LAT1-dependent placental methionine uptake is a key player in fetal programming of metabolic disease.

The Developmental Origins of Health and Disease hypothesis sustains that exposure to different stressors during prenatal development prepares the offspring for the challenges to be encountered after birth. We studied the gestational period as a particularly vulnerable window where different stressors can have strong implications for fetal programming of the offspring's life-long metabolic status via alterations of specific placentally expressed nutrient transporters. To study this mechanism, we used a murine prenatal stress model, human preeclampsia, early miscarriage, and healthy placental tissue samples, in addition to in vitro models of placental cells. In stressed mice, placental overexpression of L-type amino acid transporter 1 (Lat1) and subsequent global placental DNA hypermethylation was accompanied by fetal and adult hypothalamic dysregulation in global DNA methylation and gene expression as well as long-term metabolic abnormalities exclusively in female offspring. In human preeclampsia, early miscarriage, and under hypoxic conditions, placental LAT1 was significantly upregulated, leading to increased methionine uptake and global DNA hypermethylation. Remarkably, subgroups of healthy term placentas with high expression of stress-related genes presented increased levels of placental LAT1 mRNA and protein, DNA and RNA hypermethylation, increased methionine uptake capacity, one-carbon metabolic pathway disruption, higher methionine concentration in the placenta and transport to the fetus specifically in females. Since LAT1 mediates the intracellular accumulation of methionine, global DNA methylation, and one-carbon metabolism in the placenta, our findings hint at a major sex-specific global response to a variety of prenatal stressors affecting placental function, epigenetic programming, and life-long metabolic disease and provide a much-needed insight into early-life factors predisposing females/women to metabolic disorders.

Vitamin C supplementation ameliorates liver function profile and antiviral treatment response in Hepatitis C patients.

An imbalance between oxidative stress and antioxidative defence mediates a variety of diseases pathogenesis. The present study aims to assess the possible outcome of supplementation of oral vitamin-C (VC), an antioxidant, in Viral Hepatitis C (HCV) treatment as an adjuvant therapy. 200 HCV-patients were selected, 100 were given Vitamin-C (1000 mg/day) along with anti HCV treatment (sofosbuvir plus daclatasvir) while the other 100 took only anti-HCV treatment for 4weeks. The serum ascorbic acid (Vitamin-C) levels and functions of the liver were tested before and after the VC supplementation. HCV patients with relatively low serum ascorbic acid showed significant improvement after the intake of vitamin C. After 4 weeks of treatment, AST, ALP, albumin, and total, direct and indirect bilirubin were improved significantly in the VC group; whereas only ALT and indirect bilirubin were improved in both groups when associated with the control subjects. Comparing the two treatment groups at 4weeks; more effective and significant improvement was observed in ALT (p<0.01), AST (p<0.001), direct (p<0.01) and indirect bilirubin (p<0.001), total proteins (p<0.001) and albumin (p<0.05) in patients with VC supplementation on anti-viral treatment compared to only anti-viral treatment group. Thus, VC supplementation improves the antiviral therapy outcome by bestowing a beneficial effect in minimizing liver damage in HCV cases.

Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage.

