BACKGROUND In the context of hepatobiliary and liver transplant surgery,ischemia-reperfusion(I/R)injury can occur due to temporary interruption of blood flow to the organ followed by a potentially damaging inflammator...BACKGROUND In the context of hepatobiliary and liver transplant surgery,ischemia-reperfusion(I/R)injury can occur due to temporary interruption of blood flow to the organ followed by a potentially damaging inflammatory response to reperfusion.Ma-crophages can drive inflammation in response to injury,but they can also pro-mote liver growth and resolution of chronic liver injury and fibrosis.In chronic liver injury models in mice,macrophage colony stimulating factor(CSF)1 stimu-lates pro-regenerative macrophages.AIM To determine whether stimulation of macrophages with macrophage CSF could promote liver repair after I/R injury.METHODS We investigated the impact of perisurgical treatment with a long-circulating CSF1-Fc conjugate on liver injury and hepatocyte proliferation after 70%ischemia for 60 minutes at 6 hours,48 hours and 7 days post reperfusion in rats.Circulating and liver tissue monocyte and macrophage subsets in the ischaemic and oxyge-nated lobes were assessed using quantitative PCR and flow cytometry.RESULTS CSF1-Fc treatment did not affect the extent of hepatocellular injury post-reperfu-sion,as indicated by serum transaminases.Liver I/R injury,especially necrotic area,was reduced in CSF1-Fc-treated rats 48 h post-surgery.This was associated with increased accumulation of macrophages in both the oxygenated and ischemic lobes(ILs),and peri-necrotic zone localization in the IL.CSF1-Fc treatment also promoted liver growth,associated with increased parenchymal and non-parenchymal cell proliferation.CSF1-Fc increased the abundance of CD43+non-classical monocytes,consistent with the role of CSF1 signaling in monocyte maturation,and increased CD163 expression on mature macrophages.CONCLUSION This study suggests CSF1 stimulation drives monocytes/macrophages towards a pro-regenerative response and perisurgical CSF1 treatment might augment liver regeneration in patients undergoing liver resection.展开更多
Endovascular treatment is increasingly employed as the treatment for symptomatic aortoiliac occlusive disease.One of the possible complications of aortoiliac stenting is the development of emboli.We present a case of ...Endovascular treatment is increasingly employed as the treatment for symptomatic aortoiliac occlusive disease.One of the possible complications of aortoiliac stenting is the development of emboli.We present a case of a 60-year-old patient presenting with right scrotal pain immediately following aortoiliac stenting for right common iliac,proximal external iliac and proximal internal iliac arteries thrombosis.He was found to have testicular ischaemia with absent blood flow on duplex ultrasonography.The patient was managed expectantly and reduced blood flow spontaneously returned to the testis over the next few weeks.展开更多
Platelet microparticles(PMPs)are membrane particles derived from the platelet membrane that enter into the blood circulation.We sought to explore the therapeutic effects of Tao-Hong-Si-Wu Decoction(THSWD)on angiogenes...Platelet microparticles(PMPs)are membrane particles derived from the platelet membrane that enter into the blood circulation.We sought to explore the therapeutic effects of Tao-Hong-Si-Wu Decoction(THSWD)on angiogenesis in a rat model of cerebral ischaemia-reperfusion(I/R).The protective effect of THSWD on I/R rats was observed morphologically by immunohistochemical expression of VEGF and CD34,along with immunofluorescence results of co-expression of Brd U and v WF.Then,PMPs from different groups of rats were extracted,and cytokine array analysis was used to screen for angiogenesis associated proteins.The results showed that THSWD can promote the expression of VEGF,CD34,Brd U and v WF.Cytokine array analysis revealed the changes in the expression of 29 related angiogenic proteins in the total protein of PMPs,which involved the Notch signalling pathway.Compared with model group,the expression levels of NICD and Hes-1 in the THSWD group were significantly increased.In the context of I/R,the angiogenesis-related proteins of PMPs are different.THSWD may involve the promotion of activation of the Notch signalling pathway to achieve therapeutic effects on cerebral ischaemia.展开更多
Situs inversus abdominus with rotational anomaly of the intestines is an extremely rare condition. Although intestinal malrotation has been recognized as a cause of obstruction in infants and children and may be compl...Situs inversus abdominus with rotational anomaly of the intestines is an extremely rare condition. Although intestinal malrotation has been recognized as a cause of obstruction in infants and children and may be complicated by intestinal ischaemia, it is very rare in adults. When it occurs in the adult patient, it may present acutely as bowel obstruction or intestinal ischaemia or chronically as vague intermittent abdominal pain. Herein, we present an acute presentation of a case of situs inversus abdominus and intestinal malrotation with Ladd＇s band leading to infarction of the intestine in a 32 year old woman.展开更多
