Effective Inhibition of TNFalpha/mTOR Axis-Mediated Liver Inflammation and Fibrosis Induced by TAA Using a Combination of Metformin and Resveratrol in Association with the Inhibition of the Profibrotic Gene and Protein Expression / Inhibición Efectiva de la Inflamación Hepática Mediada por el Eje TNF-alfa/mTOR y la Fibrosis Inducida por TAA Utilizando una Combinación de Metformina y Resveratrol en Asociación con la Inhibición del Gen Profibrótico y la Expresión de Proteínas

SUMMARY: The response of the immune system to harmful stimuli leads to inflammation, and the adverse effects of the toxic hepatitis chemical, thioacetamide (TAA) on the human body are well documented. This article investigated the degree of protection provided by the combined pleotropic drug, metformin (Met) and the plant polyphenolic and the antiinflammatory compound, resveratrol (Res) on liver tissue exposed to TAA possibly via the inhibition of the inflammatory cytokine, tumor necrosis factor-α (TNF-α) / mammalian target of rapamycin (mTOR) axis-mediated liver fibrosis, as well as amelioration of profibrotic gene and protein expression. Rats were either given TAA (200 mg/kg via intraperitoneal injection) for 8 weeks beginning at the third week (experimental group) or received during the first two weeks of the experiment combined doses of metformin (200 mg/kg) and resveratrol (20 mg/kg) and continued receiving these agents and TAA until experiment completion at week 10 (treated group). A considerable damage to hepatic tissue in the experimental rats was observed as revealed by tissue collagen deposition in the portal area of the liver and a substantial increase (p<0.0001) in hepatic levels of the inflammatory marker, tumor necrosis factor-α (TNF-α), as well as blood levels of hepatocellular injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TAA also augmented hepatic tissue levels of the signalling molecule that promotes liver fibrosis (mTOR), and profibrogenic markers; alpha-smooth muscle actin (α-SMA) protein, tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA, and matrix metalloproteinase-9 (MMP-9) mRNA. All these parameters were protected (p≤0.0016) by Met+Res. In addition, a significant correlation was detected between liver fibrosis score and inflammation, liver injury enzymes, mTOR, and profibrogenesis markers. Thus, these findings suggest that Met+Res effectively protect the liver against damage induced by thioacetamide in association with the downregulation of the TNF-α/mTOR/fibrosis axis.

La respuesta del sistema inmunológico a estímulos dañinos conduce a la inflamación y los efectos adversos de la tioacetamida (TAA), una sustancia química tóxica para el hígado, están bien documentadas. Este artículo investigó el grado de protección proporcionado por el fármaco pleotrópico combinado metformina (Met), el polifenólico vegetal y el compuesto antiinflamatorio resveratrol (Res) en el tejido hepático expuesto a TAA, posiblemente a través de la inhibición de la citoquina inflamatoria, factor de necrosis tumoral α (TNF-α)/objetivo de la fibrosis hepática mediada por el eje de rapamicina (mTOR), así como mejora de la expresión de genes y proteínas profibróticas. Las ratas recibieron TAA (200 mg/kg mediante inyección intraperitoneal) durante 8 semanas a partir de la tercera semana (grupo experimental) o recibieron durante las dos primeras semanas del experimento dosis combinadas de metformina (200 mg/kg) y resveratrol (20 mg/kg) y continuaron recibiendo estos agentes y TAA hasta completar el experimento en la semana 10 (grupo tratado). Se observó un daño considerable al tejido hepático en las ratas experimentales, como lo revela el depósito de colágeno tisular en el área portal del hígado y un aumento sustancial (p<0,0001) en los niveles hepáticos del marcador inflamatorio, el factor de necrosis tumoral-α (TNF- α), así como los niveles sanguíneos de biomarcadores de lesión hepatocelular, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). TAA también aumentó los niveles en el tejido hepático de la molécula de señalización que promueve la fibrosis hepática (mTOR) y marcadores profibrogénicos; proteína actina del músculo liso alfa (α- SMA), inhibidor tisular de las metaloproteinasas-1 (TIMP-1) mRNA y matriz metaloproteinasa-9 (MMP-9) mRNA. Todos estos parámetros fueron protegidos (p≤0.0016) por Met+Res. Además, se detectó una correlación significativa entre la puntuación de fibrosis hepática y la inflamación, las enzimas de lesión hepática, mTOR y los marcadores de profibrogénesis. Por lo tanto, estos hallazgos sugieren que Met+Res protege eficazmente el hígado contra el daño inducido por la tioacetamida en asociación con la regulación negativa del eje TNF-α/mTOR/fibrosis.

Zarzio Ameliorates Non-alcoholic Fatty Liver Induced By a High Fat Diet in a Rat Experimental Model: A Histological and Immunohistochemical Study

SUMMARY: The therapeutic effect of a granulocyte-colony stimulating factor (G-CSF) biosimilar drug, zarzio, on non-alcoholic fatty liver disease (NAFLD) in a rat model was investigated in this study. Thirty-two rats were randomly divided into four groups. Groups I and II were fed a standard laboratory diet, whereas groups III and IV were fed a high fat diet (HFD) for 14 weeks. After 12 weeks of feeding, groups I and III were administered normal saline, and groups II and IV were intraperitoneally administered zarzio (200 mg/kg/day) for two consecutive weeks. Hematoxylin-eosin (H&E) staining was used to assess hepatic and pancreatic morphology in all groups, oil red O (ORO) staining for lipid accumulation, Masson's staining for fibrosis, and immunohistochemistry assay for hepatic protein expression of insulin receptor substrate 1 (IRS1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumour necrosis factor alpha (TNF-α) and pancreatic caspase-3. The NAFLD rats (group III) developed hepatic steatosis with increased lipid accumulation, perisinusoidal fibrosis, upregulated IRS1, TNF-α (all P<0.05) without a significant increase in Nrf2 protein expression compared with normal control. In comparison, model rats treated with zarzio (group IV) showed significant rejuvenation of the hepatic architecture, reduction of fat accumulation, and fibrosis. This was accompanied by the upregulation of Nrf2, downregulation of IRS1 and TNF-α protein expression (all P<0.05). No correlation was detected between NAFLD and non-alcoholic fatty pancreas disease (NAFPD). However, the pancreatic β-cells in group III showed increased caspase-3 expression, which was decreased (P<0.05) in group IV. In conclusion, zarzio ameliorates NAFLD by improving the antioxidant capacity of liver cells, reducing hepatic IRS1, TNF-α protein expression and pancreatic β-cells apoptosis, suggesting that zarzio could be used as a potential therapy for NAFLD.

En este estudio se investigó el efecto terapéutico de un fármaco biosimilar del factor estimulante de colonias de granulocitos (G-CSF), zarzio, sobre la enfermedaddel hígado graso no alcohólico (NAFLD) en un modelo de rata. Treinta y dos ratas se dividieron aleatoriamente en cuatro grupos. Los grupos I y II fueron alimentados con una dieta estándar de laboratorio, mientras que los grupos III y IV fueron alimentados con una dieta alta en grasas (HFD) durante 14 semanas. Después de 12 semanas de alimentación, a los grupos I y III se les administró solución salina normal, y a los grupos II y IV se les administró zarzio por vía intraperitoneal (200 mg/kg/ día) durante dos semanas consecutivas. Se utilizó tinción de hematoxilina-eosina (H&E) para evaluar la morfología hepática y pancreática en todos los grupos, tinción con rojo aceite O (ORO) para la acumulación de lípidos, tinción de Masson para la fibrosis y ensayo de inmunohistoquímica para la expresión de la proteína hepática del sustrato 1 del receptor de insulina (IRS1), factor nuclear eritroide 2 relacionado con el factor 2 (Nrf2), factor de necrosis tumoral alfa (TNF-α) y caspasa-3 pancreática. Las ratas NAFLD (grupo III) desarrollaron esteatosis hepática con aumento de la acumulación de lípidos, fibrosis perisinusoidal, IRS1 y TNF-α regulados positivamente (todos P <0,05) sin un aumento significativo en la expresión de la proteína Nrf2 en comparación con el control normal. En comparación, las ratas modelo tratadas con zarzio (grupo IV) mostraron un rejuvenecimiento significativo de la arquitectura hepática, una reducción de la acumulación de grasa y fibrosis. Esto estuvo acompañado por la regulación positiva de Nrf2, la regulación negativa de la expresión de la proteína IRS1 y TNF-α (todas P <0,05). No se detectó correlación entre NAFLD y la enfermedad del páncreas graso no alcohólico (NAFPD). Sin embargo, las células β pancreáticas en el grupo III mostraron una mayor expresión de caspasa-3, que disminuyó (P <0,05) en el grupo IV. En conclusión, zarzio mejora la NAFLD al mejorar la capacidad antioxidante de las células hepáticas, reduciendo el IRS1 hepático, la expresión de la proteína TNF-α y la apoptosis de las células β pancreáticas, lo que sugiere que zarzio podría usarse como una terapia potencial para la NAFLD.

