TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulato...TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.展开更多
Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by widespread inflammation,diffuse alveolar damage,and pulmonary edema,often leading to respiratory failure a...Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by widespread inflammation,diffuse alveolar damage,and pulmonary edema,often leading to respiratory failure and death.Despite significant advances in clinical care,ALI/ARDS remains the leading cause of death among intensive care unit patients.Sepsis is the primary risk factor for the development of ALI/ARDS,as excessive inflammatory responses contribute to organ injury and high mortality in critically ill patients.展开更多
The Middle East is the home of ethnic groups from three main backgrounds: Semitic (Arabs and Jews), Indo-European (Persians and Kurdish) and Turkic (Turkish and Turkmens). Its geographic location, which has been under...The Middle East is the home of ethnic groups from three main backgrounds: Semitic (Arabs and Jews), Indo-European (Persians and Kurdish) and Turkic (Turkish and Turkmens). Its geographic location, which has been under continuous influences from Asia, Europe and Africa, has made it an ideal site for epidemiological studies on Helicobacter pylori (H. pylori) infection and genotyping. The gastric cancer rate differs in this region from very high in Iran (26.1/105) to low in Israel (12.5/105) and very low in Egypt (3.4/105). Epidemiological studies showed that the prevalence of H. pylori is almost similar in those countries with a high level of infection in childhood. Importantly, the frequency of vacA s1 and m1 regions and cagA+ genotypes were higher in non Semitic populations who inhabit the North than Semitic populations, the inhabitants of Southern parts of the Middle East. H. pylori infection prevalence, distribution pattern of virulence factors, diet and smoking could not have explained the difference in cancer rate. This reflects the multifactorial aetiology of gastric cancer and suggests that H. pylori infection does not always directly correlate with the risk for gastrointestinal disease, such as gastric cancer. Further detailed investigations and international comparative studies of each risk factor needto be performed to investigate whether this represents a true enigma.展开更多
Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on fun...Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.展开更多
The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulu...The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum.However,during protein folding,unfolded and/or misfolded proteins are prone to occur,which may lead to endoplasmic reticulum stress.Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control(ERQC)and endoplasmic reticulum-associated degradation(ERAD),which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins.The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored.Therefore,this paper reviews the process and function of protein folding and ERAD in mammalian cells,in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.展开更多
Despite numerous advances and emerging data,liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications.In an era of persistent organ shortage an...Despite numerous advances and emerging data,liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications.In an era of persistent organ shortage and increasing organ demand,allocation of liver grafts must be considered carefully.While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation,tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes.As more studies seeking to expand the oncologic indications for liver transplantation are emerging,it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes.In addition,time from diagnosis to transplantation appears to correlate with survival,as stable disease over time portends better outcomes post-operatively.Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques.While tumor size and stage are important prognostic predictors for most malignancies,patient and tumor selection protocols are necessary.As the fields of medical and surgical oncology continue to evolve,it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively.Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms.Current data evaluating liver transplantation for expanded oncologic indications such as:expanded criteria hepatocellular carcinoma,intrahepatic cholangiocarcinoma,mixed tumors,and liver limited metastatic colorectal carcinomas,incorporate multi-modal therapies and evaluation of tumor treatment response.While further investigation is necessary,initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.展开更多
Acute kidney injury(AKI)affects approximately 13.3 million individuals and contributes to about 1.7 million deaths globally per year.As estimated 85% of those affected live in the developing world[1].Although there ar...Acute kidney injury(AKI)affects approximately 13.3 million individuals and contributes to about 1.7 million deaths globally per year.As estimated 85% of those affected live in the developing world[1].Although there are various measures to prevent or treat AKI,including renal protective drugs and continuous renal replacement therapy,most of them have limited success or are still in their infancy[2,3].展开更多
Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.U...Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.展开更多
