Experimental study on the toxicokinetics and gastrointestinal damage in rats poisoned with acute diquat poisoning at different exposure doses / 中华危重病急救医学

OBJECTIVE@#To observe the toxicokinetic parameters, absorption characteristics and pathomorphological damage in different parts of the gastrointestinal tract of rats poisoned with different doses of diquat (DQ).@*METHODS@#Ninety-six healthy male Wistar rats were randomly divided into a control group (six rats) and low (115.5 mg/kg), medium (231.0 mg/kg) and high (346.5 mg/kg) dose DQ poisoning groups (thirty rats in each dose group), and then the poisoning groups were randomly divided into 5 subgroups according to the time after exposure (15 minutes and 1, 3, 12, 36 hours; six rats in each subgroup). All rats in the exposure groups were given a single dose of DQ by gavage. Rats in the control group was given the same amount of saline by gavage. The general condition of the rats was recorded. Blood was collected from the inner canthus of the eye at 3 time points in each subgroup, and rats were sacrificed after the third blood collection to obtain gastrointestinal specimens. DQ concentrations in plasma and tissues were determined by ultra-high performance liquid chromatography and mass spectrometry (UPHLC-MS), and the toxic concentration-time curves were plotted to calculate the toxicokinetic parameters; the morphological structure of the intestine was observed under light microscopy, and the villi height and crypt depth were determined and the ratio (V/C) was calculated.@*RESULTS@#DQ was detected in the plasma of the rats in the low, medium and high dose groups 5 minutes after exposure. The time to maximum plasma concentration (Tmax) was (0.85±0.22), (0.75±0.25) and (0.25±0.00) hours, respectively. The trend of plasma DQ concentration over time was similar in the three dose groups, but the plasma DQ concentration increased again at 36 hours in the high dose group. In terms of DQ concentration in gastrointestinal tissues, the highest concentrations of DQ were found in the stomach and small intestine from 15 minutes to 1 hour and in the colon at 3 hours. By 36 hours after poisoning, the concentrations of DQ in all parts of the stomach and intestine in the low and medium dose groups had decreased to lower levels. Gastrointestinal tissue (except jejunum) DQ concentrations in the high dose group tended to increase from 12 hours. Higher doses of DQ were still detectable [gastric, duodenal, ileal and colonic DQ concentrations of 6 400.0 (1 232.5), 4 889.0 (6 070.5), 10 300.0 (3 565.0) and 1 835.0 (202.5) mg/kg respectively]. Light microscopic observation of morphological and histopathological changes in the intestine shows that acute damage to the stomach, duodenum and jejunum of rats was observed 15 minutes after each dose of DQ, pathological lesions were observed in the ileum and colon 1 hour after exposure, the most severe gastrointestinal injury occurred at 12 hours, significant reduction in villi height, significant increase in crypt depth and lowest V/C ratio in all segments of the small intestine, damage begins to diminish by 36-hour post-intoxication. At the same time, morphological and histopathological damage to the intestine of rats at all time points increased significantly with increasing doses of the toxin.@*CONCLUSIONS@#The absorption of DQ in the digestive tract is rapid, and all segments of the gastrointestinal tract may absorb DQ. The toxicokinetics of DQ-tainted rats at different times and doses have different characteristics. In terms of timing, gastrointestinal damage was seen at 15 minutes after DQ, and began to diminish at 36 hours. In terms of dose, Tmax was advanced with the increase of dose and the peak time was shorter. The damage to the digestive system of DQ is closely related to the dose and retention time of the poison exposure.

Protective effect and mechanism of exenatide on HRMCs injured by fluctuating hyperglycemia / 天津医药

Objective To observe the effect of exenatide on endoplasmic reticulum stress (ERS) in human renal mesangial cells (HRMCs) injured by fluctuating hyperglycemia culture,and to explore the mechanism.Methods HRMCs were randomly divided into three groups:control group (group N,cells were cultured in 5.6 mmol/L glucose for 24 h),fluctuating hyperglycemia group (group F,cells were cultured in 30 mmol/L glucose for 3 h,5.6 mmol/L glucose for 2 h,repeated three times in one day,then 5.6 mmoll/L glucose overnight),fluctuating hyperglycemia and exenatide group (group F+G,HRMCs were cultured in fluctuating hyperglycemia and 100 nmol/L exenatide).MTT assay was used to measure the viability in each group.The apoptosis rates were detected by flow cytometry in three groups.The relative expression of glucose regulated protein78 (GRP78) and CCAAT/enhancerbinding protein homologous protein (CHOP) were tested by Western blot assay.Results Compared with the group N,the cell proliferation level decreased,the cell apoptosis rate increased,and the expression levels of GRP78 and CHOP increased in F group (P ＜ 0.05).After treatment with exenatide,the cell proliferation rate increased,cell apoptosis rate decreased (P ＜ 0.05),and the expression levels of GRP78 and CHOP decreased in F+G group,compared with those of the group F (P ＜ 0.05).Conclusion Exenatide can reduce the damage of fluctuating hyperglycemia on HRMCs by down-regulating the stress levels of the endoplasmic reticulum stress.