PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Li Liang,Weiliang Sun,Xiaoxuan Wei,Li Wang,Huaqiang Ruan,Junchuan Zhang,Suyan Li,Bi Zhao,Mengshi Li,Zhengwen Cai,Jie'an Huang
Chinese herb Radix sophorae tonkinensis extract oxymatrine shows anticancer effects. This study evaluated the role of oxymatrine in colorectal cancer (CRC) and the underlying molecular events in vitro and in vivo. CRC cells were treated with different doses of oxymatrine to assess cell viability, reactive oxygen species production, gene expression, and gene alterations. Meanwhile, mouse xenograft and liver metastasis models were used to assess the effects of oxymatrine using histology examination, transmission electron microscopy, and Western blot, respectively. Our results showed that oxymatrine treatment triggered CRC cell mitophagy to inhibit CRC cell growth, migration, invasion, and metastasis in vitro and in vivo. At the gene level, oxymatrine inhibited LRPPRC to promote Parkin translocation into the mitochondria and reduce the mitophagy-activated NLRP3 inflammasome. Thus, oxymatrine had an anticancer activity through LRPPRC inhibition, mitophagy induction, and NLRP3 inflammasome suppression in the CRC cell xenograft and liver metastasis models. In conclusion, the study demonstrates the oxymatrine anti- CRC activity through its unique role in regulating CRC cell mitophagy and NLRP3 inflammasome levels in vitro and in vivo.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Neuroscience Bulletin
·
2020
·Vol. 36
·期 4
·346-358
·
IF 4.326
Su Cun-Jin,Shen Zhu,Cui Ru-Xiao,Huang Ya,Xu De-Lai,Zhao Feng-Lun,Pan Jie,Shi Ai-Ming,Liu Tong,Yu Yun-Li
Patients with diabetes mellitus have a higher risk of developing Parkinson’s disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.
研究领域:
神经科学
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分子生物学
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细胞生物学
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糖尿病研究
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神经退行性疾病
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PubMed
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2024
·Vol. 28
·期 12
·e18407
·
IF 4.3
Zijun Zhou,Qiusheng Zhao,Yuting Huang,Shan Meng,Xin Chen,Guoxin Zhang,Yanbang Chi,Dengyue Xu,Zongtao Yin,Hui Jiang,Liming Yu,Huishan Wang
Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2024
·
IF 3.5
Wang Liwei,Zhang Lu,Yun Yang,Liang Tingting,Yan Chaoqun,Mao Zhuoya,Zhang Jingfang,Liu Baoshe,Zhang Jian,Liang Taigang
Occupational and unintentional exposure of zinc oxide nanoparticles (ZnONPs) raises concerns regarding their neurotoxic potential and there is an urgent need for the development of effective agents to protect against the toxic effects of ZnONPs. Astragalus memeranaceus (AM), a famous Traditional Chinese Medicine, as well as its bioactive components, showing a potential neuroprotective function. This study aims to investigate the neuroprotective effects of bioactive components of AM against ZnONPs-induced toxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. The cell apoptosis, ROS generation, MMP changes, mitochondrial fission/fusion, biogenesis, and mitophagy were assessed. In this study, AM treatment inhibited ZnONPs-induced cell apoptosis and ROS overproduction in SH-SY5Y cells. And astragaloside IV (ASIV) played a dominant role in the attenuation of cytotoxicity after ZnONPs exposure, rather than flavonoids and polysaccharides. ASIV treatment significantly reduced ROS generation and MMP collapse in ZnONPs-exposed cells. Furthermore, the protein expressions of mitochondrial biogenesis (PGC-1α), fusion (Mfn1 and Mfn2), and fission (Drp1) were markedly increased. Meanwhile, the PINK1/Parkin-mediated mitophagy was activated after ASIV administration, which ameliorated ZnONPs-induced SH-SY5Y cell death. Collectively, ASIV administration mitigated ZnONPs-induced cytotoxicity in SH-SY5Y cells through restoring mitochondrial quality control process, which hinted the protective role of ASIV in ZnONPs-induced neurotoxicity. Graphical abstract
