Nitrooxidative Stress and Neuroinflammation Caused by Air Pollutants Are Associated with the Biological Markers of Neurodegenerative Diseases.

Millions of people around the world are exposed to air pollutants, such as particulate matter 2.5 (PM2.5) and ozone (O3). Such exposure usually does not exclude these two types of pollutants and their harmful effects could be additive or synergistic. O3 is a highly oxidizing gas that reacts with the cellular environment just as PM2.5, triggering nitrooxidative damage. Once nitrooxidative stress overcomes the endogenous antioxidant system, an acute neuroinflammatory process is generated, and once it becomes chronic, it favors the formation of neurodegenerative disease markers. The presence of these markers becomes potentially dangerous in people who have a genetic predisposition and are at a higher risk of developing neurodegenerative diseases such as Alzheimer's and Parkinson's. Our experimental approach for nitrooxidative damage and neuroinflammation caused by air pollutants has focused on the exposure of rats to O3 in an isolated chamber. The hippocampus is the most studied brain structure because of its neuronal connectivity network with the olfactory epithelium, its weak antioxidant defense, and its fundamental roll in cognitive processes. However, other brain structures may exhibit a different degree of damage upon exposure to O3 and PM2.5, making their involvement an important factor in developing other CNS diseases. The age spectrum for augmented sensibility to air pollutants seems to mostly affect the pre-postnatal (autism spectrum) period and the elderly (neurodegenerative). Thus, a new approach could be the estimation of the damage caused by PM2.5 and O3 through a controlled exposure paradigm to determine the extent of damage caused by both pollutants.

Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer.

Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the "cancer hallmarks" of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.

Effect of Lupinus rotundiflorus gamma conglutin treatment on JNK1 gene expression and protein activation in a rat model of type 2 diabetes.

CONTEXT: Gamma conglutin (Cγ) from lupine species represents a potential complementary treatment for type 2 diabetes mellitus (T2DM) because of its hypoglycaemic effect. However, its underlying mechanism of action is not fully known. OBJECTIVE: To evaluate whether Cγ from Lupinus rotundiflorus M. E. Jones (Fabaceae) modulates c-Jun N-terminal kinase 1 (JNK1) expression and activation in a T2DM rat model. MATERIALS AND METHODS: Gamma conglutin isolated from L. rotundiflorus seeds was characterized by SDS-PAGE. Fifteen Wistar rats with streptozotocin-induced T2DM (HG) were randomized into three groups (n = 5): vehicle administration (HG-Ctrl), oral treatment with Cγ (120 mg/kg/day) (HG-Lr) for one week, and treatment with metformin (300 mg/kg/day) (HG-Met); a healthy group (Ctrl, n = 5) was included as control. The levels of glucose and biomarkers of renal and hepatic function were measured pre- and post-treatment. Hepatic Jnk1 expression and phosphorylation of JNK1 were evaluated by qRT-PCR and western blot, respectively. RESULTS: Oral treatment with either Cγ or metformin reduced serum glucose level to 86.30 and 74.80 mg/dL, respectively (p ˂ 0.05), from the basal levels. Jnk1 expression was 0.65- and 0.54-fold lower (p ˂ 0.05) in the HG-Lr and HG-Met groups, respectively, than in HG-Ctrl. Treatment with Cγ decreased JNK1 phosphorylation. However, Cγ did not change the levels of kidney and liver biomarkers. DISCUSSION AND CONCLUSIONS: Treatment with Cγ from L. rotundiflorus inhibited Jnk1 expression, in vivo, suggesting JNK1 as a potential therapeutic target in diabetes and revealing one mechanism underlying the hypoglycaemic effect of lupine Cγ. Nevertheless, further studies are required.

Association of the PNPLA2, SCD1 and Leptin Expression with Fat Distribution in Liver and Adipose Tissue From Obese Subjects.

The expansion of adipose tissue is regulated by insulin and leptin through sterol regulatory element-binding protein-1c (SREBP-1c), up-regulating lipogenesis in tissues by Stearoylcoenzyme A desaturase 1 (SCD1) enzyme, while adipose triglyceride lipase (ATGL) enzyme is key in lipolysis. The research objective was to evaluate the expression of Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1), SCD1, Patatin Like Phospholipase Domain Containing 2 (PNPLA2), and leptin (LEP) genes in hepatic-adipose tissue, and related them with the increment and distribution of fat depots of individuals without insulin resistance. Thirty-eight subjects undergoing elective cholecystectomy with liver and adipose tissue biopsies (subcutaneous-omental) are included. Tissue gene expression was assessed by qPCR and biochemical parameters determined. Individuals are classified according to the body mass index, classified as lean (control group, n=12), overweight (n=11) and obesity (n=15). Abdominal adiposity was determined by anthropometric and histopathological study of the liver. Increased SCD1 expression in omental adipose tissue (p=0.005) and PNPLA2 in liver (p=0.01) were found in the obesity group. PNPLA2 decreased expression in subcutaneous adipose tissue was significant in individuals with abdominal adiposity (p=0.017). Anthropometric parameters positively correlated with liver PNPLA2 and the expression of liver PNPLA2 with serum leptin. SCD1 increased levels may represent lipid storage activity in omental adipose tissue. Liver PNPLA2 increased expression could function as a primary compensatory event of visceral fat deposits associated to the leptin hormone related to the increase of adipose tissue.

