Youguang Gao

First Affiliated Hospital of Fujian Medical University

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Xianzhong Lin

Fujian Medical University

Bo Lin

Sinopec (China)

Tao Li

Chenzhou First People's Hospital

Zhongqing Chen

Southern Medical University

Caizhu Lin

Fujian Medical University

Zhenhua Zeng

Southern Medical University

Weihuang Qiu

Fujian Medical University

Tingjie Wang

Henan Cancer Hospital

Yunfeng Li

China Geological Survey

Binmei Yu

Fujian Medical University

Cooperative Institutions

Fujian Medical University

First Affiliated Hospital of Fujian Medical University

Southern Medical University

Nanfang Hospital

Chenzhou First People's Hospital

University of South China

Central South University

Xiangnan University

Chinese Academy of Sciences

Guangdong Provincial People's Hospital

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Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome

Laboratory Investigation (2019)

Tao Li Youtan Liu Wei Xu Xingui Dai Ruimeng Liu

Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin-/- mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.

10.1038/s41374-019-0191-3

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Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury

Journal of Translational Medicine (2020)

Youguang Gao Xingui Dai Yunfeng Li Guicheng Li Xianzhong Lin

Abstract Background We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsis-induced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. Methods Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. Key results PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin−/− mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkin-dependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. Conclusions These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

10.1186/s12967-020-02283-2

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Ulinastatin mediates protection against vascular hyperpermeability following hemorrhagic shock.

PubMed (2015)

Bo Lin Youtan Liu Tao Li Kai Zeng Shumin Cai

Recent studies have suggested that intrinsic apoptotic signaling cascade is involved in endothelial barrier dysfunction following hemorrhagic shock (HS), which results in vascular hyperpermeability. Our previous study demonstrated that ulinastatin (UTI) inhibits oxidant-induced endothelial hyperpermeability and apoptotic signaling. In present study, we hypothesized that UTI would improve HS-induced vascular hyperpermeability by regulating the intrinsic apoptotic signaling cascade.Hemorrhagic shock was induced in rats by withdrawing blood to reduce the mean arterial pressure to 40-45 mmHg for 60 min, followed by reperfusion. Mesenteric postcapillary venules were examined for changes in hyperpermeability by intravital microscopy. In vitro, Rat lung microvascular endothelial cells (RLMVECs) were exposed in hemorrhagic shock serum for 120 min, followed by transendothelial electrical resistance (TER) estimation. Mitochondrial release of cytochrome c and caspase-3 activation was estimated in vivo. In vitro, ratio of cell apoptosis was evaluated by Annexin-V/PI double stain assay; mitochondrial membrane potential (∆Ψm) was determined with JC-1; intracellular ATP content was assayed by a commercial kit; reactive oxygen species (ROS) was measured by DCFH-DA; adherens junction protein β-catenin was detected by immunofluorescense staining.In vivo, UTI attenuated HS-induced vascular hyperpermeability versus the HS group (P < 0.05); In vitro, UTI attenuated shock serum induced RLMEC monolayer hyperpermeability (P < 0.05). In vivo, UTI inhibited HS-induced cytochrome c release and caspase-3 activation (P < 0.05). In vitro, shock serum induced cell apoptosis, low ATP level, ∆Ψm depolarization, ROS increase were improved by UTI pre-treatment (P < 0.05). UTI improved shock serum induced disruption of endothelial cell adherens junction.UTI inhibits vascular hyperpermeability following HS. UTI regulates oxidative stress and intrinsic apoptotic signaling following HS.

