metallothionein and Intestinal-Diseases

Cadmium has been shown to manifest its toxicity in human and animals by mainly accumulating in almost all of the organs and kidney is the main target organ where it is concentrated mainly in cortex. Environmental exposure of cadmium occurs via food, occupational industries, terrestrial and aquatic ecosystem. At molecular level, cadmium interferes with the utilization of essential metals e.g. Ca, Zn, Se, Cr and Fe and deficiencies of these essential metals including protein and vitamins, exaggerate cadmium toxicity, due to its increased absorption through the gut and greater retention in different organs as metallothionein (Cd-Mt). Cadmium transport, across the intestinal and renal brush border membrane vesicles, is carrier mediated and it competes with zinc and calcium. It has been postulated that cadmium shares the same transport system. Cadmium inhibits protein synthesis, carbohydrate metabolism and drug metabolizing enzymes in liver of animals. Chronic environmental exposure of cadmium produces hypertension in experimental animals. Functional changes accompanying cadmium nephropathy include low molecular weight proteinuria which is of tubular origin associated with excess excretion of proteins such as beta 2 microglobulin, metallothionein and high molecular weight proteinuria of glomerular origin (excretion of proteins such as albumin IgG, transferrin etc.). Recent data has shown that metallothionein is more nephrotoxic to animals. Cadmium is also toxic to central nervous system. It causes an alterations of cellular functions in lungs. Cadmium affects both humoral and cell mediated immune response in animals. Cadmium induces metallothionein in liver and kidney but under certain nutritional deficiencies like protein-calorie malnutrition and calcium deficiency, enhanced induction and greater accumulation of cadmium metallothionein has been observed.

Topics: Aging; Animals; Bone Diseases; Cadmium; Calcium; Central Nervous System Diseases; Chromium; Copper; Dietary Proteins; Drug Interactions; Environmental Exposure; Female; Half-Life; Humans; Hypertension; Immunity; Intestinal Absorption; Intestinal Diseases; Iron; Kidney Diseases; Liver; Lung; Male; Metallothionein; Ovary; Selenium; Sex Factors; Testis; Tissue Distribution; Vitamins; Zinc

Radiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy.. The radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression.. Using a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy.. PS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage.. As stated in the Acknowledgments.

Topics: Animals; Biopsy; Caco-2 Cells; Computational Biology; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Gene Ontology; Humans; Intestinal Diseases; Intestinal Mucosa; Male; Metallothionein; Mice; Pravastatin; Radiation Injuries; Radiation, Ionizing; Swine; Swine, Miniature; Tight Junctions

The biochemical and histological sequelae resulting from a diet containing 50.20 mg cadmium/kg were studied in Lohmann brown cockerels from hatching until 30 days of age. The additional cadmium chloride (CdCl(2)) to the diet induced the formation of lipid peroxides, which via a chain reaction led to accumulation of malondialdehyde in intestinal mucosa. At the end of the study (after 30 days of cadmium exposure) total protein and metallothionein levels in the intestinal mucosa and the relative ileal and duodenal weight increased. Histological data show that CdCl(2) causes an increase in number of goblet cells and granular lymphocytes in the intestinal mucosa. Down-regulation of the serotonin-positive cells in the cadmium-treated animals was observed. Growth retardation (by 27%) occurred in chicken fed the cadmium-enriched diet for 30 days. Cadmium accumulation in the intestine was markedly higher (154 times) in the cadmium-treated animals compared to the control group. Cadmium induced a decrease in zinc (but not copper) content in intestinal mucosa. We suggest that cadmium uptake triggers an inflammatory and secretory response in chicken small intestine.