Expression of the receptor of advanced glycation end-products (RAGE) and membranal location in peripheral blood mononuclear cells (PBMC) in obesity and insulin resistance.

OBJECTIVES: The present study aimed to evaluate the receptor of advanced glycation end-products (RAGE), NF-kB, NRF2 gene expression, and RAGE cell distribution in peripheral blood mononuclear cells (PBMC) in subjects with obesity and IR compared with healthy subjects. MATERIALS AND METHODS: The mRNA expression levels of RAGE, NF-kB, NRF2, and GAPDH were determined in PBMC by qPCR in 20 obese (OB), 17 obese with insulin resistance (OB-IR), and 20 healthy subjects (HS), matched by age and sex. RAGE protein expression and its localization were determined by Western Blot and immunocytochemistry (ICC) analysis, total soluble RAGE (sRAGE) and MCP-1 plasma levels by ELISA. RESULTS: RAGE, NF-kB, and NRF2 genes mRNA expression in PBMCs did not show variation between groups. RAGE protein was lower in OB and OB-IR groups; RAGE was located predominantly on the cell-surface in the OB-IR group compared to the HS group (22% vs 9.5%, P<0.001). OB-IR group showed lower sRAGE plasma levels, and correlated negatively with HOMA-IR, ALT parameters (r= -0.374, r= -0.429, respectively), and positively with NFE2L2 mRNA (r= 0.540) P<0.05. CONCLUSION: In this study, OB-IR subjects did not reflect significant differences in gene expression; however, correlations detected between sRAGE, biochemical parameters, and NRF2, besides the predominant RAGE distribution on the cell membrane in PBMC could be evidence of the early phase of the inflammatory cascade and the subsequent damage in specific tissues in subjects with OB-IR.

Asociación de los polimorfismos -319 C/T y +49 A/G del gen CTLA-4 en pacientes con infección por el virus de la hepatitis C / Association of -319 C/T and +49 A/G polymorphisms of CTLA-4gene in patients with hepatitis C virus infection

Introducción y objetivo: Cambios moleculares en el gen CTLA-4 pueden modificar la habilidad para controlar la proliferación de los linfocitos T, y promover la persistencia o eliminación del virus de la hepatitis C (VHC). Nuestro objetivo fue investigar la frecuencia y asociación de los polimorfismos −319 C/T y +49 A/G del gen CTLA-4, en pacientes con infección por VHC. Métodos: Los polimorfismos del gen CTLA-4 (−319 C/T en la región promotora y +49 A/G en el exón 1) fueron analizados por T-ARMS-PCR en 420 individuos, incluidos 205 pacientes con infección crónica por VHC y 215 sujetos sanos. Resultados: Se encontró una asociación positiva del alelo +49G con la infección por VHC (OR 1,48; IC 95% 1,09-2,02; p=0,02), y con el sexo masculino (OR 1,80; IC 95% 1,16-2,79; p=0,02), ambos en enfermedad crónica (sin cirrosis). Se observaron diferencias significativas en la distribución de los genotipos del polimorfismo +49 A/G, entre los pacientes con infección por VHC y los sujetos sanos en un modelo genético dominante (GG+GA frente a AA; OR1,57; IC 95% 1,05-2,33; p=0,04). No se observaron diferencias en las frecuencias del polimorfismo −319 C/T, entre pacientes con VHC y sujetos sanos. El haplotipo -319C/+49G confiere susceptibilidad a la infección por el genotipo 3 del VHC (OR 10,68; IC 95% 1,17-96,97; p=0,04). Conclusiones: El alelo +49G confiere susceptibilidad a infección por VHC y a infección en el sexo masculino, ambos en enfermedad crónica. Además, el haplotipo -319C/+49G confiere susceptibilidad a la infección por el genotipo 3 del VHC. Nuestros resultados evidencian una implicación importante de los polimorfismos −319 C/T y +49 A/G en la infección por VHC

