Echinococcosis or hydatid disease （HD） is a zoonosis caused by the larval stages of taeniid cestodes belong- ing to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated...Echinococcosis or hydatid disease （HD） is a zoonosis caused by the larval stages of taeniid cestodes belong- ing to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinoc- cus multilocularis （E. multi/ocular/s） and Echinococcus granulosus （E. granulosus） infection, respectively. Cys- tic echinococcosis （CE） has a worldwide distribution, while hepatic alveolar echinococcosis （AE） is endemic in the Northern hemisphere, including North America and several Asian and European countries, like France, Germany and Austria. E. granulosus young cysts are spherical, unilocular vesicles, consisting of an internal germinal layer and an outer acellular layer. Cyst expansion is associated with a host immune reaction and the subsequent development of a fibrous layer, called the per/cyst; old cysts typically present internal septa- tions and daughter cysts. E. multilocularis has a tumor-like, infiltrative behavior, which is responsible for tissue destruction and finally for liver failure. The liver is the main site of HD involvement, for both alveolar and cystic hydatidosis. HD is usually asymptomatic for a long period of time, because cyst growth is commonly slow; the most frequent symptoms are fatigue and abdominal pain. Patients may also present jaundice, hepatomegaly or anaphylaxis, due to cyst leakage or rupture. HD diagnosis is usually accomplished with the combined use of ultrasonography and immunodiagnosis; furthermore, the improvement of surgical techniques, the introduction of minimally invasive treatments [such as puncture, aspiration, injection, re-aspiration （PAIR）] and more effective drugs （such as benzoimidazoles） have deeply changed life expectancy and quality of life of patients with HD. The aim of this article is to provide an up-to-date review of biological, diagnostic, clinical and therapeutic aspects of hepatic echinococcosis.展开更多
AIM:To clarify whether nonalcoholic fatty liver disease(NAFLD)increases the risk of cardiovascular disease.METHODS:We carried out a prospective observational study with a total of 1637 apparently healthy Japanese men ...AIM:To clarify whether nonalcoholic fatty liver disease(NAFLD)increases the risk of cardiovascular disease.METHODS:We carried out a prospective observational study with a total of 1637 apparently healthy Japanese men and women who were recruited from a health check-up program.NAFLD was diagnosed by abdominal ultrasonography.The metabolic syndrome(MS)was defined according to the modified National Cholesterol Education Program(NCEP)ATP Ⅲ criteria.Five years after the baseline evaluations,the incidence of cardiovascular disease was assessed by a self-administered questionnaire.RESULTS:Among 1221 participants available for outcome analyses,the incidence of cardiovascular disease was higher in 231 subjects with NAFLD at baseline(5 coronary heart disease,6 ischemic stroke,and 1 cerebral hemorrhage)than 990 subjects without NAFLD(3 coronary heart disease,6 ischemic stroke,and 1 cerebral hemorrhage).Multivariate analyses indicated that NAFLD was a predictor of cardiovascular disease independent of conventional risk factors(odds ratio 4.12,95% CI,1.58 to 10.75,P = 0.004).MS was alsoindependently associated with cardiovascular events.But simultaneous inclusion of NAFLD and MS in a multivariate model revealed that NAFLD but not MS retained a statistically significant correlation with cardiovascular disease.CONCLUSION:Although both of them were predictors of cardiovascular disease,NAFLD but not MS retained a statistically significant correlation with cardiovascular disease in a multivariate model.NAFLD is a strong predictor of cardiovascular disease and may play a central role in the cardiovascular risk of MS.展开更多
The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alte...The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may 展开更多
The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply, With a predominant role in innate immunity, the liver ...The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply, With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer （NK） cells play important roles in host defense and in maintaining immune balance, Hepatic NK cells were first described as ＇pit cells＇ in the rat liver in the 1970s, Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK （cNK） cells, are present in this organ, Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit ceils and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity,展开更多
