Multifaceted functions of Drp1 in hypoxia/ischemia-induced mitochondrial quality imbalance: from regulatory mechanism to targeted therapeutic strategy.

Hypoxic-ischemic injury is a common pathological dysfunction in clinical settings. Mitochondria are sensitive organelles that are readily damaged following ischemia and hypoxia. Dynamin-related protein 1 (Drp1) regulates mitochondrial quality and cellular functions via its oligomeric changes and multiple modifications, which plays a role in mediating the induction of multiple organ damage during hypoxic-ischemic injury. However, there is active controversy and gaps in knowledge regarding the modification, protein interaction, and functions of Drp1, which both hinder and promote development of Drp1 as a novel therapeutic target. Here, we summarize recent findings on the oligomeric changes, modification types, and protein interactions of Drp1 in various hypoxic-ischemic diseases, as well as the Drp1-mediated regulation of mitochondrial quality and cell functions following ischemia and hypoxia. Additionally, potential clinical translation prospects for targeting Drp1 are discussed. This review provides new ideas and targets for proactive interventions on multiple organ damage induced by various hypoxic-ischemic diseases.

Activated Drp1 regulates p62-mediated autophagic flux and aggravates inflammation in cerebral ischemia-reperfusion via the ROS-RIP1/RIP3-exosome axis.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that can occur when the blood supply to the ischemic brain tissue is restored. However, the mechanism underlying such injury remains elusive. METHODS: The 150 male C57 mice underwent middle cerebral artery occlusion (MCAO) for 1 h and reperfusion for 24 h, Among them, 50 MCAO mice were further treated with Mitochondrial division inhibitor 1 (Mdivi-1) and 50 MCAO mice were further treated with N-acetylcysteine (NAC). SH-SY5Y cells were cultured in a low-glucose culture medium for 4 h under hypoxic conditions and then transferred to normal conditions for 12 h. Then, cerebral blood flow, mitochondrial structure, mitochondrial DNA (mtDNA) copy number, intracellular and mitochondrial reactive oxygen species (ROS), autophagic flux, aggresome and exosome expression profiles, cardiac tissue structure, mitochondrial length and cristae density, mtDNA and ROS content, as well as the expression of Drp1-Ser616/Drp1, RIP1/RIP3, LC3 II/LC3 I, TNF-α, IL-1ß, etc., were detected under normal or Drp1 interference conditions. RESULTS: The mtDNA content, ROS levels, and Drp1-Ser616/Drp1 were elevated by 2.2, 1.7 and 2.7 times after CIRI (P < 0.05). However, the high cytoplasmic LC3 II/I ratio and increased aggregation of p62 could be reversed by 44% and 88% by Drp1 short hairpin RNA (shRNA) (P < 0.05). The low fluorescence intensity of autophagic flux and the increased phosphorylation of RIP3 induced by CIRI could be attenuated by ROS scavenger, NAC (P < 0.05). RIP1/RIP3 inhibitor Necrostatin-1 (Nec-1) restored 75% to a low LC3 II/LC3 I ratio and enhanced 2 times to a high RFP-LC3 after Drp1 activation (P < 0.05). In addition, although CIRI-induced ROS production caused no considerable accumulation of autophagosomes (P > 0.05), it increased the packaging and extracellular secretion of exosomes containing p62 by 4 - 5 times, which could be decreased by Mdivi-1, Drp1 shRNA, and Nec-1 (P < 0.05). Furthermore, TNF-α and IL-1ß increased in CIRI-derived exosomes could increase RIP3 phosphorylation in normal or oxygen-glucose deprivation/reoxygenation (OGD/R) conditions (P < 0.05). CONCLUSIONS: CIRI activated Drp1 and accelerated the p62-mediated formation of autophagosomes while inhibiting the transition of autophagosomes to autolysosomes via the RIP1/RIP3 pathway activation. Undegraded autophagosomes were secreted extracellularly in the form of exosomes, leading to inflammatory cascades that further damaged mitochondria, resulting in excessive ROS generation and the blockage of autophagosome degradation, triggering a vicious cycle.

Characteristics of aerosol optical depth dynamics and their causes over typical cities along the 21st Century Maritime Silk Road.

