Systemic Inflammation but not Oxidative Stress Is Associated with Physical Performance in Moderate Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) patients manifest muscle dysfunction and impaired muscle oxidative capacity, which result in reduced exercise capacity and poor health status. The aim of this study was to compare the physical performance, systemic inflammation, and oxidative stress of patients with moderate COPD, and to associate physical performance with inflammatory and oxidative stress plasma markers. Twenty CONTROL (n = 10) and moderate COPD (n = 10) patients participated in this study. Systematic inflammation and oxidative stress plasma markers, maximal aerobic capacity (VO2peak), and maximal isometric strength (MVIC) of the knee extensor (KE) muscles were measured. VO2peak was 31.3% greater in CONTROL compared to COPD (P = 0.006). The MVIC strength of the KE was 43.9% greater in CONTROL compared to COPD (P = 0.002). Tumor necrosis factor-alpha (TNF-α) was 79.6% greater in COPD compared to CONTROL (P < 0.001). Glutathione peroxidase activity (GPx) activity was 27.5% lesser in COPD compared to CONTROL (P = 0.05). TNF-α concentration was correlated with KE MVC strength (R = -0.48; P = 0.045) and VO2peak (R = -0.58; P = 0.01). Meanwhile, malondialdehyde (MDA) and GPx activity were not associated with KE strength or VO2peak (P = 0.74 and P = 0.14, respectively). COPD patients showed lesser muscle strength and aerobic capacity than healthy control individuals. Furthermore, patients with COPD showed greater systemic inflammation and lesser antioxidant capacity than healthy counterparts. A moderate association was evident between levels of systemic inflammation and physical performance variables.

Brief research report pesticide occupational exposure leads to significant inflammatory changes in normal mammary breast tissue.

Studies have documented the high occurrence of several tumors, including female breast cancer, in populations occupationally exposed to pesticides worldwide. It is believed that in addition to direct DNA damage, other molecular alterations that indicate genomic instability are associated, such as epigenetic modifications and the production of inflammation mediators. The present study characterized the profile of inflammatory changes in the breast tissue of women without cancer occupationally exposed to pesticides. In samples of normal breast tissue collected during biopsy and evaluated as negative for cancer by a pathologist, oxidative stress levels were assessed as inflammatory markers through measurements of lipoperoxides and total antioxidant capacity of the sample (TRAP) by high-sensitivity chemiluminescence, as well as levels of nitric oxide (NOx) metabolites. The levels of inflammation-modulating transcription factors PPAR-γ (peroxisome proliferator-activated receptor gamma) and NF-κB (nuclear factor kappa B) were also quantified, in addition to the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12). The levels of lipoperoxides, TRAP, and NOx were significantly lower in the exposed group. On the other hand, PPAR-γ levels were increased in the breast tissue of exposed women, with no variation in NF-κB. There was also a rise of TNF-α in exposed women samples without significant variations in IL-12 levels. These findings suggest an inflammatory signature of the breast tissue associated with pesticide exposure, which may trigger mechanisms related to mutations and breast carcinogenesis.

Effect of heat stress on TNF-α, TNFRI and TNFRII expression in BLV infected dairy cattle.

High temperatures for extended periods, which do not allow animals to recover from heat stress, affect in particular those BLV-infected animals that carry a high proviral load. For this study, animals were discriminated between BLV (+) and BLV (-), and those belonging to the first group, were classified based on their proviral load. The expression of the inflammatory cytokine TNF-α and its receptors, which play an important role in disease progression, were quantified by qPCR in two different seasons. During the summer, average temperature was 19.8 °C, maximums higher than 30 °C were frequent. Instead, during the autumn, the average temperature was 12.63 °C, and temperatures never exceeded 27 °C. During this season, almost no periods of temperatures exceeded the comfort limit. Our results revealed that the expression levels of TNF-α and its receptors were downregulated in animals with high proviral load. This fact could affect their antiviral response and predispose to viral dissemination; over time, animals with a poorer immune system are prone to acquiring opportunistic diseases. Conversely, animals with LPL maintained their expression profile, with behavior comparable to non-infected animals. These findings should be considered by producers and researchers, given the problems that global warming is causing lately to the planet.

Newborns from Mothers Who Intensely Consumed Sucralose during Pregnancy Are Heavier and Exhibit Markers of Metabolic Alteration and Low-Grade Systemic Inflammation: A Cross-Sectional, Prospective Study.