Longstanding research describes the mechanisms whereby the restoration of blood flow and reoxygenation(reperfusion) aggravates the ischaemic injury caused by a period of anoxia to a donor liver. This phenomenon, calle...Longstanding research describes the mechanisms whereby the restoration of blood flow and reoxygenation(reperfusion) aggravates the ischaemic injury caused by a period of anoxia to a donor liver. This phenomenon, called ischaemia-reperfusion injury(IRI), leads to parenchymal cell death,microcirculatory failure, and inflammatory immune response. Clinically, IRI is the main factor responsible for the occurrence of posttransplant graft dysfunction and ischaemic-type biliary lesions. While extended criteria donor livers are more vulnerable to IRI, their utilisation is required to address the shortfall in donor organs. Thus, the mitigation of IRI should drive the setting of a new benchmark for marginal organ preservation. Herein, strategies incorporating different modalities of machine perfusion of the liver to alleviate IRI are discussed in conjunction with advantages and disadvantages of individual protocols.Techniques leading to reperfusion of the liver during machine perfusion(in situ normothermic regional perfusion and ex situ normothermic machine perfusion)may mitigate IRI by shortening the ischaemic period of the organs. This benefit potentially escalates from the minimum level, obtained following just partial alleviation of the ischaemic period, to the maximum level, which can be potentially achieved with ischaemia-free organ transplantation. Techniques that do not lead to reperfusion of the liver during machine perfusion(hypothermic,subnormothermic, and controlled-oxygenated rewarming) optimise mitochondrial oxidative function and replenish cellular energy stores, thereby lowering reactive oxygen species production as well as the activation ofdownstream inflammatory pathways during reperfusion. Further mechanistic insights into IRI may guide the development of donor-specific protocols of machine perfusion on the basis of the limitations of individual categories of extended criteria donor organs.展开更多
Objective Autophagy was prominently activated by cerebral ischaemia.This study was to investigate the exact role of autophagy in ischaemic stroke.Methods Two rat models of transient middle cerebral artery occlusion(tM...Objective Autophagy was prominently activated by cerebral ischaemia.This study was to investigate the exact role of autophagy in ischaemic stroke.Methods Two rat models of transient middle cerebral artery occlusion(tMCAO)and permanent MCAO(pMCAO)were prepared.The brain tissues in the penumbra were obtained to observe the dynamic variations of autophagy activity with Beclin1 and LC3 antibodies by Western blotting.At the characteristic time points,when autophagy activity was markedly elevated or reduced,the autophagy activation signaling was intervened with rapamycin and 3-methyladenine,respectively.Thereafter,key proteins in the autopahgic/lysosomal pathway were detected with the antibodies of LC3,p62,ubiquitin,LAMP-1 and cathepsin B.Meanwhile,TTC staining,neurological score and immunofluorescence were performed to evaluate brain infarct volume,neurological deficit and neuron survival,respectively.Results Both Beclin1 and LC3 expression levels were remarkably altered at 6 h,12 h,2 days and 7 days after tMCAO.Interestingly,the dynamic changes of autophagy activity following pMCAO were identical to those after tMCAO.Neither autophagy induction nor autophagy inhibition was able to ameliorate the pMCAO-induced neurological injury due to lysosomal dysfunction,as indicated by low levels of LAMP-1 and cathepsin B,accompanied with the accumulation of LC3-II,ubiquitin and insoluble p62.Comparatively,autophagy induction elicited overt neuroprotection at 2 and 7 days after tMCAO,and this neuroprotection might be elicited by the enhancement of autophagy flux.Conclusion Our study suggests that autophagy confers neuroprotection at the subacute phase of tMCAO but has few effects on neurological outcomes after pMCAO.展开更多
OBJECTIVE Propane-2-sulfonic acid octadec-9-enyl-amide(N15),an analogue of oleoylethanolamide(OEA),is a novel PPARα/γdual agonist.Our previous studies verified the positive effects of OEA on the acute and delayed st...OBJECTIVE Propane-2-sulfonic acid octadec-9-enyl-amide(N15),an analogue of oleoylethanolamide(OEA),is a novel PPARα/γdual agonist.Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischaemia.However,it is not clear whether N15 is effective against ischaemic cerebral injury.In the present study,male Kunming mice were subjected to middle cerebral artery occlusion(MCAO).METHODS To evaluate its preventive effects,N15(50,100 or 200 mg·kg-1,ip)was administered for3 d before ischaemia.To evaluate its therapeutic effects,N15(200 mg·kg-1,ip)was administered 1 h before reperfusion or 0,1,2 or 4 h after reperfusion.Neurological deficit scores,infarct volume and the degree of brain oedema were determined at 24 h after reperfusion.Blood brain barrier(BBB)disruption was evaluated by Evans blue(EB)leakage at 6 h after reperfusion.The activation/inflammatory responses of microglia were detected using immunohistochemistry and Western blotting.RESULTS N15 pretreatment improved neurological dysfunction,reduced infarct volume and alleviated brain oedema in a dose-dependent manner;the most effective dose was 200 mg·kg-1.The therapeutic time window was within 2 h after reperfusion.Moreover,N15was more potent in the treatment of cerebral ischaemia injury than OEA.N15 treatment preserved the BBB integrity and suppressed the activation of microglia.N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide(LPS)-stimulated BV-2microglial cells.Moreover,N15 decreased the phosphorylation levels of NF-κBp65,STAT3,and ERK1/2 both in vivo and in vitro.CONCLUSION Our findings demonstrated that N15 exerts neuroprotective effects and was more potent than OEA.Additionally,the neuroprotective effects of N15 on cerebral ischaemia may be attributed to its anti-inflammatory properties,at least in part,by enhancing PPARα/γdual signalling and inhibiting the activation of the NF-κB,STAT3,and ERK1/2 signalling pathways.These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischaemic stroke.展开更多
