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 ...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.展开更多
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 re...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/I, TNF-α,IL-1β, 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/RIP3inhibitor Necrostatin-1(Nec-1) restored 75% to a low LC3 II/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-1βincreased 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.展开更多
This prospective study was conducted to compare risk factors and pregnancy outcomes between women with complete placenta previa and those with incomplete placenta previa diagnosed in mid-pregnancy. The study was carri...This prospective study was conducted to compare risk factors and pregnancy outcomes between women with complete placenta previa and those with incomplete placenta previa diagnosed in mid-pregnancy. The study was carried out from April 2014 to December 2015, during which 70 patients with complete previa and 113 with incomplete previa between 20＋0 weeks and 25＋6 weeks of gestation were included. Maternal demographics and pregnancy outcomes were compared between the two groups. Comparisons between categorical variables were tested by chi-squared test and those between continuous variables by Student t test. Resolution ofprevia occurred in 87.43% of the studied women. The mean gestational age at resolution was 32.1＋4.4 weeks. Incidence of maternal age ≥35 years and incidence of prior uterine operation 〉3 were high in women with complete previa （28.6% vs. 8.8%, P=0.003; 28.6% vs. 8.8%, P=0.003）. Resolution ofprevia occurred less often in complete previa group （74.3% vs. 95.6%, P=0.001）. Women with complete previa admitted earlier （37.3±2.0 weeks vs. 38.1±1.4 weeks, P=0.011） and delivered earlier （37.7±1.2 weeks vs. 38.3±1.4 weeks, P=0.025）. Maternal age ≥35 years and prior uterine operation 〉3 increase the risk of complete previa in mid-pregnancy. Placenta previa is more likely to persist in women with complete previa than those with incomplete previa diagnosed in mid- pregnancy. What is more, women with complete previa in mid-pregnancy delivers earlier.展开更多
Objective： Ventilator associated pneumonia （VAP） has been shown to be associated with significant morbidity and mortality（ Chastre and Fagon, 2002; klompas, 2007） among mechanically venti- lated patients in the i...Objective： Ventilator associated pneumonia （VAP） has been shown to be associated with significant morbidity and mortality（ Chastre and Fagon, 2002; klompas, 2007） among mechanically venti- lated patients in the intensive care unit （ICU）, with the incidence ranging from 9% to 27% ; crude mortality ranges from 25% to 50%.1-3 A meta-analysis of published studies was undertaken to combine information regarding the effect of subglottic secretion drainage （SSD） on the incidence of ventilated associated pneumonia in adult ICU patients. Methods： Reports of studies on SSD were identified by searching the PUBMED, EMBASE, and COCHRANCE LIBRARY databases （December 30, 2010）. Randomized trials of SSD compared to usual care in adult mechanically ventilated ICU patients were included in this meta-analysis. Results： Ten RCTs with 2,314 patients were identified. SSD significantly reduced the incidence of VAP [ relative risk （RR） =0.52, 95% confidence interval （C/）： 0.42-0.64, P〈0.000 01]. When SSD was compared with the control groups, the overall RR for ICU mortality was 1.00 （95% CI, 0.84-1.19） and for hospital mortality was 0.95 （95% CI, 0. 80-1.13）. Overall, the subglottic drainage effect on the days of mechanical ventilation was -1.52 days （95% CI, -2.94 to -0.11） and on the ICU length of stay （LOS） was -0.81days （95% CI, -2.33 to -0.7）. Conclusions： In this meta-analysis, when an endotracheal tube （ETT） with SSD was compared with an ETT without SSD, there was a highly significant reduction in the VAP rate of approxi- mately 50%. Time on mechanical ventilation （MV） and the ICU LOS may be reduced, but no reduction in ICU or hospital mortality has been observed in published trials,展开更多
Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for de novo mutations(DNMs)in congenital heart disease(CHD)probands.However,risk gene identification based on DNMs alone remains st...Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for de novo mutations(DNMs)in congenital heart disease(CHD)probands.However,risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.Methods:In this manuscript,we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted variants.Through integrative modeling of multiple types of genetic variants,gene-level annotations,and reference data from large population cohorts,our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs only.Results:Applied to WES data of 2,645 CHD proband-parent trios,our method identified 15 significant genes,half of which are novel,leading to new insights into the genetic bases of CHD.Conclusion:These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.展开更多