研究领域:
药理学
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毒理学
·
神经科学
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细胞生物学
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DOI
PubMed
高影响因子
Nature Communications
·
2022
·Vol. 13
·期 1
·1-12
·
IF 17.694
Zhai Yansheng,Huang Xiaoyan,Zhang Keren,Huang Yuchen,Jiang Yanlong,Cui Jingwei,Zhang Zhe,Chiu Cookson K. C.,Zhong Weiye,Li Gang
Enzymatic-based proximity labeling approaches based on activated esters or phenoxy radicals have been widely used for mapping subcellular proteome and protein interactors in living cells. However, activated esters are poorly reactive which leads to a wide labeling radius and phenoxy radicals generated by peroxide treatment may disturb redox-sensitive pathways. Herein, we report a photoactivation-dependent proximity labeling (PDPL) method designed by genetically attaching photosensitizer protein miniSOG to a protein of interest. Triggered by blue light and tunned by irradiation time, singlet oxygen is generated, thereafter enabling spatiotemporally-resolved aniline probe labeling of histidine residues. We demonstrate its high-fidelity through mapping of organelle-specific proteomes. Side-by-side comparison of PDPL with TurboID reveals more specific and deeper proteomic coverage by PDPL. We further apply PDPL to the disease-related transcriptional coactivator BRD4 and E3 ligase Parkin, and discover previously unknown interactors. Through over-expression screening, two unreported substrates Ssu72 and SNW1 are identified for Parkin, whose degradation processes are mediated by the ubiquitination-proteosome pathway.
研究领域:
蛋白质组学
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细胞生物学
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分子生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2026
·
IF 4.3
Ngwe Phar Ku,Zhu Jing,Ling Hao,Gao Mengmeng,Guo Chengxiang,Hu Yinan,Wang Jicang
Lead (Pb), a persistent and highly toxic environmental contaminant, induces severe multi-organ toxicity, with the liver as a primary target. Naringenin (Nar), a natural flavonoid with established antioxidant properties, shows potential in mitigating chemical-induced liver injury; however, its protective mechanism against Pb hepatotoxicity remains unclear. This study investigated the hepatoprotective effects and underlying mechanisms of Nar in Pb-exposed rats. Thirty-six five-week-old male Sprague-Dawley rats were randomly assigned to six groups ( n = 6): control, three Pb-treated groups (15, 30, and 60 mg/kg), co-treatment group (60 mg/kg Pb + 50 mg/kg Nar), and Nar-alone group (50 mg/kg). After 8 weeks, Pb exposure induced significant liver injury, evidenced by histopathological lesions (e.g., central venous congestion and inflammation), elevated serum levels of ALT, AST, and LDH, and oxidative stress (increased MDA; decreased CAT, T-SOD, and GSH). At the molecular level, Pb exposure suppressed the Nrf2/NQO1 pathway, upregulated Keap1, and impaired autophagic flux, as indicated by a decreased LC3-II/LC3-I ratio, accumulated p62, and a disrupted PINK1/Parkin pathway. Corroborating the impaired flux, transmission electron microscopy (TEM) revealed an accumulation of autophagic vacuoles, indicative of blocked autophagic degradation. Crucially, Nar co-treatment effectively mitigated these Pb-induced disturbances by activating the Nrf2/NQO1 pathway to counteract oxidative stress and restored autophagic flux, which was supported by the reversal of p62 accumulation and normalization of the LC3-II/LC3-I ratio. In conclusion, Nar protects against Pb-induced hepatotoxicity by concurrently alleviating oxidative stress and restoring autophagic function, supporting its potential as a therapeutic agent. Graphical
