Probing stereoselective inhibition of the acyl binding site of cholesterol esterase with four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol

BACKGROUND: Recently there has been increased interest in pancreatic cholesterol esterase due to correlation between enzymatic activity in vivo and absorption of dietary cholesterol. Cholesterol esterase plays a role in digestive lipid absorption in the upper intestinal tract, though its role in cholesterol absorption in particular is controversial. Serine lipases, acetylcholinesterase, butyrylcholinesterase, and cholesterol esterase belong to a large family of proteins called the α/β-hydrolase fold, and they share the same catalytic machinery as serine proteases in that they have an active site serine residue which, with a histidine and an aspartic or glutamic acid, forms a catalytic triad. The aim of this work is to study the stereoselectivity of the acyl chain binding site of the enzyme for four diastereomers of an inhibitor. RESULTS: Four diastereomers of 2'-N-α-methylbenzylcarbamyl-1, 1'-bi-2-naphthol (1) are synthesized from the condensation of R-(+)- or S-(-)-1, 1'-bi-2-naphthanol with R-(+)- or S-(-)-α-methylbenzyl isocyanate in the presence of a catalytic amount of pyridine in CH(2)Cl(2). The [α](25)(D )values for (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1 are +40, +21, -21, and -41°, respectively. All four diastereomers of inhibitors are characterized as pseudo substrate inhibitors of pancreatic cholesterol esterase. Values of the inhibition constant (K(i)), the carbamylation constant (k(2)), and the bimolecular rate constant (k(i)) for these four diastereomeric inhibitors are investigated. The inhibitory potencies for these four diastereomers are in the descending order of (1R, αR)-1, (1R, αS)-1, (1S, αR)-1, and (1S, αS)-1. The k(2 )values for these four diastereomers are about the same. The enzyme stereoselectivity for the 1, 1'-bi-2-naphthyl moiety of the inhibitors (R > S, ca. 10 times) is the same as that for 2'-N-butylcarbamyl-1, 1'-bi-2-naphthol (2). The enzyme stereoselectivity for the α-methylbenzylcarbamyl moiety of the inhibitors is also R > S (2–3 times) due to the constraints in the acyl binding site. CONCLUSION: We are the first to report that the acyl chain binding site of cholesterol esterase shows stereoselectivity for the four diastereomers of 1

Chronic constant light exposure aggravates high fat diet-induced renal injury in rats

Obesity-related kidney disease is now recognized as a global health issue, with a substantial number of patients developing progressive renal failure and end-stage renal disease. Interestingly, recent studies indicate light pollution is a novel environmental risk factor for chronic kidney disease. However, the impact of light pollution on obesity-related kidney disease remains largely unknown, with its underlying mechanism insufficiently explained. Renal hypoxia induced factor 1α (HIF1α) is critical in the development of glomerulosclerosis and renal fibrosis. The present study explored effects of constant light exposure on high fat diet (HFD) -induced renal injury and its association with HIF1α signal pathway. Thirty-two male Sprague Dawley rats were divided into four groups according to diet (HFD or normal chow diet) and light cycles (light/dark or constant light). After 16 weeks treatment, rats were sacrificed and pathophysiological assessments were performed. In normal chow fed rats, constant light exposure led to glucose abnormalities and dyslipidemia. In HFD fed rats, constant light exposure exacerbated obesity, glucose abnormalities, insulin resistance, dyslipidemia, renal functional decline, proteinuria, glomerulomegaly, renal inflammation and fibrosis. And, constant light exposure caused an increase in HIF1α and a decrease in prolyl hydroxylase domain 1 (PHD1) and PHD2 expression in kidneys of HFD-fed rats. Then, we demonstrated that BMAL1 bound directly to the promoters of PHD1 in mouse podocyte clone 5 cell line (MPC5) by ChIP assays. In conclusion, chronic constant light exposure aggravates HFD-induced renal injuries in rats, and it is associated with activation of HIF1α signal pathway

Tunable Atomically Wide Electrostatic Barriers Embedded in a Graphene WSe2 Heterostructure

Inducing and controlling electrostatic barriers in two-dimensional (2D) quantum materials has shown extraordinary promise to enable control of charge carriers, and is key for the realization of nanoscale electronic and optoelectronic devices1-10. Because of their atomically thin nature, the 2D materials have a congenital advantage to construct the thinnest possible p-n junctions1,3,7,9,10. To realize the ultimate functional unit for future nanoscale devices, creating atomically wide electrostatic barriers embedded in 2D materials is desired and remains an extremely challenge. Here we report the creation and manipulation of atomically wide electrostatic barriers embedded in graphene WSe2 heterostructures. By using a STM tip, we demonstrate the ability to generate a one-dimensional (1D) atomically wide boundary between 1T-WSe2 domains and continuously tune positions of the boundary because of ferroelasticity of the 1T-WSe2. Our experiment indicates that the 1D boundary introduces atomically wide electrostatic barriers in graphene above it. Then the 1D electrostatic barrier changes a single graphene WSe2 heterostructure quantum dot from a relativistic artificial atom to a relativistic artificial molecule

Diaqua­bis(5-carb­oxy-2-methyl-1H-imidazole-4-carboxyl­ato-κ2 N 3,O 4)manganese(II)