The Effects of White Tea (Camellia Sinensis) and Infliximab Against Cisplatin- Induced Testicular Damage via Oxidative Stress and Apoptosis / Efectos del Té Blanco (Camellia Sinensis) e Infliximab Contra el Daño Testicular Inducido por Cisplatino a Través del Estrés Oxidativo y la Apoptosis

SUMMARY: Cisplatin (Cis) is an important chemotherapeutic agent used in cancer treatment. Males exposed to Cis were reported to exhibit testicular toxicity. Cis-induced testicular toxicity is mediated by oxidative stress, inflammation, testosterone inhibition and apoptosis. Accordingly, this study was conducted to evaluate the potential protective roles of infliximab (IFX), which is an anti- TNF-a agent, and of white tea (Camellia sinensis), which is known to possess antioxidant, anti-apoptotic, and anti-inflammatory effects, against Cis-induced testicular toxicity in rats. Rats were randomly assigned into five groups as follows: control group, Cisplatin (7 mg/kg) treatment group, Cisplatin (7 mg/kg) + infliximab (7 mg/kg) treatment group, cisplatin + white tea (WT) treatment group, and Cisplatin+ WT+IFX combined treatment group. In the present study, Cis exposure reduced the sperm count. It also increased testicular oxidative stress as well as the levels of inflammatory and apoptotic markers. Histopathological assays supported the biochemical findings. Treatment with IFX and/or WT restored testicular histology, preserved spermatogenesis, suppressed oxidative stress and apoptosis, and significantly ameliorated Cis-induced damage. It was concluded that white tea and infliximab could potentially serve as therapeutic options for the protection of testicular tissue against the harmful effects of Cis.

El cisplatino (Cis) es un importante agente quimioterapéutico utilizado en el tratamiento del cáncer. Se informó que los hombres expuestos a Cis exhibieron toxicidad testicular. La toxicidad testicular inducida por Cis está mediada por el estrés oxidativo, la inflamación, la inhibición de la testosterona y la apoptosis. En consecuencia, este estudio se realizó para evaluar las posibles funciones protectoras de infliximab (IFX), un agente anti-TNF-α, y del té blanco (Camellia sinensis), conocido por sus propiedades antioxidantes, antiapoptóticas y anti-TNF-α -efectos inflamatorios, contra la toxicidad testicular inducida por Cis en ratas. Cinco grupos de ratas se asignaron al azar de la siguiente manera: grupo control, grupo de tratamiento con cisplatino (7 mg/ kg), grupo de tratamiento con cisplatino (7 mg/kg) + infliximab (7 mg/kg), grupo de tratamiento con cisplatino + té blanco (WT), y grupo de tratamiento combinado Cisplatino+ WT+IFX. En el presente estudio, la exposición a Cis redujo el conteo de espermatozoides. También aumentó el estrés oxidativo testicular, así como los niveles de marcadores inflamatorios y apoptóticos. Los ensayos histopatológicos respaldaron los hallazgos bioquímicos. El tratamiento con IFX y/o WT restauró la histología testicular, preservó la espermatogénesis, suprimió el estrés oxidativo y la apoptosis, y mejoró significativamente el daño inducido por Cis. Se concluyó que el té blanco y el infliximab podrían potencialmente servir como opciones terapéuticas para la protección del tejido testicular contra los efectos nocivos de Cis.

Metformin Inhibits ROS/TNF-alpha Axis-Mediated Chronic Kidney Disease Induced by TAA Independent of Leukocyte Infiltration in Association with the Inhibition of Kidney Injury Biomarkers / La Metformina Inhibe la Enfermedad Renal Crónica Mediada por el Eje ROS/TNF-alfa Inducida por TAA Independientemente de la Infiltración de Leucocitos en Asociación con la Inhibición de Biomarcadores de Lesión Renal

SUMMARY: The toxic effects of thioacetamide (TAA) and carbon tetrachloride on the human body are well recognized. In this study, we examined whether TAA intoxication can induce kidney leukocyte infiltration (measured as leukocyte common antigen CD45) associated with the augmentation of the reactive oxygen species (ROS)/tumor necrosis factor-alpha (TNF-α) axis, as well as biomarkers of kidney injury with and without metformin treatment. Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (experimental group) or were pre-treated with metformin (200 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment, at week 10 (protective group). Using basic histology staining, immunohistochemistry methods, and blood chemistry analysis, we observed profound kidney tissue injury such as glomerular and tubular damage in the experimental group, which were substantially ameliorated by metformin. Metformin also significantly (p0.05) increase in kidney expression of CD45 positive immunostaining cells. In conclusion, we found that TAA induces kidney injury in association with the augmentation of ROS/TNF-α axis, independent of leukocyte infiltration, which is protected by metformin.

Son bien conocidosos los efectos tóxicos de la tioacetamida (TAA) y el tetracloruro de carbono en el cuerpo humano. En este estudio, examinamos si la intoxicación por TAA puede inducir la infiltración de leucocitos renales (medida como antígeno leucocitario común CD45) asociada con el aumento de las especies reactivas de oxígeno (ROS)/factor de necrosis tumoral-alfa (TNF-α), así como biomarcadores de daño renal con y sin tratamiento con metformina. A las ratas se les inyectó TAA (200 mg/kg; dos veces por semana durante 8 semanas) antes de sacrificarlas a las 10 semanas (grupo experimental) o se les pretrató con metformina (200 mg/kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuaron recibiendo ambos agentes hasta el final del experimento, en la semana 10 (grupo protector). Usando tinción histológica básica, métodos de inmunohistoquímica y análisis químico de la sangre, observamos una lesión profunda del tejido renal, como daño glomerular y tubular en el grupo experimental, que mejoraron sustancialmente con la metformina. La metformina también inhibió significativamente (p0,05) en la expresión renal de células de inmunotinción positivas para CD45. En conclusión, encontramos que el TAA induce la lesión renal en asociación con el aumento del eje ROS/TNF-α, independientemente de la infiltración de leucocitos, que está protegida por metformina.

Comparative Analysis of TNF-alpha, TNF-R1, and TNF-R2 in Patients with Low-impact Fractures Due to Osteoporosis / Análise comparativa de TNF-alfa, TNF-R1 e TNF-R2 em pacientes com fraturas de baixo impacto decorrentes de osteoporose

Abstract Objective To analyze the serum levels of TNF-alpha and its TNF-R1 and TNF-R2 receptors in the blood of patients with low-impact fractures due to osteoporosis, comparing between genders and with healthy patients. Methods The present study was conducted with a blood sample of 62 patients, divided into patients with osteoporosis and healthy patients. The results were obtained using the ELISA method. Cytokine concentrations were determined based on the absorbance values obtained. Results Serum TNF-alpha levels were undetectable in female patients, while in males they were found only in one patient, with no significant difference. Similar results were found in the analyses of TNF-R1 and TNF-R2 levels, a significant increase in levels of TNF-alpha receptors in the groups of patients with osteoporosis compared with the control groupinbothsexes.There wasnosignificant difference between the sexes in the dosage of both receptors within the group with osteoporosis. There was also a positive and significant correlation in the levels of TNF-R1 and TNF-R2 only in women. Conclusion The significant increase in TNF-R1 and TNF-R2 levels in women with osteoporosis suggest that the release and expression of these receptors may be contributing differently to the development of osteoporosis in men and women.