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PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 10
·4582-4590
·
IF 5.396
Xue-Yan Dai,Yi Zhao,Jing Ge,Shi-Yong Zhu,Mu-Zi Li,Milton Talukder,Jin-Long Li
Lycopene (Lyc) has been discussed as a potential effector in the prevention and therapy of various diseases. Di(2-ethylhexyl) phthalate (DEHP) is regarded as a universal environmental pollutant. To clarify the potential protective effect of Lyc on DEHP-induced splenic injury, 140 male mice were randomized into seven groups: control (distilled water), vehicle control (corn oil per day), Lyc (5 mg per kg BW per day), DEHP (500 or 1000 mg per kg BW per day), and DEHP combined Lyc group, respectively. All experimental animals were treated by oral gavage for 28 days. The results that showed DEHP exposure significantly up-regulated the mRNA and protein expression of the sirtuin family (except SIRT4-5), PGC-1α, OPA1, Drp1, MFN1/2, NRF1, TFAM, Parkin and PINK in DEHP-treated alone groups and the SOD2 and LC3-II protein expression were also in accordance with the above changes. These were accompanied with an increase of the number of inflammatory cells and rate of mitochondrial damage, and autophagosome formation in the spleen. Notably, Lyc supplementation facilitated all these changes to effectively return to the normal level, indicating that Lyc exerts protective effects against DEHP-induced splenic toxicity. Altogether, the protective effects of Lyc may be a strategy to ameliorate DEHP-induced spleen damage.
研究领域:
毒理学
·
药理学
·
分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Yi Wang,Nahui Liu,Lifan Hu,Jingsong Yang,Mengmeng Han,Tianjiao Zhou,Lei Xing,Hulin Jiang
Leber’s hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing it. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
研究领域:
眼科学
·
线粒体生物学
·
纳米技术
·
治疗学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Wen-Qiao Qiu,Wei Ai,Feng-Dan Zhu,Yue Zhang,Min-Song Guo,Betty Yuen-Kwan Law,Jian-Ming Wu,Vincent Kam-Wai Wong,Yong Tang,Lu Yu,Qi Chen,Chong-Lin Yu,Jian Liu,Da-Lian Qin,Xiao-Gang Zhou,An-Guo Wu
Activation of the NLRP3 inflammasome and its mediated neuroinflammation are implicated in neurodegenerative diseases, while mitophagy negatively regulates NLRP3 inflammasome activation. SHP-2, a protein-tyrosine phosphatase, is critical for NLRP3 inflammasome regulation and inflammatory responses. In this study, we investigated whether triterpenoid saponins in Radix Polygalae inhibit the NLRP3 inflammasome via mitophagy induction. First, we isolated the active fraction (polygala saponins (PSS)) and identified 17 saponins by ultra-performance liquid chromatography coupled with diode-array detection and tandem quadrupole time-of-flight mass spectrometry (UHPLC-DAD-Q/TOF-MS). In microglial BV-2 cells, PSS induced mitophagy as evidenced by increased co-localization of LC3 and mitochondria, as well as an increased number of autophagic vacuoles surrounding the mitochondria. Furthermore, the mechanistic study found that PSS activated the AMPK/mTOR and PINK1/parkin signaling pathways via the upregulation of SHP-2. In Aβ(1-42)-, A53T-α-synuclein-, or Q74-induced BV-2 cells, PSS significantly inhibited NLRP3 inflammasome activation, which was attenuated by bafilomycin A1 (an autophagy inhibitor) and SHP099 (an SHP-2 inhibitor). In addition, the co-localization of LC3 and ASC revealed that PSS promoted the autophagic degradation of the NLRP3 inflammasome. Moreover, PSS decreased apoptosis in conditioned medium-induced PC-12 cells. In APP/PS1 mice, PSS improved cognitive function, ameliorated Aβ pathology, and inhibited neuronal death. Collectively, the present study, for the first time, shows that PSS inhibit the NLRP3 inflammasome via SHP-2-mediated mitophagy in vitro and in vivo, which strongly suggests the therapeutic potential of PSS in various neurodegenerative diseases.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经退行性疾病
