4,4-Diallyl curcumin bis(2,2-hydroxymethyl)propanoate ameliorates nonalcoholic steatohepatitis in methionine-choline-deficient diet and Western diet mouse models.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that causes severe liver damage, fibrosis, and scarring. Despite its potential to progress to cirrhosis or hepatic failure, approved drugs or treatments are currently unavailable. We developed 4,4-diallyl curcumin bis(2,2-hydroxymethyl)propanoate, also known as 35e, which induces upregulation of mitochondrial proteins including carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II, heat shock protein 60, and translocase of the outer mitochondrial membrane 20. Among these proteins, the upregulated expression of CPT-I was most prominent. CPT-I plays a crucial role in transporting carnitine across the mitochondrial inner membrane, thereby initiating mitochondrial ß-oxidation of fatty acids. Given recent research showing that CPT-I activation could be a viable pathway for NASH treatment, we hypothesized that 35e could serve as a potential agent for treating NASH. The efficacy of 35e in treating NASH was evaluated in methionine- and choline-deficient (MCD) diet- and Western diet (WD)-induced models that mimic human NASH. In the MCD diet-induced model, both short-term (2 weeks) and long-term (7 weeks) treatment with 35e effectively regulated elevated serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) concentrations and histological inflammation. However, the antisteatotic effect of 35e was obtained only in the short-term treatment group. As a comparative compound in the MCD diet-induced model, curcumin treatment did not produce significant regulatory effects on the liver triglyceride/total cholesterol, serum ALT/AST, or hepatic steatosis. In the WD-induced model, 35e ameliorated hepatic steatosis and hepatic inflammation, while increasing serum AST and hepatic lipid content. A decrease in epididymal adipose tissue weight and serum free fatty acid concentration suggested that 35e may promote lipid metabolism or impede lipid accumulation. Overall, 35e displayed significant antilipid accumulation and antifibrotic effects in the two complementary mice models. The development of new curcumin derivatives with the ability to induce CPT-I upregulation could further underscore their efficacy as anti-NASH agents.

Activation of free fatty acid receptors, FFAR1 and FFAR4, ameliorates ulcerative colitis by promote fatty acid metabolism and mediate macrophage polarization.

OBJECTIVE: To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization. METHODS: Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry. RESULTS: The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments. CONCLUSION: Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.

Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.

Propionate alleviates itch in murine models of atopic dermatitis by modulating sensory TRP channels of dorsal root ganglion.

BACKGROUND: Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism. METHODS: Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary-cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two-photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism. RESULTS: Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper-excitability in sensory neurons in MC903-induced AD model, and inhibited capsaicin-evoked hTRPV1 currents (IC50 = 20.08 ± 1.11 µM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene-related peptide by nerves in MC903-induced AD mouse model, which further attenuated itch and skin inflammation. CONCLUSION: Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD.

Efecto de los corticoesteroides intranasales tópicos en los valores de eosinófilos en mucosa nasal en pacientes adultos con rinitis alérgica / Effect of topical intranasal corticosteroids on eosinophil values in nasal mucosa in adult patients with allergic rhinitis / Efeito dos corticosteróides intranasais tópicos nos valores de eosinófilos na mucosa nasal em pacientes adultos com rinite alérgica

INTRODUCCIÓN: La citología nasal es utilizada como método complementario diagnóstico de la rinitis y el hallazgo de eosinófilos; en la misma aumenta la sensibilidad para confirmar una alergia a casi el 80%. Los corticoesteroides intranasales tópicos se utilizan actualmente como primera línea de tratamiento de la rinitis porque reducen la inflamación de la mucosa que subyace a los signos y síntomas de la enfermedad. MATERIAL Y MÉTODOS: Estudio observacional, retrospectivo y analítico. Se incluyeron pacientes entre 16 a 65 años edad inclusive, que consultaron al Servicio de Otorrinolaringología y Alergia e Inmunología de la Clínica Universitaria Reina Fabiola entre agosto de 2016 y julio de 2017 con diagnóstico de rinitis alérgica. La información de las variables cuantitativas se sometió a una comprobación estadística realizada mediante el test de Wilcoxon apareado. Se consideró significativo un valor de p<0,05…

