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BACKGROUND: Ultraviolet radiation (UV) is the main environmental factor that causes histological degenerative changes of the skin giving rise to a chronic process called photodamage. Non-melanoma skin cancer induced by UVB radiation is a result of a cascade of molecular events caused by DNA damage in epidermis cells, including persistent inflammation, oxidative stress, and suppression of T cell-mediated immunity. Retinoids such as tretinoin have been widely used in skin to treat photoaging and photodamage, though its secondary adverse effects have been recognized. Pirfenidone (PFD) has emerged as an antifibrogenic, anti-inflammatory and antioxidant agent, and in this work its efficacy was evaluated in a model of UVB-induced photodamage. METHODS: Epidermal, dermal, and inflammatory changes were measured by histomorphometric parameters. In addition, gene, and protein expression of key molecules in these processes were evaluated. RESULTS: Our results revealed an anti-photodamage effect of topical PFD with absence of inflammatory skin lesions determined by dermoscopy. In addition, PFD reduced elastosis, improved organization, arrangement, and deposition of dermal collagens, downregulated several pro-inflammatory markers such as NF-kB, IL-1, IL-6 and TNFα, and decreased keratinocyte damage. CONCLUSION: Topical pirfenidone represents a promising agent for the treatment of cell photodamage in humans. Clinical trials need to be carried out to explore this premise.
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Envelhecimento da Pele , Raios Ultravioleta , Animais , Camundongos , Humanos , Raios Ultravioleta/efeitos adversos , Camundongos Pelados , Pele , EpidermeRESUMO
BACKGROUND/OBJECTIVE: Rheumatoid arthritis (RA) patients might experience anxiety and depressive symptoms. Deficient vitamin D levels may be a trigger for these conditions. The aim of this study was to determine the frequency of depression, anxiety symptoms, and suicidal risk or ideation in patients with RA associated with vitamin D serum levels. METHODS: In this cross-sectional study, we recruited RA patients older than 18 years, classified into 3 groups according to serum vitamin D levels: sufficient, ≥30 ng/mL; insufficient, 20-29 ng/mL; and deficient, <20 ng/mL. Based on the self-reported Plutchik and the Hospital Anxiety and Depression Scale, we evaluated the association of suicidal risk, depression, and anxiety with the vitamin D levels in RA and the Rheumatoid Arthritis Quality-of-Life Questionnaire. RESULTS: We studied 72 patients with RA between January and October 2019. We found an inverse correlation between Plutchik score and suicidal risk with inadequate vitamin D levels, but not with the Hospital Anxiety and Depression Scale. Suicidal ideation was associated with a higher score on the Rheumatoid Arthritis Quality-of-Life Questionnaire. CONCLUSIONS: Despite the high prevalence of depressive and anxiety symptoms in RA patients, a Plutchik low correlation coefficient with inadequate serum levels of vitamin D was found. However, in the analysis of covariance, we were able to find that vitamin D levels remain associated with a reduction of suicide ideation. Further studies are needed to identify a risk profile for early psychological interventions to improve the quality of life in RA patients.
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Artrite Reumatoide , Suicídio , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Estudos Transversais , Humanos , Qualidade de Vida/psicologia , Vitamina DRESUMO
PURPOSE: Obesity is associated with systemic insulin resistance and cardiac hypertrophy with fibrosis. Peroxisome proliferator-activated receptors (PPARs) regulate carbohydrate and lipid metabolism, improving insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. We previously demonstrated that prolonged-release pirfenidone (PR-PFD) is an agonistic ligand for Pparα with anti-inflammatory and anti-fibrotic effects, and might be a promising drug for cardiac diseases-treatment. Here, we investigated the effects of PR-PFD in ventricular tissue of mice with nonalcoholic steatohepatitis (NASH) and obesity induced by high-fat/high-carbohydrate (HFHC) diet. METHODS: Five male C57BL/6 J mice were fed with normal diet (ND) and ten with HFHC diet for 16 weeks; at 8 weeks of feeding, five mice with HFHC diet were administered PR-PFD (350 mg/kg/day) mixed with HFHC diet. RESULT: Systemic insulin resistance, heart weight/body weight ratio, myocardial steatosis with inflammatory foci, hypertrophy, and fibrosis were prevented by PR-PFD. In addition, HFHC mice showed significantly increased desmin, Tgfß1, Timp1, collagen I (Col I), collagen III (Col III), TNF-α, and Nrf2 mRNA levels, including α-SMA, NF-kB, Nrf2, troponin I, Acox1, Cpt1A, and Lxrα protein levels compared with the ND ventricular tissues. Mechanistically, HFHC mice with PR-PFD treatment significantly decreased these genes overexpressed by HFHC diet. Furthermore, PR-PFD overexpressed the Pgc1a mRNA levels and Pparα, Pparγ, Acox1, and Cpt1A protein levels. CONCLUSIONS: The results suggest that PR-PFD could be a promising drug for the prevention and treatment of cardiac steatosis and fibrosis induced by obesity.