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DOI
PubMed
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2018
·
IF 6.5
Chengyong He,Shengwei Jiang,Huan Yao,Liyin Zhang,Chuanli Yang,Shan Jiang,Fengkai Ruan,Denglin Zhan,Gang Liu,Zhongning Lin,Yuchun Lin,Xiaoyuan Chen
Mitophagy , a selective autophagy of mitochondria, clears up damaged mitochondria to maintain cell homeostasis . We performed high-content analysis (HCA) to detect the increase of PINK1, an essential protein controlling mitophagy, in hepatic cells treated with several nanoparticles (NPs). PINK1 immunofluorescence-based HCA was more sensitive than assays and detections for cell viability and mitochondrial functions. Of which, superparamagnetic iron oxide (SPIO)-NPs or graphene oxide-quantum dots (GO-QDs) was selected as representatives for positive or negative inducer of mitophagy. SPIO-NPs, but not GO-QDs, activated PINK1-dependent mitophagy as demonstrated by recruitment of PARKIN to mitochondria and degradation of injured mitochondria. SPIO-NPs caused the loss of mitochondrial membrane potential , decrease in ATP , and increase in mitochondrial reactive oxide species and Ca 2+ . Blocking mitophagy with PARKIN siRNA aggravated the cytotoxicity of SPIO-NPs. Taken together, PINK1 immunofluorescence-based HCA is considered to be an early, sensitive, and reliable approach to evaluate the bioimpacts of NPs.
研究领域:
毒理学
·
细胞生物学
·
纳米技术
·
药理学
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产品关联
DOI
PubMed
高影响因子
Jove-Journal of Visualized Experiments
·
2023
·
IF 1.2
Tianxiao Yang,Pingping Zhou,Ziwei Zhang,Xinyu Hao,Shaowei Liu,Haoyu Chen,Yuhua Wang,Yangang Wang
This research aims to explore the therapeutic effect and potential mechanisms of Huazhuojiedu decoction (HZJD) for alleviating precancerous lesions of gastric cancer (PLGC) both in vivo and in vitro. HZJD is a traditional Chinese herbal formula consisting of 11 herbs. Sprague-Dawley (SD) rats were randomly divided into four subgroups: control group, model group, positive drug group, and HZJD group. Hematoxylin-eosin (H&E) staining, high iron diamine-alcian blue (HID-AB) staining, alcian blue-periodic acid Schiff (AB-PAS) staining, immunohistochemistry, immunofluorescence, RT-qPCR, and Western blot assays were performed after 10 weeks of HZJD treatment. In vitro, the cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to detect cell proliferation. RT-qPCR and Western blot assays were performed to evaluate mitophagy levels. The results indicated that HZJD could retard the pathological progression in PLGC rats and reduce PLGC cell proliferation. Treatment with HZJD significantly increased the mRNA and protein expression levels of Sirt3, Foxo3a, Parkin, and LC3 II/I, while decreasing the mRNA and protein expression levels of p62 and Tomm20. HZJD was found to have the ability to reverse the decline in mitophagy activity both in vivo and in vitro. In conclusion, the study assessed the impact of HZJD and provided evidence regarding its potential molecular mechanism.
研究领域:
中医药
·
肿瘤学
·
分子生物学
·
病理学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-17
·
IF 40.8
Peng Fu,Liao Minru,Jin Wenke,Liu Wei,Li Zixiang,Fan Zhichao,Zou Ling,Chen Siwei,Zhu Lingjuan,Zhao Qian,Zhan Gu,Ouyang Liang,Peng Cheng,Han Bo,Zhang Jin,Fu Leilei
Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide + (NAD + )-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
研究领域:
心血管药理学
·
分子生物学
·
细胞生理学
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DOI
高影响因子
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