Introduction and objective: Molecular changes in the CTLA-4 gene can modify the ability to control T lymphocyte proliferation, and promote the persistence or elimination of the hepatitis C virus (HCV). We aimed to investigate the frequency and association of -319 C/T and +49 A/G polymorphism in the CTLA-4 gene in patients infected with HCV. Methods: The CTLA-4 gene polymorphisms (-319 C/T in the promoter region, and +49 A/G in exon 1) were analysed by T-ARMS-PCR in 420 individuals, including 205 chronic HCV infected patients and 215 healthy subjects. Results: We found a positive association of +49G allele with HCV infection (OR 1.48; 95% CI 1.09-2.02; p=.02), and with males (OR 1.80; 95% CI 1.16-2.79; p=.02), both in chronic disease (without cirrhosis). Also, significant differences in +49 A/G genotypes distribution between HCV infected patients and healthy subjects were shown in a dominant genetic model (GG+GA versus AA; OR 1.57; 95% CI 1.05-2.33; p=.04). No significant differences were observed in the -319 C/T polymorphism between HCV infected patients and healthy subjects. Moreover, -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection (OR 10.68; 95% CI 1.17-96.97; p=.04). Conclusions: The +49G allele confers susceptibility to HCV infection and with male gender, both in chronic disease. In addition, the −319C/+49G haplotype confers susceptibility to HCV genotype 3 infection. Our results support an important role of the −319 C/T and +49 A/G polymorphisms in HCV infection

Association of -319 C/T and +49 A/G polymorphisms of CTLA-4 gene in patients with hepatitis C virus infection. / Asociación de los polimorfismos −319 C/T y +49 A/G del gen CTLA-4 en pacientes con infección por el virus de la hepatitis C.

INTRODUCTION AND OBJECTIVE: Molecular changes in the CTLA-4 gene can modify the ability to control T lymphocyte proliferation, and promote the persistence or elimination of the hepatitis C virus (HCV). We aimed to investigate the frequency and association of -319 C/T and +49 A/G polymorphism in the CTLA-4 gene in patients infected with HCV. METHODS: The CTLA-4 gene polymorphisms (-319 C/T in the promoter region, and +49 A/G in exon 1) were analysed by T-ARMS-PCR in 420 individuals, including 205 chronic HCV infected patients and 215 healthy subjects. RESULTS: We found a positive association of +49G allele with HCV infection (OR 1.48; 95% CI 1.09-2.02; p=.02), and with males (OR 1.80; 95% CI 1.16-2.79; p=.02), both in chronic disease (without cirrhosis). Also, significant differences in +49 A/G genotypes distribution between HCV infected patients and healthy subjects were shown in a dominant genetic model (GG+GA versus AA; OR 1.57; 95% CI 1.05-2.33; p=.04). No significant differences were observed in the -319 C/T polymorphism between HCV infected patients and healthy subjects. Moreover, -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection (OR 10.68; 95% CI 1.17-96.97; p=.04). CONCLUSIONS: The +49G allele confers susceptibility to HCV infection and with male gender, both in chronic disease. In addition, the -319C/+49G haplotype confers susceptibility to HCV genotype 3 infection. Our results support an important role of the -319 C/T and +49 A/G polymorphisms in HCV infection.

Fibrogenic actions of acetaldehyde are ß-catenin dependent but Wingless independent: a critical role of nucleoredoxin and reactive oxygen species in human hepatic stellate cells.

We investigated whether the fibrogenic actions of acetaldehyde, the immediate oxidation product of ethanol, are mediated via Wingless (WNT) and/or ß-catenin pathways in human hepatic stellate cells (HSC). First, we show that both ß-catenin small inhibitory RNA and a dominant negative-MYC expression vector markedly down-regulated the expressions of fibrogenic genes in freshly isolated HSC. We further show that acetaldehyde up-regulated platelet-derived growth factor receptor beta mRNA and protein expressions ranging from 4.0- to 7.2-fold (P<0.001). Acetaldehyde induced MYC and collagen type-1 alpha-2 mRNA and protein expressions were WNT independent because DKK1, an antagonist of the canonical WNT/ß-catenin pathway, completely failed to block these inductions. Acetaldehyde increased phospho-glycogen synthase kinase-3 beta (GSK3B) protein by 31% (P<0.01), whereas phospho-ß-catenin protein decreased by 50% (P ≤ 0.01). Significantly, in contrast to 43% (P<0.01) inhibition of ß-catenin nuclear translocation in nucleoredoxin (NXN)-overexpressed HSC, acetaldehyde profoundly stimulated ß-catenin nuclear translocation by 51%, (P<0.01). Acetaldehyde also increased the cellular reactive oxygen species level 2-fold (P<0.001) with a concomitant 2-fold (P<0.001) increase in 4-hydroxynonenal adducts. Conversely, there was a 44% decrease (P<0.001) in glutathione levels with a concomitant 76% (P<0.001) decrease in the level of NXN/ disheveled (DVL) complex. Based on these findings, we conclude that actions of acetaldehyde are mediated by a mechanism that inactivates NXN by releasing DVL, leading to the inactivation of GSK3B, and thereby blocks ß-catenin phosphorylation and degradation. Thus, the stabilized ß-catenin translocates to the nucleus where it up-regulates the fibrogenic pathway genes. This novel mechanism of action of acetaldehyde has the potential for therapeutic interventions in liver fibrosis induced by alcohol.