Pathogenesis of most chronic human diseases, including chronic infections, autoimmune diseases and cancers, often involves a persistent, unresolved inflammatory response. The molecular mechanisms that determine the co...Pathogenesis of most chronic human diseases, including chronic infections, autoimmune diseases and cancers, often involves a persistent, unresolved inflammatory response. The molecular mechanisms that determine the conversion of an acute inflammatory response into a chronic process had puzzled researchers for many years. Recent studies reveal that B7-H1 （CD274, PD-L1）, a newly identified co-stimulatory molecule, possesses dual functions of co-stimulation of naive T cells and inhibition of activated effector T cells. The aberrant cellular expression and deregulated function of B7-H1 have been reported during chronic viral and intracellular bacterial infection, as well as in many autoimmune diseases and cancers. Importantly, the deregulation of B7-H1＇s dual functions appears to be associated with a prolonged and incomplete immune response by luring naive T cells for activation and dampening activated effector T cells. Moreover, development of strategies targeting B7-H1 signals provides a new and promising approach to manipulate the devastating diseases associated with chronic inflammation. Thus, B7-H1 may play a critical immunoregulatory role in the chronicity of inflammatory responses. Cellular ＆ Molecular Immunology. 2006;3（3）：179-187.展开更多
Currently,detecting SARS-CoV-2 RNAs is a standard approach for COVID-19 diagnosis.However,there is an urgent need for reliable and rapid serological diagnostic methods to screen SARS-CoV-2-infected people including th...Currently,detecting SARS-CoV-2 RNAs is a standard approach for COVID-19 diagnosis.However,there is an urgent need for reliable and rapid serological diagnostic methods to screen SARS-CoV-2-infected people including those who do not have overt symptoms.Most emerging studies described serological tests based on detection of SARS-CoV-2-specific IgM and IgG.1–4 Although detection of SARS-CoV-2-specific IgA in serum has been reported in few papers,5,6 analyses of IgA levels in a larger number of COVID-19 patients are still lacking.展开更多
Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human dise...Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.展开更多
The clinical course of infections with the hepatitis B virus (HBV) substantially varies between individuals, as a consequence of a complex interplay between viral, host, environmental and other factors. Due to the hig...The clinical course of infections with the hepatitis B virus (HBV) substantially varies between individuals, as a consequence of a complex interplay between viral, host, environmental and other factors. Due to the high genetic variability of HBV, the virus can be categorized into different HBV genotypes and subgenotypes, which considerably differ with respect to geographical distribution, transmission routes, disease progression, responses to antiviral therapy or vaccination, and clinical outcome measures such as cirrhosis or hepatocellular carcinoma. However, HBV (sub)genotyping has caused some controversies in the past due to misclassifications and incorrect interpretations of different genotyping methods. Thus, an accurate, holistic and dynamic classification system is essential. In this review article, we aimed at highlighting potential pitfalls in genetic and phylogenetic analyses of HBV and suggest novel terms for HBV classification. Analyzing full-length genome sequences when classifying genotypes and subgenotypes is the foremost prerequisite of this classification system. Careful attention must be paid to all aspects of phylogenetic analysis, such as bootstrapping values and meeting the necessary thresholds for (sub)genotyping. Quasi-subgenotype refers to subgenotypes that were incorrectly suggested to be novel. As many of these strains were misclassified due to genetic differences resulting from recombination, we propose the term “recombino-subgenotype”. Moreover, immigration is an important confounding facet of global HBV distribution and substantially changes the geographic pattern of HBV (sub)genotypes. We therefore suggest the term “immigro-subgenotype” to distinguish exotic (sub)genotypes from native ones. We are strongly convinced that applying these two proposed terms in HBV classification will help harmonize this rapidly progressing field and allow for improved prophylaxis, diagnosis and treatment.展开更多
Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experim...Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.展开更多
Follicular helper T cells （Tfh） have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset...Follicular helper T cells （Tfh） have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.展开更多
AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (10...AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mm展开更多
Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attrac...Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis （PBC） is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls （HCs）, and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA （miRNA） populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14＋ monocytes, whereas CD40 up-regulated on CD11c＋ dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease.展开更多
Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role ...Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD4＋ T-cell type 17 （Th17） and regulatory T cells （Treg）. Th17 and Treg are closely related cell fates that are determined by orchestrated cytokine signaling. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how such interaction affects Th 17/Treg development and function. This review will focus on the most recent discoveries concerning the roles of nuclear receptors in the context of therapeutic applications in autoimmune diseases.展开更多