Purpose: Gut permeability and microvascular injury following ischaemia/reperfusion (IR) have been implicated in the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Taurine (TAU), a sul...Purpose: Gut permeability and microvascular injury following ischaemia/reperfusion (IR) have been implicated in the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Taurine (TAU), a sulfur-containing amino acid, is a powerful antioxidant and regulator of intracellular calcium and several studies have established that treatment with TAU protects cerebral, cardiac and testicular tissue from (IR) injury. This study investigates the protective effect of taurine in an experimental model of I/R-induced gut injury in rats. Methods: Sprague-Dawley rats were randomized into three groups: Control, I/R, TAU + I/R. TAU was given by gavage or intravenous injection before I/R. Ischaemia was induced by cross-clamping superior mesenteric and coeliac vascular pedicle for 20 - 30 min, followed by 60 - 180 min reperfusion. Gut permeability, blood flux, tissue oedema, leucocytes infiltration and eNOS expression were measured at 3 hrs following reperfusion using FD4. Leukocyte-endothelial interactions were determined by intra-vital microscopy during I/R. In vitro studies assessed the protective effect of TAU on endothelial cell function and survival. Results: Treatment with TAU significantly attenuated IR-induced gut hyper permeability, tissue oedema, leukocyte adhesion and infiltration. TAU also prevented the reduction in gut blood flow, leukocyte rolling velocity and eNOS expression induced by IR. TAU protects against I/R-induced endothelial cell injury by reduced anti-oxidant activity and modulation of eNOS expression and intracellular calcium fluxes. Conclusions: TAU protects the gut from intestinal barrier dysfunction induced by surgical I/R.展开更多
Introduction: Ischaemic heart disease is the number one cause of deaths in the world. As these patients experience severe distress due to a number of associated reasons, it is important to focus on both physiological ...Introduction: Ischaemic heart disease is the number one cause of deaths in the world. As these patients experience severe distress due to a number of associated reasons, it is important to focus on both physiological and psychological needs of the patients in the management. Beyond the standard medical and surgical treatments, relaxation therapies such as relaxing music have been identified as having impact in reducing morbidity in ischaemic heart disease. Even though several studies have been conducted to find out the impact of music on pain, anxiety, heart rate and stress associated with myocardial ischaemia, it is hard to find literature on the long-term effects of music on ischaemia. Therefore the effort of this study was to determine the long-term effects of Indian classical music on state of ischaemia in stable angina. Methodology: A single blind randomized clinical trial was conducted on 60 patients of 45 to 65 years of age with stable angina. Intervention group (n = 30) listened to a music based on Indian classical system at home twice a day complementary to their regular treatment for a period of one month. Control group (n = 30) was only on their usual treatment. Both groups were assessed before and one month after the study period for state of ischaemia based on exercise ECG results. Results: Significant improvement in state of ischaemia (p 0.05). Conclusion: Systematic, regular listening of music based on Indian classical system significantly improved the severity of the state of ischaemia associated with stable angina. Hence music therapy has a potential benefit in considering for use as complementary to angina treatment in reducing morbidity.展开更多
The rising number of patients with acute limb ischemia (ALI) brings the question if there is an opportunity to make a diagnosis safely and accurately. The current “gold standard” for diagnosis is digital subtraction...The rising number of patients with acute limb ischemia (ALI) brings the question if there is an opportunity to make a diagnosis safely and accurately. The current “gold standard” for diagnosis is digital subtraction angiography (DSA). However, current times show that computed tomography angiogram (CTA) builds popularity among doctors working in vascular surgery departments. The aim of this study is to collect evidence of the use of CTA for the assessment of patients with ALI and compare it to the “gold standard” (DSA). Methodology: This is a narrative synthesis, the search of 4 databases is done for relevant articles within a period from 2000 to 2021. Information extracted will be compared to leading guidelines for ALI published in 2 recent reviews by the American College of Radiology and the European Society for Vascular Surgery. Results: In total 48 articles were obtained: reviews (n = 13), studies (n = 4) and case reports (n = 31). Case reports were excluded from the study. CTA has multiple benefits, which can be put into 4 different groups: availability and accessibility, accuracy, affordability and additional information. Further disadvantages and similarities were discussed in 2 separate groups. Conclusion: The use of CTA in patients with ALI has a notable advantage in all 4 categories (availability, accuracy, affordability, and additional information). Disadvantages and similarities between CTA and DSA, do not vary and do not significantly affect the end decision. This makes CTA a valid tool as the first step in the assessment of the patient with ALI.展开更多
