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.

Detection of hepatitis C virus NS5 protein and genome in Chinese carcinoma of the extrahepatic bile duct and its significance

AIM To investigate the hepatitis C virus(HCV)infection in the tissues of carcinoma ofextrahepatic bile duct and study theircorrelation.METHODS HCV NS5 protein and HCV RNA weredetected by labeled streptavidin biotin(LSAB)method and in situ reverse transcriptionpolymerase chain reaction(IS-RT-PCR)insections of 51 cases of carcinoma ofextrahepatic bile duct and 34 cases of controlgroup(without malignant biliary disease).RESULTS In 51 cases of carcinoma ofextrahepatic bile duct,HCV NS5 protein wasdetected in 14(27.5%),which was clearlystained in the cytoplasm of cancer cell but not inthe nucleus or cell membrane.HCV RNA wasdetected in 18(35.4%),which was located inthe nucleus of cancer cell in 12 cases and in thecytoplasm in 6 cases.HCV NS5 protein and RNAcoexistence was found in 2 cases.In 34 cases ofcontrol group,HCV RNA was detected in 2(5.9%).HCV NS5 protein and RNA positive cellswere found either scattered or in clusters.CONCLUSION The prevalence of hepatitis C viral infection in the tissues of carcinoma ofextrahepatic bile duct was significantly higherthan in control group(X^2=9.808,P=0.002).The findings suggest a correlation between HCVinfection and carcinoma of extrahepatic bileduct,which is different from the traditionalviewpoint.HCV infection might be involved inthe development of carcinoma of extrahepaticbile duct.

Association of polymorphisms of IL and CD14 genes with acute severe pancreatitis and septic shock

AIM. To investigate IL-1β＋3 594 in the 5^th intron, IL-10-1 082 and CD14-159 polymorphisms in patients with acute pancreatitis （AP） and septic shock.METHODS： The study induded 215 patients （109 with acute severe pancreatitis （SAP）, 106 with acute mild pancreatitis （MAP）） and 116 healthy volunteers. Genomic DNA was prepared from peripheral blood leukocytes. Genotypes and allele frequencies were determined in patients and healthy controls using restriction fragment length polymorphism analysis of PCR products.RESULTS： The frequencies of IL-β＋3 594T, IL-10-1082G and CD14-159T allele were similar in patients with mild or severe pancreatitis and in controls. Within SAP patients, no significant differences were found in the allele distribution examined when etiology was studied again. Patients with septic shock showed a significantly higher prevalence of IL-10-1082G allele than those without shock （X^2 = 5.921,P= 0.015）.CONCLUSION： IL-10-1082G plays an important role in the susceptibility of SAP patients to septic shock. Genetic factors are not important in determination of disease severity or susceptibility to AP.

Effects of recombinant human growth hormone on enterocutaneous fistula patients

AIM： To explore the effects of recombinant human growth hormone （rhGH） on intestinal mucosal epithelial cell proliferation and nutritional status in patients with enterocutaneous fistula. METHODS： Eight patients with enterocutaneous fistulas received recombinant human growth hormone （10 ug/d） for 7 d. Image analysis and immunohistochemical techniques were used to analyse the expression of proliferating cell nuclear antigen （PCNA） in intestinal mucosal epithelial cells in biopsy samples from the patients who had undergone an endoscopic biopsy through the fistula at day 0, 4 and 7. Body weights, nitrogen excretion, serum levels of total proteins, albumin, prealbumin, transferrin and fibronectin were measured at day 0, 4 and 7. RESULTS： Significant improvements occurred in the expression of PCNA in the intestinal mucosal epithelial cells at day 4 and 7 compared to day 0 （24.93 ± 3.41%, 30.46 ± 5.24% vs 12.92 ± 4.20%, p 〈 0.01）. These changes were accompanied by the significant improvement of villus height （500.54 ± 53.79 um, 459.03 ± 88.98um vs 210.94 ± 49.16 um, P 〈 0.01）, serum levels of total proteins （70.52 ± 5.13 g/L, 74.89 ± 5.16 g/L vs 63.51 ± 2.47 g/L, P 〈 0.01）, albumin （39.44 ± 1.18 g/L, 42.39 ± 1.68 g/L vs 35.74 ± 1.75 g/L, P 〈 0.01） and fibronectin （236.3 4- 16.5 mg/L, 275.8± 16.9 mg/L vs 172.5 ± 21.4 mg/L, P 〈 0.01） at day 4 and 7, and prealbumin （286.38 ± 65.61 mg/L vs 180.88 ± 48.28 mg/L, P 〈 0.05）, transferrin （2.61 ± 0.12 g/L vs 2.41 ±0.14 g/L, P 〈 0.05） at day 7. Nitrogen excretion was significantly decreased at day 7 （3.40 ± 1.65 g/d vs 7.25 ± 3.92 g/d, P 〈 0.05）. No change was observed in the body weight. CONCLUSION： Recombinant human growth hormone could promote intestinal mucosal epithelial cell proliferation and protein synthesis in patients with enterocutaneous fistula.

