Regulatory pathway of hypoxia-inducible factor and its role in intestinal diseases

Intestinal tract is the largest organ of the human body. It plays an important role in the absorption of nutrients and the resistance to pathogens. At the same time, it is also regulated by oxygen supply. Hypoxia-inducible factor (HIF) is a key factor in the regulation of hypoxia and plays a key role in maintaining the homeostasis of the intestinal environment. In the development of inflammatory bowel disease, intestinal tumor, ischemia-perfusion injury and intestinal flora imbalance, HIF responds to inflammation and hypoxia, and causes an important adaptive response in intestinal mucosa, thus maintaining the function of the intestinal epithelium or promoting the development of intestinal tumors. In this review, the recent advances in HIF structure, function and regulatory pathways, and its role in intestinal diseases are reviewed.     

Research progress of intestinal immune system and diabetes mellitus

The intestinal immune system plays an important role in the pathogenesis of diabetes mellitus. The transplantation of mesenteric lymphocytes can transmit diabetes, which indicates the islet-damaging T cells may be derived from the intestine. Intestinal virus infection, oral gluten antigen and intestinal flora changes are associated with diabetes. The immune cells in gut including T cells, macrophage, natural killer cells, dendritic cells and so on are also confirmed to be involved in the pathogenesis of diabetes. In addition, intestinal immune system influences the occurrence and development of diabetes by modulating the intestinal barrier permeability, the expression of pattern recognition receptors, the changes of incretin and the damage of immune tolerance. The induction of gut immune tolerance and regulation of intestinal flora for the treatment of diabetes have also been widespread concerned. This article summarizes the research progress on the relation of diabetes and intestinal immune system, and also briefly introduces the development of the intestine immune therapy.     

Role of intestinal microbiota-farnesoid X receptor axis in metabolic diseases

Intestinal microbiota is associated with metabolic diseases such as obesity, nonalcoholic fatty liver disease and insulin resistance. Farnesoid X receptor (FXR), also known as bile acid receptor, is a typical nuclear receptor, which is involved in the regulation of bile acid and glycolipid metabolism. Intestinal microbiota regulates FXR activity by affecting bile acid composition, where bile acid hydrolase plays an important role. Recent studies have found that intestinal microbiota affects the development of metabolic diseases through regulating the FXR, and the intestinal microbiota-FXR axis may be an ideal drug target for metabolic diseases.     

Repair effect of purple sweet potato anthocyanin on intestinal barrier injury in mice with ulcerative colitis induced by DSS

AIM To explore the repair effect of purple sweet potato anthocyanin on intestinal barrier injury of ulcerative colitis mice induced by dextrin sulfate sodium （DSS）. METHODS The mice were randomly divided into normal drinking group， DSS model group， different doses of purple sweet potato anthocyanin （12.5， 25， 50 and 75 mg/kg） groups， and 5-aminosalicylic acid （5-ASA） positive drug control group. Except using normal drinking water for control group， the mice in the other groups were treated with 2.5% DSS in drinking water for 7 days to induce the ulcerative colitis model. The mice in purple sweet potato anthocyanin treatment group and the 5-ASA positive drug control group were given the drug by intragastric gavage on the first day of modeling. The body weight of the mice and the hematocheziawere recorded every day. After continuous administration for 8 days， the mice in each group were killed and colon tissue was retained. Immunohistochemical technique （IHC） was used to detect the expression of tight junction protein ZO-1 and occludin and inflammatory factors tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in the colon of mice. The expression of mucin in goblet cells of colon tissue was observed by glycogen PAS staining. The protein expression of ZO-1， occludin， TNF-α were determined by Western blot， Sirius red staining was used to detect colonic fibrosis in mice. RESULTS Compared with control group， the disease activity index and histological injury of DSS model mice were significantly increased（P<0.01）. Compared with model group， the disease activity index scores of the mice in different dose groups of purple sweet potato anthocyanin were decreased. The expression and distribution of ZO-1 and occludin in colon tissues were increased， and the expression and distribution of TNF-α and IL-6 in colon tissues were decreased. Glycogen PAS staining showed a significant increase in the distribution and expression of mucin in goblet cells of colon tissues in the purple sweet potato anthocyanin treatment group. Sirius red staining also showed that the degree of fibrosis in the purple sweet potato anthocyanin treatment groups was lower than that in model group. CONCLUSION Purple sweet potato anthocyanins has therapeutic effect on ulcerative colitis in mice induced by DSS， mainly through up-regulating the expression of tight junction proteins ZO-1 and occludin， to protect the integrity of intestinal barrier， inhibiting the expression of inflammatory cytokines TNF-α and IL-6 and intestinal fibrosis， to suppress the development of colonic inflammation.     

