Epigenetic programming mediates abnormal gut microbiota and disease susceptibility in offspring with prenatal dexamethasone exposure.

Prenatal dexamethasone exposure (PDE) can lead to increased susceptibility to various diseases in adult offspring, but its effect on gut microbiota composition and the relationship with disease susceptibility remains unclear. In this study, we find sex-differential changes in the gut microbiota of 6-month-old infants with prenatal dexamethasone therapy (PDT) that persisted in female infants up to 2.5 years of age with altered bile acid metabolism. PDE female offspring rats show abnormal colonization and composition of gut microbiota and increased susceptibility to cholestatic liver injury. The aberrant gut microbiota colonization in the PDE offspring can be attributed to the inhibited Muc2 expression caused by decreased CDX2 expression before and after birth. Integrating animal and cell experiments, we further confirm that dexamethasone could inhibit Muc2 expression by activating GR/HDAC11 signaling and regulating CDX2 epigenetic modification. This study interprets abnormal gut microbiota and disease susceptibility in PDT offspring from intrauterine intestinal dysplasia.

Protective effects of catalpol on cardio-cerebrovascular diseases: A comprehensive review.

Catalpol, an iridoid glucoside isolated from Rehmannia glutinosa, has gained attention due to its potential use in treating cardio-cerebrovascular diseases (CVDs). This extensive review delves into recent studies on catalpol's protective properties in relation to various CVDs, such as atherosclerosis, myocardial ischemia, infarction, cardiac hypertrophy, and heart failure. The review also explores the compound's anti-oxidant, anti-inflammatory, and anti-apoptotic characteristics, emphasizing the role of vital signaling pathways, including PGC-1α/TERT, PI3K/Akt, AMPK, Nrf2/HO-1, estrogen receptor (ER), Nox4/NF-κB, and GRP78/PERK. The article discusses emerging findings on catalpol's ability to alleviate diabetic cardiovascular complications, thrombosis, and other cardiovascular-related conditions. Although clinical studies specifically addressing catalpol's impact on CVDs are scarce, the compound's established safety and well-tolerated nature suggest that it could be a valuable treatment alternative for CVD patients. Further investigation into catalpol and related iridoid derivatives may unveil new opportunities for devising natural and efficacious CVD therapies.

Prenatal dexamethasone exposure induces nonalcoholic fatty liver disease in male rat offspring via the miR-122/YY1/ACE2-MAS1 pathway.

Epidemiological studies have shown that nonalcoholic fatty liver disease (NAFLD) has an intrauterine developmental origin. We aimed to demonstrate that NAFLD is caused by prenatal dexamethasone exposure (PDE) in adult male rat offspring and to investigate the intrauterine programming mechanism. Liver samples were obtained on gestational day (GD) 21 and postnatal week (PW) 28. The effects and epigenetic mechanism of dexamethasone were studied with bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and other cell models. In the PDE group, lipid accumulation increased, triglyceride synthesis-related gene expression increased, and oxidation-related gene expression decreased in livers of adult male rat offspring. In utero, hepatic triglyceride synthesis increased and oxidative function decreased in PDE fetal male rats. Moreover, low hepatic miR-122 expression, high Yin Yang-1 (YY1) expression and angiotensin-converting enzyme 2 (ACE2)-Mas receptor (MAS1) signaling pathway inhibition were observed before and after birth. At the cellular level, dexamethasone (100-2500 nM) elevated the intracellular triglyceride content, increased triglyceride synthesis-related gene expression and decreased oxidation-related gene expression. Dexamethasone treatment also decreased miR-122 expression, increased YY1 expression and inhibited the ACE2-MAS1 signaling pathway. Interference or overexpression of glucocorticoid receptor (GR), miR-122, YY1 and ACE2 could reverse the changes in downstream gene expression. In summary, PDE could induce NAFLD in adult male rat offspring. The programming mechanism included inhibition of miR-122 expression after GR activation, and dexamethasone increased hepatocyte YY1 expression; these effects resulted in ACE2-MAS1 signaling pathway inhibition, which led to increased hepatic triglyceride synthesis and decreased oxidative function. The increased triglyceride synthesis and decreased oxidative function of hepatocytes caused by low miR-122 expression due to dexamethasone could continue postnatally, eventually leading to NAFLD in adult rat offspring.

Involvement of organic cation transporter 2 in the metformin-associated increased lactate levels caused by contrast-induced nephropathy.

The application of iodinated contrast medium has become a risk factor for metformin-associated lactic acidosis (MALA), which leads to the accumulation of metformin in vivo is one of the principal reasons for MALA. However, the molecular mechanism of the adverse event is not yet clear. In this study, iohexol injection was used as a model drug. The contrast agent acute kidney injury rat model, in vivo rat pharmacokinetic study, kidney slices and HK-2 cells were performed to elucidate the pharmacokinetic molecular mechanism of accumulation of metformin caused by contrast-induced nephropathy (CIN). Plasma exposure of metformin was increased significantly in the CIN group compared with that in the normal and control groups. The AUC of metformin was from 2791 ±â€¯382 µg min mL-1 to 4784 ±â€¯767 µg min mL-1. The cumulative urinary excretion of metformin was also reduced in the CIN group. The uptake of metformin decreased in kidney slices in the CIN group. Compared with the normal and control groups, the blood lactate concentration was increased after intravenous administration of metformin in the CIN group followed a similar trend to the plasma concentrations of metformin. After treatment with contrast medium, the expression of OCT2 was reduced in rat kidney and HK-2 cells. These findings highlight that OCT2 deficiency was associated with increased lactate levels during metformin treatment caused by CIN.

The anti-tumor effects of the recombinant toxin protein rLj-RGD3 from Lampetra japonica on pancreatic carcinoma Panc-1 cells in nude mice.

Recombinant Lampetra japonica RGD peptide (rLj-RGD3) is a soluble toxin protein with three RGD (Arg-Gly-Asp) motifs and a molecular weight of 13.5kDa. The aim of this study was to investigate the effects and mechanisms of rLj-RGD3 on tumor growth and survival in pancreatic carcinoma Panc-1 cell-bearing mice. A Panc-1 human pancreatic carcinoma-bearing nude mouse model was successfully generated, and the animals were treated with different doses of rLj-RGD3 for 3 weeks. The volume and weight of the subcutaneous tumors, the survival of the nude mice, histopathological changes, the intratumoral MVD, the number of apoptotic Panc-1 cells, and apoptosis-related proteins and gene expressions were determined. rLj-RGD3 significantly decreased the tumor volumes and weights, and the maximum tumor volume and weight IR values were 53.2% (p<0.001) and 55.9% (p<0.001), respectively. The life expectancy of Panc-1-bearing nude mice treated with rLj-RGD3 was increased by 56.3% (p<0.001). Meanwhile, rLj-RGD3 promoted the expression of Bax, caspase-3, and caspase-9 and inhibited Bcl-2 and VEGF expression. In addition, rLj-RGD3 did not change FAK, PI3K and Akt expression, but p-FAK, p-PI3K and p-Akt, levels were down-regulated. These results show that rLj-RGD3 induced potent anti-tumor activity in vivo and suppressed the growth of transplanted Panc-1 cells in a nude mouse model, implying that rLj-RGD3 may serve as a potent clinical therapeutic agent for human pancreatic carcinoma.