INTRODUCTION: Nasal cytology is used as a complementary diagnostic method of rhinitis and the finding of eosinophils in it increases the sensitivity to confirm an allergy to almost 80%. Topical intranasal corticosteroids are currently used as the first line of treatment for rhinitis because they reduce the inflammation of the mucosa that underlies the signs and symptoms of the disease. MATERIAL AND METHODS: Observational, retrospective and analytical study. Patients between the ages of 16 and 65 years were included, who consulted the Otorhinolaryngology and Allergy and Immunology Department of the Reina Fabiola University Clinic between August 2016 and July 2017 with a diagnosis of allergic rhinitis. The information of the quantitative variables was subjected to a statistical check carried out by means of the paired Wilcoxon test. A value of p...

Nuevas estrategias farmacológicas para el tratamiento del hígado graso no alcohólico / New pharmacological strategies for the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents an increasing health problem in Chile and worldwide. In some cases NAFLD presents with a progressive form that can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current pharmacological therapies (pioglitazone and vitamin E) show limited response and are associated to significant adverse effects. During recent years several novel and promising pharmacological therapies have been developed to prevent fibrosis, liver cirrhosis and reduce liver related deaths. The present article summarizes some of these promising strategies, including reported efficacy in clinical trials and associated adverse effects. Hopefully in the near future these new therapies will help to improve NAFLD management and reduce liver related complications.

El hígado graso no alcohólico (HGNA) es un creciente problema de salud pública en Chile y el mundo. En un subgrupo de sujetos, el HGNA puede presentarse con un fenotipo de daño hepático progresivo que puede evolucionar a fibrosis progresiva, cirrosis y carcinoma hepatocelular. Las estrategias farmacológicas actuales (pioglitazona y vitamina E) presentan eficacia limitada y no están exentas de efectos adversos. Durante los últimos años se han desarrollado múltiples estrategias farmacológicas novedosas y promisorias que buscan evitar la progresión hacia cirrosis y reducir la mortalidad de causa hepática. El presente artículo resume los principales nuevos fármacos, los efectos beneficiosos reportados y sus efectos adversos. Es de esperar que en un futuro próximo estas terapias permitan cambiar el pronóstico de nuestros pacientes con HGNA.

El impacto de los nuevos corticosteroides tópicos en el tratamiento de la dermatitis atópica / The impact of new topical corticosteroids on the management of atopic dermatitis

La dermatitis atópica es una frecuente enfermedad inflamatoria cutánea de los niños. Aunque las formas graves requieren terapias agresivas (corticosteroides sistémicos, ciclosporina), en la mayoría de los casos el uso de los corticoides tópicos pueden resultar satisfactorio. En los últimos 10 años han aparecido nuevos preparados de uso tópico eficaces y seguros. Las características comunes a todos ellos son su potencia alta tipo clase III y la escasez de efectos secundarios. Entre ellos se encuentran la budesonida, prednicarbato, metilprednisolona aceponato, furoato de mometasona y propionato de fluticasona. Los pacientes afectados por dermatitis atópica tienen un alto riesgo de desarrollar una sensibilización a los corticoides. Éste es uno de los efectos secundarios más importantes causados por los nuevos corticoides, en particular la budesonida (AU)

Efeitos do lactato de amônio tópico sobre a atrofia cutânea causada por um corticosteróide tópico potente / Effects of topical ammonium lactate on cutaneous atrophy from a potent topical corticosteroid