The title complex, [Mn(C6H5N2O4)2(H2O)2], was obtained by hydro­thermal synthesis. The MnII atom, which lies on an inversion centre, displays a slightly distorted octa­hedral geometry. In the crystal packing, complex mol­ecules are linked by inter­molecular O—H⋯O and N—H⋯O hydrogen bonds to form a three-dimensional supramolecular structure. The title complex is isostructural with the corresponding cadmium(II) complex [Nie, Wen, Wu, Liu & Liu (2007 ▶). Acta Cryst. E63, m753–m755]

Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD

Highlights Metformin alleviates HIO and ferroptosis in HFD-induced NAFLD FPN is involved in the molecular mechanism of metformin on HIO in HFD-induced NAFLD Metformin upregulates FPN expression by reducing lysosomal ubiquitination degradation Summary Metformin prevents progression of non-alcoholic fatty liver disease (NAFLD). However, the potential mechanism is not entirely understood. Ferroptosis, a recently recognized nonapoptotic form of regulated cell death, has been reported to be involved in the pathogenesis of NAFLD. Here, we investigated the effects of metformin on ferroptosis and its potential mechanism in NAFLD. We found that metformin prevented the progression of NAFLD, and alleviated hepatic iron overload (HIO), ferroptosis and upregulated ferroportin (FPN) expression in vivo and in vitro. Mechanically, metformin reduced the lysosomal degradation pathway of FPN through activation AMPK, thus upregulated the expression of FPN protein, alleviated HIO and ferroptosis, and prevented progression of NAFLD. These findings discover a mechanism of metformin, suggesting that targeting FPN may have the therapeutic potential for treating NAFLD and related disorders

Multi-target siRNA based on DNMT3A/B homologous conserved region influences cell cycle and apoptosis of human prostate cancer cell line TSU-PR1

Abnormal genome hypermethylation participates in the tumorigenesis and development of prostate cancer. Prostate cancer cells highly express DNA methyltransferase 3 (DMNT3) family genes, essential for maintaining genome methylation. In the present study, multi-target siRNA, based on the homologous region of the DNMT3 family, was designed for the in vitro investigation of its effects on the proliferation, migration, and invasion of TSU-PR1 prostate cancer cells. The consequential cell-cycle derangement, through DNMT3A/B or only DNMT3B silencing, was partially efficient, without affecting apoptosis. DNMT3A silencing had absolutely no effect on changing TSU-PR1 cell biological behavior. Hence, DNMT3B alone apparently plays a key role in maintaining the unfavorable behavior of prostate-cancer cells, thereby implying its potential significance as a promising therapeutic target, with DNMT3A simply in the role of helper

Hyaluronan Regulates Cell Behavior: A Potential Niche Matrix for Stem Cells

Hyaluronan is a linear glycosaminoglycan that has received special attention in the last few decades due to its extraordinary physiological functions. This highly viscous polysaccharide is not only a lubricator, but also a significant regulator of cellular behaviors during embryogenesis, morphogenesis, migration, proliferation, and drug resistance in many cell types, including stem cells. Most hyaluronan functions require binding to its cellular receptors CD44, LYVE-1, HARE, layilin, and RHAMM. After binding, proteins are recruited and messages are sent to alter cellular activities. When low concentrations of hyaluronan are applied to stem cells, the proliferative activity is enhanced. However, at high concentrations, stem cells acquire a dormant state and induce a multidrug resistance phenotype. Due to the influence of hyaluronan on cells and tissue morphogenesis, with regards to cardiogenesis, chondrogenesis, osteogenesis, and neurogenesis, it is now been utilized as a biomaterial for tissue regeneration. This paper summarizes the most important and recent findings regarding the regulation of hyaluronan in cells

Constant Light Exposure Alters Gut Microbiota and Promotes the Progression of Steatohepatitis in High Fat Diet Rats

Background: Non-alcoholic fatty liver disease (NAFLD) poses a significant health concern worldwide. With the progression of urbanization, light pollution may be a previously unrecognized risk factor for NAFLD/NASH development. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. Interestingly, recent studies indicate the gut microbiota affects NAFLD/NASH development. Therefore, the present study explored effects of constant light exposure on NAFLD and its related microbiotic mechanisms. Material and method: Twenty-eight SD male rats were divided into four groups (n=7 each): rats fed a normal chow diet, and exposed to standard light-dark cycle (ND-LD); rats fed a normal chow diet, and exposed to constant light (ND-LL); rats fed a high fat diet, and exposed to standard light-dark cycle (HFD-LD); and rats on a high fat diet, and exposed to constant light (HFD-LL). Body weight, hepatic pathophysiology, gut microbiota, and short/medium chain fatty acids in colon contents, serum lipopolysaccharide (LPS) and liver LPS-binding protein (LBP) mRNA expression were documented post intervention and compared among groups. Result: In normal chow fed groups, rats exposed to constant light displayed glucose abnormalities and dyslipidemia. In HFD-fed rats, constant light exposure exacerbated glucose abnormalities, insulin resistance, inflammation and liver steatohepatitis. Constant light exposure altered composition of gut microbiota in both normal chow and HFD fed rats. Compared with HFD-LD group, HFD-LL rats displayed less Butyricicoccus, Clostridium and Turicibacter, butyrate levels in colon contents, decreased colon expression of occludin-1 and zonula occluden‐1 (ZO-1) , and increased serum LPS and liver LBP mRNA expression. Conclusion: Constant light exposure impacts gut microbiota and its metabolic products, impairs gut barrier function and gut-liver axis, promotes NAFLD/NASH progression in HFD rats