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Fibrose/prevenção & controle , Cardiopatias/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/fisiopatologia , PPAR alfa/agonistas , Piridonas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Fibrose/fisiopatologia , Cardiopatias/fisiopatologia , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Distribuição AleatóriaRESUMO
Obesity is now a worldwide epidemic ensuing an increase in comorbidities' prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.
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Doenças Cardiovasculares/patologia , Doenças Metabólicas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia , Animais , Doenças Cardiovasculares/etiologia , Humanos , Doenças Metabólicas/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicaçõesRESUMO
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs' critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Hepatopatias/tratamento farmacológico , Hepatopatias/patologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Preparações Farmacêuticas/administração & dosagem , Animais , Humanos , Hepatopatias/metabolismo , Terapia de Alvo MolecularRESUMO
Targeted therapies for regulating processes such as inflammation, apoptosis, and fibrogenesis might modulate human HCC development. Pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory functions in both clinical and experimental studies. The aim of this study was to evaluate PPARγ expression and localization in samples of primary human tumors and assess PFD-effect in early phases of hepatocarcinogenic process. Human HCC tissue samples were obtained by surgical resection. Experimental hepatocarcinogenesis was induced in male Fischer-344 rats. TGF-ß1 and α-SMA expression was evaluated as fibrosis markers. NF-kB cascade, TNFα, IL-6, and COX-2 expression and localization were evaluated as inflammation indicators. Caspase-3, p53, and PARP-1 were used as apoptosis markers, PCNA for proliferation. Finally, PPARα and PPARγ expression were evaluated to understand the effect of PFD on the activation of such pathways. PPARγ expression was predominantly localized in cytoplasm in human HCC tissue. PFD was effective to prevent histopathological damage and TGF-ß1 and α-SMA overexpression in the experimental model. Anti-inflammatory effects of PFD correlate with diminished IKK and decrease in both IkB-phosphorylation/NF-kB p65 expression and p65-translocation into the nucleus. Pro-apoptotic PFD-induced effects are related with p53 expression, Caspase-3 p17 activation, and PARP-1-cleavage. In conclusion, PFD acts as a tumor suppressor by preventing fibrosis, reducing inflammation, and promoting apoptosis in MRHM.
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Carcinoma Hepatocelular/metabolismo , PPAR gama/metabolismo , Piridonas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Carcinogênese , Carcinoma Hepatocelular/prevenção & controle , Fibrose , Inflamação/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/prevenção & controle , Masculino , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Piridonas/metabolismo , Ratos , Ratos Endogâmicos F344 , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Gene therapy using urokinase-type plasminogen activator (uPA) has been shown to induce extracellular matrix degradation, hepatocyte proliferation and liver tissue function restoration in liver cirrhosis models. Physiologically, uPA activates plasminogen conversion to plasmin, which leads, depending on the organ, to thrombolysis or extracellular matrix degradation. The purpose of this study was to compare the regenerative effect of gene therapy with adenoviruses encoding wild-type uPA (huPA), as well as its truncated isoform (ΔhuPA), in healthy and cirrhotic animals. In addition, possible adverse effects on coagulation were assessed. METHODS: 6 x 1011 vp/kg of Ad-huPA or Ad-ΔhuPA were administered via the iliac vein to healthy male Wistar rats or to male Wistar rats with cirrhosis induced by chronic poisoning with carbon tetrachloride (CCl4). The animals were sacrificed at day 2, 4 or 6 post-treatment. Liver fibrosis, proliferating cell nuclear antigen expression, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels and coagulation markers were evaluated. RESULTS: On day 6 post-treatment, a fibrosis reversal of 48.7-41.5% was achieved. AST and ALT levels did not change in cirrhotic animals treated with ΔhuPA, but showed an elevation in healthy animals. Cell proliferation increased in healthy and cirrhotic animals with both transgene isoforms. No coagulation adverse effects were observed in the ΔhuPA group, and by day 6, they had disappeared in the huPA group. CONCLUSIONS: Gene therapy with Ad-huPA and Ad-ΔhuPA favors cell proliferation in cirrhotic animals, without important side effects.