Listeria monocytogenes is a foodborne pathogen capable of surviving under challenging conditions both outside and inside the host. During the transition from exponential to stationary phase it experiences a series of ...Listeria monocytogenes is a foodborne pathogen capable of surviving under challenging conditions both outside and inside the host. During the transition from exponential to stationary phase it experiences a series of environmental changes that require an appropriate response to maintain cell viability. In this study the autolytic behaviour of a L. monocytogenes strain was investigated by two-dimensional electrophoresis. The study was done at the permissive autolysis temperature, 30℃ and at 20℃, an autolysis non-permissive temperature. An autolytic strain proteome was also compared to a non-autolytic strain at the permissive autolysis temperature. The autolytic strain proteome at 30℃ in comparison to 20℃ evidenced increased synthesis of the P60 autolysin, glycolytic enzymes and proteins related with environmental stress responses. The over-production of P45 autolysin, was observed when the autolytic strain proteome was compared with the non-autolytic strain. The proteomes at the non-permissive temperature and the proteome of the non-autolytic strain were characterized by a diminished synthesis of several stress related proteins. The lack of autolysis seems to be associated to the over-production of proteins linked to fatty acid and amino acid synthesis, transcription regulation and cell morphogenesis as evidenced by the proteome at the non-permissive temperature and the non-autolytic strain. Autolysis proteome evidenced the over-production of P60 autolysins, glycolysis and stress proteins whereas the proteome obtained in conditions of absence of autolysis reveal a completely different group of proteins. Possible targets to activate listerial autolysis were identified.展开更多
INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structu...INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structures such as inducible bronchus-associated lymphoid tissue(iBALT)and tertiary lymphoid structure(TLS)play essential roles in modulating lung local immune responses.While the identification of iBALTs or TLS is generally dependent on conventional histology,it remains poorly understood how immune cells are spatiotemporally coordinated in the lung at single-cell resolution to effectively eliminate malignant cells and invading pathogens.Recently studies have revealed the presence of dendritic cell(DC)-T immunity hubs in human lung with close association with tumor immunotherapy response[1],antiviral immunity[2],and inflammation resolution[3].展开更多
Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better u...Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy.Here,we observed the nucleus accumulation of ZBTB20,a member of ZBTB-protein family,in the chondrocytes of early-stage OA.Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress,restored the balance of extracellular matrix anabolism and catabolism.The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation.Furthermore,the subcellular localization of ZBTB20 was modulated by the kinase LATS1.Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis,improving the abnormal behavior and moderating cartilage degeneration.The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.展开更多
Background:Previous studies have not clarified the treatment of large pancreatic radiolucent stones(≥5 mm).The primary objective of this study was to assess the clinical features and therapeutic efficacy in patients ...Background:Previous studies have not clarified the treatment of large pancreatic radiolucent stones(≥5 mm).The primary objective of this study was to assess the clinical features and therapeutic efficacy in patients with chronic pancreatitis who have large radiolucent stones,and to propose a treatment strategy.Methods:This analysis examined the data of patients with large pancreatic ductal stones(≥5 mm)from March 2011 to June 2018.Patients with radiolucent stones were classified as the radiolucent stones group,while those with pancreatic radiopaque stones presented at the same time were randomly selected as controls in a 1:2 ratio.Data on demographics,disease courses and treatment details were retrieved,and stone clearance and pain relief during the follow-up were compared between the two groups.Results:A total of 52 patients with large radiolucent stones and 104 patients with large radiopaque stones were included in the study.Pancreatic extracorporeal shock wave lithotripsy(ESWL)was the ini-tial treatment for large radiopaque stone.Endoscopic retrograde cholangiopancreatography(ERCP)was the first-step treatment for all patients in the radiolucent stones group,of which one patient received medication after failed ERCP cannulation,and four who failed stone extraction were treated with ESWL following the placement of a nasopancreatic catheter.There was no significant difference in the complete stone clearance rate(75.0%vs.78.8%;P=0.553)between the two groups.Among the 51 patients in the large radiolucent stones group who were followed up for 5.8 years(range 2.1-12.6),complete pain relief was achieved in 42 patients(82.4%),with no significant difference compared with the radiopaque group(82.4%vs.76.4%;P=0.409).Conclusions:ERCP is an effective endotherapy for large radiolucent stone and should be considered the first-step treatment.When stone extraction failed during ERCP,ESWL is recommended following the placement of a nasopancreatic catheter.展开更多
BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease tra...BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.AIM To explore the complex relationship between chronic hepatitis B(CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements.The HF group was further subdivided into four subgroups:F1,F2,F3,and F4.Data on clinical indicators were collected.Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome.Microbiota diversity,relative abundance,and linear discriminant analysis effect size(LEfSe)were analyzed in different groups.Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed.The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota.The Shapley additive explanations were used to evaluate microbiota importance.RESULTS Integrating the results from univariate analysis,LEfSe,and machine learning,we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF.Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients,and the presence of Dorea shows significant variations across different stages of HF(P<0.05).The relative abundance of Dorea significantly decreases with increasing HF severity(P=0.041).Moreover,the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators,such asγ-glutamyl transferase,alkaline phosphatase,total bilirubin,and the aspartate aminotransferase/alanine transaminase ratio(P<0.05).The associated pathways were predominantly enriched in biosynthesis,degradation/utilization/assimilation,generation of precursors,metabolites,and energy,among other categories.CONCLUSION HF affects the composition of the gut microbiota,indicating that the gut microbiota plays a crucial role in its pathophysiological processes.The abundance of Dorea varies significantly across various stages of HF,making it a potential microbial marker for identifying HF onset and progression.展开更多
Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiatio...Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process.Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism.Therefore,maintaining mitochondrial homeostasis is an important strategy to mitigate OA.Mitophagy is a vital process for autophagosomes to target,engulf,and remove damaged and dysfunctional mitochondria,thereby maintaining mitochondrial homeostasis.Cumulative studies have revealed a strong association between mitophagy and OA,suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA.By reviewing the literature on mitophagy and OA published in recent years,this paper elaborates the potential mechanism of mitophagy regulating OA,thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.展开更多
AIM: To evaluate the prognostic significance of p27kip1 in colorectal cancer patients. METHODS: Cytoplasmic and nuclear p27kip1 expression was evaluated in 418 colorectal cancers using tissue microarrays. Data were as...AIM: To evaluate the prognostic significance of p27kip1 in colorectal cancer patients. METHODS: Cytoplasmic and nuclear p27kip1 expression was evaluated in 418 colorectal cancers using tissue microarrays. Data were associated with known patient and tumor variables and long-term patient outcomes, providing further insight into the mechanisms by which p27kip1 may influence tumor development. RESULTS: Nuclear and cytoplasmic p27Kip1 expressions were detected in 59% and 19% of tumors respectively. Cytoplasmic p27Kip1 was almost invariably associated with positive nuclear p27Kip1 expression. Neither case correlat- ed with known clinical or pathological variables, includ- ing tumor stage, grade or extramural vascular invasion. Furthermore, nuclear p27kip1 expression had no impact on survival. However, we identified a significant correla- tion between expression of cytoplasmic p27kip1 and longer disease-specific survival times. On multivariate analysis, TNM stage and extramural vascular invasion were highly significant independent prognostic factors, with positive cytoplasmic p27 expression showing a trend towards im- proved patient survival (P = 0.059).CONCLUSION: These findings support the recent evi- dence that cytoplasmic p27kip1 has a distinct and impor- tant biological role that can influence tumor outcome.展开更多
The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation.Robust evidence from numerous randomized controlled trials has been pooled by ...The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation.Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses,providing the highest available evidence on the protective effect of machine perfusion(MP)over static cold storage in liver transplantation(LT).Based on a protective effect with less complications and improved graft survival,the field has seen a paradigm shift in organ preservation.This editorial focuses on the role of MP in LT and how it could become the new“gold standard”.Strong collaborative efforts are needed to explore its effects on long-term outcomes.展开更多
Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training i...Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease.Methods:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,2023.All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included.The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool.Results:A total of 14,565 records were identified.After screening the titles,abstracts,and full texts,87 were eligible for the systematic review.These studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise interventions.Regular exercise interventions combined with multiple exercise modes were associated with greater benefits.Conclusion:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence.This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease.Most patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at best.Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.展开更多
Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients(RTRs) remain at an increased risk of fatal and non-fatal cardiovascular(CV) events comp...Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients(RTRs) remain at an increased risk of fatal and non-fatal cardiovascular(CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease(CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Nontraditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population.展开更多
AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min w...AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective i NOS inhibitor 1400W(10 mg/kg) was administered before reperfusion(n = 6) vs control group(n = 7). Creatinine(1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples. RESULTS: Kidneys treated with 1400 W had a higher level of creatinine clearance(CrC l) [area under the curve(AUC) CrC l: 2.37 ± 0.97 mL /min per 100 g vs 0.96 ± 0.32 mL /min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium(AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400 W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400 W group after 1 h of reperfusion(1h Pr/Cr: 1400 W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400 W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400 W 139 ± 47 pg/L/mmol/L, P = 0.041].CONCLUSION: This study demonstrated that 1400 W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress.展开更多
CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchest...CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.展开更多
基金We thank Dr.Bingjing Wang for helpful discussion.This work was supported by grants from the National Natural Science Foundation of China(81788101,81922032)CAMS Innovation Fund for Medical Sciences(2016-12M-1-003).