Robust data in animals show that sucralose intake during gestation can predispose the offspring to weight gain, metabolic disturbances, and low-grade systemic inflammation; however, concluding information remains elusive in humans. In this cross-sectional, prospective study, we examined the birth weight, glucose and insulin cord blood levels, monocyte subsets, and inflammatory cytokine profile in 292 neonates at term from mothers with light sucralose ingestion (LSI) of less than 60 mg sucralose/week or heavy sucralose intake (HSI) of more than 36 mg sucralose/day during pregnancy. Mothers in the LSI (n = 205) or HSI (n = 87) groups showed no differences in age, pregestational body mass index, blood pressure, and glucose tolerance. Although there were no differences in glucose, infants from HSI mothers displayed significant increases in birth weight and insulin compared to newborns from LSI mothers. Newborns from HSI mothers showed a substantial increase in the percentage of inflammatory nonclassical monocytes compared to neonates from LSI mothers. Umbilical cord tissue of infants from HSI mothers exhibited higher IL-1 beta and TNF-alpha with lower IL-10 expression than that found in newborns from LSI mothers. Present results demonstrate that heavy sucralose ingestion during pregnancy affects neonates' anthropometric, metabolic, and inflammatory features.

Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

Relationship between IL-17, TNF-α, IL-10, IFN-γ, and IL-18 polymorphisms with the outcome of hepatitis B virus infection in the Turkish population

SUMMARY OBJECTIVE: Hepatitis B virus is a global threat that can lead to liver cirrhosis and hepatocellular carcinoma. For the treatment of chronic hepatitis B virus, polymorphisms might be an option for gene treatments. This study aimed to investigate the effects of IL-17, TNF-α, IL-10, IFN-γ, and IL-18 gene polymorphisms on hepatitis B virus infection in the Turkish population. METHODS: The genotypes and allele distribution of 75 patients exposed to hepatitis B virus and 50 healthy control individuals were analyzed. The real-time polymerase chain reaction method was used for identification. RESULTS: A correlation was observed between susceptibility to hepatitis B virus infection and IL-17 Exon 3/3'UTR (rs1974226) C, IL-17 Exon 3 (rs763780) A, IL-18 (-607) (rs1946518) A alleles, and IL-17 Exon 3 (rs763780) AA genotype (p=0.006, p=0.009, p=0.025, and p=0.008, respectively). Furthermore, IL-18 (-137) (rs187238) TT genotype and TNF-α-308 (rs1800629) G and A alleles, were associated with protection against hepatitis B virus infection (p=0.0351 and p=0.032, respectively). CONCLUSION: This study demonstrated that TNF-α (-308), IL-17 (Exon 3/3' UTR), IL-17 (Exon 3), and IL-18 (-607) polymorphisms are associated with hepatitis B virus infection. Therefore, these may serve as potential therapeutic targets for chronic viral hepatitis in the Turkish population.

IL10/AMPK pathway was associated with the hippocampal anti-inflammatory response to high-sugar and high-fat diet withdrawal.

OBJECTIVE: The present experimental study aimed to evaluate the effect of consuming an obesogenic diet (OD) on serum and hippocampal inflammation and proteins related to energy metabolism, alongside, we evaluated how the same parameters responded to an OD withdrawal. SUBJECTS: Thirty male 60-days-old Wistar rats were used. METHODS: The control group (n = 10) was fed the control diet across the whole experiment. The remaining animals were fed a high-sugar/high-fat (HSHF) diet for 30 days (n = 20) and half of them were placed on the control diet for 48 h (n = 10) afterwards. RESULTS: OD intake decreased hippocampal AMPK phosphorylation, although, it did not increase serum inflammation and only increased hippocampal pNFκBp65 levels without any increase in the cytokines assessed. Moreover, OD withdrawal led to higher inflammatory markers in the serum and hippocampus and higher hippocampal AMPK phosphorylation. The mediation models applied suggested that the effect of OD withdrawal on hippocampal inflammation was driven by serum inflammation, which activated the hippocampal IL10/AMPK anti-inflammatory pathway as a response. CONCLUSION: Our analyses suggest that OD withdrawal increases serum inflammation with hippocampal consequent inflammatory alterations. Despite the general assumption that improving diet improves health, this may not be immediate.

Is a negative correlation between sTNFR1 and TNF in patients with chronic Chagas disease the key to clinical progression?

