Intraarticular monomethyl fumarate as a perspective therapy for osteoarthritis by macrophage polarization.

BACKGROUND: Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF). RESULTS: DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats' joints on the seventh day (inflammatory phase). CONCLUSIONS: Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.

Effects of grape juice intake on the cell migration properties in overweight women: Modulation mechanisms of cell migration in vitro by delphinidin-3-O-glucoside.

Overweight and obesity are typical conditions of chronic low-intensity systemic inflammatory responses, and both have become more common in recent decades, which emphasizes the necessity for healthier diet intake. Fruits such as grapes are rich in anthocyanins, one of which is delphinidin, a promising chemopreventive agent with anti-inflammatory properties. Considering that polymorphonuclear cells (PMNs) are rapidly mobilized to tissues when the inflammatory process is initiated, this study aimed to understand the impact of grape juice intake and delphinidin on the migration properties of PMNs. Overweight women ingested 500 mL of grape juice for 28 days, and then lipid and inflammatory profiles, as well as the white blood cell count (WBC), were evaluated. Additionally, the gene expression of inflammatory markers and quantified migration molecules such as CD11/CD18, ICAM-1 and VCAM-1 were evaluated in PMNs. The influence of delphinidin-3-O-glucoside in vitro on some migration properties was also evaluated. Grape juice intake did not influence the lipid profile or affect the WBC. However, NFκB gene expression was reduced in PMNs, also reducing the circulating values of IL-8, sICAM-1, and sVCAM-1. The in vitro results demonstrated that delphinidin significantly reduced the migration potential of cells and reduced CD11-/CD18-positive cells, the gene expression of ICAM-1, and the phosphorylation and gene expression of NFκB. Additionally, delphinidin also reduced the production of IL-6, IL-8, and CCL2. Grape juice, after 28 days of intervention, influenced some properties related to cell migration, and delphinidin in vitro can modify the cell migration properties.

Blood orange juice intake changes specific bacteria of gut microbiota associated with cardiometabolic biomarkers.

Blood orange juice is an important source of flavanones and anthocyanins, mainly hesperidin, narirutin, and cyanidin-3-O-glucoside. The benefits of these bioactive compounds have been reported, but the mechanistic details behind their biological effects are not well established. This study investigated the effects of Moro orange (Citrus sinensis L. Osbeck) juice (MOJ) on gut microbiota composition and cardiometabolic biomarkers in overweight women. In this study, 12 overweight women (BMI from 25.0 to 29.9 kg/m2), aged 18-37 years, consumed 500 mL of MOJ every day for 4 weeks. We assessed the gut microbiota composition, levels of short-chain fatty acids (SCFAs), cardiometabolic biomarkers, and insulin resistance (HOMA-IR) at baseline and after 2 weeks and 4 weeks of MOJ intake. The results suggested that MOJ intake affected the abundance of specific operational taxonomic units (OTUs) of the gut microbiota but did not significantly alter the diversity and general composition of the gut microbiota. However, MOJ intake increased the production of SCFAs, especially propionic and isobutyric acids, and significantly improved cardiometabolic biomarkers such as blood pressure and plasma VCAM-1 levels in the overweight women. Additionally, we observed significant associations between gut microbiota OTUs belonging to the Bacteroidetes phyla and Prevotella 9 genera and the cardiometabolic biomarkers. Furthermore, MOJ reduced fasting glucose and insulin levels and HOMA-IR values, thereby enhancing insulin sensitivity in the insulin-resistant overweight women. Finally, we highlighted the importance of orange juice intake duration because some beneficial changes such as blood pressure improvements were evident at the 2-week time interval of the intervention, but other changes became significant only at the 4-week interval of MOJ intake. In conclusion, our study demonstrated that changes in specific OTUs of the gut microbiota in response to MOJ intake were associated with significant improvements in some cardiometabolic biomarkers and SCFA levels in overweight women with insulin resistance.

Blood orange juice intake modulates plasma and PBMC microRNA expression in overweight and insulin-resistant women: impact on MAPK and NFκB signaling pathways.