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Inhibiting SIRT2 Attenuates Sepsis-Induced Acute Kidney Injury via FOXO1 Acetylation-Mediated Autophagy Activation

Shock (2024)

Binmei Yu Lijun Weng Jiaxin Li Tingjie Wang Weihuang Qiu

Sepsis-associated acute kidney injury (SAKI), a common complication in intensive care units (ICUs), is linked to high morbidity and mortality. Sirtuin 2 (SIRT2), an NAD+-dependent deacetylase, has been shown to have distinct effects on autophagy regulation compared to other sirtuins, but its role in SAKI remains unclear. This study explored the potential of SIRT2 as a therapeutic target for SAKI. We found that inhibition of SIRT2 with the antagonist AGK2 improved the survival of septic mice. SIRT2 inhibition reduced kidney injury, as indicated by lower levels of KIM-1, NGAL, serum creatinine (Scr), blood urea nitrogen (BUN), and proinflammatory cytokines following cecal ligation and puncture (CLP). Pretreatment with AGK2 in septic mice increased autophagosome and autolysosome formation in renal tubular epithelial cells (RTECs) and upregulated LC3 II expression in the renal cortex. Consistent with in vivo findings, SIRT2 gene silencing promoted autophagy in LPS-treated HK-2 cells, whereas SIRT2 overexpression inhibited it. Mechanistically, SIRT2 inhibition increased FOXO1 acetylation, inducing its nuclear-to-cytoplasmic translocation, which promoted kidney autophagy and alleviated SAKI. Our study suggests SIRT2 as a potential target for SAKI therapy.

SIRT2

FOXO1

10.1097/shk.0000000000002505

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小浪底水库调水调沙生态效应研究

Scientia Sinica Technologica (2024)

Bing Han Chang Zhang Youguang Gao Ying Yu Shimin Tian

10.1360/sst-2024-0260

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Activating Sig-1R inhibits microvascular permeability by reducing LRRK2 expression in lipopolysaccharide-induced acute lung injury

Free Radical Biology and Medicine (2024)

Bo Lin Yuying Li Yi Yao Binmei Yu Ke Peng

Endothelial cells are the first and most damaged target cells during acute lung injury (ALI). Endothelial dysfunction increases pulmonary microvascular permeability, subsequently leading to pulmonary oedema and organ dysfunction; however, clinical treatments against microvascular permeability show poor efficacy. Herein, we aimed to explore the role of the Sigma-1 receptor (Sig-1R) in pulmonary microvascular permeability by constructing ALI animal and cell models, and further investigated the specific mechanisms. The effects of Sig-1R on lung injury and endothelial barrier disruption were examined in lipopolysaccharide (LPS)-induced mice and human umbilical vein endothelial cells (HUVECs), respectively. Transcriptome sequencing was carried out to identify possible targets of Sig-1R, and the specific mechanisms of Sig-1R action were investigated using RNA interference and plasmid transfection. Analysis of a Gene expression omnibus dataset suggested that Sig-1R plays a protective role against vascular hyperpermeability in ALI. Downregulation of Sig-1R expression and endothelial barrier disruption were both observed in mice and HUVECs upon LPS stimulation. Sig-1R agonists attenuated vascular hyperpermeability in vivo and in vitro, further improving ALI. Sig-1R activation downregulated Leucine-rich repeat kinase 2 (LRRK2) expression in mice and HUVECs. LRRK2 knockdown ameliorated endothelial barrier disruption in mice and HUVECs. Overexpression of LRRK2 reversed the protective effect of Sig-1R activation on LPS-induced endothelial hyperpermeability. Furthermore, Sig1r knockdown exacerbated LPS-induced microvascular hyperpermeability, which was rescued by inhibition of LRRK2. Sig-1R activation exerts a protective effect against LPS-induced microvascular hyperpermeability by downregulating LRRK2 expression, which could lead to the development of novel therapeutic strategies for treating ALI.

10.1016/j.freeradbiomed.2024.11.015

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Construction of a bicistronic recombinant adenoviral vector for human interleukin-10 and enhanced green fluorescent protein expression in bone marrow mesenchymal stem cells.