Soluble TNF receptors (sTNFR1 and sTNFR2) are natural endogenous inhibitors of TNF and are elevated in inflammatory, autoimmune, and chronic degenerative diseases. In Chagas disease, pleiotropic cytokine TNF is considered key in immunopathology. Thus, we aimed to evaluate the levels of TNF, sTNFR1, and sTNFR2 in the serum of patients with chronic Chagas disease. TNF and its soluble receptors were quantified using Cytometric Bead Array in the serum of 132 patients, of which 51 had the indeterminate form (IND), 39 the mild cardiac form (CARD 1), 42 the severe cardiac form (CARD 2), and 20 non-infected individuals (NI). The results indicate that the soluble receptors may regulate TNF in Chagas disease, as their leves were higher in T. cruzi-infected individuals when compared to non-infected individuals. We found a moderate negative correlation between sTNFR1 and TNF in individuals with the IND form, suggesting a relationship with non-progression to more severe forms, such as heart disease. sTNFR1 and sTNFR2 were increased in all clinical forms, but with a moderate positive correlation in more severe patients (r = 0.50 and p = 0.0005). TNF levels showed no statistical differences in the groups of patients. These findings suggest the importance of the endogenous balance of the levels of soluble TNF receptors in the protection and balance in patients with chronic Chagas disease, besides revealing the immunological complexity in chronic T. cruzi-infected individuals.

Cognition-immune interactions between executive function and working memory, tumour necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNFR1 and sTNFR2) in bipolar disorder.

OBJECTIVES: This study examined cognition-immune interactions, specifically executive function, working memory, peripheral levels of tumour necrosis factor-alpha (TNF-α), and soluble tumour necrosis factor receptors-1 and -2 (sTNFR1 and 2) levels in bipolar disorder (BD) patients in comparison with controls. METHODS: Thirty-one BD participants and twenty-seven controls participated in the study. The neurocognitive assessment was performed through three of CogState Research BatteryTM tasks for executive function and working memory. Plasma levels of TNF-α, sTNFR1, and sTNFR2 were measured after overnight fasting. Sociodemographic data and symptom severity of depression and mania were assessed. RESULTS: BD presented a significantly worse performance in the working memory task (p = .005) and higher levels of TNF-α (p = .043) in comparison to controls. A trend level of significance was found for sTNFR1 between groups (p = .082). Among BD participants, there were significant correlations between sTNFR2 and neurocognitive tasks (Groton Maze Learning Task: ρ = .54, p = .002; Set-Shifting Task: ρ = .37, p = .042; and the Two-Back Task: ρ = -.49, p = .005), and between sTNFR1 and mania, depression and anxiety symptoms (respectively ρ = .37, p = .038; ρ = -.38, p = .037; and ρ = .42, p = .002). CONCLUSION: TNF-α and its receptors might be an important variable in cognitive impairment in BD. Future studies might focus on the development of anti-inflammatory therapeutic targets for cognitive dysfunction in BD.

In Silico Drug Repurposing for Anti-Inflammatory Therapy: Virtual Search for Dual Inhibitors of Caspase-1 and TNF-Alpha.

Inflammation involves a complex biological response of the body tissues to damaging stimuli. When dysregulated, inflammation led by biomolecular mediators such as caspase-1 and tumor necrosis factor-alpha (TNF-alpha) can play a detrimental role in the progression of different medical conditions such as cancer, neurological disorders, autoimmune diseases, and cytokine storms caused by viral infections such as COVID-19. Computational approaches can accelerate the search for dual-target drugs able to simultaneously inhibit the aforementioned proteins, enabling the discovery of wide-spectrum anti-inflammatory agents. This work reports the first multicondition model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mtc-QSAR-MLP) for the virtual screening of agency-regulated chemicals as versatile anti-inflammatory therapeutics. The mtc-QSAR-MLP model displayed accuracy higher than 88%, and was interpreted from a physicochemical and structural point of view. When using the mtc-QSAR-MLP model as a virtual screening tool, we could identify several agency-regulated chemicals as dual inhibitors of caspase-1 and TNF-alpha, and the experimental information later retrieved from the scientific literature converged with our computational results. This study supports the capabilities of our mtc-QSAR-MLP model in anti-inflammatory therapy with direct applications to current health issues such as the COVID-19 pandemic.