Protective effects of glutamine pretreatment on occludin protein in rats with intestinal ischemia-reperfusion injury

AIM: To determine the effects of glutamine(Gln) pretreatment on occludin protein in the rats with intestinal ischemia-reperfusion(I/R) injury. METHODS: Male Wistar rats(n=30) were randomly divided into 3 groups(n=10):sham group, I/R group and Gln pretreatment group. The rats in Gln pretreatment group were pretreated with Gln at dose of 1 g·kg^-1·d^-1 by orogastric route for 7 d, and those in the other 2 groups were pretreated with the same volume of normal saline. Intestinal I/R was induced by 30-min occlusion of the superior mesenteric artery followed by 24 h of reperfusion. After the operation, the levels of IL-10, IL-2, TNF-α, SOD and MDA were measured. The occludin protein was determined by the methods of immunohistochemistry and Western blotting. RESULTS: The occludin protein level in I/R group was significantly lower than that in sham group and Gln group(P<0.05). The levels of MDA and TNF-α in I/R group were significantly higher than those in sham group and Gln group(P<0.05). The levels of SOD, IL-10 and IL-2 in I/R group were significantly lower than those in sham group and Gln group(P<0.05). CONCLUSION: Glutamine has a protective effect on occludin protein in intestinal ischemia-reperfusion injury. The mechanism may be rela-ted to oxidative stress response and inflammatory inhibition.     

Effect of intestinal endotoxemia on ICAM-1 expression in the liver of rats

AIM: To investigate the effect of intestinal endotoxemia on intercellular adhesion molecule-1(ICAM-1) expression in the hepatic tissue.METHODS:Rat intestinal endotoxemia was induced by thioacetamide(TAA).Changes in ICAM-1 protein in the liver were detected by Western blot. RESULTS: The molecular weight of the ICAM-1 is 95 kD.Western blot analysis of hepatic tissue from control rats and rats injected with TAA within 6 hours revealed low ICMA-1 expression. ICAM-1 expression upregulation occured in rats with intestinal endotoxemia in experimental liver injury induced by TAA 12 h after TAA injection. ICAM-1 expression, plasma endotoxin level and alanine transaminase activity is of equal rank.CONCLUSION: Intestinal endotoxemia can upregulate ICAM-1 expression in the hepatic tissue and the latter is related to liver injury.     

Effects of glutamine pretreatment on intestinal ischemia-reperfusion injury in rats

AIM：To determine the effects of glutamine (Gln) pretreatment on intestinal ischemia-reperfusion (I/R) injury in the rats. METHODS：Thirty male Wistar rats were randomly divided into 3 groups (n=10): sham group, I/R group and Gln pretreatment group. The rats in Gln pretreatment group were pretreated with 1 g·kg-1·d-1 Gln by orogastric route for 7 d, the rats in the other 2 groups were pretreated with normal saline. Intestinal I/R was induced by 30-min occlusion of the superior mesenteric artery followed by 24 h of reperfusion. After the operation, the plasma endotoxin, serum D-lactic acid, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. The intestinal mucosal injury was observed with HE staining and evaluated using Chius scoring. RESULTS：Serum D-lactic acid, endotoxin level, MDA level and Chiu's score in I/R group were significantly higher than those in sham group and Gln group (all P<0.05). Serum SOD activity was significantly lower than that in sham group and Gln group (P<0.05). CONCLUSION：Glutamine has a protective effect on the intestines during ischemia-reperfusion injury. The mechanism may be related to oxidative stress response.     