The activation of heme oxygenase-1(HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catab...The activation of heme oxygenase-1(HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide(CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection.In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload(with signs of a chronic hepatitis) and iron deficiency anemia(with paradoxical increased levels of ferritin).Hypoxia induces HO-1 expression in multiple rodent,bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types(endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.展开更多
The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon d...The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans,accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an "endocrine organ"with potential to alter host physiology, perhaps to their own favor. We propose the term "sterolbiome" to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed.展开更多
Background Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines...Background Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells. Methods Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA. The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells. Results Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells.Conclusion This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial arowth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT sianalina Pathways.展开更多
AIM:To determine antibiotic resistance of Helicobacter pylori(H.pylori) in Pakistan and its correlation with host and pathogen associated factors.METHODS:A total of 178 strains of H.pylori were isolated from gastric b...AIM:To determine antibiotic resistance of Helicobacter pylori(H.pylori) in Pakistan and its correlation with host and pathogen associated factors.METHODS:A total of 178 strains of H.pylori were isolated from gastric biopsies of dyspeptic patients.Susceptibility patterns against first and second-line antibiotics were determined and trends of resistance were analyzed in relation to the sampling period,gastric conditions and cagA gene carriage.The effect of cagA gene on the acquisition of resistance was investigated by mutant selection assay.RESULTS:The observations showed that monoresistant strains were prevalent with rates of 89% for metronidazole,36% for clarithromycin,37% for amoxicillin,18.5% for ofloxacin and 12% for tetracycline.Furthermore,clarithromycin resistance was on the rise from 2005 to 2008(32% vs 38%,P = 0.004) and it is significantly observed in non ulcerative dyspeptic patients compared to gastritis,gastric ulcer and duodenal ulcer cases(53% vs 20%,18% and 19%,P = 0.000).On the contrary,metronidazole and ofloxacin resistance were more common in gastritis and gastric ulcer cases.Distribution analysis and frequencies of resistant mutants in vitro correlated with the absence of cagA gene with metronidazole and ofloxacin resistance.CONCLUSION:The study confirms the alarming levels of antibiotic resistance associated with the degree of gastric inflammation and cagA gene carriage in H.pylori strains.展开更多
Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumo...Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor(CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy.展开更多
AIM To investigate the effects of hydrogen-rich water(HRW) treatment on prevention of ethanol(Et OH)-induced early fatty liver in mice.METHODS In vitro reduction of hydrogen peroxide by HRW was determined with a chemi...AIM To investigate the effects of hydrogen-rich water(HRW) treatment on prevention of ethanol(Et OH)-induced early fatty liver in mice.METHODS In vitro reduction of hydrogen peroxide by HRW was determined with a chemiluminescence system. Female mice were randomly divided into five groups: control,Et OH,Et OH + silymarin,Et OH + HRW and Et OH + silymarin + HRW. Each group was fed a Lieber-De Carli liquid diet containing Et OH or isocaloric maltose dextrin(control diet). Silymarin was used as a positive control to compare HRW efficacy against chronic Et OH-induced hepatotoxicity. HRW was freshly prepared and given at a dosage of 1.2 m L/mouse trice daily. Blood and liver tissue were collected after chronic-binge liquid-diet feeding for 12 wk.RESULTS The in vitro study showed that HRW directly scavenged hydrogen peroxide. The in vivo study showed that HRW increased expression of acyl ghrelin,which was correlated with food intake. HRW treatment significantly reduced Et OH-induced increases in serum alanine aminotransferase,aspartate aminotransferase,triglycerol and total cholesterol levels,hepatic lipid accumulation and inflammatory cytokines,including tumor necrosis factor-alpha(TNF-α) and interleukin(IL)-6. HRW attenuated malondialdehyde level,restored glutathione depletion and increased superoxide dismutase,glutathione peroxidase and catalase activities in the liver. Moreover,HRW reduced TNF-α and IL-6 levels but increased IL-10 and IL-22 levels.CONCLUSION HRW protects against chronic Et OH-induced liver injury,possibly by inducing acyl ghrelin to suppress the pro-inflammatory cytokines TNF-α and IL-6 and induce IL-10 and IL-22,thus activating antioxidant enzymes against oxidative stress.展开更多
Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates...Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates up to 20%despite state-of-the-art treatment.Thus,prophylactic measures are of utmost importance to improve outcomes of patients with PH.Several high-quality studies have demonstrated that non-selective beta blockers(NSBBs)or endoscopic band ligation(EBL)are effective for primary prophylaxis of variceal bleeding.In secondary prophylaxis,a combination of NSBB+EBL should be routinely used.Once esophageal varices develop and variceal bleeding occurs,standardized treatment algorithms should be followed to minimize bleeding-associated mortality.Special attention should be paid to avoidance of overtransfusion,early initiation of vasoconstrictive therapy,prophylactic antibiotics and early endoscopic therapy.Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding,and potentially in Child B patients with active bleeding at endoscopy.The use of carvedilol,safety of NSBBs in advanced cirrhosis(i.e.with refractory ascites)and assessment of hepatic venous pressure gradient response to NSBB is discussed.In the present review,we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.展开更多
文摘Echinococcosis or hydatid disease （HD） is a zoonosis caused by the larval stages of taeniid cestodes belong- ing to the genus Echinococcus. Hepatic echinococcosis is a life-threatening disease, mainly differentiated into alveolar and cystic forms, associated with Echinoc- cus multilocularis （E. multi/ocular/s） and Echinococcus granulosus （E. granulosus） infection, respectively. Cys- tic echinococcosis （CE） has a worldwide distribution, while hepatic alveolar echinococcosis （AE） is endemic in the Northern hemisphere, including North America and several Asian and European countries, like France, Germany and Austria. E. granulosus young cysts are spherical, unilocular vesicles, consisting of an internal germinal layer and an outer acellular layer. Cyst expansion is associated with a host immune reaction and the subsequent development of a fibrous layer, called the per/cyst; old cysts typically present internal septa- tions and daughter cysts. E. multilocularis has a tumor-like, infiltrative behavior, which is responsible for tissue destruction and finally for liver failure. The liver is the main site of HD involvement, for both alveolar and cystic hydatidosis. HD is usually asymptomatic for a long period of time, because cyst growth is commonly slow; the most frequent symptoms are fatigue and abdominal pain. Patients may also present jaundice, hepatomegaly or anaphylaxis, due to cyst leakage or rupture. HD diagnosis is usually accomplished with the combined use of ultrasonography and immunodiagnosis; furthermore, the improvement of surgical techniques, the introduction of minimally invasive treatments [such as puncture, aspiration, injection, re-aspiration （PAIR）] and more effective drugs （such as benzoimidazoles） have deeply changed life expectancy and quality of life of patients with HD. The aim of this article is to provide an up-to-date review of biological, diagnostic, clinical and therapeutic aspects of hepatic echinococcosis.
基金Supported by a grant from the Gifu Medical Association
文摘AIM:To clarify whether nonalcoholic fatty liver disease(NAFLD)increases the risk of cardiovascular disease.METHODS:We carried out a prospective observational study with a total of 1637 apparently healthy Japanese men and women who were recruited from a health check-up program.NAFLD was diagnosed by abdominal ultrasonography.The metabolic syndrome(MS)was defined according to the modified National Cholesterol Education Program(NCEP)ATP Ⅲ criteria.Five years after the baseline evaluations,the incidence of cardiovascular disease was assessed by a self-administered questionnaire.RESULTS:Among 1221 participants available for outcome analyses,the incidence of cardiovascular disease was higher in 231 subjects with NAFLD at baseline(5 coronary heart disease,6 ischemic stroke,and 1 cerebral hemorrhage)than 990 subjects without NAFLD(3 coronary heart disease,6 ischemic stroke,and 1 cerebral hemorrhage).Multivariate analyses indicated that NAFLD was a predictor of cardiovascular disease independent of conventional risk factors(odds ratio 4.12,95% CI,1.58 to 10.75,P = 0.004).MS was alsoindependently associated with cardiovascular events.But simultaneous inclusion of NAFLD and MS in a multivariate model revealed that NAFLD but not MS retained a statistically significant correlation with cardiovascular disease.CONCLUSION:Although both of them were predictors of cardiovascular disease,NAFLD but not MS retained a statistically significant correlation with cardiovascular disease in a multivariate model.NAFLD is a strong predictor of cardiovascular disease and may play a central role in the cardiovascular risk of MS.
