingly, ALDH2 is also regulated by CREB1, and the ALDH2 enzyme activity was decreased with elevated pHi. What's more, the elevated pHi caused by impaired ALDH2 activity promotes the biosynthesis of lipid droplets to counteract ferroptosis. At last, the effect of ALDH2 on ferroptosis and chemosensitivity is confirmed in patient-derived organoids and xenograft models. Collectively, this study demonstrates that ALDH2 deficiency confers sensitivity to platinum through ferroptosis in LUAD, and targeting ALDH2 is a promising new strategy to enhance the sensitivity of platinum-based chemotherapy for the treatment of LUAD patients.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2024
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IF 4.4
Zheng-Ming Cao,Su Fu,Chao Dong,Teng-Yue Yang,Xiao-Kang Liu,Chun-Lin Zhang,Dong-Zhe Li
The progression of osteoarthritis (OA) includes the initial inflammation, subsequent degradation of the extracellular matrix (ECM), and chondrocyte apoptosis. Down syndrome candidate region 1 (DSCR1) is a stress-responsive gene and expresses in varied types of cells, including chondrocytes. Bioinformatics analysis of GSE103416 and GSE104739 datasets showed higher DSCR1 expression in the inflamed cartilage tissues and chondrocytes of OA. DSCR1 had two major isoforms, isoform 1 (DSCR1–1) and isoform 4 (DSCR1–4). We found that DSCR1–1 had a faster ( in vitro ) and higher expression ( in vivo ) response to OA compared to DSCR1–4. IL-1β-induced apoptosis, inflammation, and ECM degradation in chondrocytes were attenuated by DSCR1–1 overexpression. DSCR1–1 triggered the phosphorylation of cAMP response element-binding 1 (CREB1) at 133 serine sites by decreasing calcineurin activity. Moreover, activated CREB1 moved into the cell nucleus and combined in the promoter regions of aldehyde dehydrogenase 2 (ALDH2), thus enhancing its gene transcription. ALDH2 could recover Wnt/β-catenin signaling transduction by enhancing phosphorylation of β-catenin at 33/37 serine sites and inhibiting the migration of β-catenin protein from the cellular matrix to the nucleus. In vivo , adenoviruses (1 × 10 8 PFU) overexpressing DSCR1–1 were injected into the articular cavity of C57BL/6 mice with medial meniscus surgery-induced OA, and it showed that DSCR1–1 overexpression ameliorated cartilage injury. Collectively, our study demonstrates that DSCR1–1 may be a potential therapeutic target of OA.
研究领域:
骨科
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Zhen-yan Song,Wen-jing Yu,Yi-jie Jin,Meng-fen Zhou,Chun-xiang He,Ze Li,Jia-wei He,Qi Chen,Ping Li,Yaqiao Yi,Shao-wu Cheng
Ethnopharmacological relevance Derived from the plant Scutellaria baicalensis Georgi, baicalin is a naturally occurring flavonoid, has demonstrated anti-inflammatory, neuroprotective, hypoglycemic, and lipid-lowering properties. While its effects on Alzheimer's disease (AD) or type 2 diabetes mellitus (T2DM) have been studied individually, its therapeutic role in AD comorbid with T2DM remains unclear. Aim of the study This study aims to explore the potential therapeutic mechanisms associated with baicalin through a rat model featuring AD combined with T2DM. Materials and methods A dual-pathology rat model was developed using a streptozotocin (STZ) and a high-fat dietary regimen injections to induce T2DM, followed by intracerebroventricular STZ to induce AD pathology. Behavioral tests, biochemical assays, histological analyses, qPCR, and Western blotting were used to evaluate baicalin's effects. Untargeted metabolomics was applied to profile metabolic alterations, while network pharmacology and molecular docking were integrated to predict key targets and pathways. Finally, cellular thermal shift assay (CETSA) was conducted to validate the direct binding of baicalin to core proteins. Results Baicalin significantly improved cognitive performance, ameliorated glucose and lipid metabolism, and suppressed neuroinflammation in AD-T2DM rats. Metabolomics identified disruptions in energy metabolism, amino acid metabolism, and purine metabolism pathways. Network pharmacology analysis revealed ALDH2, NOS2, GOT1, GPT, and XDH as key targets associated with these metabolic disturbances. Molecular docking demonstrated strong binding affinities between baicalin and the identified targets. qPCR confirmed the regulation of ALDH2 and NOS2 gene expression by baicalin, and CETSA experiments further validated the thermal stabilization of these proteins, supporting direct interactions in vivo. Conclusions Baicalin exerts therapeutic effects by targeting ALDH2 and NOS2 to modulate arginine and proline metabolism and regulate key metabolites such as GABA and L-arginine. This mechanism improves neuronal function and insulin sensitivity, highlighting baicalin as a promising multi-target treatment for AD with T2DM.