Effects of Sini decoction on the ultrastructure of small intestinal epithelial cells in rats with intestinal ischemia-reperfusion

AIM: To investigate the effect of Sini decoction (SND)on the ultrastructure of small intestinal epithelial cells in rats with intestinal ischemia-reperfusion. METHODS: Thirty-two Sprague-Dawley rats of both sexes were randomly divided into 4 groups: (1) Control group in which sham operation was performed; (2) Model group in which intestinal I/R was produced by clamping super mesenteric artery(SMA) for 1 hour and declamping SMA for 3 hours; (3) SND1 group in which SD (0.6 g/200 g rat) was given via stomach tube 3 d before intestinal I/R; (4) SND2 group in which SD (1.2 g/200 g rat)was given via stomach tube 3 d before intestinal I/R. A strip of small intestine was taken from distal end of ileum for electron microscopic examination. The two-dimensional structural parameters and three-dimensional structural parameters of mitochondria were calculated. RESULTS: (1)Morphological changes of small intestine: In control group, epithelial cells were orderly arranged, with normal mitochondria and intestinal villi. In model group, the gaps between epithelial cells widened. There were a lot of apoptotic cells. Microvilli were short and swelled. Mitochondria were swelled obviously with broken ridges. Endoplasmatic reticulum was severely dilated. In SND1 and SND2 groups, microvilli and epithelial cells were orderly arranged relatively, mitochondria was slightly swelled. (2) Structural parameters of mitochondria: In model group, there were the least mitochondria and the swelling of mitochondria was severe. In SND1 and SND2 groups, the mitochondria was more than that of model group and the swelling were slight. CONCLUSION: Sini decoction can protect small intestine from ischemia-reperfusion injury without dose-dependent effect.     

Effects of new cannabis preparations O-1602 and cannabidiol on LPS-induced intestinal motility disorder in rodents

AIM: To investigate the therapeutic effects and related mechanisms of two new cannabis preparations, O-1602 and cannabidiol (CBD), on lipopolysaccharide (LPS)-induced rodent models of intestinal motility disorder in vivo and in vitro. METHODS: The animal model of intestinal motility disorder was induced by intraperitoneal injection of LPS in mice. The gastrointestinal transit was measured by gavaging charcoal marker. Western blotting was applied to evaluate the protein expression of G-protein-coupled receptor 55 (GPR55). Meanwhile, the levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were tested by ELISA to assess the inflammatory degree. Smooth muscle strips from the rat and mouse ileum were incubated with LPS in vitro to establish motility disorder, and both the spontaneous contraction and electrically-evoked contraction were recorded using the organ bath technique. The traditional intracellular microelectrode technique was used to record the changes of membrane potential of smooth muscle cells. The method of determining phosphorus content was applied to assay the Ca²⁺-ATPase activity in smooth muscle tissues. RESULTS: In vivo, LPS resulted in significant inflammation and the disorder of gut movement (P<0.01). Pretreatment with CBD decreased both the level of IL-6 (P<0.01) and the expression of GPR55 (P<0.01), and further improved the motility of gut movement (P<0.05). O-1602 and CBD selectively normalized LPS-induced spontaneous and electrically-evoked contraction disorder of intestinal smooth muscle strips of rats and mice in vitro (P<0.05 or P<0.01), but they had no effect on the membrane potential of the smooth muscle cells both in normal and pathophysiological states. CBD also decreased the elevated Ca²⁺-ATPase activity in smooth muscle tissues induced by LPS (P<0.05). CONCLUSION: In vivo, CBD shows protective effect on LPS-induced intestinal motility disorder by reducing inflammation and down-regulating GPR55 expression. O-1602 and CBD counterbalance LPS-induced intestinal motility disorder to some extent in vitro, and the possible mechanism may be involved in regulating the Ca²⁺-ATPase activity of smooth muscle tissues, but not including the change of membrane potential.     