in order to clarify the pesible role of the bcl-2 gene imolved in the cell death Program,and the relatiouship of glutamate receptors with bcl-2 gene expressin, this study examied the expression of bcl-2 gene protein...in order to clarify the pesible role of the bcl-2 gene imolved in the cell death Program,and the relatiouship of glutamate receptors with bcl-2 gene expressin, this study examied the expression of bcl-2 gene protein, the neuronal status of apoptosis and the effects of MK-801 using immunohistochemistry and in situ terminal.labelling methods after 30 min of.middle cerebral artery(MCA) occlusion and followed by 24 h of reperfusion. The presence of bcl-2 gene protein increased in the ipeilateral hemisphere of ischaemis espeially in the MCA territory MK-801 enhanced the expresion of the bcl-2 gene protein. No DNA fragmentation was detected in this experiment. In conclusion. bcl-2 gene activity increased during transient focal ischaemia, and was potentiated by MK MK801, which may be an endogenous protective mechanism .against ischaemic apoptosis. Apoptosis wasnot detected after tranient focal ischoemia. for 30 min rollowed by 24 h of reperfusiou.展开更多
Background In clinical liver transplantation, whether the delay of hepatic arterial ischaemia increases biliary fibrosis or not is controversial. We designed a liver transplantation model to test this controversy and ...Background In clinical liver transplantation, whether the delay of hepatic arterial ischaemia increases biliary fibrosis or not is controversial. We designed a liver transplantation model to test this controversy and explore its mechanism. Methods Twelve dogs were divided into two groups randomly： hepatic arterial ischaemia （HAI） and control groups. In HAI group, hepatic artery was perfused 60 minutes after portal perfusion, but in control group, hepatic arterial perfusion was simultaneous with portal perfusion. The pathological changes of intrahepatic bile ducts were observed. Transforming growth factor beta 1 （TGF-β1）, expressed in epithelial cells of intrahepatic bile duct, was detected by immunohistochemical streptoadividin-biotin complex method. Expressions of Smad3, P-Smad3 and the transcriptional levels of alpha smooth muscle actin （α-SMA） mRNA in intrahepatic bile ducts were detected by Western blotting and RT-PCR respectively.Results Compared with the control group, more collagen deposition and leucocytic infiltration could be seen in biliary vessel walls. Significantly more buffy particles, which are the proteins of TGF-β1, could be seen in biliary epithelial cells. P-Smad3 and α-SMA mRNA （as ratio to corresponding β-actin） in intrahepatic bile ducts were 1.82±0.18 and 1.86±0.73 respectively in HAI group, significantly higher than those in control group （0.59±0.09 and 0.46±0.18, respectively）. Conclusions Hepatic arterial ischaemia could increase the deposition of collagen fibres, trigger the transdifferentiation of myofibroblasts in intrahepatic bile duct and might result in biliary fibrosis by activating the TGF-β1 signalling pathway.展开更多
Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoqu...Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoquinolinone （DPQ）, a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms. Methods Studies were performed with I/R rats＇ hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB （NF-KB）, intercellular adhesion molecule-1 （ICAM-1）, cyclooxygenase-2 （COX-2） and matrix metalloproteinase-9 （MMP-9） were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-313 （GSK- 3β） and forkhead transcription factor FOXO3a. Results Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from （35±5）% to （20±4）% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-KB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3β and phosphor-FOXO3a. Conclusion The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly （ADP-ribose） polymerase reduced heart I/R injury in rats.展开更多
Acute myocardial ischaemia is a common acute .disease and a common cause of sudden death.However, it is difficult to diagnose in patients who died within 6 hours after the onset of myocardial ischaemia. The occurrence...Acute myocardial ischaemia is a common acute .disease and a common cause of sudden death.However, it is difficult to diagnose in patients who died within 6 hours after the onset of myocardial ischaemia. The occurrence of sudden cardiac death often has pathological basis of primary heart diseases, which may lead to a series of changes in metabolism and gene expression.1 Recent research found that hypoxia inducible factor 1 alpha （HIF-1α） is a sensitive marker of hypoxia; its gene expression is upregulated within several minutes after acute myocardial ischaemia, followed by the upregulation of its protein and its expression will remain high if the inducement continues. Its expression in nonhypoxic cardiac muscle is very low. This characteristic may be used to differentiate hypoxic factors from nonhypoxic factors, and help to judge the cause of death. This study explored the expression of HIF-1α in hypoxic cardiac muscle by establishing an acute myocardial ischaemia model in mice, and observed its dynamic changes to provide reference for analysing causes of death within 48 hours after death.展开更多
基金Supported by the German Research Foundation(Deutsche Forschungsgemeinschaft)and the Australian National Health and Medical Research Council and the Mater Foundation.