Histórico: Os corticosteróides tópicos produzem alteraçöes atróficas na pele, inclusive diminuiçäo da espessura da epiderme e da substância essencial dérmica. Observamos que o lactato de amônio a 12 por cento produziu aumento da espessura da epiderme e aumento na qualidade de glicosaminoglicanos dérmicos. Objetivo: Determinar se o lactato de amônio a 12 por cento poderia minimizar a atrofia cutânea produzida por um corticosteróide tópico potente. Métodos: Ambos, o propionato de clobetasol e o lactato de amônio a 12 por cento, foram aplicados repetidas vezes sob patches oclusivos, bem como em patches abertos nos antebraços de voluntários durante 3 a 4 semanas. As amostras para biópsia foram avaliadas por análise de imagem quanto à espessura da epiderme e quanto à quantidade de glicosaminoglicanos dérmicos. Resultados: O lactato de amônio a 12 por cento atenuou significativamente a atrofia da epiderme e da derme sem nenhuma influência sobre a biodisponibilidade ou sobre as propriedades antiinflamatórias do corticosteróide. Conclusäo: O lactato de amônio a 12 por cento pode ser útil na atenuaçäo dos efeitos adversos do corticosteróide na pele

Experiencias clínicas con ácido tiaproténico inyectable en diferentes enfermedades reumáticas: estudio multicéntrico / Clinical trials with intramuscular tiaprofenic acid in different rheumatic diseases: a multicenter study

Se realizó un estudio multicéntrico abierto, en el que participaron 55 investigadores de siete ciudades de la república, para determinar la eficacia y seguridad del ácido tiaprofénico* a dosis de 200 mg cada 12 h por vía intramuscular en 487 pacientes con diferentes padecimientos reumáticos agudos o crónicos en fase de agudización. Se valoraron, antes y después del tratamiento, los siguientes parámetros: dolor, aumento de volumen, limitación funcional y rigidez matutina. Al final del estudio se observó una disminución estadísticamente significativa (p<0.01 y p<0.005) en todos los diagnósticos. Se valoró el tiempo de instalación del efecto antálgico, el cual instaló en menos de 60 minutos en el 85%, con una duración de ocho a 12 horas, en más de 50% de los casos. En la valoración global se catalogó el efecto como: bueno, muy bueno y excelente, en más del 84% para el total de casos, según paciente e investigador. No se registraron efectos indeseables de importancia

Eficacia del ácido tiaprofénico en lesiones traumáticas agudas / Efficiency of thiaprophenic acid in traumatic lesions

Se realizó un estudio abierto no comparativo para valorar eficacia y tolerancia del ácido tiaprofénico en el tratamiento de lesiones traumáticas agudas, producidas durante la actividad deportiva. Se estudiaron 50 pacientes masculinos cocn lesiones traumáticas diversas. Los parámetros valorados fueron: dolor, aumento de volumen y limitación funcional antes y después del tratamiento, obteniéndose mejoría significativa (p < 0.005) después de cinco días de tratamiento. La instalación del efecto antálgico en 92% de los casos fue dentro de los primeros 30 minutos y la duración del efecto fue de ocho a 12 horas en 82%. La valoración global muestra resultados excelentes y buenos en 88 y 92% según pacientes e investigador. El ácido tiaprofénico fue bien tolerado. Se concluye que el ácido tiaprofénico por su rápido efecto antinflamatorio y natálgico como por su buena tolerancia, es un medicamento eficaz en el tratamiento de las lesiones traumapticas agudas

El ácido tiaprofénico en el tratamiento de la etapa inflamatoria aguda de la osteartrosis: estudio multicéntrico / Triapofenic acid in the management of the acute inflamatory stage of osteoarthrosis

El ácido tiaprofénico en dosis de 300 mg por vez, ha demostrado en el análisis realizado sobre 3052 pacientes: alta eficacia, rapidez de acción, y excelente tolerancia en el tratamiento de la etapa inflamatoria aguda de los procesos osteoartrósicos en sus diversas localizaciones (AU)

El ácido tiaprofénico en el tratamiento de la etapa inflamatoria aguda de la osteartrosis: estudio multicéntrico / Triapofenic acid in the management of the acute inflamatory stage of osteoarthrosis

El ácido tiaprofénico en dosis de 300 mg por vez, ha demostrado en el análisis realizado sobre 3052 pacientes: alta eficacia, rapidez de acción, y excelente tolerancia en el tratamiento de la etapa inflamatoria aguda de los procesos osteoartrósicos en sus diversas localizaciones