Resumo Objetivo Analisar os níveis séricos de TNF-alfa e de seus receptores TNF-R1 e TNF-R2 no sangue de pacientes com fraturas de baixo impacto, decorrentes de osteoporose, comparando entre os sexos e com pacientes saudáveis. Métodos Oestudofoi realizadocom amostradesanguede 62 pacientes,divididos em pacientes com osteoporose e pacientes saudáveis. Os resultados foram obtidos através do método de ELISA. As concentrações de citocinas foram determinadas com base nos valores de absorbância obtidos. Resultados Os níveis séricos de TNF-alfa foram indetectáveis nos pacientes do sexo feminino, enquanto no masculino encontrou-se somente em um paciente, não havendo diferença significativa. Encontrou-se resultados semelhantes nas análises dos níveis de TNF-R1 e TNF-R2, aumento significativo nos níveis dos receptores de TNF-alfa nos grupos de pacientes com osteoporose em comparação com o grupo controle, em ambos os sexos. Não houve diferença significativa entre os sexos na dosagem de ambos os receptores dentro do grupo com osteoporose. Houve ainda correlação positiva e significativa nos níveis de TNF-R1 e TNF-R2 apenas nas mulheres. Conclusão O aumento significativo nos níveis de TNF-R1 e TNF-R2 em mulheres com osteoporose sugerem que a liberação e expressão destes receptores pode estar contribuindo de maneira distinta no desenvolvimento da osteoporose em homens e mulheres.

Captopril inhibits thioacetamide-induced chronic liver injury associated with the suppression of inflammation / hypoxia- inducible factor 1-alpha / profibrogenic axis-mediated hepatotoxicity in rats / Captopril inhibe la lesión hepática crónica inducida por tioacetamida asociada con la supresión de la inflamación/factor 1-alfa inducible por hipoxia/hepatotoxicidad mediada por el eje profibrogénico en rata

SUMMARY: Liver transplantation is the only available method to treat liver failure induced by chronic liver injury. We sought to determine whether the angiotensin-converting enzyme inhibitor, captopril, can inhibit the development of chronic liver injury induced by the hepatotoxic agent thioacetamide (TAA) in association with the suppression of inflammation (hsCRP, TNF-α, and IL-6) / hypoxia- inducible factor 1-alpha (HIF-1α) / profibrosis (TIMP-1, MMP-9, and α-SMA) axis that mediates liver injury. Therefore, the model group of rats was injected for eight weeks with 200 mg/kg TAA starting at week two. The protective group was pretreated with 150 mg/ kg captopril daily for two weeks prior to TAA injections and continued receiving both capropril and TAA agents until being humanely scrificed at week 10. We observed a substantial damage to liver tissue in the model group as demonstrated by a significant (p<0.0001) increase in blood and hepatic tissue levels of high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-a (TNF-α), interleukin- 6 (L-6), HIF-1α, tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), alpha-smooth muscle actin (α-SMA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). All these parameters were significantly (p<0.0244) protected by captopril. Also, a significant (p<0.0001) positive correlation was observed between a-SMA (profibrosis) and the serum and tissue levels of hsCRP, TNF-α, HIF-1α, TIMP-1, MMP-9, and ALT. Thus, these findings suggest that the induction of chronic liver injury by the hepatotoxic compound, TAA is associated with the upregulation of inflammation/HIF-1α/profibrosis, with captopril exhibiting beneficial hepatic pleotropic effects.

El trasplante de hígado es el único método disponible para tratar la insuficiencia hepática inducida por una lesión hepática crónica. Buscamos determinar si el inhibidor de la enzima convertidora de angiotensina, captopril, puede inhibir el desarrollo de lesión hepática crónica inducida por el agente hepatotóxico tioacetamida (TAA) en asociación con la supresión de la inflamación (hsCRP, TNF-α e IL-6) / factor inducible por hipoxia 1-alfa (HIF-1α) / profibrosis (TIMP-1, MMP-9 y α- SMA) eje que media la lesión hepática. Por lo tanto, al grupo modelo de ratas se le inyectó durante ocho semanas 200 mg/kg de TAA a partir de la semana dos. El grupo protector fue pretratado con 150 mg/kg de captopril al día durante dos semanas antes de las inyecciones de TAA y continuó recibiendo capropril y agentes TAA hasta que fue sacrificado en la semana 10. Observamos un daño sustancial en el tejido hepático en el grupo modelo, como lo demuestra un aumento significativo (p<0,0001) de los niveles en sangre y tejido hepático de proteína C reactiva de alta sensibilidad (hsCRP), factor de necrosis tumoral-α (TNF-a), interleucina-6 (L-6), HIF-1α, inhibidor tisular de metaloproteinasas-1 (TIMP-1), metaloproteinasa de matriz-9 (MMP-9), actina de músculo liso alfa (α-SMA), alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Todos estos parámetros estaban significativamente (p<0,0244) protegidos por captopril. Además, se observó una correlación positiva significativa (p<0,0001) entre α-SMA (profibrosis) y los niveles séricos y tisulares de hsCRP, TNF-α, HIF-1α, TIMP- 1, MMP-9 y ALT. Por lo tanto, estos hallazgos sugieren que la inducción de daño hepático crónico por el compuesto hepatotóxico, TAA, está asociada con la regulación al alza de la inflamación/HIF-1α/profibrosis, con captopril exhibiendo efectos pleotrópicos hepáticos beneficiosos.

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.

The role of TNF-α and NFkß in an experimental model of intestinal carcinogenesis with 1, 2-dimethyhydrazine

Purpose: To analyze the potential of tumor necrosis factor-α (TNF-α) and factor nuclear kappa B (NF-κB) as colorectal cancer (CRC) biomarkers in an experimental model of intestinal carcinogenesis with 1,2-dimethyhydrazine (1,2-DMH). Methods: Twenty-four male Wistar rats were divided into two groups: sham and 1,2-DMH. First, 1,2-DMH (20 mg/kg/week) was administered for 15 consecutive weeks. In the 25th week, proctocolectomy was conducted. Histopathological analysis, immunohistochemistry, and gene expression of TNF-α and NF-κB were performed. Statistical analysis was performed using GraphPad Prism. The location of aberrant crypt foci (ACF) was analyzed by Kruskal-Wallis' test. For analyses with two groups with parametric data, the t-test was used; for non-parametric data, the Mann-Whitney's test was used. P < 0.05 was considered significant. Results: The number of ACF and macroscopic lesions was significantly higher (p < 0.5) in the 1,2-DMH group compared to the sham group, and most ACF were concentrated in the distal segment of the colon. There was a statistically significant increase (p < 0.5) in protein and gene expression of TNF-α and NF-κB in the 1,2-DMH group compared to the sham group. Conclusions: Our results provide supportive evidence that TNF-α and NF-κB pathways are strongly involved in CRC development in rats and might be used as early biomarkers of CRC pathogenesis in experimental studies.