Topics: Animals; Body Weight; Cadmium Chloride; Chickens; Intestinal Diseases; Intestinal Mucosa; Lipid Peroxides; Male; Malondialdehyde; Metallothionein; Poultry Diseases

Oral administration of zinc or bovine whey-derived growth factor extract (WGFE) is known to reduce intestinal permeability and ameliorate methotrexate (MTX)-induced mucositis, respectively.. We examined the effects of zinc, WGFE, and zinc plus WGFE on gut damage in MTX-treated rats.. Rats (n = 16/group) were fed zinc (1000 mg/kg diet), WGFE (32 mg/kg diet), zinc plus WGFE, or control (10 mg Zn/kg diet) diets for 7 d and then injected subcutaneously with MTX (2.5 mg/kg) for 3 d to induce gut damage. Gut histology and intestinal permeability were assessed.. The Zn+WGFE diet was associated with both reduced gut damage on day 5 and enhanced recovery on day 7. The WGFE diet ameliorated gut damage, whereas the Zn and Zn+WGFE diets enhanced repair. Gut metallothionein and tissue zinc concentrations were significantly (P < 0.01) higher with Zn and Zn+WGFE on days 5 and 7 than without zinc supplementation. The Zn and Zn+WGFE diets significantly (P < 0.05) decreased gut permeability on days 3-4 compared with the control diet. Intestinal permeability was significantly (P < 0.05) increased on days 5-6. On days 6-7, only the WGFE diet improved gut permeability (by 80%) compared with the control diet.. Dietary administration of WGFE and a pharmacologic dose of zinc reduced intestinal damage and enhanced recovery, respectively. WGFE also improved gut permeability after MTX-induced bowel damage. In combination, zinc and WGFE hastened repair of gut damage, which may have clinical application in chemotherapy-induced mucositis.

Topics: Administration, Oral; Animals; Antimetabolites, Antineoplastic; Cattle; Cheese; Dietary Supplements; Growth Substances; Intestinal Diseases; Intestinal Mucosa; Male; Metallothionein; Methotrexate; Milk Proteins; Permeability; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Whey Proteins; Zinc

Antibody to rat liver metallothionein prepared by the method of Brady and Kafka (1979) was used to localise immunoreactive metallothionein using a sensitive DNP hapten sandwich technique applied to formalin fixed wax embedded tissues. Rat tissues examined were liver, kidney and small intestine, taken from normal animals, from animals fasted after receiving either an oral dose of water, or 1 ml zinc acetate solution either orally or by intraperitoneal injection, (3-4 mg Zn++/Kg body weight). Human tissues examined were 6 histologically normal liver biopsies and small intestine including histologically normal jejunal biopsies and samples of ileum obtained at operation. Pathological tissue including liver from cases of Indian childhood cirrhosis with copper retention and ileum from cases of inflammatory bowel disease were also examined. Immunoreactive metallothionein (IMT) was found in both rat and human liver localised in the hepatocyte cytoplasm, nucleus, sinusoids and canaliculi. In some livers IMT was found in the portal and hepatic veins. In the small intestine the IMT was localised consistently in the enterocyte cytoplasm and nucleus, and in the basement membrane region. The rat kidney IMT was localised in the cytoplasm of the distal convoluted tubules the collecting tubules and the ducts of Bellini. The distribution of IMT in rat tissues showed changes associated with fasting, stress and zinc administration. In man, inflammatory bowel disease appeared to decrease the intestinal IMT and no significant difference was seen when patients had received steroid therapy. The greatest amounts of IMT were seen in the control group of patients. The distribution of IMT in human liver in Indian childhood cirrhosis did not correspond with that of copper associated protein.

Topics: Animals; Basement Membrane; Cell Nucleus; Crohn Disease; Cytoplasm; Dinitrophenols; Fasting; Histocytochemistry; Humans; Immunoenzyme Techniques; Intestinal Diseases; Intestinal Neoplasms; Intestine, Small; Kidney; Liver; Liver Cirrhosis; Metallothionein; Rats; Tissue Distribution

Topics: Animals; Homeostasis; Indomethacin; Intestinal Absorption; Intestinal Diseases; Liver; Male; Metalloproteins; Metallothionein; Rats; Zinc