ANTECEDENTES Y OBJETIVOS: La terapia génica empleando el activador de plasminógeno tipo urocinasa (huPA) ha demostrado que induce la degradación de matriz extracelular, la proliferación de hepatocitos y el restablecimiento de la funcionalidad tisular en modelos de cirrosis hepática. Fisiológicamente, el uPA activa la conversión del plasminógeno en plasmina, lo que conlleva, dependiendo del órgano, una trombólisis o a degradación de la matriz extracelular. El objetivo de este estudio fue comparar el efecto regenerador de la terapia génica con adenovirus codificando la forma silvestre (huPA), así como su isoforma truncada (DhuPA) en animales sanos y cirróticos. Además, se valoraron los posibles efectos adversos sobre la coagulación. MÉTODOS: Se administró 6x1011 pv/kg del Ad-huPA o Ad-ΔhuPA a ratas Wistar macho sanas o con cirrosis por intoxicación crónica con tetracloruro de carbono (CCl4) vía vena ilíaca. El sacrificio fue al día 2, 4 o 6 postratamiento. Se evaluó la fibrosis hepática, la expresión de antígeno nuclear de proliferación celular y niveles séricos de alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST), y marcadores de coagulación. RESULTADOS: Al día 6 postratamiento se alcanzó una reversión de fibrosis del 48.7-41.5%. Los niveles de AST y ALT no cambiaron en animales cirróticos tratados con DhuPA, pero aumentaron en animales sanos comparados con el control sano no tratado. La proliferación aumenta en animales sanos y cirróticos con ambas isoformas del transgén. No se observaron efectos adversos en la coagulación en el grupo DhuPA y para el día 6 habían desaparecido en el grupo huPA. CONCLUSIONES: La terapia génica con Ad-uPA y Ad-ΔhuPA favorece la proliferación celular en animales cirróticos, sin efectos secundarios importantes.
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Fígado , Ativador de Plasminogênio Tipo Uroquinase , Animais , Tetracloreto de Carbono , Terapia Genética , Masculino , Ratos , Ratos Wistar , Ativador de Plasminogênio Tipo Uroquinase/genéticaRESUMO
PURPOSE: Solid organ transplant recipients are highly susceptible to Toxoplasma gondii infection. We aimed to describe the 12-month follow-up risk of seroconversion in renal transplant recipients. METHODOLOGY: Anti-T gondii antibodies were investigated in donors and recipients of renal transplants. In donors, anti-T gondii were evaluated before transplantation. In recipients, anti-T gondii were monitored over a 12-month period to evaluate potential seroconversion or reactivation. IgG and IgM anti-T gondii antibodies were investigated through enzyme immunoassay and Western blot. Molecular diagnosis was performed on peripheral blood leukocytes using PCR to amplify fragments corresponding to the T gondii B1 gene and the repetitive 529-bp element. RESULTS: The basal frequency of seropositive IgG anti-T gondii antibodies was higher in donors than in recipients (38.4% vs 25.2%; P = .03). During the 12-month follow-up, the accumulated seroconversion to IgG and IgM antibodies was 3/99 (3.0%), and the accumulated reactivation was 11/99 (11.0%). None of the samples exhibited positivity to T gondii DNA. CONCLUSIONS: This study showed that there is an increased risk of seroconversion or reactivation in renal transplant recipients over a 12-month follow-up. Our data suggest that prophylaxis with trimethoprim and sulfamethoxazole effectively prevented toxoplasmosis, since neither T gondii DNA nor clinical toxoplasmosis was detected.