Application of a 3D-printed ”fistula stent” in plugging enteroatmospheric fistula with open abdomen: A case report

BACKGROUND Open abdomen(OA) has been generally accepted for its magnificent superiority and effectiveness in patients with severe trauma, severe intra-abdominal infection, and abdominal compartment syndrome. In the meantime, OA calls for a mass of nursing and the subsequent enteroatomospheric fistula(EAF), which is one of the most common complications of OA therapy, remains a thorny challenge.CASE SUMMARY Our team applied thermoplastic polyurethane as a befitting material for producing a 3 D-printed "fistula stent" in the management of an EAF patient,who was initially admitted to local hospital because of abdominal pain and distension and diagnosed with bowel obstruction. After a series of operations and OA therapy, the patient developed an EAF.CONCLUSION Application of this novel "fistula stent" resulted in a drastic reduction in the amount of lost enteric effluent and greatly accelerated rehabilitation processes.

Predictors of irreversible intestinal resection in patients with acute mesenteric venous thrombosis

BACKGROUND Acute mesenteric venous thrombosis(AMVT)can cause a poor prognosis.Prompt transcatheter thrombolysis(TT)can achieve early mesenteric revascularization.However,irreversible intestinal ischemia still occurs and the mechanism is still unclear.AIM To evaluate the clinical outcomes of and to identify predictive factors for irreversible intestinal ischemia requiring surgical resection in AMVT patients treated by TT.METHODS The records of consecutive patients with AMVT treated by TT from January 2010 to October 2017 were retrospectively analyzed.We compared patients who required resection of irreversible intestinal ischemia to patients who did not require.RESULTS Among 58 patients,prompt TT was carried out 28.5 h after admission.A total of 42(72.4%)patients underwent arteriovenous combined thrombolysis,and 16(27.6%)underwent arterial thrombolysis alone.The overall 30-d mortality rate was 8.6%.Irreversible intestinal ischemia was indicated in 32(55.2%)patients,who had a higher 30-d mortality and a longer in-hospital stay than patients without resection.The significant independent predictors of irreversible intestinal ischemia were Acute Physiology and Chronic Health Evaluation(APACHE)II score(odds ratio=2.368,95% confidence interval:1.047-5.357,P=0.038)and leukocytosis(odds ratio=2.058,95% confidence interval:1.085-3.903,P=0.027).Using the receiver operating characteristic curve,the cutoff values of the APACHE II score and leukocytosis for predicting the onset of irreversible intestinal ischemia were calculated to be 8.5 and 12×10^9/L,respectively.CONCLUSION Prompt TT could achieve a favorable outcome in AMVT patients.High APACHE II score and leukocytosis can significantly predict the occurrence of irreversible intestinal ischemia.Therefore,close monitoring of these factors may help with the early identification of patients with irreversible intestinal ischemia,in whom ultimately surgical resection is required,before the initiation of TT.

Protective effects of terminal ileostomy against bacterial translocation in a rat model of intestinal ischemia/reperfusion injury

AIM: To investigate the effects of terminal ileostomy on bacterial translocation (BT) and systemic inflammation after intestinal ischemia/reperfusion (I/R) injury in rats.

Polymorphism of heat shock protein 70-2 and enterocutaneous fistula in Chinese population

AIM: To investigate whether the heat shock protein 70-2 (HSP70-2) polymorphism is associated with enterocutaneous fistulas in a Chinese population.

Current knowledge on the multiform reconstitution of intestinal stem cell niche

The development of“mini-guts”organoid originates from the identification of Lgr5+intestinal stem cells(ISCs)and circumambient signalings within their specific niche at the crypt bottom.These in vitro self-renewing“mini-guts”,also named enteroids or colonoids,undergo perpetual proliferation and regulated differentiation,which results in a high-performance,self-assembling and physiological organoid platform in diverse areas of intestinal research and therapy.The triumphant reconstitution of ISC niche in vitro also relies on Matrigel,a heterogeneous sarcoma extract.Despite the promising prospect of organoids research,their expanding applications are hampered by the canonical culture pattern,which reveals limitations such as inaccessible lumen,confine scale,batch to batch variation and low reproducibility.The tumor-origin of Matrigel also raises biosafety concerns in clinical treatment.However,the convergence of breakthroughs in cellular biology and bioengineering contribute to multiform reconstitution of the ISC niche.Herein,we review the recent advances in the microfabrication of intestinal organoids on hydrogel systems.