TNFA -308G>A and IL10 -1082A>G polymorphisms seem to be predictive biomarkers of chronic HCV infection.

BACKGROUND: Genetic changes may induce dysregulated cytokine production and affect the progression of the chronic disease caused by the hepacivirus C (HCV) because the balance of pro- and anti-inflammatory cytokines determines the outcome of infection. This study evaluated the TNFA -308G>A and IL10 -1082A>G polymorphisms in the susceptibility and progress of chronic hepatitis C. METHOD: The study included 101 samples from patients with chronic hepatitis C and 300 samples from healthy donors. Polymorphisms were typed by real-time PCR and were analyzed for associations with histopathological parameters (according to METAVIR classification) and HCV viral load. RESULTS: The polymorphic genotype for the TNFA -308G>A variant was not present in the group of patients with chronic hepatitis C and its absence could be associated with protection against HCV infection (p = 0.0477). Patients with the polymorphic genotype of the IL10 -1082A>G polymorphism had higher HCV viral load than wild-type patients (p = 0.0428). Neither polymorphism was associated with different levels of necroinflammatory activity or fibrosis scores. CONCLUSION: Our results suggest the polymorphic genotype at TNFA -308G>A as protective against chronic HCV infection, and the polymorphic genotype at the IL10 -1082A>G variant associated with higher HCV viral load. Further studies must be performed in order to confirm these associations.

Leptin Elicits In Vivo Eosinophil Migration and Activation: Key Role of Mast Cell-Derived PGD2.

Eosinophils are key regulators of adipose tissue homeostasis, thus characterization of adipose tissue-related molecular factors capable of regulating eosinophil activity is of great interest. Leptin is known to directly activate eosinophils in vitro, but leptin ability of inducing in vivo eosinophilic inflammatory response remains elusive. Here, we show that leptin elicits eosinophil influx as well as its activation, characterized by increased lipid body biogenesis and LTC4 synthesis. Such leptin-triggered eosinophilic inflammatory response was shown to be dependent on activation of the mTOR signaling pathway, since it was (i) inhibited by rapamycin pre-treatment and (ii) reduced in PI3K-deficient mice. Local infiltration of activated eosinophils within leptin-driven inflammatory site was preceded by increased levels of classical mast cell-derived molecules, including TNFα, CCL5 (RANTES), and PGD2. Thus, mice were pre-treated with a mast cell degranulating agent compound 48/80 which was capable to impair leptin-induced PGD2 release, as well as eosinophil recruitment and activation. In agreement with an indirect mast cell-driven phenomenon, eosinophil accumulation induced by leptin was abolished in TNFR-1 deficient and also in HQL-79-pretreated mice, but not in mice pretreated with neutralizing antibodies against CCL5, indicating that both typical mast cell-driven signals TNFα and PGD2, but not CCL5, contribute to leptin-induced eosinophil influx. Distinctly, leptin-induced eosinophil lipid body (lipid droplet) assembly and LTC4 synthesis appears to depend on both PGD2 and CCL5, since both HQL-79 and anti-CCL5 treatments were able to inhibit these eosinophil activation markers. Altogether, our data show that leptin triggers eosinophilic inflammation in vivo via an indirect mechanism dependent on activation of resident mast cell secretory activity and mediation by TNFα, CCL5, and specially PGD2.

Uric Acid Has Direct Proinflammatory Effects on Human Macrophages by Increasing Proinflammatory Mediators and Bacterial Phagocytosis Probably via URAT1.

The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0.23, 0.45, or 0.9 mmol/L uric acid for 12 h, in the presence or absence of 1 mmol/L probenecid. Flow cytometry was used to measure proinflammatory marker production and phagocytic activity that was quantified as a percentage of GFP-labeled Escherichia coli positive macrophages. qPCR was used to measure the macrophage expression of the urate anion transporter 1 (URAT1). As compared to control cells, the production of tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and cluster of differentiation (CD) 11c was significantly increased by uric acid. In contrast, macrophages expressing CD206, CX3C-motif chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 2 (CCR2) were significantly reduced. Uric acid progressively increased macrophage phagocytic activity and downregulated URAT1 expression. Probenecid-a non-specific blocker of URAT1-dependent uric acid transport-inhibited both proinflammatory cytokine production and phagocytic activity in macrophages that were exposed to uric acid. These results suggest that uric acid has direct proinflammatory effects on macrophages possibly via URAT1.

