Homocysteine (Hcy) is a sulfur-containing amino acid. An elevated level of Hcy is a risk factor for diabetes development. However, the mechanism of its effect on pancreatic ß-cell function is unclear. In this study, we constructed a hyperhomocysteinemia (HHcy) mouse model by feeding mice a high methionine diet (HMD). The mice suffered impaired glucose tolerance and reduced insulin secretion. Furthermore, at the cellular level, INS1 cells exhibited impaired insulin secretory function after the Hcy intervention. Transcriptomics revealed that Zbtb20 expression was downregulated and the downstream gene Fbp1 was upregulated in HHcy-induced mice compared with mice fed with normal diet. Insulin secretion could be restored by Zbtb20 overexpression or fructose 1,6-bisphosphatase (FBPase) activity inhibition in INS1 cells. In conclusion, our study suggested that Hcy inhibited the insulin secretory function of pancreatic ß-cells by suppressing Zbtb20 expression, leading to the development of diabetes. Zbtb20 may be a key target in the development of diabetes associated with elevated Hcy levels.
Diabetes Mellitus , Glucose Intolerance , Mice , Animals , Insulin/metabolism , Insulin Secretion , Transcription Factors/genetics , Transcription Factors/metabolism
Objective: To investigate the alleviating effect of hydrogen (H2) on homocysteine (Hcy) levels and non alcoholic fatty liver in rats with hyperhomocysteinemia (HHcy). Methods: After one week of adaptive feeding, Wistar rats were randomly divided into three groups: the general diet group (CHOW), the high methionine group (HMD), and the high methionine plus hydrogen rich water group (HMD+HRW), with 8 rats in each group. The CHOW group was fed with AIN-93G feed, while the HMD and HMD+HRW groups were fed with AIN-93G+2% methionine feed to construct an HHcy model. The HMD+HRW group was also gavaged with hydrogen rich water (3 ml/animal, twice a day, with a hydrogen concentration of 0.8 mmol/L), and body weight data were recorded. After 6 weeks of feeding, the plasma and liver samples were processed and collected. The plasma homocysteine (Hcy) and lipid contents of each group were measured, and the histological morphology of the liver was observed. The activities of key enzymes in the Hcy metabolism pathway and mRNA expression were detected in the liver. Results: Compared with the CHOW group rats, the Hcy level in the blood of HMD rats was significantly increased significantly (Pï¼0.05). Pathological tissue sections showed liver enlargement, injury, and fatty liver in the rats; Compared with the HMD group rats, the HMD+HRW group rats showed a significant decrease in Hcy in the blood, reduced liver damage, and increased Hcy metabolism key enzyme activity and mRNA expression in the liver, with statistical differences (Pï¼0.05). Conclusion: Hydrogen has a significant improvement effect on liver injury induced by HMD diet in HHcy rats, possibly by enhancing the three metabolic pathways of Hcy to reduce excessive Hcy in the body, thereby improving liver metabolic function and symptoms of non-alcoholic fatty liver disease.
Hyperhomocysteinemia , Non-alcoholic Fatty Liver Disease , Rats , Animals , Methionine , Rats, Wistar , Racemethionine , Diet , Homocysteine , Hydrogen , Water , RNA, Messenger
A one-pot difluoromethylthiolation of alkyl electrophiles with thiourea and diethyl bromodifluoromethylphosphonate is described. The transition-metal-free approach, readily available reagents, and mild conditions provide a practical way for the synthesis of difluoromethyl thioethers. By changing the "H" source to the most commonly used "D" sources CD3OD and D2O, this strategy enables efficient synthesis of SCF2D-substituted molecules in good yields with high levels of D incorporation.
The fluoromethoxymethylation of nitrogen heterocyclic compounds with fluoromethyl iodide has been reported for the first time. In this reaction, a number of unexplored fluoromethoxymethylated nitrogen heterocyclic compounds including indoles, carbazoles, and 1H-indazoles were efficiently formed. Mechanistic studies indicated that this transformation consists of electrophilic monofluoromethylation, rapid hydrolysis, and another electrophilic monofluoromethylation. This method makes it possible to synthesize complex bioactive molecules containing a CH2OCH2F group, which have the potential to be a new series of fluorine-containing chemical entities for medicinal chemists.
A highly carbon-selective monofluoromethylation of a broad range of ß-ketoesters with fluoromethyl iodide under mild conditions is described. The uses of lithium tert-butoxide as the base and diglyme as the solvent made great contributions to the high C/O regioselectivity.
Trifluoromethanesulfinyl chloride (CF3 SOCl) has been introduced as a new reagent for C-H trifluoromethylthiolation of indoles, thiophenes, and ketones under catalyst-free conditions and in the absence of reductant. The disproportionation of CF3 SOCl to CF3 SO2 Cl and CF3 SCl provides two pathways for the trifluoromethylthiolation. Direct trifluoromethylthiolation with CF3 SCl or trifluoromethylsulfoxidation with CF3 SOCl is followed by reduction with CF3 SOCl. This reagent can be used to functionalize benzothiophenes, benzofurans, and indenes under the promotion of Ag2 CO3 . It can also be used for trifluoromethylthiolation of thiols and benzeneselenols, and 1,2-bifunctional chlorotrifluoromethylthiolation of indoles, styrenes, and alkyenes. The method can also be extended for difluorometylthiolation reactions using CF2 HSOCl.
The unprecedented use of CF3SO2Cl for direct bifunctional chloro-trifluoromethylthiolation of alkenes and alkynes is reported. CF3SCl, which is generated by the reduction of PPh3, undergoes electrophilic addition and then chlorination to give the bifunctionalized products without using an additional chlorine source. The method is also applicable for chloro-difluoromethylthiolation using CF2HSO2Cl.
A straightforward one-pot synthesis of difluoromethyl thioethers from thiourea and diethyl bromodifluoromethylphosphonate has been developed. Thiourea is a cheap and friendly sulfur reagent, while diethyl bromodifluoromethylphosphonate is a low-cost and stable difluorocarbene precursor. The strategy enabled the introduction of SCF2H moieties into indoles, pyrroles, and activated arenes and formed a number of difluoromethyl thioethers.