Blood orange consumption presents potential health benefits and may modulate epigenetic mechanisms such as microRNAs (miRNAs) expression. MiRNAs are non-coding RNAs responsible for post-transcriptional gene regulation, and these molecules can also be used as biomarkers in body fluids. This study was designed to investigate the effect of chronic blood orange juice (BOJ) intake on the inflammatory response and miRNA expression profile in plasma and blood cells in overweight women. The study cohort was comprised of twenty women aged 18-40 years old, diagnosed as overweight, who consumed 500 mL/d of BOJ for four weeks. Clinical data were collected at baseline and after 4 weeks of juice consumption, e.g., anthropometric and hemodynamic parameters, food intake, blood cell count, and metabolic and inflammatory biomarkers. BOJ samples were analyzed and characterized. Additionally, plasma and blood cells were also collected for miRNA expression profiling and evaluation of the expression of genes and proteins in the MAPK and NFκB signaling pathways. BOJ intake increased the expression of miR-144-3p in plasma and the expression of miR-424-5p, miR-144-3p, and miR-130b-3p in peripheral blood mononuclear cells (PBMC). Conversely, the beverage intake decreased the expression of let-7f-5p and miR-126-3p in PBMC. Computational analyses identified different targets of the dysregulated miRNA on inflammatory pathways. Furthermore, BOJ intake increased vitamin C consumption and the pJNK/JNK ratio and decreased the expression of IL6 mRNA and NFκB protein. These results demonstrate that BOJ regulates the expression of genes involved in the inflammatory process and decreases NFкB-protein expression in PBMC.

Low Birth Weight Intensifies Changes in Markers of Hepatocarcinogenesis Induced by Fructose Consumption in Rats.

Intrauterine growth restriction (IUGR) due to fetal exposure to glucocorticoid excess results in metabolic inflexibility and hepatic steatosis upon nutritional stress during adulthood. We previously demonstrated that rats born to dexamethasone (DEX)-treated mothers developed hepatic steatosis when exposed to 10% fructose solution during adult life. Persistent triacylglyceride (TAG) accumulation in the liver, in turn, is a feature of non-alcoholic fatty liver disease (NAFLD), which serves as a risk factor for non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). In the present study, we demonstrate that the combination of IUGR and fructose treatment during adulthood also results in increased hepatic myeloperoxidase (MPO) activity, AKT phosphorylation and serum aspartate transaminase. Growth-restricted rats also presented reduced hepatic TRIB3 and GADD45a after fructose treatment. Other markers of cell proliferation, such as Cyclin D, PCNA, Hgf and Hspa4/Hsp70 expression and the number of Ki-67 positive cells, were all increased in the liver of growth- restricted rats treated with fructose. On the other hand, the combination of IUGR and fructose treatment during adult life reduced the levels of IGF-1. In conclusion, our data indicate that after exposure to fructose, adult rats subjected to dexamethasone-induced IUGR display exacerbated molecular changes in markers of NASH and HCC.

Cellular reprogramming, chemoresistance, and dietary interventions in breast cancer.

Breast cancer (BC) diagnosis has been associated with significant risk factors, including family history, late menopause, obesity, poor eating habits, and alcoholism. Despite the advances in the last decades regarding cancer treatment, some obstacles still hinder the effectiveness of therapy. For example, chemotherapy resistance is common in locally advanced or metastatic cancer, reducing treatment options and contributing to mortality. In this review, we provide an overview of BC metabolic changes, including the impact of restrictive diets associated with chemoresistance, the therapeutic potential of the diet on tumor progression, pathways related to metabolic health in oncology, and perspectives on the future in the area of oncological nutrition.

Ingestion of orange juice prevents hyperglycemia and increases plasma miR-375 expression.