基金Supported by Japanese Society of Gastroenterology Research Foundation(to Nosho K)Pancreas Research Foundation of Japan(to Nosho K)+4 种基金Medical Research Encouragement Prize of The Japan Medical Association(to Nosho K)The Japan Society for the Promotion of Science Challenging Exploratory Researchgrant No.25670371(to Shinomura Y)Ono Cancer Research Foundation(to Ito M)
文摘The human intestinal microbiome plays a major role in human health and diseases, including colorectal cancer. Colorectal carcinogenesis represents a heterogeneous process with a differing set of somatic molecular alterations, influenced by diet, environmental and microbial exposures, and host immunity. Fusobacterium species are part of the human oral and intestinal microbiota. Metagenomic analyses have shown an enrichment of Fusobacterium nucleatum(F. nucleatum) in colorectal carcinoma tissue. Using 511 colorectal carcinomas from Japanese patients, we assessed the presence of F. nucleatum. Our results showed that the frequency of F. nucleatum positivity in the Japanese colorectal cancer was 8.6%(44/511), which was lower than that in United States cohort studies(13%). Similar to the United States studies, F. nucleatum positivityin Japanese colorectal cancers was significantly associated with microsatellite instability(MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets(i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis. There is also evidence to indicate that molecular features of colorectal cancer, especially MSI, influence T-cell-mediated adaptive immunity. Concerning the association between the gut microbiome and immunity, F. nucleatum has been shown to expand myeloid-derived immune cells, which inhibit T-cell proliferation and induce T-cell apoptosis in colorectal cancer. This finding indicates that F. nucleatum possesses immunosuppressive activities by inhibiting human T-cell responses. Certain micro RNAs are induced during the macrophage inflammatory response and have the ability to regulate host-cell responses to pathogens. Micro RNA-21 increases the levels of IL-10 and prostaglandin E2, which suppress antitumor T-cell-mediated adaptive immunity through the inhibition of the antigen-presenting capacities of dendritic cells and T-cell proliferation in colorectal cancer cells. Thus, emerging evidence may
基金This work was supported by the Ministry of Science ＆ Technology of China （973 Basic Science Project #2013CB944902）, the Natural Science Foundation of China （#81361120388, #31300727, and #81571522）, and the Key Program of the Chinese Academy of Sciences （KJZD-EW-L10 -003）.
文摘The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply, With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer （NK） cells play important roles in host defense and in maintaining immune balance, Hepatic NK cells were first described as ＇pit cells＇ in the rat liver in the 1970s, Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK （cNK） cells, are present in this organ, Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit ceils and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity,
文摘Pathogenesis of most chronic human diseases, including chronic infections, autoimmune diseases and cancers, often involves a persistent, unresolved inflammatory response. The molecular mechanisms that determine the conversion of an acute inflammatory response into a chronic process had puzzled researchers for many years. Recent studies reveal that B7-H1 （CD274, PD-L1）, a newly identified co-stimulatory molecule, possesses dual functions of co-stimulation of naive T cells and inhibition of activated effector T cells. The aberrant cellular expression and deregulated function of B7-H1 have been reported during chronic viral and intracellular bacterial infection, as well as in many autoimmune diseases and cancers. Importantly, the deregulation of B7-H1＇s dual functions appears to be associated with a prolonged and incomplete immune response by luring naive T cells for activation and dampening activated effector T cells. Moreover, development of strategies targeting B7-H1 signals provides a new and promising approach to manipulate the devastating diseases associated with chronic inflammation. Thus, B7-H1 may play a critical immunoregulatory role in the chronicity of inflammatory responses. Cellular ＆ Molecular Immunology. 2006;3（3）：179-187.
基金We acknowledge funding support from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030104)National Natural Science Foundation of China(Grant Nos.:31870731 and U1732109)+2 种基金the Fundamental Research Funds for the Central Universities(WK2070000108)a COVID-19 special task grant supported by Chinese Academy of Science Clinical Research Hospital(Hefei)(YD2070002017 and YD2070002001)the new medical science fund of USTC(WK2070000130).
文摘Currently,detecting SARS-CoV-2 RNAs is a standard approach for COVID-19 diagnosis.However,there is an urgent need for reliable and rapid serological diagnostic methods to screen SARS-CoV-2-infected people including those who do not have overt symptoms.Most emerging studies described serological tests based on detection of SARS-CoV-2-specific IgM and IgG.1–4 Although detection of SARS-CoV-2-specific IgA in serum has been reported in few papers,5,6 analyses of IgA levels in a larger number of COVID-19 patients are still lacking.