PubMed (2012)

Jianqing Lin Caizhu Lin Xianzhong Lin Kai Zeng Youguang Gao

Human interleukin-10 (hIL-10) is a cytokine synthesis inhibitory factor, which is involved in various immune responses. The purpose of this study was to construct an adenoviral vector carrying the hIL-10 gene for expression of biologically active hIL-10 in rat bone marrow mesenchymal stem cells (rMSCs).A pSNAV2.0-hIL10 plasmid was used as a template to obtain a hIL-10 cDNA fragment that was subcloned by restriction enzyme digestion and ligation into a pDC316-IRES-EGFP-lacZ alpha plasmid carrying an enhanced green fluorescent protein (EGFP) marker gene. The pDC316-hIL-10-IRES-EGFP plasmid was linearized by PmeI digestion and used to transfect HEK293 packaging cells using the adenovirus packaging system AdMax. Virus particles were amplified by repeatedly infecting HEK293 cells with the seed virus and then purified by ion exchange. After the number of virus particles and titer was determined, rMSCs were infected with the adenoviral vector. The infection rate was determined by fluorescence microscopy and flow cytometry, and hIL-10 protein expression in rMSCs was measured by Western blotting.The virus particle concentration, OD260/280 value and virus titer of the amplified and purified recombinant adenovirus were 3.2 × 10(11) VP/ml, approximately 2.0, and 1.1 × 10(10) TCID50/ml, respectively. Bright green fluorescence was observed by fluorescence microscopy and flow cytometry in the recombinant adenovirus-infected rMSCs. GFP expression was considered the multiplicity of infection (MOI) and was time-dependent. The infection rate was 92.9% at 100 MOI.A bicistronic recombinant adenoviral vector for hIL-10 and EGFP gene expression were successfully constructed. The infection rate of rMSCs by the adenovirus was high (92.9% at 100 MOI) and the target gene hIL-10 was highly expressed in cells. The present study provides an experimental basis for further research of immunosuppressive therapy using hIL-10. The expression level of hIL-10 protein as detected by Western blotting was also MOI- and time-dependent.

Multiplicity of infection

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Clinical observation on protective effect of Ulinastatin against hemorrhagic shock-induced neuron mitochondrial dysfunction

Guoji yiyao weisheng daobao (2014)

Bo Lin Youguang Gao Caizhu Lin

Objective To investigate protective effect of Ulinastatin on hemorrhagic shock-induced neuron mitochondrial dysfunction.Methods 18 rats were randomly divided into control group,shock+normal saline (NS) group and shock+Ulinastatin group.Rats were received homologous NS or Ulinastatin treatment after hemorrhagic shock induction.Ultrastructure of neuron mitochondria was detected by electron microscope; change of mitochondrial membrane potential (△ ψm) by JC-1 mitochondrial membrane potential kit; content of ATP by fluorescein-luciferase assay kit; lipid hydroperoxide (LPO) in serum by LPO assay kit.Results Compared with control group,mitochondrial swelling with poorly defined cristas,remarkably increased number of platelets with low mitochondrial membrane potential (△ ψm) (P ＜ 0.05),decreased ATP content (P ＜ 0.05),and increased serum LPO level (P ＜ 0.05) were detected in NS group.These alterations mentioned were marked improved by Ulinastatin treatment (P ＜ 0.05).Conclusion Ulinastatin treatment can improve hemorrhagic shock-induced neuron mitochondrial injury and dysfunction via depression oxidative stress. Key words: Hemorrhagic shock; Ulinastatin; Mitochondria

Ulinastatin

Hemorrhagic shock

10.3760/cma.j.issn.1007-1245.2014.11.021

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Genipin attenuates mitochondrial-dependent apoptosis, endoplasmic reticulum stress, and inflammation via the PI3K/AKT pathway in acute lung injury

International Immunopharmacology (2019)

Xu Luo Bo Lin Youguang Gao Xianghui Lei Xiang Wang

Genipin

LY294002

10.1016/j.intimp.2019.105842

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