Low Serum Interleukin-6 Is a Differential Marker of Obesity-Related Metabolic Dysfunction in Women and Men.

There is scant information regarding the role of interleukin (IL)-6 in obesity-related metabolic dysfunction in humans. Thus, we studied the serum levels of IL-6 in normal weight, overweight, and obese subjects, and examined associations of IL-6 with hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation. One hundred three women and men were included in the study. Anthropometric parameters, blood glucose, insulin, total cholesterol, and triglycerides were measured. Serum levels of tumor necrosis factor-alpha (TNF-alpha), IL-10, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). One-way analysis of variance (ANOVA) showed a 2.5-fold significant decrease in serum IL-6 in overweight and obese individuals when compared with normal weight controls. Serum IL-6 exhibited significant inverse correlations with body mass index (r = -0.39/P < 0.0001), waist circumference (r = -0.42/P < 0.001), blood glucose (r = -0.40/P < 0.0001), triglycerides (r = -0.34/P < 0.0001), and TNF-alpha (r = -0.48/P < 0.0001), whereas a strongly positive correlation was found with IL-10 (r = 0.77/P < 0.0001). Multiple linear regression analysis revealed that behavior of IL-6 was mainly influenced by IL-10 (beta = 0.28/P = 1.95 × 10-6), TNF-alpha (beta = -0.67/P = 0.0017), and body fat percentage (beta = -5.95/P = 7.67 × 10-5) in women. In contrast, IL-10 (beta = 0.37/P = 1.34 × 10-9), TNF-alpha (beta = -0.85/P = 0.0005), and triglycerides (beta = 1.07/P = 0.0007) were major influencing factors of IL-6 in men. This study demonstrates that IL-6 is a marker of metabolic dysfunction that is differentially regulated in obese women and men. [Figure: see text].

Prevalence of Metabolic Syndrome Among Patients with Psoriasis Treated with TNF Inhibitors and the Effects of Anti-TNF Therapy on Their Lipid Profile: A Prospective Cohort Study.

Background: Tumor necrosis factor (TNF) is an important inflammatory cytokine in the pathogenesis of psoriasis and metabolic syndrome (MS). Patients with psoriasis have higher rates of MS; therefore, some authors suggest an MS screening within this population. In addition, TNF inhibitor treatment often modifies the metabolic profiles of these patients. This study describes the epidemiological, clinical, and laboratory characteristics of patients with psoriasis undergoing anti-TNF treatment and evaluates whether anti-TNF treatments influence changes in their metabolic parameters. Methods: A prospective 6-month cohort study followed patients who underwent three consecutive consultations at 0, 3, and 6 months. The sample composed of 83 patients with psoriasis using anti-TNF. Results: The mean age and disease duration of the patients were 48 ± 11 and 16 ± 9 years, respectively. Most patients were men (61.5%). The prevalence of MS was 36%, and high rates of abdominal obesity (59%) and overweight (82%) were observed. Anti-TNF treatment significantly altered total cholesterol levels (195.5 ± 36.17 vs. 183.5 ± 41.23, P = 0.04) and low-density lipoprotein (LDL) cholesterol levels (128.5 ± 31.26 vs. 113 ± 36.31, P = 0.04). This study has some limitations, such as small sample size, brief follow-up period (6 months), patient recruitment from a tertiary-level referral center, and no control group. Conclusions: Patients with psoriasis have high rates of MS, overweight, and obesity, but anti-TNF treatment seems to improve the metabolic profile of these patients by decreasing their total and LDL cholesterol levels.

Prenatal LPS induces sickness behaviour and decreases maternal and predatory behaviours after an LPS challenge.