文摘TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
基金supported by National Natural Science Foundation of China(82471792,82270004,81870061,82202382,31770945)Beijing Municipal Natural Science Foundation(7242135)Zhejiang Provincial Natural Science Foundation(LY20H010003).
文摘Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by widespread inflammation,diffuse alveolar damage,and pulmonary edema,often leading to respiratory failure and death.Despite significant advances in clinical care,ALI/ARDS remains the leading cause of death among intensive care unit patients.Sepsis is the primary risk factor for the development of ALI/ARDS,as excessive inflammatory responses contribute to organ injury and high mortality in critically ill patients.
文摘The Middle East is the home of ethnic groups from three main backgrounds: Semitic (Arabs and Jews), Indo-European (Persians and Kurdish) and Turkic (Turkish and Turkmens). Its geographic location, which has been under continuous influences from Asia, Europe and Africa, has made it an ideal site for epidemiological studies on Helicobacter pylori (H. pylori) infection and genotyping. The gastric cancer rate differs in this region from very high in Iran (26.1/105) to low in Israel (12.5/105) and very low in Egypt (3.4/105). Epidemiological studies showed that the prevalence of H. pylori is almost similar in those countries with a high level of infection in childhood. Importantly, the frequency of vacA s1 and m1 regions and cagA+ genotypes were higher in non Semitic populations who inhabit the North than Semitic populations, the inhabitants of Southern parts of the Middle East. H. pylori infection prevalence, distribution pattern of virulence factors, diet and smoking could not have explained the difference in cancer rate. This reflects the multifactorial aetiology of gastric cancer and suggests that H. pylori infection does not always directly correlate with the risk for gastrointestinal disease, such as gastric cancer. Further detailed investigations and international comparative studies of each risk factor needto be performed to investigate whether this represents a true enigma.
基金This work was supported by grants from the Heart and Stroke Foundation of Canada(Nos.G-13-0002596&G-18-0022157,to HHCNo.G-16-00014085,to AFRS)+2 种基金the Natural Science and Engineering Research Council of Canada(No.RGPIN/06212-2014,to HHC,No.RGPIN/2016-04985,to AFRS)the Canadian Institutes of Health Research(No.201610PJT,to HHC)HHC is also supported by a Mid-Career Investigator Award(No.7506)from the Heart and Stroke Foundation of Ontario.How to cite this article:Cruz SA。
文摘Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.
基金This work was supported by the National Natural Science Foundation of China(No.82071762)the Shanghai Key Lab of Human Performance(Shanghai University of Sport)(No.11DZ2261100)the 2021 Capacity Building of Shanghai Universities(No.21010503600),China。
文摘The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum.However,during protein folding,unfolded and/or misfolded proteins are prone to occur,which may lead to endoplasmic reticulum stress.Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control(ERQC)and endoplasmic reticulum-associated degradation(ERAD),which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins.The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored.Therefore,this paper reviews the process and function of protein folding and ERAD in mammalian cells,in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.
文摘Despite numerous advances and emerging data,liver transplantation in the setting of gastrointestinal malignancies remains controversial outside of certain accepted indications.In an era of persistent organ shortage and increasing organ demand,allocation of liver grafts must be considered carefully.While hepatocellular carcinoma and hilar cholangiocarcinoma have become accepted indications for transplantation,tumor size and standardized multi-disciplinary treatment protocols are necessary to ensure optimal patient outcomes.As more studies seeking to expand the oncologic indications for liver transplantation are emerging,it is becoming increasingly clear that tumor biology and response to therapy are key factors for optimal oncologic outcomes.In addition,time from diagnosis to transplantation appears to correlate with survival,as stable disease over time portends better outcomes post-operatively.Identifying aggressive disease pre-transplant remains difficult with current imaging and tissue sampling techniques.While tumor size and stage are important prognostic predictors for most malignancies,patient and tumor selection protocols are necessary.As the fields of medical and surgical oncology continue to evolve,it is clear that a protocolized interdisciplinary treatment approach is necessary for combatting any cancer effectively.Disease stability over time and response to neoadjuvant therapy may be the best predictors for successful patient outcomes and can be easily incorporated in our treatment paradigms.Current data evaluating liver transplantation for expanded oncologic indications such as:expanded criteria hepatocellular carcinoma,intrahepatic cholangiocarcinoma,mixed tumors,and liver limited metastatic colorectal carcinomas,incorporate multi-modal therapies and evaluation of tumor treatment response.While further investigation is necessary,initial results suggest there is an expanded role for transplant surgery in malignancy in a new era of liver transplant oncology.