基金supported by the National Natural Science Foundation of China(31871380,32000500,32070730,32170756,32170804,81330008,81671377,81725010,81725010,81872874,81921006,81922027,81971312,81991512,82030041,82103167,82122024,82125009,82125011,82130044,91749126,91949101,91949207,92049302)the National Key Research and Development Program of China(2017YFA0506400,2018YFA0800200,2018YFA0800700,2018YFA0900200,2018YFC2000100,2018YFC2000400,2018YFE-0203700,20192ACB70002,2019YFA0802202,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002800,2020YFC-2002900,2021ZD0202401)+11 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100,XDA16010603,XDA16020400,XDB29020000,XDB39000000,XDB39000000,XDB39030300)the China Association for Science and Technology(2021QNRC001)the Beijing Municipal Science and Technology Commission(Z200022)the Natural Science Foundation of Shanghai(21JC1406400)the Key Programs of the Jiangxi ProvinceChina(20192ACB70002)the“Shu Guang”Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation(19SG18)the Shanghai Sailing Program(22YF1434300)the Research Project of Joint Laboratory of University of Science and Technology of China and Anhui Mental Health Center(2019LH03)the Fundamental Research Funds for the Central Universities(WK2070210004)the Young Elite Scientists Sponsorship Program by China Association for Science and Technology(YESS20210002)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022083)。
文摘Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.
基金Supported by Mahmoud Reza Pourkarim is supported by a postdoctoral grant from the''Fonds voor Wetenschappelijk Onderzoek Vlaanderen''
文摘The clinical course of infections with the hepatitis B virus (HBV) substantially varies between individuals, as a consequence of a complex interplay between viral, host, environmental and other factors. Due to the high genetic variability of HBV, the virus can be categorized into different HBV genotypes and subgenotypes, which considerably differ with respect to geographical distribution, transmission routes, disease progression, responses to antiviral therapy or vaccination, and clinical outcome measures such as cirrhosis or hepatocellular carcinoma. However, HBV (sub)genotyping has caused some controversies in the past due to misclassifications and incorrect interpretations of different genotyping methods. Thus, an accurate, holistic and dynamic classification system is essential. In this review article, we aimed at highlighting potential pitfalls in genetic and phylogenetic analyses of HBV and suggest novel terms for HBV classification. Analyzing full-length genome sequences when classifying genotypes and subgenotypes is the foremost prerequisite of this classification system. Careful attention must be paid to all aspects of phylogenetic analysis, such as bootstrapping values and meeting the necessary thresholds for (sub)genotyping. Quasi-subgenotype refers to subgenotypes that were incorrectly suggested to be novel. As many of these strains were misclassified due to genetic differences resulting from recombination, we propose the term “recombino-subgenotype”. Moreover, immigration is an important confounding facet of global HBV distribution and substantially changes the geographic pattern of HBV (sub)genotypes. We therefore suggest the term “immigro-subgenotype” to distinguish exotic (sub)genotypes from native ones. We are strongly convinced that applying these two proposed terms in HBV classification will help harmonize this rapidly progressing field and allow for improved prophylaxis, diagnosis and treatment.
基金This work was supported by awards from the National Nature Science Foundation of China(#81771732 and 81620108002 to Xiong Ma,#81400608 to Ruqi Tang).
文摘Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.
基金brue de la Ferollerie, Orleans, France ACKNOWLEDGEMENTS This work was supported in part by grants from the National Institutes of Health ROI AR 059103, Arthritis Foundation Wright Foundation the Outstanding Youth Scientist Investigator Award from National Nature Science Foundation of China （30728007） and the American College of Rheumatology Research and Education＇s Within Our Reach： Finding a Cure for Rheumatoid Arthritis campaign （all to SGZ）, National Nature Science Foundation of China （30972951） （XH） and Le Studium and European FEDER grant support （BR）.
文摘Follicular helper T cells （Tfh） have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.