Purpose: The influence of a challenge dose of lipopolysaccharide (LPS) on the behavioural selection between maternal (MB) and predatory behaviours (PB) of female rats prenatally treated with the same endotoxin or saline solution (F1 generation) were studied.Material and methods: Thus, in adult age, these female rats were mated and, at lactation days 5 or 6, the following groups were formed: (1) LPS + LPS group-female rats prenatally treated with LPS and received an LPS challenge dose; (2) S + LPS group-female rats prenatally treated with saline solution and received a challenge LPS dose (3) S + S group-females rats prenatally treated with saline which received a saline injection. MB, PB to cockroaches, exploratory behaviour, periaqueductal grey (PAG) expression of the astrocytic biomarker glial fibrillary acidic protein (GFAP), and corticosterone and TNF-alpha serum levels were evaluated.Results: Showed that: (1) relative to the S + S group, the LPS + S group showed decreased MB and slightly increased PB, without inducing sickness behaviour; (2) the LPS + LPS group showed decreased MB but few effects on PB; (3) there was increased sickness behaviour associated with increased TNF-alpha serum levels in the LPS + LPS group; (4) a significant increase in GFAP expression was observed in both LPS groups, which was greater in the LPS + LPS group and (5) no differences in the corticosterone of all groups.Conclusions: Prenatal LPS impaired the switch from MB to PB in female rats of the LPS + LPS group by increased sickness behaviour as well as an increase in plasmatic TNF-alpha levels inducing PAG astrogliosis.

Macrophages from a type 1 diabetes mouse model present dysregulated Pl3K/AKT, ERK 1/2 and SAPK/JNK levels.

Diabetes causes dysregulation in signal transduction in immune cells leading to an impaired response to pathogens. Herein, we investigated the impact of type 1 diabetes (T1D) in bone marrow-derived macrophages (BMDM), using male non-diabetic and diabetic C57BL/6 mice (alloxan 60 mg/kg, i.v., CEUA/FCF/USP - 467). Diabetic BMDM expressed impaired phosphoinositide 3-kinase (PI3K), being lower p-PI3K p55 levels and higher levels of PI3K p110 alpha, whereas protein kinase B (PKB/Akt) (Ser-473 and Thr-308), extracellular signal-regulated kinases (ERK 1/2), and stress-activated protein kinase (SAPK/JNK) were enhanced compared to non-diabetic BMDM. Further evaluation of the responsiveness to lipopolysaccharide (LPS; 0.1 and 1 ug/mL), diabetic BMDM and peritoneal macrophage secreted dysregulated levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 levels. In 24 h, diabetic BMDM stimulated by LPS presented lower metabolic activity, with no differences in cell surveillance. Therefore, LPS re-stimulation (0.1 ug/mL) in diabetic BMDM resulted in higher secretion of TNF-α compared to non-diabetic BMDM. However, diabetic peritoneal macrophages secreted similar IL-6 levels in the first and additional 24 h of LPS stimulation. In general, our results demonstrated that diabetes exerts an impact in both BMDM and peritoneal macrophages ability to secrete cytokine under LPS stimulation.

Implicación del factor de necrosis tumoral alfa en el síndrome de ovario poliquístico / Involvement of TNF-alpha in the polycystic ovary syndrome

Resumen: ANTECEDENTES: De 6 a 14% de las mujeres padecen síndrome de ovario poliquístico. En la práctica clínica este síndrome se subdianostica, circunstancia que deriva en complicaciones propias del padecimiento que incluyen: obesidad, resistencia a la insulina, alteraciones metabólicas e infertilidad. La fisiopatología no se ha definido por completo y en la actualidad se plantea la asociación de un proceso metabólico e inflamatorio crónico, donde las citocinas inflamatorias pueden tener alteraciones en su efecto y en su señalización. OBJETIVO: Comunicar lo encontrado en una revisión sistemática actualizada de la implicación del factor de necrosis tumoral alfa en pacientes con síndrome de ovario poliquístico. METODOLOGÍA: Revisión narrativa de artículos científicos indexados en Pub Med-NCBI, Web of Science, Google Scholar y Scopus, publicados en inglés o español entre 2014 y 2018 que en el título y resumen incluyeron los conceptos y asociación del síndrome de ovario poliquístico y del factor de necrosis tumoral alfa. RESULTADOS: Se identificaron 43 artículos; luego de eliminar los duplicados quedaron 29 y, al final, la síntesis se efectuó con 11 artículos. Las publicaciones provinieron de distintos países: 54% de los estudios se efectuaron en Chile, Estados Unidos e Irán, proporcionalmente; el resto de los estudios se llevaron a cabo en Rusia, China, Korea, Egipto y Pakistán. CONCLUSIONES: El factor de necrosis tumoral alfa es una citocina asociada con diferentes sistemas que tiene participación en el síndrome de ovario poliquístico.