Atmospheric aerosols, i.e., suspension of liquid and/or solid particles in air, have serious impacts on human health. Exploring the variation and patterns of regional atmospheric aerosols is of great significance to monitor and evaluate atmosphere quality, especially in urban areas with large population. Here, with nine typical pivotal cities along the 21st Century Maritime Silk Road through Southeast Asia, South Asia to West Asia as case studies, based on MCD19A2 550 nm AOD products, combined meteorological factors, land use data, and nighttime light data, we analyzed the spatio-temporal distribution, variation features, influencing and/or driving factors of aerosols in developed urban areas over Asia. The results showed that the descending sequence of the annual aerosol optical depth (AOD) of the nine cities was Karachi, Doha, Chittagong, Bangkok, Colombo, Ho Chi Minh, Singapore, Gwadar, and Yangon during 2013-2018. Due to the influence of regional climate system and atmospheric aerosol types, the time series of annual, seasonal, and monthly AODs were significantly different. The high values of AODs in most cities were mainly located in the urban center or rapid socio-economic (e.g., industrial and agricultural) development regions. The effects of different meteorological factors on the AODs varied in different cities. The rainfall, relative humidity, and wind speed had great impacts on AODs in Ho Chi Minh, Bangkok, Singapore, and Yangon. Temperature, relative humidity, and wind speed had close correlations with AODs in Chittagong, Colombo, Karachi, and Gwadar of South Asia and Doha in West Asia. The urban area's AOD was influenced by the combined and synergistic effects of socio-economy, urbanization, and meteorological factors, with that in Karachi being the most significant.

Role of resveratrol in protecting vasodilatation function in septic shock rats and its mechanism.

BACKGROUND: Vascular dysfunction is a major cause of sepsis-induced multiple-organ dysfunction. Resveratrol is a polyphenol compound with extensive pharmacological effects including anti-inflammation. The aim of this study was to determine the role and mechanism of resveratrol in protecting vascular function following sepsis. METHODS: The cecal ligation and puncture method was used to establish a septic shock rat model. Resveratrol (5 mg/kg and 10 mg/kg) was administered intravenously immediately and at 12 hours after cecal ligation and puncture, respectively. The effects of resveratrol on vasodilatation function, blood flow velocity, hemodynamics, and vital organ function and its relationship to Rac-1 and HIF-1α were observed. RESULTS: Vascular relaxation reactivity and blood flow velocity were significantly decreased after septic shock, both were significantly improved by resveratrol 5 mg/kg and 10 mg/kg, and the effect of 10 mg/kg was greater. The relaxation reactivity of the superior mesenteric artery to acetylcholine (Ach) was increased by 43.2%. The blood flow velocity of mesenteric arterioles and venules was increased by 47.1% and 51%, respectively, after resveratrol (10 mg/kg) administration compared with the septic shock group. The hemodynamics and both liver and kidney blood flow were significantly decreased after septic shock, which were significantly improved them by resveratrol, which enhanced the vascular relaxation reactivity in septic shock rats. The 72-hour survival rate of septic shock rats in the resveratrol group (62.5%) was significantly higher than that in the septic shock group (6.3%). Resveratrol significantly upregulated the expression of endothelial nitric oxide synthase (eNOS) and downregulated the expression of inducible NOS, Rac-1, and HIF-1α. Inhibitors of Rac-1 and HIF-1α significantly improved the expression of eNOS, and inhibition of eNOS (L-NAME, 5 mg/kg) antagonized the resveratrol-induced improvement in vascular relaxation reactivity and survival. CONCLUSION: Resveratrol was beneficial for vasodilatation function in rats with septic shock, which is the major contribution to resveratrol improving hemodynamics and organ perfusion. The mechanism involved resveratrol upregulating the expression of eNOS by inhibiting Rac-1 and HIF-1α.

Neuropsychological rehabilitation and psychotherapy of adult traumatic brain injury patients with depression: a systematic review and meta-analysis.