基金the Physicians’Services Incorporated Foundation 10q2083(Joy TR and Beaton MD)Academic Medical Organization of Southwestern Ontario,No.F10-002(Beaton MD)+1 种基金partly funded through academic research funds from the Program of Experimental Medicine(Joy TR)Department of Medicine Academic Funds(Joy TR)from Western University,London,Ontario,Canada
文摘AIMTo evaluate the effect of sitagliptin vs placebo on histologic and non-histologic parameters of non-alcoholic steatohepatitis (NASH).METHODSTwelve patients with biopsy-proven NASH were randomized to sitagliptin (100 mg daily) (n = 6) or placebo (n = 6) for 24 wk. The primary outcome was improvement in liver fibrosis after 24 wk. Secondary outcomes included evaluation of changes in NAFLD activity score (NAS), individual components of NAS (hepatocyte ballooning, lobular inflammation, and steatosis), glycemic control and insulin resistance [including measurements of glycated hemoglobin (HbA1C) and adipocytokines], lipid profile including free fatty acids, adipose distribution measured using magnetic resonance imaging (MRI), and thrombosis markers (platelet aggregation and plasminogen activator inhibitor 1 levels). We also sought to determine the correlation between changes in hepatic fat fraction (%) [as measured using the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) MRI technique] and changes in hepatic steatosis on liver biopsy.RESULTSSitagliptin was not significantly better than placebo at reducing liver fibrosis score as measured on liver biopsy (mean difference between sitagliptin and placebo arms, 0.40, P = 0.82). There were no significant improvements evident with the use of sitagliptin vs placebo for the secondary histologic outcomes of NAS total score as well as for the individual components of NAS. Compared to baseline, those patients who received sitagliptin demonstrated improved HbA1C (6.7% ± 0.4% vs 7.9% ± 1.0%, P = 0.02), and trended towards improved adiponectin levels (4.7 ± 3.5 μg/mL vs 3.9 ± 2.7 μg/mL, P = 0.06) and triglyceride levels (1.26 ± 0.43 mmol/L vs 2.80 ± 1.64 mmol/L, P = 0.08). However, when compared with placebo, sitagliptin did not cause a statistically significant improvement in HbA1C (mean difference, -0.7%, P = 0.19) nor triglyceride levels (mean difference -1.10 mm
文摘Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis （PBC） is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls （HCs）, and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA （miRNA） populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14＋ monocytes, whereas CD40 up-regulated on CD11c＋ dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease.
文摘Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD4＋ T-cell type 17 （Th17） and regulatory T cells （Treg）. Th17 and Treg are closely related cell fates that are determined by orchestrated cytokine signaling. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how such interaction affects Th 17/Treg development and function. This review will focus on the most recent discoveries concerning the roles of nuclear receptors in the context of therapeutic applications in autoimmune diseases.
基金Supported by Brazilian Foundation-FAPESP(Fundao deapoio à pesquisa do Estado de So Paulo),No.07/07139-3,10/02024-6 and CNPq
文摘The activation of heme oxygenase-1(HO-1) appears to be an endogenous defensive mechanism used by cells to reduce inflammation and tissue damage in a number of injury models. HO-1, a stress-responsive enzyme that catabolizes heme into carbon monoxide(CO), biliverdin and iron, has previously been shown to protect grafts from ischemia/reperfusion and rejection.In addition, the products of the HO-catalyzed reaction, particularly CO and biliverdin/bilirubin, have been shown to exert protective effects in the liver against a number of stimuli, as in chronic hepatitis C and in transplanted liver grafts. Furthermore, the induction of HO-1 expression can protect the liver against damage caused by a number of chemical compounds. More specifically, the CO derived from HO-1-mediated heme catabolism has been shown to be involved in the regulation of inflammation; furthermore, administration of low concentrations of exogenous CO has a protective effect against inflammation. Both murine and human HO-1 deficiencies have systemic manifestations associated with iron metabolism, such as hepatic overload(with signs of a chronic hepatitis) and iron deficiency anemia(with paradoxical increased levels of ferritin).Hypoxia induces HO-1 expression in multiple rodent,bovine and monkey cell lines, but interestingly, hypoxia represses expression of the human HO-1 gene in a variety of human cell types(endothelial cells, epithelial cells, T cells). These data suggest that HO-1 and CO are promising novel therapeutic molecules for patients with inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 in liver injuries and in particular, we focus on the implications of targeted induction of HO-1 as a potential therapeutic strategy to protect the liver against chemically induced injury.
文摘The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans,accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an "endocrine organ"with potential to alter host physiology, perhaps to their own favor. We propose the term "sterolbiome" to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed.
文摘Background Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells. Methods Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA. The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells. Results Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells.Conclusion This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial arowth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT sianalina Pathways.