Avaliação da influência do tabagismo no desenvolvimento da periodontite apical em ratos wistar / Evaluation of smoking influence on the development of apical periodontitis in wistar rats

A infecção endodôntica ocorre a após contaminação do tecido pulpar levando à uma colonização bacteriana dos canais radiculares resultando em uma resposta inflamatória dos tecidos periapicais e formação de uma lesão periapical, a periodontite apical (PA). O tabagismo, por sua vez, tem impactos prejudiciais à saúde oral e sistêmica sendo considerado um importante fator de risco para as doenças periodontais. Este trabalho tem por finalidade investigar a influência do tabagismo no desenvolvimento da periodontite apical em ratos. Trinta e dois ratos machos Wistar foram divididos em 4 grupos experimentais (n=8): Controle (sem periodontite apical induzida e sem inalação da fumaça do cigarro); FU (com inalação a fumaça do cigarro); PA (com periodontite apical induzida); FU+PA (com inalação a fumaça do cigarro e periodontite apical induzida). Para a inalar a fumaça do cigarro, grupo de cinco animais permaneceram em uma câmara de tabagismo inalando a fumaça de 10 cigarros por 8 minutos, três vezes ao dia, durante 50 dias. Decorridos 20 dias de inalação de fumaça do cigarro, foi realizada a cirurgia para indução da periodontite apical nos animais do grupo PA e FU+PA, no primeiro molar inferior direto, o qual permaneceu aberto na cavidade bucal por 30 dias. Nesses 30 dias subsequentes da indução da PA, os animais do grupo FU+PA e FU continuaram com a inalação a fumaça do cigarro. No 50º dia, os animais foram eutanasiados e coletados amostras de tecido hematológico para avalição dos níveis séricos de nicotina, cotinina, fosfatase alcalina, cálcio, fósforo, série vermelha e série branca. As hemimandibula removidas foram escaneadas em microtomógrafo para avaliar o volume da destruição óssea e processadas histologicamente para avaliação do perfil inflamatório e expressão das citocinas IL-6, IL-1ß, TNF-α e dos marcadores do metabolismo ósseo RANKL e OPG. Os dados foram tabulados e aplicados os testes estatísticos de Mann-Whitney para os dados não paramétricos e teste t para os dados paramétricos, a um nível de significância de P< 0.05. Com relação a análise histológica o grupo FU+PA apresentou infiltrado inflamatório mais intenso em relação aos demais grupos (P< 0,05). As citocinas pró-inflamatórias IL-6, IL-1ß, TNF-α apresentaram alto padrão de imunomarcação para o grupo FU+PA (P< 0,05). A análise histométrica mostrou maior área de reabsorção óssea no grupo FU+PA, assim como na análise microtomográfica (P< 0,05). As citocinas RANKL esteve mais expressa no grupo FU+PA (P< 0,05) e OPG teve maior expressão no grupo PA (P< 0,05). Na análise hematológica houve um aumento na concentração de hemácias, hemoglobina e leucócitos para o FU+PA (P< 0,05). Os níveis séricos de cálcio foram menores no FU+PA (P> 0,05), a fosfatase alcalina e o cálcio se manteve constante em todos os grupos experimentais (P> 0,05). A concentração sérica de nicotina e cotinina no grupo FU e FU+PA foram compatíveis com fumante humano(AU)

Endodontic infection occurs mainly after pulp tissue contamination by a carious process, leading to bacterial colonization of root canal system and inflammatory response of periapical tissues, followed by formation of apical periodontitis (AP). It is widely known that smoking has harmful impacts on oral and systemic health and is considered a risk factor for periodontal diseases. The objective of this research was to investigate the influence of smoking on the development of AP in rats. Thirty-two male Wistar rats were divided into 4 experimental groups (n = 8): C - Control (no induced AP and no cigarette smoke inhalation); CSI (cigarette smoke inhalation); AP (induced apical periodontitis); CSI + AP (cigarette smoke inhalation and induced apical periodontitis). To inhale cigarette smoke, group with five animals remained in a smoking chamber inhaling smoke from 10 cigarettes for 8 minutes, three times daily, for 50 days. After 20 days of cigarette smoke inhalation, pulp chamber access was performed to induce apical periodontitis in the first mandibular right molar, which remained with pulp chamber exposed to oral cavity for 30 days in animals in the AP and CSI + AP group. During these 30 days after the AP induction, animals in the CSI + AP and CSI group continued to inhale cigarette smoke. On the 50th day, animals were euthanized and blood sample collected to assess serum levels of nicotine, cotinine, alkaline phosphatase, calcium, phosphorus, red series and white series. The hemimandibles were removed and scanned in microtomograph to assess bone volume and histologically processed to assess inflammatory profile and expression of cytokines IL-6, IL-1ß, TNF-α and bone metabolism markers RANKL and OPG. Data were tabulated and statistically analyzed using Mann-Whitney tests for nonparametric data and analysis of variation test for parametric data, with a significance level of P< 0.05. Regarding histological analysis, CSI+AP group showed more intense inflammatory infiltrate compared to other groups (P < 0.05). Histometric analysis showed a larger area of bone resorption in the CSI + AP group, also observed in the microtomographic analysis (P< 0.05). Group CSI+AP had elevated pro-inflammatory cytokines IL-6, IL-1ß, TNF-α expression (P< 0.05). The RANKL cytokines were also more expressed in the CSI+AP group (P< 0.05), while OPG was more expressed in the AP group (P< 0.05). The hematological analysis revealed an increase in the concentration of red blood cells, hemoglobin, and leukocytes for CSI+AP (P< 0.05). Serum calcium levels were lower in CSI+AP (P> 0.05), and alkaline phosphatase and calcium remained constant in all experimental groups (P> 0.05). The serum concentrations of nicotine and cotinine in the CSI and CSI+AP group were compatible with human smokers(AU)

Relación de IMC con marcadores de inflamación y hemoglobina glicosilada en niños y jóvenes con diabetes mellitus 1 / Relationship of BMI with markers of inflammation and glycosylated hemoglobin in children and young adults with diabetes mellitus 1

La diabetes mellitus tipo 1 (DM1) es una enfermedad autoinmune que genera dependencia exógena de insulina de forma permanente, presenta inflamación subclínica crónica lo que conlleva a una elevación de marcadores de inflamación como factor de necrosis tumoral alfa (TNF-α), proteína C reactiva (PCR) e interleuquina 6 (IL-6). OBJETIVO: determinar la relación entre el IMC sobre los marcadores de inflamación y el control metabólico en niños y jóvenes con DM1 entre 5 a 15 años de edad. METODOLOGÍA: Se realizó un estudio clínico, observacional, exploratorio. A partir de La recolección de datos de fichas clínicas y muestras de sangre en el Instituto de Investigaciones Materno Infantil (IDIMI) del Hospital San Borja Arriarán de la Universidad de Chile. Clasificación del estado nutricional utilizando datos registrados en ficha clínica. Marcadores de inflamación por medio de ELISA, hemoglobina glicosilada mediante métodos estándares. El análisis estadístico incluyó correlaciones mediante test de Spearman y diferencia de medias mediante test de Kruskal-Wallis seguido de post hoc Dunns. RESULTADOS: Un 30% de los pacientes con DM1 presentaron malnutrición por exceso. Al analizar la relación entre los niveles de marcadores inflamatorios y Hb glicosilada se observó la existencia de asociacion positiva entre usPCR y HbA1c (r= 0,30; p=0,0352) y entre IL-6 y HbA1c (r= - 0,038; p=0,0352). CONCLUSIONES: este estudio describe una posible asociación entre parámetros clásicos de inflamación con la hemoglobina glicosilada en las categorias de sobrepeso y obesidad en pacientes con DM1.