To the Editor:Percutaneous nephrolithotomy(PNL)constitutes the first-line of treatment for complex and staghorn stones.Performing PNL in morbidly obese patients is challenging because of potential risks and higher mor...To the Editor:Percutaneous nephrolithotomy(PNL)constitutes the first-line of treatment for complex and staghorn stones.Performing PNL in morbidly obese patients is challenging because of potential risks and higher morbidity rates.[1]Previous literature has confirmed the safety and feasibility of the surgery under fluoroscopy.However,the efficiency of total ultrasound(US)-guided access established procedures in morbidly obese patients has not been proved before,with the traditional view holding that obesity is a risk factor that increases the difficulty of accessing the renal collecting system under US.US is sometimes used to reduce radiation exposure in some Western countries,whereas the spread of X-ray-free technique for PNL in China has been lasting for>10 years.This study aims to investigate the feasibility and safety of total US-guided PNL in morbidly obese patients and to highlight the difficulties and problems,which can be encountered and effectively resolved.展开更多
To the Editor：Synovial sarcoma （SS） is a relatively rare type of soft tissue sarcoma that constitutes approximately 8% of all soft tissue sarcomas.SS frequently occurs in the para-articular structures of the limbs ...To the Editor：Synovial sarcoma （SS） is a relatively rare type of soft tissue sarcoma that constitutes approximately 8% of all soft tissue sarcomas.SS frequently occurs in the para-articular structures of the limbs and is predominantly found in the lower limbs.The other involved locations of invasion are lung,lymph nodes,and bone.However,the skin is rarely involved.[1-3] Here,we reported an extremely rare case ofbiphasic SS presenting with disseminated cutaneous metastases.展开更多
基金This work was supported by the National Natural Science Foundation of China(82272252,82270378)the Senior Medical Talents Program of Chongqing for Young and Middle-agedthe Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University.
文摘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.
基金supported by the National Natural Science Foundation of China (81700429)the China Postdoctoral Science Foundation (2021MD703924)+1 种基金the Chongqing Postdoctoral Innovative Talents Support Program (CQBX2021018)the Kuanren Talents Program of the second affiliated hospital of Chongqing Medical University。
文摘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/I, TNF-α,IL-1β, 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/RIP3inhibitor Necrostatin-1(Nec-1) restored 75% to a low LC3 II/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-1βincreased 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.
基金This project was supported by grants from National Natural Science Foundation of China （Nos. 81701476 and 81200354）, Hubei Provincial Population and Family Planning Commission of China （No. JS-20130017）, and Applied Basic Research Plan of Wuhan （No. 2015060101010037）.
文摘This prospective study was conducted to compare risk factors and pregnancy outcomes between women with complete placenta previa and those with incomplete placenta previa diagnosed in mid-pregnancy. The study was carried out from April 2014 to December 2015, during which 70 patients with complete previa and 113 with incomplete previa between 20＋0 weeks and 25＋6 weeks of gestation were included. Maternal demographics and pregnancy outcomes were compared between the two groups. Comparisons between categorical variables were tested by chi-squared test and those between continuous variables by Student t test. Resolution ofprevia occurred in 87.43% of the studied women. The mean gestational age at resolution was 32.1＋4.4 weeks. Incidence of maternal age ≥35 years and incidence of prior uterine operation 〉3 were high in women with complete previa （28.6% vs. 8.8%, P=0.003; 28.6% vs. 8.8%, P=0.003）. Resolution ofprevia occurred less often in complete previa group （74.3% vs. 95.6%, P=0.001）. Women with complete previa admitted earlier （37.3±2.0 weeks vs. 38.1±1.4 weeks, P=0.011） and delivered earlier （37.7±1.2 weeks vs. 38.3±1.4 weeks, P=0.025）. Maternal age ≥35 years and prior uterine operation 〉3 increase the risk of complete previa in mid-pregnancy. Placenta previa is more likely to persist in women with complete previa than those with incomplete previa diagnosed in mid- pregnancy. What is more, women with complete previa in mid-pregnancy delivers earlier.