Research progress and important scientific issues of organ fibrosis

Organ fibrosis is a common pathogenetic change of parenchymal organs under chronic conditions, characterized by increased fibrous connective tissues and reduced parenchymal cells. The essence of renal fibrosis is the "repair of scars" after renal tissue damage. It involves a loss of renal parenchyma cells, activation of myofibroblasts, deposition of extracellular matrix, imbalance of metabolism and abnormal interactions with organs. Hepatic fibrosis is a kind of repair response induced by various chronic hepatic diseases, including viral hepatitis and metabolic liver disease, and it is the common pathological basis of end-stage hepatic disease. Pulmonary fibrosis is a progressive and fatal inflammatory interstitial lung disease, characterized by inflammatory destruction and extracellular matrix deposition. Myocardial fibrosis is a process of pathological repair after a variety of injuries caused by hypertension, hypertrophic cardiomyopathy, viral cardiomyopathy, valve disorders, myocardial ischemia, diabetes, obesity and other metabolic abnormalities. Organ fibrosis indicates some common pathogenesis, but the exact mechanisms differ from organs and still need further investigation to identify biomarkers for early diagnosis and to devise drugs specifically for fibrosis. This article comprehensively summarizes the recent developments in organ fibrosis over the last 3 years, including underlying mechanisms and urgent scientific issues remained.     

Protective effect of recombinant SCR15-18 domain of human complement receptor type 1 on intestinal ischemia and reperfusion injury

AIM: To investigate the protective effect of recombinant SCR15-18 domain of human complement receptor type 1 (CR1-SCR-15-18) on intestinal ischemia and reperfusion in a rat model. METHODS: Sprague-Dawley rats were randomly divided into 3 groups: sham operation(SO) group, ischemia and reperfusion (I/R) group and CR1-SCR15-18 treatment group. The superior mesenteric artery of the rats was clamped for 30 min followed by 60 min of reperfusion. PBS alone or CR1-SCR15-18 protein (30 mg/kg) in PBS was intravenously administered 5 min before reperfusion. Intestinal vascular permeability, myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. The histopathological changes of intestinal mucosa were examined by HE staining and complement 3 was detected by immunohistochemical analysis. RESULTS: Compared with SO group, the vascular permeability, the activity of MPO and the content of MDA in I/R group were significantly increased, and the activity of SOD was decreased. HE staining demonstrated that I/R induced severe intestinal histological damages and the increased amount of complement 3 and its derivates were deposited in the necrosis area. Compared with I/R group, the vascular permeability, the activity of MPO and the content of MDA were decreased and the activity of SOD was significantly increased in CR1-SCR15-18 treatment group. CR1-SCR15-18 also significantly attenuated intestinal histological injury, and reduced the deposition of complement 3 and its derivates in the necrosis zone. CONCLUSION: sCR1-SCR15-18 protein exerts a protective effect against intestinal I/R injury in rats, possibly by inhibiting the activation of complement.     

Changes of gut mucosa antioxidant system and liver,renal function in rats after intestinal ischemia-reperfusion injury

AIM: To investigate the changes of the gut mucosa antioxidant system and liver, renal functions during rat intestinal ischemia-reperfusion injury. METHODS: 30 male Wistar rats underwent 45 min of intestinal ischemia by clamping the superior mesenteric artery followed by reperfusion. The levels of malondialdehyde (MDA), glutathione (GSH), the activities of antioxidant enzymes in the gut mucosa including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), glutathione S- transferase (GST) activity and serum ALT, AST, BUN, Cr were assayed at 2, 4, 8, 12 and 24 h after reperfusion. RESULTS: The levels of MDA and GSH in the gut mucosa increased and decreased significantly at 2 h of reperfusion, respectively (P<0.05). MDA was still lower than sham at 24 h of reperfusion (P<0.05), while GSH decreased to 40% of sham at 4 h of reperfusion (P<0.01) but returned to the level of control at 12 h. The activities of CAT, SOD and GSH-Px did not show significant changes in rat after intestinal ischemia reperfusion. GST decreased 39% at 2 h of reperfusion compared with the sham group and decreased to 56% of sham at 4 h (P<0.05), but returned to the level of control at 12 h after reperfusion. Serum ALT, AST, BUN and Cr increased significantly at 2 h of reperfusion (P<0.05) and increased 208%, 100%, 103%, 41% compared with control at 4 h of reperfusion (P<0.01). However, at 24 h of reperfusion, they returned to normal. CONCLUSION: Intestinal ischemia/reperfusion diminishes GSH level and GST activity, increases MDA level and causes liver and renal reversible damages.     