基金Supported by The grants of Higher Education Commission of Pakistan and University of Karachi awarded to Adnan Khan
文摘AIM:To determine antibiotic resistance of Helicobacter pylori(H.pylori) in Pakistan and its correlation with host and pathogen associated factors.METHODS:A total of 178 strains of H.pylori were isolated from gastric biopsies of dyspeptic patients.Susceptibility patterns against first and second-line antibiotics were determined and trends of resistance were analyzed in relation to the sampling period,gastric conditions and cagA gene carriage.The effect of cagA gene on the acquisition of resistance was investigated by mutant selection assay.RESULTS:The observations showed that monoresistant strains were prevalent with rates of 89% for metronidazole,36% for clarithromycin,37% for amoxicillin,18.5% for ofloxacin and 12% for tetracycline.Furthermore,clarithromycin resistance was on the rise from 2005 to 2008(32% vs 38%,P = 0.004) and it is significantly observed in non ulcerative dyspeptic patients compared to gastritis,gastric ulcer and duodenal ulcer cases(53% vs 20%,18% and 19%,P = 0.000).On the contrary,metronidazole and ofloxacin resistance were more common in gastritis and gastric ulcer cases.Distribution analysis and frequencies of resistant mutants in vitro correlated with the absence of cagA gene with metronidazole and ofloxacin resistance.CONCLUSION:The study confirms the alarming levels of antibiotic resistance associated with the degree of gastric inflammation and cagA gene carriage in H.pylori strains.
基金supported by grants from the Ministry of Science and Technology of China(2014CB910104)the National Natural Science Foundation of China(81171899+1 种基金81372230)the Claudia Adams Barr Program for Innovative Cancer Research
文摘Natural killer(NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex(MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor(CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy.
基金Supported by a grant from the Chung Shan Medical University,No.CSMU0150011
文摘AIM To investigate the effects of hydrogen-rich water(HRW) treatment on prevention of ethanol(Et OH)-induced early fatty liver in mice.METHODS In vitro reduction of hydrogen peroxide by HRW was determined with a chemiluminescence system. Female mice were randomly divided into five groups: control,Et OH,Et OH + silymarin,Et OH + HRW and Et OH + silymarin + HRW. Each group was fed a Lieber-De Carli liquid diet containing Et OH or isocaloric maltose dextrin(control diet). Silymarin was used as a positive control to compare HRW efficacy against chronic Et OH-induced hepatotoxicity. HRW was freshly prepared and given at a dosage of 1.2 m L/mouse trice daily. Blood and liver tissue were collected after chronic-binge liquid-diet feeding for 12 wk.RESULTS The in vitro study showed that HRW directly scavenged hydrogen peroxide. The in vivo study showed that HRW increased expression of acyl ghrelin,which was correlated with food intake. HRW treatment significantly reduced Et OH-induced increases in serum alanine aminotransferase,aspartate aminotransferase,triglycerol and total cholesterol levels,hepatic lipid accumulation and inflammatory cytokines,including tumor necrosis factor-alpha(TNF-α) and interleukin(IL)-6. HRW attenuated malondialdehyde level,restored glutathione depletion and increased superoxide dismutase,glutathione peroxidase and catalase activities in the liver. Moreover,HRW reduced TNF-α and IL-6 levels but increased IL-10 and IL-22 levels.CONCLUSION HRW protects against chronic Et OH-induced liver injury,possibly by inducing acyl ghrelin to suppress the pro-inflammatory cytokines TNF-α and IL-6 and induce IL-10 and IL-22,thus activating antioxidant enzymes against oxidative stress.
基金Supported by the Austrian Science Fund FWF,No.J4396the Christian Doppler Society/Boehringer Ingelheim.
文摘Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates up to 20%despite state-of-the-art treatment.Thus,prophylactic measures are of utmost importance to improve outcomes of patients with PH.Several high-quality studies have demonstrated that non-selective beta blockers(NSBBs)or endoscopic band ligation(EBL)are effective for primary prophylaxis of variceal bleeding.In secondary prophylaxis,a combination of NSBB+EBL should be routinely used.Once esophageal varices develop and variceal bleeding occurs,standardized treatment algorithms should be followed to minimize bleeding-associated mortality.Special attention should be paid to avoidance of overtransfusion,early initiation of vasoconstrictive therapy,prophylactic antibiotics and early endoscopic therapy.Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding,and potentially in Child B patients with active bleeding at endoscopy.The use of carvedilol,safety of NSBBs in advanced cirrhosis(i.e.with refractory ascites)and assessment of hepatic venous pressure gradient response to NSBB is discussed.In the present review,we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.