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Anticorpos Antiprotozoários/sangue , Doadores de Tecidos/estatística & dados numéricos , Toxoplasmose/diagnóstico , Transplantados/estatística & dados numéricos , DNA de Protozoário , Seguimentos , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Transplante de Rim , Estudos Longitudinais , México , Soroconversão , Toxoplasma/genéticaRESUMO
BACKGROUND: The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson's disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion recovers from parkinsonism. The plasmids phDAT-BDNF-flag and phDAT-EGFP, coding for enhanced green fluorescent protein, were transfected using neurotensin (NTS)-polyplex, which enables delivery of genes into the dopaminergic neurons via neurotensin-receptor type 1 (NTSR1) internalization. RESULTS: Two weeks after transfections, RT-PCR and immunofluorescence techniques showed that the residual dopaminergic neurons retain NTSR1 expression and susceptibility to be transfected by the NTS-polyplex. phDAT-BDNF-flag transfection did not increase dopaminergic neurons, but caused 7-fold increase in dopamine fibers within the SN and 5-fold increase in innervation and dopamine levels in the striatum. These neurotrophic effects were accompanied by a significant improvement in motor behavior. CONCLUSIONS: NTS-polyplex-mediated BDNF overexpression in dopaminergic neurons has proven to be effective to remit hemiparkinsonism in the rat. This BDNF gene therapy might be helpful in the early stage of Parkinson's disease.
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Fator Neurotrófico Derivado do Encéfalo/biossíntese , Neurônios Dopaminérgicos , Neurotensina , Doença de Parkinson , Substância Negra , Transfecção/métodos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Terapia Genética/métodos , Masculino , Neurotensina/química , Neurotensina/farmacologia , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Ratos , Ratos Wistar , Receptores de Neurotensina/metabolismo , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
Pirfenidone (PFD) is a non-peptide synthetic molecule issued as a broad-spectrum anti-fibrotic drug with the ability to decrease TGF-ß1, TNF-α, PDGF and COL1A1 expression, which is highly related to prevent or remove excessive deposition of scar tissue in several organs. Basic and clinical evidence suggests that PFD may safely slow or inhibit the progressive fibrosis swelling after tissue injuries. Furthermore, a number of evidence suggests that this molecule will have positive effects in the treatment of other inflammatory diseases. This review contains current research in which PFD has been used as the treatment of several diseases, and focus mainly in the outcomes related to improve inflammation and fibrogenesis. Therefore, the main goal of this review is to focus on the novel findings of PFD efficacy rather than deepen in the chemical aspects of the molecule.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose/tratamento farmacológico , Piridonas/uso terapêutico , Animais , Olho/patologia , Humanos , Rim/patologia , Cirrose Hepática/tratamento farmacológico , Miocárdio/patologia , Fibrose Pulmonar/tratamento farmacológico , Piridonas/efeitos adversosRESUMO
OBJECTIVE: The study aimed to assess the effect of a symbiotic gel on presence and severity of gastrointestinal symptoms (GIS) in hemodialysis patients. DESIGN: A double-blinded, placebo-controlled, randomized, clinical trial was designed. The study was conducted at 2 public hospitals in Guadalajara, Mexico. SUBJECTS AND INTERVENTION: Twenty-two patients were randomized to the intervention group (nutritional counseling + symbiotic gel) and 20 patients were randomized to the control group (nutritional counseling + placebo), during 2 months of follow-up. MAIN OUTCOME MEASURE: Presence and monthly episodes of GIS were assessed by direct interview and severity by using the self-administered GIS questionnaire. Additionally, biochemical parameters, inflammatory markers, and nutritional status (dietary intake, subjective global assessment, anthropometry, and body composition) were evaluated. RESULTS: After a 2-month treatment, intervention group had a significant reduction in prevalence and monthly episodes of vomit, heartburn, and stomachache, as well as a significant decrease in GIS severity compared with control group. Moreover, intervention group had a greater yet not significant decrease in the prevalence of malnutrition and a trend to reduce their C-reactive protein and tumor necrosis factor α levels compared with control group. No symbiotic-related adverse side effects were shown in these patients. Clinical studies with longer follow-up and sample size are needed to confirm these results. CONCLUSIONS: We concluded that administration of a symbiotic gel is a safe and simple way to improve common GIS in dialysis patients.