文摘Objective： Ventilator associated pneumonia （VAP） has been shown to be associated with significant morbidity and mortality（ Chastre and Fagon, 2002; klompas, 2007） among mechanically venti- lated patients in the intensive care unit （ICU）, with the incidence ranging from 9% to 27% ; crude mortality ranges from 25% to 50%.1-3 A meta-analysis of published studies was undertaken to combine information regarding the effect of subglottic secretion drainage （SSD） on the incidence of ventilated associated pneumonia in adult ICU patients. Methods： Reports of studies on SSD were identified by searching the PUBMED, EMBASE, and COCHRANCE LIBRARY databases （December 30, 2010）. Randomized trials of SSD compared to usual care in adult mechanically ventilated ICU patients were included in this meta-analysis. Results： Ten RCTs with 2,314 patients were identified. SSD significantly reduced the incidence of VAP [ relative risk （RR） =0.52, 95% confidence interval （C/）： 0.42-0.64, P〈0.000 01]. When SSD was compared with the control groups, the overall RR for ICU mortality was 1.00 （95% CI, 0.84-1.19） and for hospital mortality was 0.95 （95% CI, 0. 80-1.13）. Overall, the subglottic drainage effect on the days of mechanical ventilation was -1.52 days （95% CI, -2.94 to -0.11） and on the ICU length of stay （LOS） was -0.81days （95% CI, -2.33 to -0.7）. Conclusions： In this meta-analysis, when an endotracheal tube （ETT） with SSD was compared with an ETT without SSD, there was a highly significant reduction in the VAP rate of approxi- mately 50%. Time on mechanical ventilation （MV） and the ICU LOS may be reduced, but no reduction in ICU or hospital mortality has been observed in published trials,
基金the National Institutes of Health(NIH)grants R01 GM134005,and the National Science Foundation(NSF)grants DMS 1902903.Dr.Sheng Chih Jin's effort was supported by the Pathway to Independence Award(K99/R00)program,grants K99HL143036-01A1 and R00HL143036-02.
文摘Background:Whole-exome sequencing(WES)studies have identified multiple genes enriched for de novo mutations(DNMs)in congenital heart disease(CHD)probands.However,risk gene identification based on DNMs alone remains statistically challenging due to heterogenous etiology of CHD and low mutation rate in each gene.Methods:In this manuscript,we introduce a hierarchical Bayesian framework for gene-level association test which jointly analyzes de novo and rare transmitted variants.Through integrative modeling of multiple types of genetic variants,gene-level annotations,and reference data from large population cohorts,our method accurately characterizes the expected frequencies of both de novo and transmitted variants and shows improved statistical power compared to analyses based on DNMs only.Results:Applied to WES data of 2,645 CHD proband-parent trios,our method identified 15 significant genes,half of which are novel,leading to new insights into the genetic bases of CHD.Conclusion:These results showcase the power of integrative analysis of transmitted and de novo variants for disease gene discovery.
基金supported by the grant from the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding(No.XMLX202118)。
文摘To the Editor:Percutaneous nephrolithotomy(PNL)constitutes the first-line of treatment for complex and staghorn stones.Performing PNL in morbidly obese patients is challenging because of potential risks and higher morbidity rates.[1]Previous literature has confirmed the safety and feasibility of the surgery under fluoroscopy.However,the efficiency of total ultrasound(US)-guided access established procedures in morbidly obese patients has not been proved before,with the traditional view holding that obesity is a risk factor that increases the difficulty of accessing the renal collecting system under US.US is sometimes used to reduce radiation exposure in some Western countries,whereas the spread of X-ray-free technique for PNL in China has been lasting for>10 years.This study aims to investigate the feasibility and safety of total US-guided PNL in morbidly obese patients and to highlight the difficulties and problems,which can be encountered and effectively resolved.
文摘To the Editor：Synovial sarcoma （SS） is a relatively rare type of soft tissue sarcoma that constitutes approximately 8% of all soft tissue sarcomas.SS frequently occurs in the para-articular structures of the limbs and is predominantly found in the lower limbs.The other involved locations of invasion are lung,lymph nodes,and bone.However,the skin is rarely involved.[1-3] Here,we reported an extremely rare case ofbiphasic SS presenting with disseminated cutaneous metastases.