文摘BACKGROUND In the context of hepatobiliary and liver transplant surgery,ischemia-reperfusion(I/R)injury can occur due to temporary interruption of blood flow to the organ followed by a potentially damaging inflammatory response to reperfusion.Ma-crophages can drive inflammation in response to injury,but they can also pro-mote liver growth and resolution of chronic liver injury and fibrosis.In chronic liver injury models in mice,macrophage colony stimulating factor(CSF)1 stimu-lates pro-regenerative macrophages.AIM To determine whether stimulation of macrophages with macrophage CSF could promote liver repair after I/R injury.METHODS We investigated the impact of perisurgical treatment with a long-circulating CSF1-Fc conjugate on liver injury and hepatocyte proliferation after 70%ischemia for 60 minutes at 6 hours,48 hours and 7 days post reperfusion in rats.Circulating and liver tissue monocyte and macrophage subsets in the ischaemic and oxyge-nated lobes were assessed using quantitative PCR and flow cytometry.RESULTS CSF1-Fc treatment did not affect the extent of hepatocellular injury post-reperfu-sion,as indicated by serum transaminases.Liver I/R injury,especially necrotic area,was reduced in CSF1-Fc-treated rats 48 h post-surgery.This was associated with increased accumulation of macrophages in both the oxygenated and ischemic lobes(ILs),and peri-necrotic zone localization in the IL.CSF1-Fc treatment also promoted liver growth,associated with increased parenchymal and non-parenchymal cell proliferation.CSF1-Fc increased the abundance of CD43+non-classical monocytes,consistent with the role of CSF1 signaling in monocyte maturation,and increased CD163 expression on mature macrophages.CONCLUSION This study suggests CSF1 stimulation drives monocytes/macrophages towards a pro-regenerative response and perisurgical CSF1 treatment might augment liver regeneration in patients undergoing liver resection.
文摘Endovascular treatment is increasingly employed as the treatment for symptomatic aortoiliac occlusive disease.One of the possible complications of aortoiliac stenting is the development of emboli.We present a case of a 60-year-old patient presenting with right scrotal pain immediately following aortoiliac stenting for right common iliac,proximal external iliac and proximal internal iliac arteries thrombosis.He was found to have testicular ischaemia with absent blood flow on duplex ultrasonography.The patient was managed expectantly and reduced blood flow spontaneously returned to the testis over the next few weeks.
基金supported by the National Natural Science Foundation of China(Nos.81473387 and 81503291)the Anhui Province Key Research and Development Program(No.1704a0802141)。
文摘Platelet microparticles(PMPs)are membrane particles derived from the platelet membrane that enter into the blood circulation.We sought to explore the therapeutic effects of Tao-Hong-Si-Wu Decoction(THSWD)on angiogenesis in a rat model of cerebral ischaemia-reperfusion(I/R).The protective effect of THSWD on I/R rats was observed morphologically by immunohistochemical expression of VEGF and CD34,along with immunofluorescence results of co-expression of Brd U and v WF.Then,PMPs from different groups of rats were extracted,and cytokine array analysis was used to screen for angiogenesis associated proteins.The results showed that THSWD can promote the expression of VEGF,CD34,Brd U and v WF.Cytokine array analysis revealed the changes in the expression of 29 related angiogenic proteins in the total protein of PMPs,which involved the Notch signalling pathway.Compared with model group,the expression levels of NICD and Hes-1 in the THSWD group were significantly increased.In the context of I/R,the angiogenesis-related proteins of PMPs are different.THSWD may involve the promotion of activation of the Notch signalling pathway to achieve therapeutic effects on cerebral ischaemia.
文摘Situs inversus abdominus with rotational anomaly of the intestines is an extremely rare condition. Although intestinal malrotation has been recognized as a cause of obstruction in infants and children and may be complicated by intestinal ischaemia, it is very rare in adults. When it occurs in the adult patient, it may present acutely as bowel obstruction or intestinal ischaemia or chronically as vague intermittent abdominal pain. Herein, we present an acute presentation of a case of situs inversus abdominus and intestinal malrotation with Ladd＇s band leading to infarction of the intestine in a 32 year old woman.