文摘Acute kidney injury(AKI)affects approximately 13.3 million individuals and contributes to about 1.7 million deaths globally per year.As estimated 85% of those affected live in the developing world[1].Although there are various measures to prevent or treat AKI,including renal protective drugs and continuous renal replacement therapy,most of them have limited success or are still in their infancy[2,3].
基金supported by grants from the Heart and Stroke Foundation of Canada(G-13-0002596&G-18-0022157,to HHCG-16-00014085,to AFRS)+4 种基金Ontario Mental Health Foundation(to HHC),the Canadian Institutes of Health Research(201610PJT#376403,to HHC201610PJT#376503,to AFRS)the Natural Science and Engineering Research Council of Canada(RGPIN/06212-2014,to HHCRGPIN/2016-04985,to AFRS)supported by a Mid-Career Investigator Award(grant#7506)from the Heart and Stroke Foundation of Ontario.
文摘Glutamate is the main exc i tatory neurotransmitter in the brain and binds to two major classes of receptors,theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid(AMPA)and the N-methyl-D-aspartate(NMDA)receptors.Unlike AMPA receptors that are immediately activated by glutamate release,NMDA receptors are blocked by magnesium and can only be activated by glutamate after membrane depolarization.Thus,NMDA receptors are only activated after repeated AMPA receptor activation by glutamate.NMDA receptors are,for the most part,calcium-permeable channels.Calcium influx through NMDA receptors modulates synaptic transmission in neurons based on prior history of excitation,and provides a means of scaling the strength of synapses required for Hebbian plasticity.
文摘Listeria monocytogenes is a foodborne pathogen capable of surviving under challenging conditions both outside and inside the host. During the transition from exponential to stationary phase it experiences a series of environmental changes that require an appropriate response to maintain cell viability. In this study the autolytic behaviour of a L. monocytogenes strain was investigated by two-dimensional electrophoresis. The study was done at the permissive autolysis temperature, 30℃ and at 20℃, an autolysis non-permissive temperature. An autolytic strain proteome was also compared to a non-autolytic strain at the permissive autolysis temperature. The autolytic strain proteome at 30℃ in comparison to 20℃ evidenced increased synthesis of the P60 autolysin, glycolytic enzymes and proteins related with environmental stress responses. The over-production of P45 autolysin, was observed when the autolytic strain proteome was compared with the non-autolytic strain. The proteomes at the non-permissive temperature and the proteome of the non-autolytic strain were characterized by a diminished synthesis of several stress related proteins. The lack of autolysis seems to be associated to the over-production of proteins linked to fatty acid and amino acid synthesis, transcription regulation and cell morphogenesis as evidenced by the proteome at the non-permissive temperature and the non-autolytic strain. Autolysis proteome evidenced the over-production of P60 autolysins, glycolysis and stress proteins whereas the proteome obtained in conditions of absence of autolysis reveal a completely different group of proteins. Possible targets to activate listerial autolysis were identified.
基金supported by Grants from the National Key R&D Program of China(2023YFA1801400)National Natural Science Foundation of China(92374115 and 82388201).
文摘INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structures such as inducible bronchus-associated lymphoid tissue(iBALT)and tertiary lymphoid structure(TLS)play essential roles in modulating lung local immune responses.While the identification of iBALTs or TLS is generally dependent on conventional histology,it remains poorly understood how immune cells are spatiotemporally coordinated in the lung at single-cell resolution to effectively eliminate malignant cells and invading pathogens.Recently studies have revealed the presence of dendritic cell(DC)-T immunity hubs in human lung with close association with tumor immunotherapy response[1],antiviral immunity[2],and inflammation resolution[3].
基金supported by grants from the National Natural Science Foundation of China(82002351,82394442,82130070,82272442)funded by the Innovation Capability Support Program of Shaanxi Province(2024SF-LCZX-16)+2 种基金the Shaanxi Province Health Scientific Research Innovation Ability Promotion Plan(2024PT-12)the Independent Exploration and Innovation Project of Xi’an Jiaotong University(xzy012023121)the project of Xi’an Postdoctoral Innovation Base.