BACKGROUND & AIMS: The intake of high-fat, high-carbohydrate (HFHC) meals is associated with an increased risk of type 2 diabetes. There is evidence that the association of orange juice to a HFHC meal can modulate the expression of microRNAs (miRNAs) linked to pancreatic ß-cell function such as miR-375. We evaluated the effect of a commercial orange juice intake with HFHC meal on plasma miRNAs expression in twelve healthy subjects in a crossover design study. METHODS: Subjects ingested water, orange juice, or an isocaloric beverage along with a 1037 kcal HFHC meal. Blood glucose and miRNAs were evaluated at baseline and 1, 3, and 5 h after the intake. RESULTS: The area under the curve (AUC) for glycemia after ingestion of HFHC + orange juice did not differ from ingestion of HPHC + glucose or HFHC + water. However, the AUC was higher in HFHC meal + glucose compared to HFHC meal + water (p = 0.034). Glucose and insulin concentrations were significantly higher in HFHC meal + glucose group after 1 h, when compared with other groups and times (p < 0.001). There was an increase in plasma miR-375 expression after 3 h of ingestion of HFHC + orange juice versus water (p = 0.026), and a decrease in plasma miR-205-5p expression after HFHC meal + glucose versus water (p = 0.023). CONCLUSIONS: A single HFHC meal + orange juice modulated plasma miR-375 expression, which is a biomarker of pancreatic ß-cell function, and contributed to preventing hyperglycemia.

Efeito crônico da ingestão de suco de laranja sanguínea sobre o perfil de expressão de microRNA e resposta inflamatória em mulheres com sobrepeso / Chronic effect of blood orange juice intake on the microRNA expression profile and inflammatory response in overweight women

Introdução: A obesidade está diretamente envolvida na etiologia de doenças crônicas não transmissíveis (DCNT). A ingestão excessiva de nutrientes associada à obesidade culmina na ativação de vias de sinalização pró-inflamatórias em diferentes locais do organismo, acarretando uma inflamação sistêmica, crônica e de baixa intensidade. microRNA (miRNA) atuam como moduladores e biomarcadores de processos inflamatórios e a análise da sua expressão pode contribuir para identificação do risco de DCNT. A laranja (Citrus sinensis) é a fruta mais produzida no Brasil, contendo concentrações significantes de flavonoides, vitamina C e carotenoides, os quais apresentam atividade antioxidante e anti-inflamatória. Neste contexto, destaca-se a laranja sanguínea, que além dos compostos nutricionais comuns em Citrus, contem antocianinas. Objetivo: Investigar o efeito da ingestão crônica de suco de laranja sanguínea Moro sobre a resposta inflamatória e o perfil de expressão de miRNA no plasma e em células mononucleares do sangue periférico (PBMC) em mulheres com sobrepeso. Métodos: Estudo de intervenção crônica em mulheres (n = 20) de 18 a 40 anos, diagnosticadas com sobrepeso (índice de massa corporal = 25,0 a 29,9 kg/m2). Durante quatro semanas, as voluntárias ingeriram, diariamente, 500 mL de suco de laranja sanguínea Moro, com colheitas de sangue realizadas nos momentos basal e após 2 e 4 semanas do início do protocolo experimental. Foram realizadas as seguintes análises: caracterização do suco de laranja sanguínea Moro; avaliação antropométrica; aferição da pressão arterial; avaliação do consumo alimentar; determinação das concentrações plasmáticas de glicose, insulina, lipopolissacarídeos, proteína ligadora de lipopolissacarídeo, cluster de diferenciação 14 solúvel, biomarcadores inflamatórios [interleucina (IL)-6, IL-10, fator de necrose tumoral alfa (TNF-α), proteína quimiotática de monócitos-1, molécula de adesão intercelular solúvel (sICAM)-1 e a molécula de adesão celular vascular solúvel (sVCAM)-1]; e determinação das concentrações séricas do perfil lipídico, proteína C reativa, fibrinogênio, D-dímero, gama glutamil transferase, alanina aminotransferase, aspartato aminotransferase, amilase, ureia, creatinina e minerais. Foram também analisadas a expressão de miRNA no plasma e em PBMC; a expressão dos genes TNF, fator nuclear kappa B subunidade p50 (NFKB1), NF-κB subunidade p65 (RELA), inibidor alfa do NF-κB (NFKBIA), IL1, IL6, IL10, e receptores do tipo toll (TLR2 e TLR4); e o conteúdo e a fosforilação das proteínas NF-κB, IκB-α, quinase c-Jun N-terminal (JNK), quinase beta inibidora do IκB-α (IKK-ß) e fator de transformação de crescimento beta 1 (TAK1). Resultados: A ingestão do suco de laranja sanguínea Moro aumentou o consumo de vitamina C (p < 0,001), a razão fosfo-JNK/JNK (p < 0,05) e a expressão de miRNA no plasma [miR-144-3p (p = 0,02)] e em PBMC [miR-424-5p (p = 0,002), miR-144-3p (p = 0,006) e miR-130b-3p (p = 0,03)]. Por outro lado, diminuiu o conteúdo proteico de NF-κB (p < 0,05) e a expressão do let-7f-5p (p = 0,007) e do miR-126-3p (p = 0,04) em PBMC. Contudo, não foram observadas alterações significativas na expressão de genes que codificam proteínas envolvidas com a resposta inflamatória e nos parâmetros antropométricos e bioquímicos analisados ao final do protocolo experimental. Conclusão: A ingestão do suco de laranja sanguínea modula a expressão de miRNA em PBMC e no plasma e diminui o conteúdo proteico de NF-κB em PBMC, sem alterar a ingestão calórica, os parâmetros antropométricos e os biomarcadores metabólicos avaliados.