基金supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham
文摘Longstanding research describes the mechanisms whereby the restoration of blood flow and reoxygenation(reperfusion) aggravates the ischaemic injury caused by a period of anoxia to a donor liver. This phenomenon, called ischaemia-reperfusion injury(IRI), leads to parenchymal cell death,microcirculatory failure, and inflammatory immune response. Clinically, IRI is the main factor responsible for the occurrence of posttransplant graft dysfunction and ischaemic-type biliary lesions. While extended criteria donor livers are more vulnerable to IRI, their utilisation is required to address the shortfall in donor organs. Thus, the mitigation of IRI should drive the setting of a new benchmark for marginal organ preservation. Herein, strategies incorporating different modalities of machine perfusion of the liver to alleviate IRI are discussed in conjunction with advantages and disadvantages of individual protocols.Techniques leading to reperfusion of the liver during machine perfusion(in situ normothermic regional perfusion and ex situ normothermic machine perfusion)may mitigate IRI by shortening the ischaemic period of the organs. This benefit potentially escalates from the minimum level, obtained following just partial alleviation of the ischaemic period, to the maximum level, which can be potentially achieved with ischaemia-free organ transplantation. Techniques that do not lead to reperfusion of the liver during machine perfusion(hypothermic,subnormothermic, and controlled-oxygenated rewarming) optimise mitochondrial oxidative function and replenish cellular energy stores, thereby lowering reactive oxygen species production as well as the activation ofdownstream inflammatory pathways during reperfusion. Further mechanistic insights into IRI may guide the development of donor-specific protocols of machine perfusion on the basis of the limitations of individual categories of extended criteria donor organs.
基金supported by grants from the National Natural Science Foundation of China(No.81960418 and No.81860411)the Yunnan Ten Thousand Talents Plan Young&Elite Talents Project(No.YNWR-QNBJ-2018-034)+2 种基金the Yunnan Applied Basic Research Projects Fund of Yunnan Provincial Department of Science&Technology(No.2019FB113 and No.202001AT070049)the Science Research Fund of Yunnan Provincial Department of Education(No.2018JS016 and No.2020J0066)the Doctoral Foundation of Kunming University of Science and Technology(No.KKSY201960010).
文摘Objective Autophagy was prominently activated by cerebral ischaemia.This study was to investigate the exact role of autophagy in ischaemic stroke.Methods Two rat models of transient middle cerebral artery occlusion(tMCAO)and permanent MCAO(pMCAO)were prepared.The brain tissues in the penumbra were obtained to observe the dynamic variations of autophagy activity with Beclin1 and LC3 antibodies by Western blotting.At the characteristic time points,when autophagy activity was markedly elevated or reduced,the autophagy activation signaling was intervened with rapamycin and 3-methyladenine,respectively.Thereafter,key proteins in the autopahgic/lysosomal pathway were detected with the antibodies of LC3,p62,ubiquitin,LAMP-1 and cathepsin B.Meanwhile,TTC staining,neurological score and immunofluorescence were performed to evaluate brain infarct volume,neurological deficit and neuron survival,respectively.Results Both Beclin1 and LC3 expression levels were remarkably altered at 6 h,12 h,2 days and 7 days after tMCAO.Interestingly,the dynamic changes of autophagy activity following pMCAO were identical to those after tMCAO.Neither autophagy induction nor autophagy inhibition was able to ameliorate the pMCAO-induced neurological injury due to lysosomal dysfunction,as indicated by low levels of LAMP-1 and cathepsin B,accompanied with the accumulation of LC3-II,ubiquitin and insoluble p62.Comparatively,autophagy induction elicited overt neuroprotection at 2 and 7 days after tMCAO,and this neuroprotection might be elicited by the enhancement of autophagy flux.Conclusion Our study suggests that autophagy confers neuroprotection at the subacute phase of tMCAO but has few effects on neurological outcomes after pMCAO.
基金The project supported by National Natural Sciences Foundation of China(81373407)the Natural Science Foundation of Fujian Province(2016D018)
文摘OBJECTIVE Propane-2-sulfonic acid octadec-9-enyl-amide(N15),an analogue of oleoylethanolamide(OEA),is a novel PPARα/γdual agonist.Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischaemia.However,it is not clear whether N15 is effective against ischaemic cerebral injury.In the present study,male Kunming mice were subjected to middle cerebral artery occlusion(MCAO).METHODS To evaluate its preventive effects,N15(50,100 or 200 mg·kg-1,ip)was administered for3 d before ischaemia.To evaluate its therapeutic effects,N15(200 mg·kg-1,ip)was administered 1 h before reperfusion or 0,1,2 or 4 h after reperfusion.Neurological deficit scores,infarct volume and the degree of brain oedema were determined at 24 h after reperfusion.Blood brain barrier(BBB)disruption was evaluated by Evans blue(EB)leakage at 6 h after reperfusion.The activation/inflammatory responses of microglia were detected using immunohistochemistry and Western blotting.RESULTS N15 pretreatment improved neurological dysfunction,reduced infarct volume and alleviated brain oedema in a dose-dependent manner;the most effective dose was 200 mg·kg-1.The therapeutic time window was within 2 h after reperfusion.Moreover,N15was more potent in the treatment of cerebral ischaemia injury than OEA.N15 treatment preserved the BBB integrity and suppressed the activation of microglia.N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide(LPS)-stimulated BV-2microglial cells.Moreover,N15 decreased the phosphorylation levels of NF-κBp65,STAT3,and ERK1/2 both in vivo and in vitro.CONCLUSION Our findings demonstrated that N15 exerts neuroprotective effects and was more potent than OEA.Additionally,the neuroprotective effects of N15 on cerebral ischaemia may be attributed to its anti-inflammatory properties,at least in part,by enhancing PPARα/γdual signalling and inhibiting the activation of the NF-κB,STAT3,and ERK1/2 signalling pathways.These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischaemic stroke.