文摘Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy.Here,we observed the nucleus accumulation of ZBTB20,a member of ZBTB-protein family,in the chondrocytes of early-stage OA.Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress,restored the balance of extracellular matrix anabolism and catabolism.The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation.Furthermore,the subcellular localization of ZBTB20 was modulated by the kinase LATS1.Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis,improving the abnormal behavior and moderating cartilage degeneration.The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.
基金supported by grants from the National Nat-ural Science Foundation of China(82270679 and 82370657)Shanghai Municipal Hospital Emerging Frontier Technology Joint Project(SHDC12021107)+1 种基金Shanghai Chenguang Program(20CG42)Shanghai New-Star Youth Doctor Program(HWRS2020087).
文摘Background:Previous studies have not clarified the treatment of large pancreatic radiolucent stones(≥5 mm).The primary objective of this study was to assess the clinical features and therapeutic efficacy in patients with chronic pancreatitis who have large radiolucent stones,and to propose a treatment strategy.Methods:This analysis examined the data of patients with large pancreatic ductal stones(≥5 mm)from March 2011 to June 2018.Patients with radiolucent stones were classified as the radiolucent stones group,while those with pancreatic radiopaque stones presented at the same time were randomly selected as controls in a 1:2 ratio.Data on demographics,disease courses and treatment details were retrieved,and stone clearance and pain relief during the follow-up were compared between the two groups.Results:A total of 52 patients with large radiolucent stones and 104 patients with large radiopaque stones were included in the study.Pancreatic extracorporeal shock wave lithotripsy(ESWL)was the ini-tial treatment for large radiopaque stone.Endoscopic retrograde cholangiopancreatography(ERCP)was the first-step treatment for all patients in the radiolucent stones group,of which one patient received medication after failed ERCP cannulation,and four who failed stone extraction were treated with ESWL following the placement of a nasopancreatic catheter.There was no significant difference in the complete stone clearance rate(75.0%vs.78.8%;P=0.553)between the two groups.Among the 51 patients in the large radiolucent stones group who were followed up for 5.8 years(range 2.1-12.6),complete pain relief was achieved in 42 patients(82.4%),with no significant difference compared with the radiopaque group(82.4%vs.76.4%;P=0.409).Conclusions:ERCP is an effective endotherapy for large radiolucent stone and should be considered the first-step treatment.When stone extraction failed during ERCP,ESWL is recommended following the placement of a nasopancreatic catheter.
基金Supported by the Zhejiang Provincial Natural Science Foundation,No.LZ22H270001.
文摘BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.AIM To explore the complex relationship between chronic hepatitis B(CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements.The HF group was further subdivided into four subgroups:F1,F2,F3,and F4.Data on clinical indicators were collected.Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome.Microbiota diversity,relative abundance,and linear discriminant analysis effect size(LEfSe)were analyzed in different groups.Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed.The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota.The Shapley additive explanations were used to evaluate microbiota importance.RESULTS Integrating the results from univariate analysis,LEfSe,and machine learning,we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF.Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients,and the presence of Dorea shows significant variations across different stages of HF(P<0.05).The relative abundance of Dorea significantly decreases with increasing HF severity(P=0.041).Moreover,the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators,such asγ-glutamyl transferase,alkaline phosphatase,total bilirubin,and the aspartate aminotransferase/alanine transaminase ratio(P<0.05).The associated pathways were predominantly enriched in biosynthesis,degradation/utilization/assimilation,generation of precursors,metabolites,and energy,among other categories.CONCLUSION HF affects the composition of the gut microbiota,indicating that the gut microbiota plays a crucial role in its pathophysiological processes.The abundance of Dorea varies significantly across various stages of HF,making it a potential microbial marker for identifying HF onset and progression.
基金This work was supported by the National Natural Science Foundation of China(No.82071762)the Shanghai Key Lab of Human Performance(Shanghai University of Sport)(No.11DZ2261100)the 2021 Capacity Building of Shanghai Universities(No.21010503600),China。
文摘Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process.Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism.Therefore,maintaining mitochondrial homeostasis is an important strategy to mitigate OA.Mitophagy is a vital process for autophagosomes to target,engulf,and remove damaged and dysfunctional mitochondria,thereby maintaining mitochondrial homeostasis.Cumulative studies have revealed a strong association between mitophagy and OA,suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA.By reviewing the literature on mitophagy and OA published in recent years,this paper elaborates the potential mechanism of mitophagy regulating OA,thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.
