Association Study between Antioxidant Nutrient Intake and Low Bone Mineral Density with Oxidative Stress-Single Nucleotide Variants: GPX1 (rs1050450 and rs17650792), SOD2 (rs4880) and CAT (rs769217) in Mexican Women.

Oxidative stress is essential in developing multiple bone metabolism diseases, including osteoporosis. Single-nucleotide variants (SNVs) have been associated with oxidative stress, promoting an imbalance between the production of reactive oxygen species and the ability to neutralize them, and it has been reported that antioxidant nutrient intake can influence bone mineral density (BMD). This work reports the association between oxidative stress-related SNVs (GPX1-rs1050450, rs17650792, SOD2-rs4880, and CAT-rs769217), BMD, and antioxidant nutrient intake. The study included 1269 Mexican women from the Health Workers Cohort Study. Genotyping was performed using predesigned TaqMan assays. Dietary data were collected using a 116-item semi-quantitative food frequency questionnaire. A dietary antioxidant quality score (DAQS) was used to estimate antioxidant-nutrient intake. Association analysis was estimated via linear, logistic, or quantile regression models. The results showed an association of the rs1050450-A and rs17650792-A alleles with femoral neck BMD (p = 0.038 and p = 0.017, respectively) and the SNV rs4880-A allele with total hip BMD (p = 0.026) in respondents aged 45 years or older. In addition, antioxidant-nutrient intake was associated with the rs4880-GG genotype, being significant for fiber (p = 0.007), riboflavin (p = 0.005), vitamin B6 (p = 0.034), and vitamin D (p = 0.002). The study showed an association between oxidative stress-related SNVs, BMD, and antioxidant-nutrient intake in Mexican women. Therefore, treatments for low BMD could be developed based on antioxidant supplementation.

Effect of Hypoxia in the Transcriptomic Profile of Lung Fibroblasts from Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by exacerbated extracellular matrix deposition that disrupts oxygen exchange. Hypoxia and its transcription factors (HIF-1α and 2α) influence numerous circuits that could perpetuate fibrosis by increasing myofibroblasts differentiation and by promoting extracellular matrix accumulation. Therefore, this work aimed to elucidate the signature of hypoxia in the transcriptomic circuitry of IPF-derived fibroblasts. To determine this transcriptomic signature, a gene expression analysis with six lines of lung fibroblasts under normoxia or hypoxia was performed: three cell lines were derived from patients with IPF, and three were from healthy donors, a total of 36 replicates. We used the Clariom D platform, which allows us to evaluate a huge number of transcripts, to analyze the response to hypoxia in both controls and IPF. The control's response is greater by the number of genes and complexity. In the search for specific genes responsible for the IPF fibroblast phenotype, nineteen dysregulated genes were found in lung fibroblasts from IPF patients in hypoxia (nine upregulated and ten downregulated). In this sense, the signaling pathways revealed to be affected in the pulmonary fibroblasts of patients with IPF may represent an adaptation to chronic hypoxia.

Inhibition of AMP-activated protein kinase in respiratory syncytial virus infection activates lipid metabolism.

Respiratory syncytial virus (RSV) is most commonly associated with upper respiratory tract infections during childhood. The lipid composition of cells and lipogenic enzymes play an important role in RSV infection. There are controversial data about whether lipid biosynthesis regulators such as AMP-activated protein kinase (AMPK) are deregulated by RSV. Hence, we examined whether the activation state of AMPK is altered in RSV-infected HEp-2 cells. Our data show that RSV infection inhibits AMPK activity, favoring the activation of downstream lipogenic effectors and cellular lipid anabolism in HEp-2 cells.

Lysosomal dysfunction induced by changes in albumin's tertiary structure: Potential key factor in protein toxicity during diabetic nephropathy.

AIMS: Increased amounts of protein, in particular albumin within renal tubular cells (TBCs), induce the expression of inflammatory and fibrogenic mediators, which are adverse prognostic factors in tubulointerstitial fibrosis and diabetic nephropathy (DN). We sought to assess the participation of the thiol-linked tertiary structure of albumin in the mechanism of protein toxicity in a model of TBCs. MATERIALS AND METHODS: Cultured human renal proximal tubular cells, HK-2, were exposed to isolated albumin from patients with and without DN (Stages 0, 1 and 4). The magnitude of change of the albumin tertiary structure, cell viability (LDH leakage), apoptosis (Annexin V), transdifferentiation and reticulum endoplasmic stress (Western blot and flow cytometry) and lysosomal enzyme activity were assessed. KEY FINDINGS: We found that albumin from Stage 4 patients presented >50% higher thiol-dependent changes of tertiary structure compared to Stages 0 and 1. Cells incubated with Stage 4 albumin displayed 5 times less viability, accompanied by an increased number of apoptotic cells; evidence of profibrogenic markers E-cadherin and vimentin and higher expression of epithelial-to-mesenchymal transition markers α-SMA and E-cadherin and of endoplasmic reticulum stress protein GRP78 were likewise observed. Moreover, we found that cathepsin B activity in isolated lysosomes showed a significant inhibitory effect on albumin from patients in advanced stages of DN and on albumin that was intentionally modified. SIGNIFICANCE: Overall, this study showed that thiol-dependent changes in albumin's tertiary structure interfere with the lysosomal proteolysis of renal TBCs, inducing molecular changes associated with interstitial fibrosis and DN progression.

Is gestational diabetes mellitus in obese women predicted by oxidative damage in red blood cells?

Obesity in pregnant women has been associated with an increased risk of maternal complications, including gestational diabetes mellitus (GDM), a process that is related to oxidative stress (OS). To evaluate the biomarkers of OS in red blood cells (RBCs), we assigned 80 pregnant women to one of three groups: control (n = 28), overweight (n = 26) and obese (n = 26). Then, we measured in plasma, the levels of glucose, triacylglycerol (TAG), insulin, free fatty acids (FFAs), leptin and cytokines (e.g. interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-alpha]) and OS biomarkers, such as lipohydroperoxides (LHP), malondialdehyde (MDA) and protein carbonylation (PC) in RBCs. We found significant positive correlations between OS biomarkers, body mass index (BMI) and pregnancy progression. Seven (26.9%) obese women who were diagnosed with GDM at 24-28 weeks of pregnancy showed significantly increased concentrations of FFAs, insulin, leptin, TNF-alpha and biomarkers of OS measured at 12-13 weeks of gestation. We propose to quantify LHP, MDA and PC in membranes of erythrocytes as possible markers to diagnose GDM from weeks 12-14.