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Gastroenteropatias/prevenção & controle , Inflamação/prevenção & controle , Inulina/administração & dosagem , Prebióticos/administração & dosagem , Probióticos/administração & dosagem , Diálise Renal/efeitos adversos , Adulto , Bifidobacterium , Método Duplo-Cego , Feminino , Gastroenteropatias/epidemiologia , Humanos , Inflamação/epidemiologia , Lactobacillus acidophilus , Masculino , Desnutrição/epidemiologia , Desnutrição/prevenção & controle , México/epidemiologia , Pessoa de Meia-Idade , Terapia Nutricional , Placebos , SimbioseRESUMO
BACKGROUND: The aim of this study was to assess whether two-years treatment with Pirfenidone influences necroinflammation, fibrosis and steatosis, serum levels of TGF-ß1, IL-6, TNF-α and CB1 and CB2 gene expression, in patients with chronic hepatitis C (CHC). METHODS: Twenty-eight patients out of 34 with CHC virus infection were enrolled in the study and received Pirfenidone (1200 mg/day) for 24 months. Six patients dropped out after 12 months of PFD. Liver biopsies and serum samples were obtained at the beginning and end of treatment. Modified HAI was calculated. CB1 and CB2 gene expression was correlated with fibrosis progression alongside with necroinflammation and steatosis. TGF-ß1, IL-6, TNF-α and liver transaminases were measured in serum at two-months intervals. HCV genotype and viral load were also assessed. Quality of life was evaluated by SF36 questionnaires and the prognosis of disease was assessed with Child-Pugh score. The Wilcoxon test matched-pair signed ranks were used to analyze the outcomes. RESULTS: Intention to treat analyses were performed for biochemistry and clinical parameters. At the end of treatment, necroinflammation grading was reduced in an average of 3.2 points in 82% of patients (p < 0.05) and Ishak's fibrosis stage decreased 2-points average in 67% of patients (p < 0.05). Steatosis decreased in 61% of patients. IL-6 and TGF-ß1 serum levels decreased significantly in 93% and 67% of patients (p < 0.05), respectively, while TNF-α diminished in 47% of patients. ALT and AST tended to normalize in 81% of patients; CB2 mRNA levels increased in 86% and CB1 expression diminished in 29% of patients. Both, quality of life and Child-Pugh score improvements were reported in all patients. CONCLUSIONS: Pirfenidone for two years benefits CHC patients and improves inflammation, fibrosis and steatosis in higher number of patients as previously shown for 12-months treatment with PFD. Additionally, PFD improved TGFß1 and IL-6 levels and diminished liver expression of anti-fibrogenic receptor CB2. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02161952. Protocol Registration Date: 06/11/2014.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Citocinas/imunologia , Hepatite C Crônica/tratamento farmacológico , Fígado/patologia , Piridonas/uso terapêutico , RNA Mensageiro/genética , Idoso , Estudos de Coortes , Fígado Gorduroso/patologia , Feminino , Expressão Gênica , Hepatite C Crônica/genética , Hepatite C Crônica/imunologia , Humanos , Interleucina-6/imunologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta1/imunologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
INTRODUCTION: Orthodontic tooth movement implies application of forces that generate an inflammatory process. The myeloperoxidase (MPO) enzyme is found inside neutrophil granules. MPO activity indirectly reflects the level of inflammation. The aim of this study was to measure MPO activity in gingival crevicular fluid (GCF) and whole saliva in orthodontic patients with different levels of dental crowding at the alignment phase of orthodontic treatment with the same archwires. METHODS: Twenty patients were classified according to the irregularity index into 2 groups: severe and minimum crowding (10 in each group). MPO activity was evaluated in GCF and saliva at 0 and 2 hours, and 7 and 14 days after the orthodontic appliances were activated. MPO activity was measured using the modified Bradley-Bozeman technique. RESULTS: In both groups, the maximum activity was at 2 hours (P <0.05) after activation. MPO activity remained elevated until day 7, and values similar to baseline were found at day 14 in the GCF and saliva samples. Enzymatic activity did not show statistical differences between the groups. CONCLUSIONS: The amount of dental crowding does not seem to influence MPO activity, which showed similar patterns in GCF and saliva, but the values in GCF reflected the inflammatory changes more accurately than did the values in saliva. The quantification of MPO activity is a useful biologic marker as an indirect measurement of inflammation generated with tooth movement independent of the amount of crowding.