Type 1 diabetes mellitus (T1D) is an autoimmune disease that generates permanent exogenous insulin dependence, accompanied by chronic subclinical inflammation that leads to an elevation of inflammation markers such as tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6). OBJECTIVE: To determine the relationship between BMI on markers of inflammation and metabolic control in children and young people with T1D between 5 and 15 years of age. METHODOLOGY: A clinical, observational and exploratory study was carried out, based on the collection of data from clinical records and blood samples of children and adolescents with DM1 at the Instituto de Investigaciones Materno Infantil (IDIMI) of the Hospital San Borja Arriarán of the Universidad de Chile. Nutritional status, levels of inflammation markers and glycosylated hemoglobin were determined by standardized methods. Statistical analysis included correlations by Spearman test and mean difference by Kruskal-Wallis test followed by post hoc Dunns test. RESULTS: A total of 56 patients with T1D were analyzed, 30% of whom presented excess malnutrition. Those children or adolescents with obesity presented significantly higher usPCR levels compared to underweight patients or patients at risk of malnutrition (p=0.039). In addition, HbA1c levels were determined which were negatively associated with usPCR (r= 0.30; p=0.0352) and IL-6 (r= - 0.038; p=0.0352) levels. CONCLUSIONS: This study points out that nutritional status is associated with usPCR levels, in agreement with what is described in the literature and shows a possible association between classical parameters of inflammation with glycosylated hemoglobin in children and adolescents with nutritional diagnosis of overweight or obesity.

Effect of pancreatin on acute pancreatitis resulting from L-arginine administration in mice, a morpho-histopathological and biochemical study

Abstract Acute pancreatitis (AP) is a life-unpleasant situation with contradictory and inadequate treatments. In this regard, the present study evaluated the effect of the possible pretreatment of lipase-pancreatin on L-arginine-induced AP. Forty adult mice were selected and divided into five groups: I) control group, II and III) AP groups (i.p.) receiving L-arginine of 2×300 and 2×400 mg/100 g body weight (b.w.), IV) AP (2×300 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase), and V) AP (2×400 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase). All AP groups displayed a significant increase in serum levels of ALT, AST, TBARS, and TNF-alpha compared to the control group. Moreover, pancreatic tissue edema, inflammation, and vacuolization of acinar cells were significantly higher in the untreated L-arginine group compared to the control and pancreatin groups. Conversely, the diameter of pancreatic islets significantly declined after induction of pancreatitis compared with control and pancreatin groups. Pancreatin treatment can be used in pancreatic dysfunction, however, this medicine showed no protective effect against L-arginine-induced AP in the mouse model.

TNF-alpha and IL-17 cytokine levels in Brazilian patients with ankylosing spondylitis after anti-TNF therapy

Abstract The aim of this study was to evaluate tumor necrosis factor alpha (TNF-α), interleukin (IL)- 17A/F levels in the serum of ankylosing spondylitis (AS) patients after anti-TNF therapy, in order to understand how these cytokines are involved in this therapeutic response. Forty-four AS patients were included in the study: thirty using anti-TNF therapy were classified according to their therapy response as responders (15) and non-responders (15) and 14 without anti-TNF therapy were classified as AS control. Fifteen healthy individuals formed the control group. Serum levels of TNF-α were determined using Luminex technology and for IL-17A and IL-17F using ELISA. The non-responder patients presented higher serum levels of TNF-α than the responders and AS control; the same results were found when HLA-B*27 positive or negative patients were separately analyzed. IL-17A and IL17F serum levels were similar for all groups. According to the clinical disease activity, AS patients with BASDAI ≥4 had higher serum levels of TNF-α than AS patients with BASDAI <4. Positive correlation was found between TNF-α levels and BASDAI. In AS patients, TNF-α serum levels were associated with anti-TNF therapy and disease activity independently of HLA-B*27, and IL-17A and IL-17F were not related to anti-TNF treatment

Avaliação da etapa final do sinal insulínico, via inflamatória, estresse oxidativo, mecanismo epigenético por metilação do DNA e expressão de GLUT4 no músculo gastrocnêmio de ratos adultos, proles de ratas com periodontite apical / Assessment of insulin signaling and inflammatory pathways in skeletal muscle and adipose tissues of adult rats, offspring of the rats with periapical lesion

A programação fetal sugere que estímulos adversos quando aplicados durante o início do desenvolvimento fetal podem alterar o metabolismo da prole, aumentando o risco de doenças na sua vida adulta. A metilação do DNA é um dos mecanismos epigenéticos envolvida nesta programação e regula a expressão gênica. Estudos anteriores verificaram que a periodontite apical (AP) materna em ratas promove em sua prole adulta: resistência insulínica (RI), alteração na etapa inicial do sinal insulínico (SI) no músculo gastrocnêmio (MG) e aumento na concentração plasmática de fator de necrose tumoral-α (TNF-α). O TNF-α pode ativar o fator de transcrição nuclear kappa B (NF-kB) que diminui a expressão gênica do transportador de glicose GLUT4. Nesse contexto, mais estudos são necessários para investigar se as alterações no SI observadas em ratos adultos, proles de ratas com AP também estão presentes na continuidade da cascata insulínica. Ademais, sabendo-se que o estresse oxidativo tem sido implicado como fator contribuinte tanto para o início quanto para a progressão do diabetes, torna-se fundamental verificar o grau de estresse oxidativo tecidual nesta prole adulta. Em vista disso, os objetivos deste estudo foram avaliar a RI, estresse oxidativo, etapa final do SI e via inflamatória no MG de ratos adultos, proles de ratas com AP. Para tanto, as 21 ratas Wistar (2 meses de idade) foram distribuídas em 3 grupos: 1) ratas controle; 2) ratas com 1 AP induzida em 1º molar superior direito; 3) ratas com 4 APs induzidas em 1os e 2os molares superiores e inferiores do lado direito. A AP foi induzida empregandose broca em aço carbono dotada de esfera de 0,1 mm na extremidade. Após 30 dias da exposição pulpar, as ratas de todos os grupos foram colocadas para acasalamento. Quando os filhotes machos de todas as ratas completaram 75 dias de idade, foram realizadas as seguintes análises plasmáticas: 1) glicemia; 2) insulinemia; 3) RI. Ademais, foram realizados os seguintes experimentos no MG: 1) grau de fosforilação em serina/treonina da Akt, após o estímulo insulínico; 2) conteúdo proteico de GLUT4; 3) grau de metilação do DNA na região promotora do gene do GLUT4; 4) expressão gênica do GLUT4 e TNF-α; 5) conteúdo proteico de TNF-α e PGC-1α; 6) grau de fosforilação de NF-kB p50 e NF-kB p65; 7) estresse oxidativo (superóxido dismutase ­ SOD e espécies reativas ao tiobarbitúrico ­ TBARS). A análise estatística foi realizada pela análise de variância, seguida do teste de Tukey. O nível de significância adotado foi de 5%. Os resultados mostraram que AP materna (tanto 1 foco de infecção como 4 focos de infecções) promoveu hiperinsulinemia, RI e diminuição na atividade antioxidante da SOD e na concentração de TBARS no MG de sua prole adulta. Entretanto, somente a AP materna em quatro dentes promoveu aumento na massa corpórea, na ingestão alimentar e no grau de fosforilação das subunidades p50 e p65 do NF-kB no MG de proles adultas. Ademais, houve diminuição no grau de fosforilação em serina e treonina da Akt (após estímulo insulínico) e na expressão gênica e conteúdo proteico de GLUT4 no MG em proles adultas de ratas com 4APs. A AP materna não promoveu alteração na glicemia de jejum, conteúdo de PGC-1α, grau de metilação do DNA na região promotora do gene do GLUT4 e expressão gênica e conteúdo proteico de TNF-α no MG de proles adultas. Esses resultados revelam o impacto que a AP materna tem em longo prazo na predisposição às alterações metabólicas na fase adulta da prole. Isso reforça a importância que a manutenção da saúde bucal materna tem sobre a saúde geral da prole(AU)