Early miscarriage (EMC) is a devastating obstetrical complication. ATP-binding cassette (ABC) transporters mediate cholesterol transfer across the placenta and enhance cell survival by effluxing substrates from target cells in the presence of stressors. Recent evidence reports an intricate interplay between autophagy and ABC transporters. We hypothesized that dysregulated autophagy and oxidative stress (OS) in the placenta leads to abnormal expression of membrane transporters contributing to poor pregnancy survival in EMC. We determined mRNA and protein expression of autophagy genes (Beclin-1/Bcl-2/LC3I/LC3II/p62) and ABC transporters (ABCA1/ABCG1/ABCG2) in placentae from EMC patients (n = 20), term controls (n = 19), first trimester (n = 6), and term controls (n = 5) controls. Oxidative/antioxidant status and biomarkers of oxidative damage were evaluated in maternal serum and placentae from EMC and healthy controls. In EMC, placental expression of LC3II/LC3I as well as of the key autophagy regulatory proteins Beclin-1 and Bcl-2 were reduced, whereas p62 was increased. Both in the serum and placentae of EMC patients, total OS was elevated reflected by increased oxidative damage markers (8-OHdG/malondialdehyde/carbonyl formation) accompanied by diminished levels of total antioxidant status, catalase, and total glutathione. Furthermore, we found reduced ABCG1 and increased ABCG2 expression. These findings suggest that a decreased autophagy status triggers Bcl-2-dependent OS leading to macromolecule damage in EMC placentae. The decreased expression of ABCG1 contributes to reduced cholesterol export to the growing fetus. Increasing ABCG2 expression could represent a protective feedback mechanism under inhibited autophagy conditions. In conclusion, dysregulated autophagy combined with increased oxidative toxicity and aberrant expression of placental ABC transporters affects materno-fetal health in EMC.

Variation of Urine Parameters among Diabetic Patients: A Cross-Sectional Study.

BACKGROUND: Diabetic kidney disease is a common and severe microvascular complication of diabetes mellitus (DM). There are limited data regarding alteration of urine parameters other than proteinuria among DM patients. METHODS: Institution based cross-sectional study was conducted from February to May 2017 to assess alteration of urine parameters among DM patients at the University of Gondar Hospital, Northwest Ethiopia. A Systematic random sampling technique was used to recruit adult (≥18 years) diabetic participants. Data were collected after ethical requirements had been fulfilled. The degree of association between variables was evaluated through bivariable and multivariable logistic regression models. RESULTS: The majority (69.4%) of the study participants were type 2 DM patients. The prevalence of altered urine chemical parameters was 11.3% proteinuria, 4.5% ketonuria, 13.6% hematuria, 53.8% glucosuria, 24.9% leukocyturia and 1.7% positive for nitrite. Diastolic blood pressure and poor glycemic control were significantly associated with proteinuria. Male participants were 2.4 times more likely to have leukocyturia than female participants. The prevalence of abnormally increased microscopic findings was red blood cells 3.1%, white blood cells 12.5%, epithelial cells 27.5%, yeast cells 1.7%, bacteria 17.8%, casts 3.7% and crystals 29.2%. CONCLUSIONS: The prevalence of altered urine parameters among DM patients is found to be considerable. These increased prevalences of altered urine parameters are potential indicators for diabetic kidney disease.

Variation of urine parameters among diabetic patients: a cross-sectional study

BACKGROUND: Diabetic kidney disease is a common and severe microvascular complication of diabetes mellitus (DM). There are limited data regarding alteration of urine parameters other than proteinuria among DM patients. METHODS: Institution based cross-sectional study was conducted from February to May 2017 to assess alteration of urine parameters among DM patients at the University of Gondar Hospital, Northwest Ethiopia. A Systematic random sampling technique was used to recruit adult (≥18 years) diabetic participants. Data were collected after ethical requirements had been fulfilled. The degree of association between variables was evaluated through bivariable and multivariable logistic regression models. RESULTS: The majority (69.4%) of the study participants were type 2 DM patients. The prevalence of altered urine chemical parameters was 11.3% proteinuria, 4.5% ketonuria, 13.6% hematuria, 53.8% glucosuria, 24.9% leukocyturia and 1.7% positive for nitrite. Diastolic blood pressure and poor glycemic control were significantly associated with proteinuria. Male participants were 2.4 times more likely to have leukocyturia than female participants. The prevalence of abnormally increased microscopic findings was red blood cells 3.1%, white blood cells 12.5%, epithelial cells 27.5%, yeast cells 1.7%, bacteria 17.8%, casts 3.7% and crystals 29.2%. CONCLUSIONS: The prevalence of altered urine parameters among DM patients is found to be considerable. These increased prevalences of altered urine parameters are potential indicators for diabetic kidney disease