TL1A promotes development of intestinal fibrosis associated with chron?ic experimental colitis by regulating IL-17 and IFN-γ

AIM To explore how tumor recrosis factor ligand-related molecule 1A (TL1A) promotes the development of intestinal fibrosis associated with chronic experimental colitis by regulating interleukin-17 (IL-17) and interferon-γ (IFN-γ). METHODS Aexperimental colitis-associated wild-type (WT) and TL1A (L-Tg) transgenic intestinal fibrosis model was established by dextran sulfate sodium (DSS) induction.The severity of colitis was evaluated by detecting the disease activity index (DAI). HE staining was used to observe the histopathological changes and pathological score of the colitis.Myeloperoxidase (MPO) was measured in each group. The collagen deposition was detected by Masson’s trichrome staining and Sirius red staining. The lamina propria, spleen and mesenteric lymph nodes(MLN) mononuclear cells were isolated and counted, and the levels of IL-17 and IFN-γ weremeasured by ELISA, andthe percentages of CD4⁺IFN-γ⁺T cells and CD4⁺IL-17⁺T cells were analyzed by flow cytometry. RESULTS After drinking DSS water,the body weight of the mice in DSS/Tg group was decreased significantly as compared with WT group(P<0.05). The DAI score, histology score and MPO activity were significantly increased(P<0.05). Thelevels of IL-17 and IFN-γ, LPMC, spleen and MLN were significantly increased. The percentages of CD4⁺IFN-γ⁺T cells and CD4⁺IL-17⁺T cells were significantlyincreased.The thickness and collagen deposition of the colon were increased inTg group. CONCLUSION TL1A promotes the development of intestinal fibrosis associated with chronic experimental colitis by regulating IL-17 and IFN-γ.     

Role of GRP78 in alteration of myocardium induced by intestinal endotoxemia in cirrhotic rats

AIM: To explore the role of glucose-regulated protein 78 (GRP78) in the alteration of myocardium induced by intestinal endotoxemia in cirrhotic rats. METHODS: Fifty-one male Wistar rats were randomly divided into liver cirrhosis groups of 4-week, 6-week and 8-week, and normal control groups at corresponding time points. The cardiac functions of the 8-week rats were measured. Tumor necrosis factor α(TNF-α) and malondialdehyde(MDA) in myocardial tissues were detected. The number of myocardial cells and the collagen volume fraction (CVF) were determined with toluidine blue and van Giesan staining, respectively. The expression of GRP78 and hypoxia-inducible facotr 1α(HIF-1α) was analyzed by the method of immnunohistochemistry. RESULTS: Compared with normal control group at corresponding time point, left ventricular end-diastolic pressure(LVEDP) and ±LV dp/dt_max in 8-week group were significantly decreased (P<0.05). The levels of TNF-α, MDA and CVF, the protein expression of GRP78 and HIF-1α in the myocardial tissues were significantly increased in every model group (P<0.05), and the number of myocardial cells was gradually decreased (P<0.05). Elevated levels of endotoxin in plasma were positively correlated with the levels of alanine aminotransferase (ALT),homocysteine (Hcy) and TNF-α in plasma, the levels of TNF-α, MDA and CVF, and protein levels of GRP78 and HIF-1α in the myocardial tissues (P<0.05). Elevated protein expression of GRP78 in the myocardial tissues was positively correlated with the levels of ALT, Hcy in plasma and MDA, CVF, HIF-1α protein in the myocardial tissues (P<0.05). CONCLUSION: Intestinal endotoxemia induced by liver cirrhosis may directly or indirectly lead to endoplasmic reticulum stress and overexpression of GRP78. GRP78 may be a key molecule in the pathogenesis of myocardial remodeling and functional alteration induced by liver cirrhosis.     