Fetal programming suggests that adverse stimuli when applied during early fetal development may alter metabolism of offspring, increasing the risk of disease in adulthood. DNA methylation is one of the epigenetic mechanisms involved in this programming and regulates gene expression. Previous studies have shown that maternal apical periodontitis (AP) in rats promotes in their adult offspring: insulin resistance (IR), alteration in the initial steps of the insulin signaling (IS) in the gastrocnemius muscle (GM) and increase in plasma concentration of tumor necrosis factor-α (TNF-α). TNF-α can activate nuclear transcription factor kappa B (NF-kB) thus decreasing gene expression of the GLUT4 glucose transporter. In this context, more studies are needed to investigate whether changes in IS observed in adult rats, offspring of rats with AP are also present in the continuity of the insulin cascade. In addition, since oxidative stress has been implicated as a contributing factor for both the onset and progression of diabetes, it is essential to verify the degree of tissue oxidative stress in this adult offspring. Therefore, the aims of this study were to evaluate IR, oxidative stress, final steps of IS and inflammatory pathway in the GM of adult rats, offspring of rats with AP. For this purpose, 21 female Wistar rats (2 months of age) were distributed into three groups: 1) control rats (CN); 2) group with one AP induced in the upper right first molar (1AP); 3) group with four APs induced in the first and second upper and lower right molars (4AP). AP was induced using a surgical round bur measuring 0.1 mm in diameter. After 30 days of pulp exposure, female rats of all groups were placed for mating. Pregnant rats were separated into individual cages. When the male offspring of all rats reached 75 days of age, the following plasma analyzes were performed: 1) glycemia; 2) insulinemia; 3) IR. Furthermore, the following analyzes were performed in the GM: 1) Akt serine/threonine phosphorylation status, after insulin stimulation; 2) GLUT4 content; 3) degree of DNA methylation in the proximal promoter region of the GLUT4 gene; 4) GLUT4 and TNF- α gene expression; 5) TNF-α and PGC-1α content; 6) p50 and p65 subunits of NF-kB phosphorylation status; 7) oxidative stress (superoxide dismutase ­ SOD and thiobarbiturate reactive species ­ TBARS). Statistical analyzes were performed by analysis of variance, followed by the Tukey test. The level of significance adopted was 5%. Results showed that maternal AP (both 1 infection focus and 4 infection focus) promoted hyperinsulinemia, IR and decrease in SOD antioxidant activity and TBARS concentration in the GM of their adult offspring. However, only maternal AP in four teeth promoted an increase in body weight, food intake and p50 and p65 subunits of NF-kB phosphorylation status in the GM of adult offspring. Furthermore, there was a decrease in Akt serine and threonine phosphorylation status (after insulin stimulation) and in gene expression and protein content of GLUT4 in the GM in adult offspring of rats with 4APs. Maternal AP did not change fasting glycemia, PGC-1α content, degree of DNA methylation in the proximal promoter region of GLUT4, gene expression and protein content of TNF-α in the GM of adult offspring. These results demonstrate that maternal AP is associated with IR and promotes important alterations in IS and inflammation pathways in adult offspring. This reinforces the importance of maternal oral health on the overall health of offspring(AU)

Vitamin E suppresses aortic ultrastructural alterations induced by toxic doses of monosodium glutamate / La vitamina E suprime las alteraciones ultraestructurales aórticas inducidas por dosis tóxicas de glutamato monosódico

SUMMARY: An association between certain food additives and chronic diseases is reported. Current study determined whether administering toxic doses of the food additive monosodium glutamate (MSG) into rats can induce aortopathy in association with the oxidative stress and inflammatory biomarkers upregulation and whether the effects of MSG overdose can be inhibited by vitamin E. MSG at a dose of (4 mg/kg; orally) that exceeds the average human daily consumption by 1000x was administered daily for 7 days to the rats in the model group. Whereas, rats treated with vitamin E were divided into two groups and given daily doses of MSG plus 100 mg/ kg vitamin E or MSG plus 300 mg/kg vitamin E. On the eighth day, all rats were culled. Using light and electron microscopy examinations, a profound aortic injury in the model group was observed demonstrated by damaged endothelial layer, degenerated smooth muscle cells (SMC) with vacuoles and condensed nuclei, vacuolated cytoplasm, disrupted plasma membrane, interrupted internal elastic lamina, clumped chromatin, and damaged actin and myosin filaments. Vitamin E significantly protected aorta tissue and cells as well as inhibited MSG-induced tissue malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). The highest used vitamin E dosage was more effective. Additionally, a significant correlation was observed between the aortic injury degree and tissue MDA, TNF-α, IL-6, and superoxide dismutase (SOD) levels (p=0.001). Vitamin E effectively protects against aortopathy induced by toxic doses of MSG in rats and inhibits oxidative stress and inflammation.

RESUMEN: Se reporta una asociación entre ciertos aditivos alimentarios y enfermedades crónicas. El objetivo de este estudio fue determinar si la administración de dosis tóxicas del aditivo alimentario glutamato monosódico (MSG) en ratas puede inducir aortopatía en asociación con el estrés oxidativo y la regulación positiva de los biomarcadores inflamatorios y si el efecto de una sobredosis de MSG se puede inhibir con vitamina E. Se administró MSG diariamente durante 7 días una dosis de (4 g/kg; por vía oral) que excede el consumo diario humano promedio, en 1000x a las ratas del grupo modelo. Mientras que las ratas tratadas con vitamina E se dividieron en dos grupos y se administraron dosis diarias de MSG más 100 mg/kg de vitamina E o MSG más 300 mg/kg de vitamina E. Todas las ratas fueron sacrificadas en el octavo día. Usando exámenes de microscopía óptica y electrónica, se observó una lesión aórtica profunda en el grupo modelo demostrada por una capa endotelial dañada, células musculares lisas degeneradas (SMC) con vacuolas y núcleos condensados, citoplasma vacuolado, membrana plasmática rota, lámina elástica interna interrumpida, cromatina agrupada y filamentos de actina y miosina dañados. La vitamina E protegió significativamente el tejido y las células de la aorta, además de inhibir el malondialdehído tisular (MDA) inducido por MSG, la interleucina-6 (IL-6) y el factor de necrosis tumoral alfa (TNF-α). La dosis más alta de vitamina E utilizada fue más efectiva. Además, se observó una correlación significativa entre el grado de lesión aórtica y los niveles tisulares de MDA, TNF-α, IL-6 y superóxido dismutasa (SOD) (p=0,001). La vitamina E efectivamente protege contra la aortopatía inducida por dosis tóxicas de MSG en ratas e inhibe el estrés oxidativo y la inflamación.

Crisis suprarrenal: prevención, corticoterapia y elección del fármaco, revisión de la evidencia actual y recomendaciones / Adrenal crisis: prevention, corticotherapy and choice of the drug, review of current evidence and recommendations

INTRODUCCIÓN. La crisis suprarrenal se refiere a la insuficiencia suprarrenal aguda; la cual es un trastorno en el que la corteza adrenal no produce suficientes hormonas esteroides (en especial cortisol) para satisfacer las demandas del cuerpo, de acuerdo al mecanismo fisiopatológico se la puede clasificar como primaria, secundaria y terciaria, siendo más común en pacientes con insuficiencia suprarrenal primaria. Es una emergencia potencialmente mortal que requiere tratamiento inmediato. OBJETIVO. Establecer una estrategia de prevención y tratamiento de la crisis suprarrenal, así como la farmacoterapia ideal y sus alternativas válidas. MATERIAL Y MÉTODOS. Se realizó una revisión bibliográfica en varias revistas virtuales de alto carácter científico como Cochrane Library, Cochrane Systematic Reviews Database, MEDLINE a través de PubMed y ClinicalTrial.gov. Se seleccionaron revisiones sistemáticas con o sin metaanálisis, ensayos clínicos y recomendaciones de expertos relacionados con prevención y tratamiento de crisis suprarrenal en general. RESULTADOS. Se obtuvieron 1819 resultados, de los cuales se seleccionaron 20 artículos con mayor validez y replicabilidad en el medio para establecer un protocolo unificado de actuación. CONCLUSIÓN. El objetivo de la terapia es el tratamiento de la hipotensión y reversión de las anomalías electrolíticas y de la deficiencia de cortisol. Se deben infundir por vía intravenosa grandes volúmenes (1 a 3 litros) de solución salina al 0,9% o dextrosa al 5% en solución salina al 0,9% y la administración de hidrocortisona (bolo de 100 mg), seguido de 50 mg cada 6 horas (o 200 mg / 24 horas como infusión continua durante las primeras 24 horas). Si no se dispone de hidrocortisona, las alternativas incluyen prednisolona, prednisona y dexametasona.