文摘Purpose: Gut permeability and microvascular injury following ischaemia/reperfusion (IR) have been implicated in the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Taurine (TAU), a sulfur-containing amino acid, is a powerful antioxidant and regulator of intracellular calcium and several studies have established that treatment with TAU protects cerebral, cardiac and testicular tissue from (IR) injury. This study investigates the protective effect of taurine in an experimental model of I/R-induced gut injury in rats. Methods: Sprague-Dawley rats were randomized into three groups: Control, I/R, TAU + I/R. TAU was given by gavage or intravenous injection before I/R. Ischaemia was induced by cross-clamping superior mesenteric and coeliac vascular pedicle for 20 - 30 min, followed by 60 - 180 min reperfusion. Gut permeability, blood flux, tissue oedema, leucocytes infiltration and eNOS expression were measured at 3 hrs following reperfusion using FD4. Leukocyte-endothelial interactions were determined by intra-vital microscopy during I/R. In vitro studies assessed the protective effect of TAU on endothelial cell function and survival. Results: Treatment with TAU significantly attenuated IR-induced gut hyper permeability, tissue oedema, leukocyte adhesion and infiltration. TAU also prevented the reduction in gut blood flow, leukocyte rolling velocity and eNOS expression induced by IR. TAU protects against I/R-induced endothelial cell injury by reduced anti-oxidant activity and modulation of eNOS expression and intracellular calcium fluxes. Conclusions: TAU protects the gut from intestinal barrier dysfunction induced by surgical I/R.
文摘Introduction: Ischaemic heart disease is the number one cause of deaths in the world. As these patients experience severe distress due to a number of associated reasons, it is important to focus on both physiological and psychological needs of the patients in the management. Beyond the standard medical and surgical treatments, relaxation therapies such as relaxing music have been identified as having impact in reducing morbidity in ischaemic heart disease. Even though several studies have been conducted to find out the impact of music on pain, anxiety, heart rate and stress associated with myocardial ischaemia, it is hard to find literature on the long-term effects of music on ischaemia. Therefore the effort of this study was to determine the long-term effects of Indian classical music on state of ischaemia in stable angina. Methodology: A single blind randomized clinical trial was conducted on 60 patients of 45 to 65 years of age with stable angina. Intervention group (n = 30) listened to a music based on Indian classical system at home twice a day complementary to their regular treatment for a period of one month. Control group (n = 30) was only on their usual treatment. Both groups were assessed before and one month after the study period for state of ischaemia based on exercise ECG results. Results: Significant improvement in state of ischaemia (p 0.05). Conclusion: Systematic, regular listening of music based on Indian classical system significantly improved the severity of the state of ischaemia associated with stable angina. Hence music therapy has a potential benefit in considering for use as complementary to angina treatment in reducing morbidity.
文摘The rising number of patients with acute limb ischemia (ALI) brings the question if there is an opportunity to make a diagnosis safely and accurately. The current “gold standard” for diagnosis is digital subtraction angiography (DSA). However, current times show that computed tomography angiogram (CTA) builds popularity among doctors working in vascular surgery departments. The aim of this study is to collect evidence of the use of CTA for the assessment of patients with ALI and compare it to the “gold standard” (DSA). Methodology: This is a narrative synthesis, the search of 4 databases is done for relevant articles within a period from 2000 to 2021. Information extracted will be compared to leading guidelines for ALI published in 2 recent reviews by the American College of Radiology and the European Society for Vascular Surgery. Results: In total 48 articles were obtained: reviews (n = 13), studies (n = 4) and case reports (n = 31). Case reports were excluded from the study. CTA has multiple benefits, which can be put into 4 different groups: availability and accessibility, accuracy, affordability and additional information. Further disadvantages and similarities were discussed in 2 separate groups. Conclusion: The use of CTA in patients with ALI has a notable advantage in all 4 categories (availability, accuracy, affordability, and additional information). Disadvantages and similarities between CTA and DSA, do not vary and do not significantly affect the end decision. This makes CTA a valid tool as the first step in the assessment of the patient with ALI.
