BACKGROUND Intestinal barrier breakdown, a frequent complication of intestinal ischemia-reperfusion (I/R) including dysfunction and the structure changes of the intestine, is characterized by a loss of tight junction and enhanced permeability of the intestinal barrier and increased mortality. To develop effective and novel therapeutics is important for the improvement of outcome of patients with intestinal barrier deterioration. Recombinant human angiopoietin-like protein 4 (rhANGPTL4) is reported to protect the blood-brain barrier when administered exogenously, and endogenous ANGPTL4 deficiency deteriorates radiation-induced intestinal injury. AIM To identify whether rhANGPTL4 may protect intestinal barrier breakdown induced by I/R. METHODS Intestinal I/R injury was elicited through clamping the superior mesenteric artery for 60 min followed by 240 min reperfusion. Intestinal epithelial (Caco-2) cells and human umbilical vein endothelial cells were challenged by hypoxia/ reoxygenation to mimic I/R in vitro . RESULTS Indicators including fluorescein isothiocyanate-conjugated dextran (4 kilodaltons; FD-4) clearance, ratio of phosphorylated myosin light chain/total myosin light chain, myosin light chain kinase and loss of zonula occludens-1, claudin-2 and VE-cadherin were significantly increased after intestinal I/R or cell hypoxia/reoxygenation. rhANGPTL4 treatment significantly reversed these indicators, which were associated with inhibiting the inflammatory and oxidative cascade, excessive activation of cellular autophagy and apoptosis and improvement of survival rate. Similar results were observed in vitro when cells were challenged by hypoxia/reoxygenation, whereas rhANGPTL4 reversed the indicators close to normal level in Caco-2 cells and human umbilical vein endothelial cells significantly. CONCLUSION rhANGPTL4 can function as a protective agent against intestinal injury induced by intestinal I/R and improve survival via maintenance of intestinal barrier structure and functions.
Taiwanofungus camphoratus is an edible and medicinal mushroom originating in Taiwan. Several researches have revealed T. camphoratus possessed various biological activities, including anti-cancer, immunomodulation, liver protection and anti-inflammation. Recently, it has been widely used in food supplements and drug development for its health benefits and medicinal properties. Therefore, the safety issue is the primary concern for consumers. The aim of this study was to evaluate the toxicological effects of T. camphoratus extract that was composed of extracts from cut-log cultivated fruiting body and solid-state culture of T. camphoratus. The genotoxicity tests, rodent and non-rodent repeated dose toxicity studies were performed. The results of the genetic toxicology tests including in vitro bacterial reverse mutation assay, in vitro chromosomal aberration test, and in vivo mouse bone marrow micronucleus assay were all negative that indicated neither mutagenicity nor clastogenicity was caused by T. camphoratus extract. Moreover, 13-week and 26-week repeated dose oral toxicity studies in rats showed that no significant adverse effects of T. camphoratus extract were found up to dosages of 3400 mg/kg and 1700 mg/kg for male and female rats, respectively. The results of 28-day repeated dose oral toxicity study in beagle dogs showed no-observed-adverse-effect-level (NOAEL) of T. camphoratus extract up to dosage of 1500 mg/kg for male and female dogs. Accordingly, these results provided the safety information of T. camphoratus extract that supported for using in food supplements or medicinal usage. Test substanceThe test article, T. camphoratus extract (named as LEAC-102), was composed of ethanol and water extracts from cut-log cultivated fruiting body (FB) and solid-state culture (SC) of T. camphoratus that provided by Taiwan Leader Biotech Corp. (Taipei, Taiwan). The cut-log cultivated FB and solid-state culture of T. camphoratus were manufactured by R&D Center of Taiwan Leader Biotech Corp. (Taichung, Taiwan). The dry powders of FB and SC were mixed in the ratio of 1:10 (w/w) and were extracted with 10 volumes of 95% ethanol for 2 hr twice, followed by extraction with 10 volumes of boiled water for 2 hr twice. The ethanol and water extracts from FB and SC were combined and concentrated to obtain LEAC-102. 1 gram of T. camphoratus extract equivalent to the extract from dried raw material of 0.22 g of fruit body and 2.2 g of solid-state culture. Bacterial reverse mutation testThe histidine-dependent Salmonella typhimurium strains TA98, TA100, TA102, TA1535 and TA1537 (Moltox Inc., Boone, NC) were used to evaluate the genotoxicity of T. camphoratus extract. T. camphoratus extract was dissolved in DMSO to obtain the dosing solution and the highest dose of this study was set at 5 mg/plate based on the results of dose range finding test in TA100. Hence, five concentrations, 0.050, 0.158, 0.50, 1.58, 5 mg/plate, were used in this study. Positive controls, negative control (sterile water), vehicle control (dimethylfloxide, ...
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