研究领域:
药理学
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神经科学
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内分泌学
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代谢组学
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民族药理学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Zixin Li,Luchen Shan,Pei Yu
Nitroglycerin (NTG) is recommended as the first-line drug in angina pectoris though its prolonged use impacts nitroglycerin tolerance. In this study, we investigated the preventive effect of Tetramethylpyrazine (TMP), a famous Chinese medicine used for cardiovascular diseases, on NTG-induced tolerance and further explained the underlying mechanism of its action. The results revealed that pretreatment of TMP improved NTG-induced tolerance in vitro thoracic aorta rings and in rats. Proteomic analysis showed oxidative stress and ribosome proteins dyshomeostasis in NTG-tolerance vessels. TMP attenuated the oxidative stress by enhancing the protein expression of ALDH2 , Nrf2 and HO-1. In addition, TMP recovered the down-regulated expression of RpL10a induced by nitroglycerin. Therefore, TMP could prevent nitroglycerin tolerance in rats, which may be mediated by up-regulation of ALDH2 and Nrf2/HO-1 signaling pathway and involved in the restoration of ribosome homeostasis . These findings indicate the potential of TMP as a promising medicine for preventing the development of nitroglycerin-induced tolerance.
研究领域:
心血管药理学
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分子生物学
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药物动力学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
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IF 5.195
Qing Yang,Xubo Wu,Zhiyu Pan,Ruifang Guan,Ping Yang,Ye Liu,Xiaolei Yang,Wandi Du,Jingru Liang,Jiarong Hu,Weimin Cai,Guo Ma
Ethnopharmacological relevance As one of the most commonly used herbs, Artemisia capillaris Thunb. (ACT) display favorable effect in the treatment of jaundice. However, mechanism of ACT in the treatment of jaundice remains unclear at present, which limits its development and application. Aim of the study To investigate effect and mechanism of Artemisia capillaris Thunb. (ACT) in the treatment of jaundice using pharmacodynamics , network pharmacology and metabolomics. Methods Effect of ACT in treating jaundice was evaluated by biochemical assays and pathological observation using the α-naphthyl isothiocyanate (ANIT)-induced mice. Jaundice-relieving mechanism of ACT was investigated by integration of network pharmacology and metabolomics. Results After the mice with jaundice were administrated ACT extract for 9 days, compared to that of the model group, serum D-BIL, T-BIL and ALP levels of the mice in the low, medium, high dose of ACT group decreased by 39.81%, 15.30% and 16.92%; 48.06%, 42.54% and 36.91%; 26.90%, 12.34% and 16.90%, respectively. The pathologic study indicated that ACT improved the symptoms of liver injury of the mice with jaundice. The network of herb (i.e., ACT)-components-targets-disease (i.e., jaundice) was established, which consisted of 17 components classified in flavonoids , chromones , organic acids, terpenoids , and 234 targets related to treatment of jaundice. Metabolomics analysis showed that, compared to that in the model group, level of 8 differential metabolites were upregulated and level of 29 differential metabolites were downregulated in the mice liver in the ACT group, respectively. The main metabolic pathways involved in treatment of jaundice by ACT were pantothenate and CoA biosynthesis, glutathione metabolism, biosynthesis of unsaturated fatty acids , primary bile acid biosynthesis in the liver, respectively. The integrated analysis of network pharmacology and metabolomics showed that 3α,7α,12α a-Trihydroxy-5β-cholanate, glycocholate , taurocholate , pantetheine 4′-phosphate, and d-4′-phosphopantothenate were the potential biomarkers for treatment of jaundice, and AKR1C4, ALDH2 and HSD11B were the potential drug targets in the treatment of jaundice by ACT. Conclusion The study based on metabolomics and network pharmacology indicated that ACT can display favorable jaundice-relieving effect by its multiple components regulating multiple biomarkers, multiple targets and multiple pathways, and may be a rational therapy for the treatment of jaundice.
研究领域:
药理学
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网络生物学
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代谢组学
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民族药理学
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肝病学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Lei Qian,Hu Xu,Ruqiang Yuan,Weijing Yun,Yufang Ma
Formononetin, an isoflavone compound, has been extensively researched due to its various biological activities, including a potent protective effect on the cardiovascular system. However, the impact of formononetin on cardiac fibrosis has not been investigated. In this study, C57BL/6 mice were used to establish cardiac fibrosis animal models by subcutaneous injecting of isoproterenol (ISO) and formononetin was orally administrated. The results showed that formononetin reversed ISO-induced heart stiffness revealed by early-to-atrial wave ratio (E/A ratio). Masson staining, western blot, immunohistochemistry and real-time PCR exhibited that the cardiac fibrosis and fibrosis-related proteins (collage III, fibronectin, TGF-β1, α-SMA, and vimentin) and genes ( Col1a1 , Col3a1 , Acta2 and Tgfb1 ) induced by ISO were significantly suppressed by formononetin. Furthermore, by combining metabolomics and network pharmacology, we found three important targets ( ALDH2 , HADH , and MAOB ), which are associated with mitochondrial function, were involved in the beneficial effect of formononetin. Further validation revealed that these three genes were more abundance in cardiomyocyte than in cardiac fibroblast. The mRNA expression of ALDH2 and HADH were decreased, while MOAB was increased in cardiomyocyte upon ISO treatment and these phenomena were reversed by formononetin. In addition, we investigated mitochondrial membrane potential and ROS production in cardiomyocytes, the results showed that formononetin effectively improved mitochondrial dysfunction induced by ISO. In summary, we demonstrated that formononetin via regulating the expressions of ALDH2 , HADH, and MAOB in cardiomyocyte to improve mitochondrial dysfunction and alleviate β-adrenergic activation cardiac fibrosis.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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代谢组学
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网络药理学
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产品关联
DOI
PubMed
高影响因子
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