Introduction: Obesity is directly involved in the etiology of chronic non-communicable diseases (NCD). The excessive intake of nutrients associated with obesity culminates in the activation of pro-inflammatory signaling pathways in different parts of the body, causing systemic, chronic, and low-intensity inflammation. microRNA (miRNA) act as modulators and biomarkers of inflammatory processes and the analysis of their expression can contribute to the identification of the risk of NCDs. Orange (Citrus sinensis) is the most produced fruit in Brazil, containing significant concentrations of flavonoids, vitamin C, and carotenoids, which have antioxidant and anti-inflammatory activity. In this context, blood orange stands out, which in addition to the common nutritional compounds in Citrus, it has anthocyanins. Objective: To investigate the effect of chronic Moro blood orange juice intake on the inflammatory response and miRNA expression profile in plasma and peripheral blood mononuclear cells (PBMC) in overweight women. Methods: Chronic intervention study in women (n = 20) aged 18 to 40 years old, diagnosed with overweight (body mass index = 25.0 to 29.9 kg/m2). For four weeks, the volunteers ingested, daily, 500 mL of Moro blood orange juice, with blood samples collected at baseline and 2 and 4 weeks after the beginning of the experimental protocol. The following analyses were carried out: characterization of Moro blood orange juice; anthropometric measurements; blood pressure measurement; dietary intake assessment; determination of plasma concentrations of glucose, insulin, lipopolysaccharides, lipopolysaccharide-binding protein, soluble cluster of differentiation 14, and inflammatory biomarkers [interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1, soluble intercellular adhesion molecule (sICAM)-1 and soluble vascular cell adhesion molecule (sVCAM)-1]; and determination of serum concentrations of lipid profile, C-reactive protein, fibrinogen, D-dimer, gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, amylase, urea, creatinine, and minerals. Were also analyzed the expression of miRNA in plasma and PBMC; the expression of genes TNF, nuclear factor kappa B p50 subunit (NFKB1), NF-κB p65 subunit (RELA), NF-κB inhibitor alpha (NFKBIA), IL1, IL6, IL10, and toll-like receptors (TLR2 e TLR4); and the content and phosphorylation of proteins NF-κB, IκB-α, c-Jun N-terminal kinase (JNK), inhibitor of NF-κB kinase subunit beta (IKK-ß) and transforming growth factor ß-activated kinase 1 (TAK1). Results: Moro blood orange juice intake increased vitamin C consumption (p < 0.001), phospho-JNK/JNK ratio (p < 0.05), and miRNA expression in plasma [miR-144-3p (p = 0.02)] and in PBMC [miR-424-5p (p = 0.002), miR-144-3p (p = 0.006), and miR-130b-3p (p = 0.03)]. Conversely, it decreased the protein content of NF-κB (p < 0.05) and the expression of let-7f-5p (p = 0.007) and miR-126-3p (p = 0.04) in PBMC. However, no significant changes were observed in the expression of genes that encode proteins involved in the inflammatory response and the anthropometric and biochemical parameters analyzed at the end of the experimental protocol. Conclusion: Ingestion of blood orange juice modulates miRNA expression in PBMC and plasma and decreases the protein content of NF-κB in PBMC, without changing caloric intake, anthropometric parameters, and metabolic biomarkers evaluated.