Gut Microbiota Community Shift with Severity of Coronary Artery Disease

Gut microbiota community shift with coronary artery disease(CAD)has been reported in several limited cohorts during the past several years.However,whether the enriched or decreased microbiota taxa with CAD can be reproducible deserves further investigation and validation.In this study,78 human subjects were recruited.Of these,19 were diagnosed without stenosis in coronary artery(control group,referred to herein as Ctrl),14 with stenosis less than 50%(LT50),and 45 with stenosis greater than 50%(GT50).Fecal samples were collected and DNA was extracted to perform 16S ribosomal RNA(rRNA)gene sequencing.The operational taxonomic units(OTUs)were analyzed to identify taxa specific to different groups;next,multivariate logistic regression was employed to test whether the defined taxa could independently predict CAD risk.We found that Deltaproteobacteria,Fusobacterium,Bilophila,Actinomyces,and Clostridium XIX were enriched in Ctrl;Prevotellaceae,Parabacteriodes,and Butyricicoccus were enriched in LT50;and Roseburia and Butyricimonas were enriched in GT50.Further analysis revealed that increased populations of Deltaproteobacteria,Fusobacterium,Bilophila,and Desulfovibrionaceae were associated with a 0.26-fold,0.21-fold,0.18-fold,and 0.26-fold decreased risk of CAD,respectively(p<0.05),and an increased Prevotellaceae population was associated with a 5.63-fold increased risk of CAD(p<0.01).A combination of the 20 microbial taxa achieved an area under the receiver operating characteristic(ROC)curve of higher than 0.88 for all discriminations between LT50 vs Ctrl,GT50 vs Ctrl,LT50+GT50 vs Ctrl,and GT50 vs Ctrl+LT50.However,the microbial taxa previously reported as enriched in CAD patients or healthy controls could not be observed in our cohort except for Bacteroides.In conclusion,CAD patients showed a different microbial taxa signature than the healthy controls.However,the non-reproducibility of the microbiota taxa enriched in CAD across different cohorts limits the use of this signature in early diagnosis and prevention.Only decreased Bacteroides abundance was found to be a reliable marker to indicate CAD progression.

Establishment and evaluation of an improved rat model of open abdomen

Introduction:This study aimed to establish an animal model of open abdomen(OA)through temporary abdominal closure via different techniques.Methods:Adult male Sprague-Dawley rats were randomly divided into three groups:group A(OA with polypropylene mesh alone);group B(OA with polypro-pylene mesh combined with a patch);and group C(OA with polypropylene mesh and a sutured patch).Vital signs,pathophysiological changes,and survival rates were closely monitored in the rats for 7 days after surgery.Abdominal X-rays and histopathological examinations were performed to assess abdominal organ changes and wound healing.Results:The results showed no significant difference in mortality rates among the three groups(p>0.05).However,rats in group B exhibited superior overall condi-tion,cleaner wounds,and a higher rate of wound healing compared to the other groups(p<0.05).Abdominal X-rays indicated that varying degrees of distal intestinal obstruction in all groups.Histopathological examinations revealed fibrous hyperpla-sia,inflammatory cell infiltration,neovascularization,and collagen deposition in all groups.Group B demonstrated enhanced granulation tissue generation,neovasculari-zation,and collagen deposition compared to the other groups(p<0.05).Conclusions:Polypropylene mesh combined with patches is the most suitable method for establishing an animal model of OA.This model successfully replicated the patho-logical and physiological changes in postoperative patients with OA,specifically the progress of abdominal skin wound healing.It provides a practical and reliable animal model for OA research.

Fast-track rehabilitation program vs conventional care after colorectal resection:A randomized clinical trial

AIM:To compare the fast-track rehabilitation program and conventional care for patients after resection of colorectal cancer.METHODS:One hundred and six consecutive patients who underwent fast-track rehabilitation program were encouraged to have early oral feeding and movement for early discharge,while 104 consecutive patients underwent conventional care after resection of colorectal cancer.Their gastrointestinal functions,postoperative complications and hospital stay time were recorded.RESULTS:The restoration time of gastrointestinal functions in the patients was significantly faster after fasttrack rehabilitation program than after conventional care(2.1 d vs 3.2 d,P < 0.01).The percentage of patients who developed complications was significantly lower 30 d after fast-track rehabilitation program than after conventional care(13.2% vs 26.9%,P < 0.05).Also,the percentage of patients who had general complications was significantly lower 30 d after fast-track rehabilitation program than after conventional care(6.6% vs 15.4%,P < 0.05).The postoperative hospital stay time of the patients was shorter after fast-track rehabilitation program than after conventional care(5 d vs 7 d,P < 0.01).No significant difference was observed in the readmission rate 30 d after fast-track rehabilitation program and conventional care(3.8% vs 8.7%).CONCLUSION:The fast-track rehabilitation program can significantly decrease the complications and shorten the time of postoperative hospital stay of patients after resection colorectal cancer.