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《园艺学报》是中国园艺学会和中国农业科学院蔬菜花卉研究所主办的学术期刊,创刊于1962年,刊载有关果树、蔬菜、观赏植物、茶及药用植物等方面的学术论文、研究报告、专题文献综述、问题与讨论、新技术新品种以     

Roles of resident cells and infiltrating cells in renal tubulointerstitial injuries

Tubulointerstitial lesions, occurring in many kinds of renal diseases, have been found to be the predominant factor in the impairment of renal function. The severe and extensive lesions often predict a poor outcome in future. It has been tested recent years that the infiltrating inflammatory cells might play impor tant roles in the onset and deterioration of tubulointerstitial injuries. On the other hand, the resident cells, including the tubular epithelial cells and the fibroblasts, also directly take part in tubulointerstitial inflammation and fibrosis. Researches also display implicated interact ions between the infiltrating cells and the resident cells, which contribute to the amplification of inflammation and the progress of fibrosis.     

Role of 78 kD glucose-regulated protein in the development of liver cirrhosis promoted by intestinal endotoxemia in rats

AIM: To explore the role of 78 kD glucose-regulated protein (GRP78) in the development of liver cirrhosis in rats promoted by intestinal endotoxemia (IETM). METHODS: Fifty-one male Wistar rats were randomly divided into liver cirrhosis groups of 4th-week, 6th-week and 8th-week, and normal control group at the corresponding time points. The rat model of hepatic cirrhosis was induced by employing multiple pathogenic factors to the animals. The liver injury and hepatic fibrosis were observed with the staining of HE and VG, respectively. The expression of GRP78 at the mRNA and protein levels was measured by the methods of RT-PCR and immnunohistochemistry, respectively. The concentrations of alanine aminotransferase(ALT), endotoxin, TNF-α and homocystine (HCY) in plasma, and the content of TNF-α, malondialdehyde(MDA) and PⅢP in liver tissues were detected. RESULTS: As liver cirrhosis developed, the levels of ALT, endotoxin, TNF-α and HCY in plasma, the expression of GRP78 at mRNA and protein, the content of TNF-α, MDA and PⅢP in liver tissues, and the index of liver fibrosis were gradually increased and were significantly higher than those in normal control group (P<0.05). Elevated endotoxin in plasma was correlated positively with the protein expression of GRP78, the content of MDA and HCY in plasma and the index of liver fibrosis (P<0.01). Elevated protein expression of GRP78 was correlated positively with the content of MDA and HCY in plasma and the index of liver fibrosis (P<0.01). CONCLUSION: GRP78 plays an important role in the development of liver cirrhosis. Endoplasmic reticulum stress is a possible mechanism in the development of liver cirrhosis promoted by IETM.     

Role of AMP-activated protein kinase in fibrogenesis

Fibrosis is a common clinical disease that occurs in a variety of organs, and mainly manifests increased connective tissue of organ tissue and decreased parenchymal cells. Continuous progression may lead to organ structural damage, dysfunction and even depletion, seriously threatening human health and life safety. Therefore, in-depth study of the pathogenesis of fibrosis and the development of effective therapeutic drugs are of great importance for the prevention and treatment of fibrosis. Recent studies provide evidence that AMP-activated protein kinase (AMPK) plays an important role in the development of fibrosis. In combination with related literatures, this paper reviews the structure and biological function of AMPK, AMPK in inflammatory response associated with fibrosis, epithelial-mesenchymal transition, extracellular matrix and myofibroblasts, and the therapeutic role of AMPK as a new target in treating fibrosis diseases.