文摘in order to clarify the pesible role of the bcl-2 gene imolved in the cell death Program,and the relatiouship of glutamate receptors with bcl-2 gene expressin, this study examied the expression of bcl-2 gene protein, the neuronal status of apoptosis and the effects of MK-801 using immunohistochemistry and in situ terminal.labelling methods after 30 min of.middle cerebral artery(MCA) occlusion and followed by 24 h of reperfusion. The presence of bcl-2 gene protein increased in the ipeilateral hemisphere of ischaemis espeially in the MCA territory MK-801 enhanced the expresion of the bcl-2 gene protein. No DNA fragmentation was detected in this experiment. In conclusion. bcl-2 gene activity increased during transient focal ischaemia, and was potentiated by MK MK801, which may be an endogenous protective mechanism .against ischaemic apoptosis. Apoptosis wasnot detected after tranient focal ischoemia. for 30 min rollowed by 24 h of reperfusiou.
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 30571765 ）.Acknowledgements： We thank Mr. JI Hong and Mr. XU Jin-kai （Department of General Surgery, Second Affiliated Hospital of Medical College, Xi＇an Jiaotong University） for skillful technical assistance.
文摘Background In clinical liver transplantation, whether the delay of hepatic arterial ischaemia increases biliary fibrosis or not is controversial. We designed a liver transplantation model to test this controversy and explore its mechanism. Methods Twelve dogs were divided into two groups randomly： hepatic arterial ischaemia （HAI） and control groups. In HAI group, hepatic artery was perfused 60 minutes after portal perfusion, but in control group, hepatic arterial perfusion was simultaneous with portal perfusion. The pathological changes of intrahepatic bile ducts were observed. Transforming growth factor beta 1 （TGF-β1）, expressed in epithelial cells of intrahepatic bile duct, was detected by immunohistochemical streptoadividin-biotin complex method. Expressions of Smad3, P-Smad3 and the transcriptional levels of alpha smooth muscle actin （α-SMA） mRNA in intrahepatic bile ducts were detected by Western blotting and RT-PCR respectively.Results Compared with the control group, more collagen deposition and leucocytic infiltration could be seen in biliary vessel walls. Significantly more buffy particles, which are the proteins of TGF-β1, could be seen in biliary epithelial cells. P-Smad3 and α-SMA mRNA （as ratio to corresponding β-actin） in intrahepatic bile ducts were 1.82±0.18 and 1.86±0.73 respectively in HAI group, significantly higher than those in control group （0.59±0.09 and 0.46±0.18, respectively）. Conclusions Hepatic arterial ischaemia could increase the deposition of collagen fibres, trigger the transdifferentiation of myofibroblasts in intrahepatic bile duct and might result in biliary fibrosis by activating the TGF-β1 signalling pathway.
基金This study was supported by grants from the Natural Science Foundation of Shandong Province, China （No.ZR2010HM069） and the Technology Development Projects of Taian City （No. 20093077）.
文摘Background Poly （ADP-ribose） polymerase （PARP） has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion （I/R） injury. 3,4-dihydro-5-[4-（1-piperidinyl）butoxy]-l（2H）-isoquinolinone （DPQ）, a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms. Methods Studies were performed with I/R rats＇ hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB （NF-KB）, intercellular adhesion molecule-1 （ICAM-1）, cyclooxygenase-2 （COX-2） and matrix metalloproteinase-9 （MMP-9） were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-313 （GSK- 3β） and forkhead transcription factor FOXO3a. Results Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from （35±5）% to （20±4）% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-KB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3β and phosphor-FOXO3a. Conclusion The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly （ADP-ribose） polymerase reduced heart I/R injury in rats.
基金National Natural Science Foundation of China(No.30500610)
文摘Acute myocardial ischaemia is a common acute .disease and a common cause of sudden death.However, it is difficult to diagnose in patients who died within 6 hours after the onset of myocardial ischaemia. The occurrence of sudden cardiac death often has pathological basis of primary heart diseases, which may lead to a series of changes in metabolism and gene expression.1 Recent research found that hypoxia inducible factor 1 alpha （HIF-1α） is a sensitive marker of hypoxia; its gene expression is upregulated within several minutes after acute myocardial ischaemia, followed by the upregulation of its protein and its expression will remain high if the inducement continues. Its expression in nonhypoxic cardiac muscle is very low. This characteristic may be used to differentiate hypoxic factors from nonhypoxic factors, and help to judge the cause of death. This study explored the expression of HIF-1α in hypoxic cardiac muscle by establishing an acute myocardial ischaemia model in mice, and observed its dynamic changes to provide reference for analysing causes of death within 48 hours after death.