INTRODUCTION. Adrenal crisis refers to acute adrenal insufficiency; which is a disorder in which the adrenal cortex does not produce enough steroid hormones (especially cortisol) to meet the body's demands, according to the pathophysiological mechanism it can be classified as primary, secondary and tertiary, being more common in patients with primary adrenal insufficiency. It is a life-threatening emergency that requires immediate treatment. OBJECTIVE. To establish a strategy for the prevention and treatment of adrenal crisis, as well as the ideal pharmacotherapy and its valid alternatives. MATERIAL AND METHODS. A literature review was performed in several highly scientific virtual journals such as Cochrane Library, Cochrane Systematic Reviews Database, MEDLINE through PubMed and ClinicalTrial.gov. Systematic reviews with or without meta-analysis, clinical trials and expert recommendations related to prevention and treatment of adrenal crisis in general were selected. RESULTS. A total of 1819 results were obtained, from which 20 articles with greater validity and replicability in the setting were selected to establish a unified protocol for action. CONCLUSIONS. The aim of therapy is the treatment of hypotension and reversal of electrolyte abnormalities and cortisol deficiency. Large volumes (1 to 3 liters) of 0.9% saline or 5% dextrose in 0.9% saline and administration of hydrocortisone (100 mg bolus), followed by 50 mg every 6 hours (or 200 mg / 24 hours as a continuous infusion for the first 24 hours) should be infused intravenously. If hydrocortisone is not available, alternatives include prednisolone, prednisone, and dexamethasone.

Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats / A serotonina endógena e exógena, mas não o sumatriptano, melhora as convulsões e a neuroinflamação no modelo de convulsão induzida por pentilenotetrazol em ratos

ABSTRACT Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

RESUMO Antecedentes: A epilepsia apresenta comorbidades neuropsiquiátricas como depressão, transtorno bipolar e ansiedade. Os medicamentos que visam o tratamento da epilepsia podem ser úteis para a epilepsia e suas comorbidades neuropsiquiátricas. Objetivo: Investigar os efeitos da modulação serotonérgica em citocinas pró-inflamatórias e as convulsões no modelo de convulsão induzida por pentilenotetrazol (PTZ) em ratos. Métodos: Ratos Wistar machos foram injetados intraperitonealmente com serotonina, inibidor seletivo da recaptação da serotonina fluoxetina, sumatriptano agonista do receptor 5-HT1B / D ou solução salina 30 min antes do tratamento com PTZ. As crises comportamentais foram avaliadas pela escala de Racine. As concentrações de IL-1β, IL-6 e TNF-α no soro e tecido cerebral foram determinadas por ELISA. Resultados: A serotonina e a fluoxetina, mas não o sumatriptano, aliviaram as convulsões induzidas por PTZ ao prolongar os tempos de início das convulsões mioclônicas e tônico-clônicas generalizadas. O efeito anticonvulsivo da fluoxetina foi maior do que o da serotonina. Da mesma forma, a serotonina e a fluoxetina, mas não o sumatriptano, reduziram os aumentos induzidos por PTZ nos níveis de IL-1β e IL-6 no soro e no tecido cerebral. Nenhum dos medicamentos administrados, incluindo PTZ, alterou as concentrações de TNF-α. Conclusões: Nossos achados sugerem que a serotonina endógena e exógena exibe efeitos anticonvulsivantes por suprimir a neuroinflamação. Aparentemente, os receptores 5-HT1B / D não medeiam os efeitos anticonvulsivantes e anti-neuroinflamatórios da serotonina.

Detection of respiratory viruses and expression of inflammatory cytokines in patients with acute exacerbation chronic obstructive pulmonary disease in Mongolia China / Detecção de vírus respiratórios e expressão de citocinas inflamatórias em pacientes com doença pulmonar obstrutiva crônica de exacerbação aguda na Mongólia, China

Chronic obstructive pulmonary disease (COPD) was estimated to be the third cause of global mortality by 2020. Acute exacerbation COPD (AECOPD) is a sudden worsening of COPD symptoms and could be due to virus/bacterial infections and air pollution. Increased expression of inflammatory markers in patients with AECOPD is associated with viral infection. This study aimed to detect different viruses and analyze the expression of various inflammatory markers associated with AECOPD patients. Three hundred and forty-seven patients diagnosed with COPD according to GOLD criteria were included in this study. Swab samples and blood were collected for the detection of viruses by RT-PCR and expression of inflammatory markers, respectively. Of the swab samples, 113 (32.6%) of samples were positive for virus detection. Of these, HRV (39.8%) was the predominant virus detected followed by FluB (27.4%) and FluA (22.1%). The presence of HRV was significantly higher (p=0.044) among the other detected viruses. When compared to healthy controls the expression levels of TNF-α, IL-6 and IL-8 were significantly higher (p<0.05) in virus-positive patients. The IL-6 and IL-8 were the next predominantly expressed in markers among the samples. The higher expression rate of IL-8 was significantly (p<0.05) associated with patients having COPD GOLD III severity level and smoking history. Although HRV was the predominant virus detected the combined prevalence of Influenza A and B surpassing the rate of HRV. The high-level expression of well known inflammatory markers of AECOPD, TNF-α, IL-6 and IL-8 indicates a chronic severe illness. These markers play an important role and could be used as a marker for determining the severity of AECOPD.

Estima-se que a doença pulmonar obstrutiva crônica (DPOC) seja a terceira causa de mortalidade global em 2020. A exacerbação aguda DPOC (AECOPD) é um agravamento súbito dos sintomas da DPOC e pode ser devido a infecções por vírus/bactérias e poluição do ar. O aumento da expressão de marcadores inflamatórios em pacientes com AECOPD está associado à infecção viral. Este estudo teve como objetivo detectar diferentes vírus e analisar a expressão de vários marcadores inflamatórios associados a pacientes com AECOPD. Trezentos e quarenta e sete pacientes com diagnóstico de DPOC de acordo com os critérios GOLD foram incluídos neste estudo. Amostras de swab e sangue foram coletadas para detecção de vírus por RT-PCR e expressão de marcadores inflamatórios, respectivamente. Das amostras de esfregaço, 113 (32,6%) amostras foram positivas para detecção de vírus. Nestas, o HRV (39,8%) foi o vírus predominante detectado, seguido do FluB (27,4%) e do FluA (22,1%). A presença de VFC foi significativamente maior (p = 0,044) entre os demais vírus detectados. Quando comparados a controles saudáveis, os níveis de expressão de TNF-α, IL-6 e IL-8 foram significativamente maiores (p <0,05) em pacientes com vírus positivo. A IL-6 e a IL-8 foram as próximas predominantemente expressas em marcadores entre as amostras. A maior taxa de expressão de IL-8 foi significativamente (p <0,05) associada a pacientes com grau de gravidade GOLD III da DPOC e história de tabagismo. Embora o HRV tenha sido o vírus predominante, a prevalência combinada de Influenza A e B ultrapassou a taxa de HRV. O alto nível de expressão de marcadores inflamatórios bem conhecidos de AECOPD, TNF-α, IL-6 e IL-8 indica uma doença crônica grave. Esses marcadores desempenham um papel importante e podem ser usados como um marcador para determinar a gravidade da AECOPD.