Abstract: BACKGROUND: Polycystic ovary syndrome (PCOS) is a pathology present in 6 to 14% of women. However, in clinical practice it is underdiagnosed, which implies a presence of complications of the pathology that includes obesity, insulin resistance, metabolic alterations and infertility. The pathophysiology is not well defined, and the association of a chronic metabolic and inflammatory process is currently being considered, where inflammatory cytokines can present alterations both in their effect and in their signaling. OBJETIVE: To present the results of an updated systematic review of the involvement of TNF-alpha in polycystic ovary syndrome. METHODOLOGY: Narrative revision of articles indexed in Pub Med-NCBI, Web of Science, Google Scholar and Scopus, published in English or Spanish between 2014 and 2018 that included the concepts and association of polycystic ovary syndrome and tumor necrosis factor alpha in the title and abstract. RESULTS: 43 articles were identified; after eliminating the duplicates, 29 remained and, in the end, the synthesis was carried out with 11 articles. The publications came from different countries: 54% of the studies were carried out in Chile, the United States and Iran, proportionally; the rest of the studies were carried out in Russia, China, Korea, Egypt and Pakistan. CONCLUSIONS: TNF-alpha is a cytokine associated with different systems that is involved in polycystic ovary syndrome.

Evaluation of the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats

Abstract INTRODUCTION: Sepsis is an important cause of mortality and morbidity, and inflammatory response and oxidative stress play major roles underlying its pathophysiology. Here, we evaluated the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats. METHODS: Twenty-eight adult Sprague Dawley rats were classified into Control (Group 1), Sepsis (Group 2), Sepsis+Cefazolin (Group 3), and Sepsis+Cefazolin+Etanercept (Group 4) groups. Kidney tissue and serum samples were obtained for biochemical and histopathological investigations and examined for the C reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), triggering receptor expressed on myeloid cells (TREM), and malondialdehyde (MDA) levels. RESULTS: The levels of TNF-α, TREM, and MDA in serum and kidney samples were significantly higher in rats from sepsis group than in rats from control group (p < 0.05). Group 3 showed a significant reduction in serum levels of TNF-α, CRP, and TREM as compared with Group 2 (p < 0.05). Serum TNF-α, CRP, TREM, and MDA levels and kidney TNF-α and TREM levels were significantly lower in Group 4 than in Group 2 (p < 0.05). Serum TNF-α and TREM levels in Group 4 were significantly lower than those in Group 3, and histopathological scores were significantly lower in Group 3 and Group 4 than in Group 2 (p < 0.05). Histopathological scores of Group 4 were significantly lower than those of Group 3 (p < 0.05). CONCLUSIONS: Etanercept, a TNF-α inhibitor, may ameliorate sepsis-induced oxidative stress, inflammation, and histopathological damage.

Activated mesenchymal stem cell administration inhibits chronic alcohol drinking and suppresses relapse-like drinking in high-alcohol drinker rats.

Neuroinflammation has been reported to follow chronic ethanol intake and may perpetuate alcohol consumption. Present studies determined the effect of human mesenchymal stem cells (hMSCs), known for their anti-inflammatory action, on chronic ethanol intake and relapse-like ethanol intake in a post-deprivation condition. Rats were allowed 12-17 weeks of chronic voluntary ethanol (10% and 20% v/v) intake, after which a single dose of activated hMSCs (5 × 105 ) was injected into a brain lateral ventricle. Control animals were administered vehicle. After assessing the effect of hMSCs on chronic ethanol intake for 1 week, animals were deprived of ethanol for 2 weeks and thereafter an ethanol re-access of 60 min was allowed to determine relapse-like intake. A single administration of activated hMSCs inhibited chronic alcohol consumption by 70% (P < 0.001), an effect seen within the first 24 hours of hMSCs administration, and reduced relapse-like drinking by 80% (P < 0.001). In the relapse-like condition, control animals attain blood ethanol ('binge-like') levels >80 mg/dl. The single hMSC administration reduced relapse-like blood ethanol levels to 20 mg/dl. Chronic ethanol intake increased by 250% (P < 0.001) the levels of reactive oxygen species in hippocampus, which were markedly reduced by hMSC administration. Astrocyte glial acidic fibrillary protein immunoreactivity, a hallmark of neuroinflammation, was increased by 60-80% (P < 0.001) by chronic ethanol intake, an effect that was fully abolished by the administration of hMSCs. This study supports the neuroinflammation-chronic ethanol intake hypothesis and suggest that mesenchymal stem cell administration may be considered in the treatment of alcohol use disorders.