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Líquido do Sulco Gengival/enzimologia , Má Oclusão/terapia , Peroxidase/análise , Saliva/enzimologia , Técnicas de Movimentação Dentária/métodos , Biomarcadores/análise , Ligas Dentárias/química , Elastômeros/química , Feminino , Seguimentos , Humanos , Masculino , Má Oclusão/classificação , Níquel/química , Braquetes Ortodônticos , Fios Ortodônticos , Proteínas e Peptídeos Salivares/análise , Titânio/química , Técnicas de Movimentação Dentária/instrumentação , Adulto JovemRESUMO
BACKGROUND: Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. AIM: To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). MATERIAL AND METHODS: HepG2 cells and primary HSC cultures were exposed to menadione 0.1 µM (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 µM, 100 µM y 1000 µM). RESULTS: In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-ß1, TIMP1, IL6, TNFα and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. CONCLUSION: Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes.
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Antioxidantes/farmacologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Piridonas/farmacologia , Ácido Tióctico/farmacologia , Células Cultivadas , Humanos , Oxirredução/efeitos dos fármacosRESUMO
Obesity has increasingly become a worldwide epidemic, as demonstrated by epidemiological and clinical studies. Obesity may lead to the development of a broad spectrum of cardiovascular diseases (CVDs), such as coronary heart disease, hypertension, heart failure, cerebrovascular disease, atrial fibrillation, ventricular arrhythmias, and sudden cardiac death. In addition to hypertension, there are other cardiometabolic risk factors (CRFs) such as visceral adiposity, dyslipidemia, insulin resistance, diabetes, elevated levels of fibrinogen and C-reactive protein, and others, all of which increase the risk of CVD events. The mechanisms involved between obesity and CVD mainly include insulin resistance, oxidative stress, inflammation, and adipokine dysregulation, which cause maladaptive structural and functional alterations of the heart, particularly left-ventricular remodeling and diastolic dysfunction. Natural products of plants provide a diversity of nutrients and different bioactive compounds, including phenolics, flavonoids, terpenoids, carotenoids, anthocyanins, vitamins, minerals, fibers, and others, which possess a wide range of biological activities including antihypertensive, antilipidemic, antidiabetic, and other activities, thus conferring cardiometabolic benefits. In this review, we discuss the main therapeutic interventions using extracts from herbs and plants in preclinical and clinical trials with protective properties targeting CRFs. Molecular mechanisms and therapeutic targets of herb and plant extracts for the prevention and treatment of CRFs are also reviewed.
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The aim of this work was to assess the tolerability, safety, and efficacy of an ophthalmic topical formulation containing helenalin from Arnica montana and hyaluronic acid 0.4% (HA) in patients with mild-to-moderate Dry Eye Disease (DED) exhibiting positive Matrix Metalloproteinase 9 (MMP-9) test results. Tolerability and safety were evaluated in 24 healthy subjects. Participants were instructed to apply one drop of the formulation three times a day in the study eye, for 2 weeks, followed by a clinical follow-up of 21 days. Efficacy was studied in 48 DED patients randomized into Study (Group 1/receiving the studied formulation) or Control (Group 2/Receiving HA 0.4% eye lubricant) groups for 1 month. Assessments included an MMP-9 positivity test, conjunctival impression cytology (CIC), Ocular Surface Disease Index (OSDI), non-invasive film tear breakup time (NIBUT), non-invasive average breakup time (NIAvg-BUT), ocular surface staining, Schirmer's test, and meibomiography. A crossover design with an additional 1-month follow-up was applied to both groups. Healthy subjects receiving the studied formulation exhibited good tolerability and no adverse events. Regarding the efficacy study, Group 1 exhibited a statistically significant reduction in the MMP-9 positivity rate compared to Group 2 (p < 0.001). Both Group 1 and Group 2 exhibited substantial improvements in OSDI and NIBUT scores (p < 0.001). However, Group 1 demonstrated a significant improvement in NI-Avg-BUT and Schirmer's test scores (p < 0.001), whereas Group 2 did not (p > 0.05). Finally, after the crossover, the proportion of MMP-9-positive subjects in Group 1 increased from 25% to 91.6%, while Group 2 showed a significant decrease from 87.5% to 20.8%. Overall, the topical formulation containing sesquiterpene helenalin from Arnica montana and hyaluronic acid was well tolerated and exhibited a favorable safety profile. Our formulation reduces DED symptomatology and modulates the ocular surface inflammatory process; this is evidenced by the enhancement of CIC, the improvement of DED-related tear film status, and the reduction of the MMP-9 positivity rate.
RESUMO
Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, ß-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.