基金Supported by the Special Trustees of Nottingham Hospitals (grant No. STR 62/03/M)
文摘AIM: To evaluate the prognostic significance of p27kip1 in colorectal cancer patients. METHODS: Cytoplasmic and nuclear p27kip1 expression was evaluated in 418 colorectal cancers using tissue microarrays. Data were associated with known patient and tumor variables and long-term patient outcomes, providing further insight into the mechanisms by which p27kip1 may influence tumor development. RESULTS: Nuclear and cytoplasmic p27Kip1 expressions were detected in 59% and 19% of tumors respectively. Cytoplasmic p27Kip1 was almost invariably associated with positive nuclear p27Kip1 expression. Neither case correlat- ed with known clinical or pathological variables, includ- ing tumor stage, grade or extramural vascular invasion. Furthermore, nuclear p27kip1 expression had no impact on survival. However, we identified a significant correla- tion between expression of cytoplasmic p27kip1 and longer disease-specific survival times. On multivariate analysis, TNM stage and extramural vascular invasion were highly significant independent prognostic factors, with positive cytoplasmic p27 expression showing a trend towards im- proved patient survival (P = 0.059).CONCLUSION: These findings support the recent evi- dence that cytoplasmic p27kip1 has a distinct and impor- tant biological role that can influence tumor outcome.
文摘The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation.Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses,providing the highest available evidence on the protective effect of machine perfusion(MP)over static cold storage in liver transplantation(LT).Based on a protective effect with less complications and improved graft survival,the field has seen a paradigm shift in organ preservation.This editorial focuses on the role of MP in LT and how it could become the new“gold standard”.Strong collaborative efforts are needed to explore its effects on long-term outcomes.
基金supported by the National Natural Science Foundation of China(NO.31801003 for DX,NO.31701040 for BL)Shanghai Key Lab of Human Performance(Shanghai University of Sport)(NO.11DZ2261100)。
文摘Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease.Methods:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,2023.All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included.The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool.Results:A total of 14,565 records were identified.After screening the titles,abstracts,and full texts,87 were eligible for the systematic review.These studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise interventions.Regular exercise interventions combined with multiple exercise modes were associated with greater benefits.Conclusion:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence.This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease.Most patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at best.Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.
基金Supported by National Institute for Health Research Diet,Lifestyle and Physical Activity Biomedical Research Unit based at University Hospitals of Leicester and Loughborough University
文摘Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients(RTRs) remain at an increased risk of fatal and non-fatal cardiovascular(CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease(CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Nontraditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population.
文摘AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective i NOS inhibitor 1400W(10 mg/kg) was administered before reperfusion(n = 6) vs control group(n = 7). Creatinine(1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples. RESULTS: Kidneys treated with 1400 W had a higher level of creatinine clearance(CrC l) [area under the curve(AUC) CrC l: 2.37 ± 0.97 mL /min per 100 g vs 0.96 ± 0.32 mL /min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium(AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400 W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400 W group after 1 h of reperfusion(1h Pr/Cr: 1400 W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400 W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400 W 139 ± 47 pg/L/mmol/L, P = 0.041].CONCLUSION: This study demonstrated that 1400 W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress.
基金supported by grants from the National Key Research and Development Program of China 2021YFA1100702(to B.Z.)National Natural Science Foundation of China grants 82271792(to L.S.),32200727(to L.S.)and 82071828(to C.S.)+5 种基金Innovation Capability Support Program of Shaanxi Province 2024CX-GXPT-45(to C.S.)Natural Science Foundation of Shaanxi Province 2017JM8148(to Lin Shi)Fundamental Research Funds for the Central Universities xtr072022002(to B.Z.)the National Natural Science Foundation of China 82350114(to L.Z.)the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province BK20220049(to L.Z.)Suzhou Municipal Key Laboratory SZS2023005(to L.Z.).
文摘CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely unknown.Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins.Here,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T cells.Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors.Mechanistically,ADAM17 regulated CD8^(+)T cells through cleavage of membrane CD122.ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T cells.Intriguingly,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid tumors.Our findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.
