Human gestational diabetes mellitus-derived exosomes impair glucose homeostasis in pregnant mice and stimulate functional maturation of offspring-islets.

AIMS: Pancreatic islets undergo critical development and functional maturation during the perinatal period when they are highly sensitive to microenvironment. We aim to determine the effects and mechanisms of gestational diabetes mellitus (GDM) hypermetabolic stress on glucose homeostasis in pregnant mice and functional maturation of the islets of their offspring. MAIN METHODS: Exosomes were extracted from the umbilical vein blood of individuals with or without GDM for administration to pregnant mice. The blood glucose, serum insulin, glycosylated hemoglobin, and lipopolysaccharide levels were measured in pregnant mice. The expression and localization of insulin, glucagon, PC1/3, PDX1, and p-S6 in the islets of neonatal rats were continuously monitored using immunofluorescence to evaluate their functional status. Primary islet cells were cultured and treated with GDM exosomes and exendin to determine the expression of GLP-1R, AKT, p-AKT, and p-S6 via western blotting. KEY FINDINGS: GDM exosomes induced remarkable oral glucose intolerance, hyperinsulinemia, and metabolic inflammation in pregnant mice. The islets of GDM offspring exhibited high insulin, glucagon, PC1/3, PDX1, and p-S6 expression at and after birth, and activation of the local GLP-1/GLP-1R axis. The functional maturation of normal-offspring islets did not commence until after birth, while it was activated prior to birth in GDM offspring, seriously disrupting the whole process. GDM exosomes activated the GLP-1/GLP-1R axis between α and ß cells, and stimulated functional maturation of ß cells via the Akt-mTORC1-pS6 pathway. SIGNIFICANCE: These findings provide preliminary insights into the mechanisms underlying the high incidence of diabetes in the offspring of mothers with GDM.

Computational investigation of sensing properties of Ca-doped zinc oxide nanotube toward formaldehyde.

Following an experimental work, we employed density functionals B3LYP, B97D, CAM-B3LYP, BMK, and M06-HF to study the impact of Ca-doping on a ZnO nanotube (ZnONT) sensing performance to the formaldehyde gas. The interaction of the pristine ZnONT with the formaldehyde gas was found to be weak, and the sensing response is 0.7 based on the B3LYP results. Doping a Ca atom into the ZnONT changes the adsorption energy of formaldehyde from - 4.2 to - 36.1 kcal/mol. Energy decomposing analysis indicated that the nature of interaction is partially electrostatic and covalent. The sensing response significantly rises to 4.2 by Ca-doping (experimental value ~ 5.28). A short recovery time of 5.6 s is found for the formaldehyde gas desorption from the Ca@ZnONT surface at 300 °C. Both theory and experiment suggest that Ca-doped ZnONT may be a formaldehyde gas sensor with a short recovery time.

Piperine protects against pancreatic ß-cell dysfunction by alleviating macrophage inflammation in obese mice.

AIMS: Piperine, the major pharmacological ingredient of pepper, can delay the procession of "obesity to diabetes". However, the underlying mechanism remains unclear. This study aims to investigate whether piperine protects against ß-cell dysfunction by inhibiting macrophage accumulation and M1-like polarization. MATERIALS AND METHODS: Pre-diabetic model was induced by feeding 60% high-fat diet (HFD) in C57BL/6C mice, piperine (15 or 30 mg/kg/day) and rosiglitazone (4 mg/kg/day) were given orally for 8 weeks. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), fasting blood glucose (FBG), total cholesterol (TC) and triglyceride (TG) were used to assay the disorder of glycolipid metabolism. Serum levels of cytokines and insulin were measured by Elisa. Hyperglycemic clamp assay was carried out to evaluate ß-cell function. RT-PCR, immunofluorescence and western blot were used to detect the expression of biomarkers associated with macrophage polarization and ß-cell dedifferentiation. KEY FINDINGS: Piperine protected against ß-cell dysfunction, indicated by the improvement of hyperinsulinemia, OGTT and increased glucose infusion rate (GIR). Piperine dramatically reduced the serum levels of lipopolysaccharide (LPS), interleukin-1ß (IL-1ß) and Galectin-3 (Gal-3), suppressed the expression of M1-like cytokines (CD11c, IL-1ß and Gal-3) in epididymal adipose tissues and islets. Furthermore, piperine partially reversed the down-regulation of Pdx1, inhibited the up-regulation of ALDH1A3 in ß-cell, and these effects were closely related to the mTOR/S6/4E-BP1 signal pathway. SIGNIFICANCE: Piperine markedly ameliorates the dedifferentiation and dysfunction of ß-cell by inhibiting the accumulation and M1-like polarization of macrophages in visceral adipose tissues and islets.

Structural and Biochemical Analysis of the Citrate-Responsive Mechanism of the Regulatory Domain of Catabolite Control Protein E from Staphylococcus aureus.

Catabolite control protein E (CcpE) is a LysR-type transcriptional regulator that positively regulates the transcription of the first two enzymes of the TCA cycle, namely, citZ and citB, by sensing accumulated intracellular citrate. CcpE comprises an N-terminal DNA-binding domain and a C-terminal regulatory domain (RD) and senses citrate with conserved arginine residues in the RD. Although the crystal structure of the apo SaCcpE-RD has been reported, the citrate-responsive and DNA-binding mechanisms by which CcpE regulates TCA activity remain unclear. Here, we report the crystal structure of the apo and citrate-bound SaCcpE-RDs. The SaCcpE-RD exhibits conformational changes between the two subdomains via hinge motion of the central ß4 and ß10 strands. The citrate molecule is located in a positively charged cavity between the two subdomains and interacts with the highly conserved Ser98, Leu100, Arg145, and Arg256 residues. Compared with that of the apo SaCcpE-RD, the distance between the two subdomains of the citrate-bound SaCcpE-RD is more than ∼3 Å due to the binding of the citrate molecule, and this form exhibits a closed structure. The SaCcpE-RD exhibits various citrate-binding-independent conformational changes at the contacting interface. The SaCcpE-RD prefers the dimeric state in solution, whereas the SaCcpE-FL prefers the tetrameric state. Our results provide insight into the molecular function of SaCcpE.

Crystal structure of the nicotinamidase/pyrazinamidase PncA from Bacillus subtilis.

The nicotinamidase/pyrazinamidase PncA is a member of a large family of hydrolase enzymes that catalyze the deamination of nicotinamide to nicotinic acid. PncA also functions as a pyrazinamidase in a wide variety of eubacteria and is an essential coenzyme in many cellular redox reactions in living systems. We report the crystal structure of substrate-free PncA from Bacillus subtilis (BsPncA) at 2.0 Šresolution to improve our understanding of the PncA family. The structure of BsPncA consists of an α/ß domain and a subdomain. The subdomain of BsPncA has a different conformation than that of PncA enzymes from other organisms. The B-factor analysis revealed a rigid structure of the α/ß domain, while the subdomain is highly flexible. Both dimers and tetramers were observed in BsPncA protein crystals, but only dimers were observed in solution. Our results provide useful information that will further enhance our understanding of the molecular functions of PncA family members.