Growth hormone stimulates remnant small bowel epithelial cell proliferation

INTRODUCTIONCurrently the major treatment choices for shortbowel syndrome are parenteral nutrition and smallbowel transplantation.Both therapies involvegreat fiscal challenge and recurring complications.Recent years have witnessed the promisingexperimental results of pharmacologicalrehabilitation of remnant small bowel.

Splanchnic vein thrombosis in necrotizing acute pancreatitis: Detection by computed tomographic venography

AIM: To assess the diagnostic accuracy of computed tomographic venography(CTV) for splanchnic vein thrombosis(SVT) detection in necrotizing acute pancreatitis(AP) patients.METHODS:Forty-three patients with necrotizing AP who underwent both CTV and digital subtraction angiography(DSA)within 3 d were analyzed in this retrospective comparative study.All CTV procedures were performed with a dual-source CT scanner.The presence and location of SVT were determined via blinded imaging data analyses.RESULTS:According to the DSA results,17(39.5%)of the total 43 patients had SVT.The sensitivity,specificity,positive and negative predictive values of CTV for SVT detection were 100%(95%CI:77.1%-100%),92.3%(95%CI:73.4%-98.7%),89.5%(95%CI:65.5%-98.2%)and 100%(95%CI:82.8%-100%),respectively.CONCLUSION:CTV is an effective examination for SVT detection in patients with necrotizing AP with high positive and negative predictive values.

Initial transcatheter thrombolysis for acute superior mesenteric venous thrombosis

AIM: To determine the optimal initial treatment modality for acute superior mesenteric vein thrombosis (ASMVT) in patients with circumscribed peritonitis.

外科感染病人胰岛素抵抗的临床意义(英文)

目的研究外科脓毒症病人胰岛素抵抗的临床意义。方法40例外科脓毒症病人入实验组,20例同期相似APACHEⅡ评分但无脓毒症的外科病人入实验对照组。实验组再分别根据病情严重度分为sepsis组和septicshock&MODS(SM)组,根据原发病分为SAP组、肠瘘组和其他组。检测病人入组后不同时间点的空腹血糖、空腹胰岛素、临床代谢指标和血浆TNF-α浓度,并评价APACHEⅡ、SOFA和SS评分。胰岛素抵抗指数通过稳态模式评估法计算。结果脓毒症状态下胰岛素抵抗存在占84%,所有脓毒症病人lgHOMA-IR检测峰值均显著大于正常值。实验组lgHOMA-IR从24h(P<0.01)到第7天(P<0.01)均显著高于对照组。SAP组、肠瘘组和其他组之间lgHOMA-IR在各时间点无显著差异(P>0.05)。SM组lgHOMA-IR在各时间点显著高于sepsis组,相关分析显示lgHOMA-IR与APACHEⅡ(r=0.591,P<0.01)、SOFA(r=0.496,P<0.01)、SS评分(r=0.553,P<0.01)和血浆TNF-α(r=0.658,P<0.01)呈显著正相关。lgHOMA-IR独立相关于LDL、前白蛋白、胆固醇和甘油三酯。R2为0.188。结论外科危重病人普遍存在胰岛素抵抗,与导致感染的原发病无关,可以作为代谢紊乱和病情严重度的预警指标。

PU.1-silenced dendritic cells prolong allograft survival in rats receiving intestinal transplantation

