AIM:To characterize tumor necrosis factor receptorassociated protein 1(TRAP1)expression in the progression of ulcerative colitis(UC)-associated colorectal cancer.METHODS:Chronic UC is an inflammatory bowel disease tha...AIM:To characterize tumor necrosis factor receptorassociated protein 1(TRAP1)expression in the progression of ulcerative colitis(UC)-associated colorectal cancer.METHODS:Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer.Immunohistochemical analysis was used to evaluate TRAP1expression on tissue microarrays containing colonic tissues from 42 UC progressors(patients with cancer or dysplasia)and 38 non-progressors(dysplasia/cancer free patients).Statistical analyses of the TRAP1immunohistochemistry staining were performed using Graph Pad Prism.Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test.Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.RESULTS:TRAP1 was up-regulated in the colon tissues from UC progressors,but not in the colon tissues from UC non-progressors.Moreover,up-regulation of TRAP1 preceded the neoplastic changes:it was present in both the dysplastic and non-dysplastic tissues of UC progressors.When TRAP1 staining in rectal tissue was used as a diagnostic marker,it could distinguish progressors from non-progressors with 59%sensitivity and 80%specificity.Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues,which could be related to the increased oxidation present in the colonic mucosa from UC progressors.We then investigated the cellular proteome changes underlying oxidative stress,and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.CONCLUSION:These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1,which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis.TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.展开更多
The gastrointestinal tract is responsible for a multitude of digestive and immune functions which depend upon the balanced interaction of the intestinal microbiota, diet, gut barrier function, and mucosal immune respo...The gastrointestinal tract is responsible for a multitude of digestive and immune functions which depend upon the balanced interaction of the intestinal microbiota, diet, gut barrier function, and mucosal immune response. Disruptions in one or more of these factors can lead to intestinal disorders or enteropathies which are characterized by intestinal inflammation, increased gut permeability, and reduced capacity to absorb nutrients. Enteropathy is frequently associated with human immunodeficiency virus(HIV) infection, inflammatory bowel disease, autoimmune enteropathy, radiation enteritis, and irritable bowel syndrome(IBS), where pathologic changes in the intestinal tract lead to abdominal discomfort, bloating, abnormal bowel function(e.g., diarrhea, urgency, constipation and malabsorption). Unfortunately, effective therapies for the management ofenteropathy and restoring intestinal health are still not available. An accumulating body of preclinical studies has demonstrated that oral administration of plasmaor serum-derived protein concentrates containing high levels of immunoglobulins can improve weight, normalize gut barrier function, and reduce the severity of enteropathy in animal models. Recent studies in humans, using serum-derived bovine immunoglobulin/protein isolate, demonstrate that such protein preparations are safe and improve symptoms, nutritional status, and various biomarkers associated with enteropathy. Benefits have been shown in patients with HIV infection or diarrhea-predominant IBS. This review summarizes preclinical and clinical studies with plasma/serum protein concentrates and describes the effects on host nutrition, intestinal function, and markers of intestinal inflammation. It supports the concept that immunoglobulin-containing protein preparations may offer a new strategy for restoring functional homeostasis in the intestinal tract of patients with enteropathy.展开更多
Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which ...Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H) , a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion (MCAO) modeled is- chemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlip- idemic condition. Additionally, lipopolysaccharide (LPS) incubation with rat brain microvessel endothelial cells (rBMECs) was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, down- regulated MMP- 9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory re- sponse in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-KB inflammatory signal and down- stream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.展开更多
基金Supported by Grants from National Institutes of Health,No.R21CA164548from Crohn’s and Colitis Foundation of America
文摘AIM:To characterize tumor necrosis factor receptorassociated protein 1(TRAP1)expression in the progression of ulcerative colitis(UC)-associated colorectal cancer.METHODS:Chronic UC is an inflammatory bowel disease that predisposes to colorectal cancer.Immunohistochemical analysis was used to evaluate TRAP1expression on tissue microarrays containing colonic tissues from 42 UC progressors(patients with cancer or dysplasia)and 38 non-progressors(dysplasia/cancer free patients).Statistical analyses of the TRAP1immunohistochemistry staining were performed using Graph Pad Prism.Differences in the TRAP1 level between non-progressors and progressors were tested for statistical significance using the Mann-Whitney test.Receiver operating characteristic curve method was used to quantify marker performance in distinguishing diseased cases from controls.RESULTS:TRAP1 was up-regulated in the colon tissues from UC progressors,but not in the colon tissues from UC non-progressors.Moreover,up-regulation of TRAP1 preceded the neoplastic changes:it was present in both the dysplastic and non-dysplastic tissues of UC progressors.When TRAP1 staining in rectal tissue was used as a diagnostic marker,it could distinguish progressors from non-progressors with 59%sensitivity and 80%specificity.Our study further showed that the increase of TRAP1 expression positively correlated with the degree of inflammation in the colorectal cancer tissues,which could be related to the increased oxidation present in the colonic mucosa from UC progressors.We then investigated the cellular proteome changes underlying oxidative stress,and found that oxidative stress could induce up-regulation of TRAP1 along with several other negative modulators of apoptosis.CONCLUSION:These results suggest that oxidative stress in long standing UC could lead to the increase of cytoprotective protein TRAP1,which in turn could promote cancer progression by preventing or protecting the oxidative damaged epithelial cells from undergoing apoptosis.TRAP1 could be a potential diagnostic marker for UC associated colorectal cancer.
文摘The gastrointestinal tract is responsible for a multitude of digestive and immune functions which depend upon the balanced interaction of the intestinal microbiota, diet, gut barrier function, and mucosal immune response. Disruptions in one or more of these factors can lead to intestinal disorders or enteropathies which are characterized by intestinal inflammation, increased gut permeability, and reduced capacity to absorb nutrients. Enteropathy is frequently associated with human immunodeficiency virus(HIV) infection, inflammatory bowel disease, autoimmune enteropathy, radiation enteritis, and irritable bowel syndrome(IBS), where pathologic changes in the intestinal tract lead to abdominal discomfort, bloating, abnormal bowel function(e.g., diarrhea, urgency, constipation and malabsorption). Unfortunately, effective therapies for the management ofenteropathy and restoring intestinal health are still not available. An accumulating body of preclinical studies has demonstrated that oral administration of plasmaor serum-derived protein concentrates containing high levels of immunoglobulins can improve weight, normalize gut barrier function, and reduce the severity of enteropathy in animal models. Recent studies in humans, using serum-derived bovine immunoglobulin/protein isolate, demonstrate that such protein preparations are safe and improve symptoms, nutritional status, and various biomarkers associated with enteropathy. Benefits have been shown in patients with HIV infection or diarrhea-predominant IBS. This review summarizes preclinical and clinical studies with plasma/serum protein concentrates and describes the effects on host nutrition, intestinal function, and markers of intestinal inflammation. It supports the concept that immunoglobulin-containing protein preparations may offer a new strategy for restoring functional homeostasis in the intestinal tract of patients with enteropathy.
文摘Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H) , a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion (MCAO) modeled is- chemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlip- idemic condition. Additionally, lipopolysaccharide (LPS) incubation with rat brain microvessel endothelial cells (rBMECs) was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, down- regulated MMP- 9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory re- sponse in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-KB inflammatory signal and down- stream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.