The Effect of Anakinra on Acrylamide-induced Peripheral Neuropathy and Neuropathic Pain in Rats

Abstract Acrylamide is a neurotoxic compound. Moreover, anakinra is an interleukin-1 (IL-1) receptor antagonist used in rheumatoid arthritis treatment. This study investigated the effect of anakinra on acrylamide-related neuropathy and neuropathic pain. Acrylamide exposure caused a significant decrease in the pain threshold; an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) levels; and a decrease in total glutathione (tGSH) values in the sciatic nerve. This indicates hyperalgesia presence, oxidative stress, and peripheral nerve tissue inflammation. Anakinra treatment significantly reduced the MDA, IL-1ß, and TNF-α levels, and increased the pain threshold and mean tGSH values. The analgesic effect of anakinra was 67.9% at the first hour, increasing to 74.9% and 76.7% at the second and third hours, respectively. The group receiving acrylamide exhibited histopathological changes (e.g., swollen and degenerated axons, hypertrophic and hyperplasic Schwann cells, and congested vessels). The use of anakinra significantly improved these morphological changes. Anakinra is concluded to reduce neuropathic pain and prevent neurotoxic effect of acrylamide on peripheral nerves due to its analgesic, antioxidant, and anti-inflammatory properties

Avaliação dos tecidos ao redor de implantes osseointegrados com e sem peri-implantite induzida e a relação com a ocorrência de osteonecrose dos maxilares associada à terapia medicamentosa / Tissue evaluation around osseointegrated implants with and without induced peri-implantitis and the relation with the occurrence of medication-related osteonecrosis of the jaw

Objetivo: O objetivo deste trabalho foi avaliar a resposta dos tecidos periimplantares em condições de normalidade e com peri-implantite induzida por ligadura, em implantes osseointegrados na maxila de ratas senescentes submetidas ao tratamento posterior com dosagem oncológica de zoledronato. Material e métodos: Foram utilizadas 28 ratas Wistar (Rattus novergicus) iniciando o experimento com aproximandamente 14 meses de idade e pesando entre 350 e 450g. Os animais foram submetidos à exodontia do incisivo superior direito e instalação imediata de um implante de titânio com 2,5 mm de diâmetro por 5,7 mm de comprimento, onde após quase 2 meses, foi realizada a cirurgia de reabertura dos implantes e instalação de um cicatrizador. Após uma semana, os animais foram divididos de acordo com os seguintes tratamentos: veículo, administração de solução salina estéril 0,9% intraperitoneal (Grupo VEI); zoledronato, com administração de 100 µg/Kg de zoledronato (Grupo ZOL); veículo com peri-implantite experimental (Grupo VEI-PIE) e; zoledronato com peri-implantite experimental (Grupo ZOL-PIE), com a indução da peri-implantite experimental (PIE) por meio de uma ligadura de algodão 5 semanas após o início do tratamento medicamentoso. A porcentagem de tecido ósseo total (PTO-T) e porcentagem de tecido ósseo não vital (PTO-NV) foram analisadas histometricamente, e foram realizadas imunomarcações para fosfatase ácida resistente ao tartarato (TRAP), fator de necrose tumoral alfa (TNFα), interleucina 1 beta (IL1-ß), fator de crescimento endotelial vascular (VEGF) e osteocalcina (OCN). Os dados foram submetidos à análise estatística. Resultados: O grupo ZOL mostrou persistência de inflamação no tecido conjuntivo peri-implantar e uma quantidade considerável de PTO-NV ao redor do implante quando comparado com VEI. A inflamação peri-implantar foi mais exacerbada em ZOL-PIE, assim como, o comprometimento da vitalidade do tecido ósseo ao redor dos implantes quando comparado com VEI-PIE. Conclusão: Conclui-se que o tratamento com altas doses de zoledronato ocasiona alterações ao nível periimplantar, dentre elas, um aumento da inflamação local, e da PTO-NV ao redor do implante osseointegrado, o que pode representar um possível fator de risco para o surgimento da osteonecrose dos maxilares associada à terapia medicamentosa relacionada ao implante odontológico (ONMM-IO). Na presença da PIE há uma exacerbação da inflamação e um aumento ainda maior da PTO-NV, o que implica em um importante fator de risco agravante para o surgimento da ONMM-IO no modelo experimental estudado(AU)

Aim: The aim of this study was to evaluate the response of peri-implant tissues under normal conditions and with ligature-induced peri-implantitis, in osseointegrated implants in the maxilla of senescent rats submitted to subsequent treatment with oncological dosage of zoledronate. Material and methods: Twenty-eight female Wistar rats (Rattus novergicus) were used, starting the experiment at approximately 14 months of age and weighing between 350 and 450g. The animals underwent extraction of the upper right incisor and immediate installation of a titanium implant 2.5 mm wide by 5.7 mm long, where after almost 2 months, surgery to reopen the implants and installation of a healer was performed. After one week, the animals were divided according to the following treatments: vehicle, administration of 0.9% sterile saline intraperitoneally (VEI Group); zoledronate, with administration of 100 µg/Kg of zoledronate (ZOL Group); vehicle with experimental peri-implantitis (VEIPIE Group) and; zoledronate with experimental peri-implantitis (ZOL-PIE Group), with the induction of experimental peri-implantitis (PIE) by means of a cotton suture 5 weeks after the start of drug treatment. The percentage of total bone tissue (PBT-T) and percentage of non-vital bone tissue (PBT-NV) were analyzed histometrically, and immunostaining for tartrate-resistant acid phosphatase (TRAP), tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL1-ß), vascular endothelial growth factor (VEGF) and osteocalcin (OCN). Data were subjected to statistical analysis. Results: The ZOL group showed persistence of inflammation in the peri-implant connective tissue and a considerable amount of PBT-NV around the implant when compared to VEI. Peri-implant inflammation was more exacerbated in ZOL-PIE, as well as compromised bone tissue vitality around the implants when compared to VEI-PIE. Conclusion: It is concluded that treatment with high doses of zoledronate causes changes at the peri-implant level, among them, an increase in local inflammation, and in PBT-NV around the osseointegrated implant, which may represent a possible risk factor for the emergence of medication-related osteonecrosis of the jaws implant- associated (MRONJ-IA). In the presence of PIE, there is an exacerbation of inflammation and an even greater increase in PBT-NV, which implies an important aggravating risk factor for the emergence of MRONJ-IA in the experimental model studied(AU)

Tuberculosis miliar en pacientes en tratamiento con adalimumab, una asociación no tan frecuente en pediatría / Miliary tuberculosis in patients treated with adalimumab, an association not so frequent in pediatrics

Los antagonistas del Factor de Necrosis Tumoral-α, son medicamentos que en los últimos años han tenido un incremento de su uso en pacientes con condiciones inflamatorias inmunomediadas en pediatría, como la Artritis Idiopática Juvenil y la Enfermedad Inflamatoria Intestinal. El uso de estos medicamentos en adultos tiene una fuerte asociación con la primoinfección o reactivación por Mycobacterium tuberculosis, pero en niños la evidencia es limitada. Se presentan 2 casos de pacientes tratados con adalimumab, quienes, a pesar de un buen control de su enfermedad y una prueba de tuberculina negativa al inicio de la terapia, desarrollaron tuberculosis miliar en el seguimiento, con importantes implicaciones para su salud. El tamizaje de tuberculosis latente con tuberculina/IGRAS (Interferón-γ release assays, por sus siglas en inglés) y un alto índice de sospecha de tuberculosis, son las herramientas disponibles para una adecuada identificación de la tuberculosis en pacientes que reciben crónicamente estas terapias.

Tumor Necrosis Factor-α antagonists are drugs that in recent years have seen an increase in their use in patients with immune-mediated inflammatory conditions in pediatrics such as Juvenile Idiopathic Arthritis and Inflammatory Bowel Disease. The use of these drugs in adults has a strong association with primary infection or reactivation by mycobacterium tuberculosis, but in children the evidence is limited. We present 2 cases of patients treated with adalimumab who, despite good control of their disease and a negative tuberculin test at the beginning of therapy, developed miliary tuberculosis during follow-up with important implications for their health. Screening for latent tuberculosis with tuberculin / IGRAS (Interferón-γ release assays) and a high index of suspicion for tuberculosis are the tools available for an adequate identification of tuberculosis in patients who receive these therapies chronically.