INTRODUCTION: There is still insufficient appreciation whether neuropsychological rehabilitation and psychotherapy are effective in attenuating depression following traumatic brain injury (TBI). This knowledge gap was addressed in the present systematic review and meta-analysis of the literature. EVIDENCE ACQUISITION: We conducted electronic database (Medline, PsychINFO, Scopus) searches (time frame: January 1st, 2005 to December 31st, 2015) for clinical studies that had tested neuropsychological rehabilitation and psychotherapy in adult TBI survivors with depression. The studies were to have experimental or quasi-experimental study design, and to include survivors from non-military TBI. Quantitative assessment of qualifying studies was done using the random effects model. We calculated the pooled size effect using standardized mean difference (SMD) as the main effect measure. EVIDENCE SYNTHESIS: We identified three studies, totaling 231 participants, which tested cognitive behavioral therapy or mindfulness-based cognitive therapy as interventions to attenuate post-TBI depression. The analysis revealed a small and non-significant decrease in depression symptoms due to intervention (SMD=-0.23 [95% CI: -050, 0.03; z=1.73, P=0.08]). Testing for publication bias was not feasible due to low number of identified studies. CONCLUSIONS: Current evidence indicates only a small therapeutic effect of psychotherapy in attenuating post-TBI depression.

Regulatory mechanisms, prophylaxis and treatment of vascular leakage following severe trauma and shock.

Vascular leakage, or increased vascular permeability, is a common but important pathological process for various critical diseases, including severe trauma, shock, sepsis, and multiple organ dysfunction syndrome (MODS), and has become one of the most important causes of death for intensive care units (ICU) patients. Currently, although there has been some progress in knowledge of the pathogenesis of these vascular disorders, the detailed mechanisms remain unclear, and effective prophylaxis and treatment are still lacking. In this study, we aimed to provide a review of the literature regarding the regulatory mechanisms and prophylaxis as well as the treatment of vascular leakage in critical diseases such as severe trauma and shock, which could be beneficial for the overall clinical treatment of vascular leakage disorders.

Lack of association of EPHX1 gene polymorphisms with risk of hepatocellular carcinoma: a meta-analysis.

Previous studies have focused on the association of a gene (EPHX1) encoding microsomal epoxide hydrolase with the carcinogenesis of hepatocellular carcinoma (HCC). In the present study, we performed a meta-analysis to systematically summarize the possible association between EPHX1 genetic polymorphisms and the risk for HCC. We conducted a search of case-control studies on the associations of EPHX1 genetic polymorphisms with susceptibility to HCC in PubMed, EMBASE, ISI Web of Science, Wanfang database in China, and the Chinese National Knowledge Infrastructure databases. Data from eligible studies were extracted for meta-analysis. HCC risk associated with EPHX1 genetic polymorphism was estimated by pooled odds ratios and 95% confidence intervals. Thirteen studies were included in the present meta-analysis. Our results showed that, for the two polymorphisms (337 T > C and 416A > G) of EPHX1 gene, neither allele frequency nor genotype distributions were associated with risk for HCC in all genetic models (all P > 0.05). This meta-analysis suggests that EPHX1 genetic polymorphisms were not associated with the risk of HCC.

Effect of different anesthesia methods on erythrocyte immune function in mice.

OBJECTIVE: To explore effect of different anesthesia methods and different anesthetics on erythrocyte immune function in mice. METHODS: The mice were anesthetized by isoflurane and ether inhalation, and also under intraperitoneal anesthesia with sodium pentobarbital and chloral hydrate. Blood was collected from the ventro-cardinal vein. Automatic blood cell analyzer was used for routine blood examination, and the canthine oxidase method was used to measure the superoxide dismutase (SOD) activity. Lipid peroxidation product malondialdehyde (MDA) was measured with TBA, and glutathione peroxidase (GSH-Px) was measured with DTNB, and then the effect of different anesthesia methods and different anesthetics on erythrocyte immune function in mice was observed. RESULTS: Hct level of chloral hydrate intraperitoneal injection group was significantly higher than the other three groups (P<0.05). And the MDA levels in the pentobarbital sodium group were significantly higher than the other three groups (P<0.05). SOD and GSH-Px of the chloral hydrate and sodium pentobarbital intraperitoneal injection group were significantly lower than the other two groups; RBC-C 3bRR and RBC-ICR of the chloral hydrate and sodium pentobarbital intraperitoneal injection group were significantly lower than the other two groups. CONCLUSIONS: Different drugs can induce changes in immune function of mice at different levels. Isoflurane and ether have less damage to animal body, while chloral hydrate and sodium pentobarbital intraperitoneal injection have a certain inhibitory effect on the animal body respiratory system and can cause greater damage to the body. Therefore, the reasonable selection and control of anesthetics are very important in order to avoid the experimental errors caused by anesthesia.