Assuntos
Carcinoma Hepatocelular , DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA , Antígeno Nuclear de Célula em Proliferação , Piridonas , Animais , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Piridonas/farmacologia , Ratos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Células Hep G2 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Masculino , Ratos Endogâmicos F344 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Dietilnitrosamina , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/genéticaRESUMO
Microbial community control is crucial for maintaining homeostasis of the gut-liver axis in metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we show that supplementation with a mixture of Mexican foodstuffs (MexMix)-Opuntia ficus indica (nopal), Theobroma cacao (cocoa) and Acheta domesticus (crickets)-enriches several beneficial taxa in MASLD mice and overweight/obese humans. Thus, MexMix induces an important prebiotic effect. In mice, a restoration of intestinal health was observed due to the increased short-chain fatty acids (SCFAs) and intestinal crypt depth, Ocln and Cldn1 expression, and decreased Il6 and Tnfa expression. MexMix significantly reduced steatosis in the mice's liver and modified the expression of 1668 genes. By PCR, we corroborated a Tnfa and Pparg decrease, and a Cat and Sod increase. In addition, MexMix increased the hepatic NRF2 nuclear translocation and miRNA-34a, miRNA-103, and miRNA-33 decline. In overweight/obese humans, MexMix improved the body image satisfaction and reduced the fat intake. These findings indicate that this new food formulation has potential as a therapeutic approach to treat conditions associated with excessive consumption of fats and sugars.
RESUMO
BACKGROUND: Breast capsular contracture (BCC) is a commonly adverse event postmammoplastly characterized by an immune response mediated by cytokines and transforming growth factor (TGF)-ß1 resulting in excessive synthesis and deposit of extracellular matrix around the breast implant. Presence of TGF-ß1 polymorphisms has been associated as a risk factor to develop fibroproliferative diseases. METHODS: This open, controlled, prospective, and pilot clinical trial with 6 months duration was carried out to evaluate the efficacy of 1800 mg a day, of oral Pirfenidone (PFD) in the treatment of BCC (Baker Score III/IV) postmammoplasty. Twenty BCC cases received PFD and 14 BCC control cases underwent capsulectomy after 6 months of enrollment. Both groups were followed up for 6 more months up to 12 months to determine the relapse in the absence of PFD. Determination of TGF-ß1 polymorphisms was performed to establish a correlation with capsular contracture. RESULTS: PFD group experienced BCC-reduction in all breasts 6 months after enrollment. Only 1 of 20 cases relapsed after follow-up. In capsulectomy group, 2 of 14 cases presented progression to grade IV during presurgical period. All capsulectomy cases relapsed at end of follow-up. Nearly hundred percent of all patients studied in this protocol had a profibrogenic homozygous TGF-ß1 polymorphism (codon 25; genotype Arg25Arg). CONCLUSIONS: PFD is useful to improve BCC (Baker Score III/IV) postmammoplasty with no relapse after drug administration. There is also an association between capsular contracture and the presence of homozygous G/G TGF-ß1 genotype.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Implante Mamário/instrumentação , Implantes de Mama , Contratura Capsular em Implantes/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Piridonas/uso terapêutico , Fator de Crescimento Transformador beta1/genética , Administração Oral , Adulto , Esquema de Medicação , Feminino , Seguimentos , Marcadores Genéticos , Homozigoto , Humanos , Contratura Capsular em Implantes/diagnóstico por imagem , Contratura Capsular em Implantes/genética , Contratura Capsular em Implantes/cirurgia , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Estudos Prospectivos , UltrassonografiaRESUMO
BACKGROUND: This case report assesses the effectiveness of surgery plus pirfenidone (PFD) as a concomitant therapy in the management of facial trauma after severe dog bite. METHODS: A 16-month-old female patient who suffered a severe attack by a big-sized dog (Rottweiler) in the midface area was managed with surgery/PFD combination and followed up for 20 months to evaluate the efficacy to control, prevent, and improve injury sequels. RESULTS: Surgery/PFD combination offered a good complementary therapy downregulating inflammatory activity, improving blood supply, and activating cytokine modulation and collagen synthesis/biosynthesis (scar control). No side effects were reported in this case report. CONCLUSIONS: Surgery/PFD management for severe facial dog bites represents a safe and effective therapeutic option to protect and improve a patient's quality of life, minimizing long-time sequels.