AIM:To investigate the function of PU.1-silenced semimature dendritic cells(DCs)and the possibility of utilizing cell immunity in rat intestinal transplantation.METHODS:DCs were isolated from the bone marrow of F344 rats and cultured using the adherent method.The PU.1 gene was knocked down in DCs using small interfering RNAs(siRNAs)for 24 h,and the cells were then incubated with lipopolysaccharide for 48 h.The PU.1 siRNA that had the highest silencing efficiency was screened using reverse transcription-polymerase chain reaction and Western blot for further study.The tolerance capacity was analyzed and compared between PU.1-silenced DCs(siRNA PU.1 group),negative control-silenced DCs(siRNA NC group)and immature DCs(control group)both in vitro and in vivo.CONCLUSION:Blocking expression of the PU.1 gene in vitro led to a reduction in DC maturation and an increased tolerance capability.PU.1-silenced DCs expressed moderate levels of major histocompatibility complex(MHC)-Ⅱand low levels of co-stimulatory molecules,and produced more interleukin(IL)-10,but less IL-12.Compared with the negative control group,surface molecules cluster of differentiation 80(CD80),CD86 and MHC-Ⅱin the siRNA PU.1 group were 27.0%±5.6%,23.6%±4.8%and 36.8%±6.8%,respectively,and showed a significantly lower trend(P<0.05).In vivo treatment of recipients with PU.1-silenced DCs injected before intestinal transplantation(siRNA PU.1group),significantly prolonged allograft survival and resulted in better tissue histopathology compared with the siRNA NC group and control group.Mean survival time after transplantation was 14.3±3.3 d in the siRNA PU.1 group(P<0.05).CONCLUSION:PU.1-silenced semi-mature DCs induced partial immune tolerance both in vitro and in vivo,which could be used as a new strategy to promote transplantation tolerance.

Delayed liver laceration following transjugular intrahepatic portosystemic shunt for portal hypertension

The transjugular intrahepatic portosystemic shunt(TIPS) is an acceptable procedure that has proven benefits in the treatment of patients who have complications from portal hypertension due to liver cirrhosis.Delayed liver laceration is a rare complication of the TIPS procedure.We describe a patient with portal hypertension due to liver cirrhosis,who suddenly presented with abdominal hemorrhage and liver laceration 8 d after TIPS.Few reports have described complications after TIPS placement.To the best of our knowledge,this is the first report describing delayed liver laceration.This potential and serious complication appears to be specific and fatal for TIPS in portal hypertension.We advocate careful attention to the technique to avoid this complication,and timely treatment is extremely important.

Research progress of acute coagulopathy of trauma-shock

Acute coagulopathy of trauma-shock （ACoTS） occurs in 25% of patients with severe trauma in the early phase, and the mortality of those patients is four-fold higher than patients without coagulopathy. The pathophysiology of this complicated phenomenon has been focused on in recent years. Tissue injury and hypoperfusion, activated protein C and Complements play important roles in the early phase after trauma. While the use of blood products, hypothermia, acidosis and inflammation are the main mechanism in late phase. Supplementing coagulation factors and platelets to improve ACoTS are inefficient. Only positive resuscitation from shock and improving tissue hypoperfusion have expected benefits.

Bioelectrical impedance analysis-guided fluid management promotes primary fascial closure after open abdomen:a randomized controlled trial

Background:Fluid overload(FO)after resuscitation is frequent and contributes to adverse outcomes among postinjury open abdomen(OA)patients.Bioelectrical impedance analysis(BIA)is a promising tool for monitoring fluid status and FO.Therefore,we sought to investigate the efficacy of BIA-directed fluid resuscitation among OA patients.Methods:A pragmatic,prospective,randomized,observer-blind,single-center trial was performed for all trauma patients requiring OA between January 2013 and December 2017 to a national referral center.A total of 140 postinjury OA patients were randomly assigned in a 1:1 ratio to receive either a BIA-directed fluid resuscitation(defined as BIA)protocol that included fluid administration with monitoring of hemodynamic parameters and different degrees of interventions to achieve a negative fluid balance targeting the hydration level(HL)measured by BIA or a traditional fluid resuscitation(TRD)in which clinicians determined the fluid resuscitation regimen according to traditional parameters during 30 d of intensive care unit(ICU)management.The primary outcome was the 30-day primary fascial closure(PFC)rate.The secondary outcomes included the time to PFC,postoperative 7-day cumulative fluid balance(CFB)and adverse events within 30 d after OA.The Kaplan–Meier method and the log-rank test were utilized for PFC after OA.A generalized linear regression model for the time to PFC and CFB was built.Results:A total of 134 patients completed the trial(BIA,n=66;TRD,n=68).The BIA patients were significantly more likely to achieve PFC than the TRD patients(83.33%vs.55.88%,P<0.001).In the BIA group,the time to PFC occurred earlier than that of the TRD group by an average of 3.66 d(P<0.001).Additionally,the BIA group showed a lower postoperative 7-day CFB by an average of 6632.80 ml(P<0.001)and fewer complications.Conclusions:Among postinjury OA patients in the ICU,the use of BIA-guided fluid resuscitation resulted in a higher PFC rate and fewer severe complications than the traditional fluid resuscitation strategy.