Pulmonary hypertension and insulin resistance: a mechanistic overview.

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease, characterized by increased blood pressure levels in pulmonary circulation, leading to a restriction in the circulation flow and heart failure. Although the emergence of new PAH therapies has increased survival rates, this disease still has a high mortality and patients that receive diagnosis die within a few years. The pathogenesis of PAH involves multiple pathways, with a complex interaction of local and distant cytokines, hormones, growth factors, and transcription factors, leading to an inflammation that changes the vascular anatomy in PAH patients. These abnormalities involve more than just the lungs, but also other organs, and between these affected organs there are different metabolic dysfunctions implied. Recently, several publications demonstrated in PAH patients a disturbance in glucose metabolism, demonstrated by higher levels of glucose, insulin, and lipids in those patients. It is possible that a common molecular mechanism can have a significant role in this connection. In this regard, this narrative review intends to focus on the recent papers that mainly discuss the molecular determinants between insulin resistance (IR) associated PAH, which included obesity subclinical inflammation induced IR, PPAR gamma and Adiponectin, BMPR2, mitochondrial dysfunction and endoplasmic reticulum stress. Therefore, the following review will summarize some of the existing data for IR associated PAH, focusing on the better understanding of PAH molecular mechanisms, for the development of new translational therapies.

Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-γ Expression in Pulmonary Artery.

Obesity and insulin resistance (IR) are well-studied risk factors for systemic cardiovascular disease, but their impact on pulmonary hypertension (PH) is not well clarified. This study aims to investigate if diet-induced obesity induces PH and if peroxisome-proliferator-activated receptor (PPAR-γ) and/or endoplasmic reticulum (ER) stress are involved in this process. Mice were maintained on a high-fat diet (HFD) for 4 months, and IR and PH were confirmed. In a separate group, after 4 months of HFD, mice were treated with pioglitazone (PIO) or 4-phenylbutyric acid for the last month. The results demonstrated that HFD for at least 4 months is able to increase pulmonary artery pressure, which is maintained, and this animal model can be used to investigate the link between IR and PH, without changes in ER stress in the pulmonary artery. There was also a reduction in circulating adiponectin and in perivascular adiponectin expression in the pulmonary artery, associated with a reduction in PPAR-γ expression. Treatment with PIO improved IR and PH and reversed the lower expression of adiponectin and PPAR-γ in the pulmonary artery, highlighting this drug as potential benefit for this poorly recognized complication of obesity.

Characterization and Safety Profile of Transfer Factors Peptides, a Nutritional Supplement for Immune System Regulation.

Imuno TF® is a nutritional supplement composed of isolated transfer factors (TF) from porcine spleen. It is composed of a specific mixture of molecules that impact functions of the biological systems and historically is linked to the immune system regulation. In this study, we demonstrate for the first time its proteomic analysis, nutritional composition, and safety profile in terms of mutagenic potential and acute oral dose (LD50). The obtained analysis indicated the product is a complex set of oligo- and polypeptides constituted of 163 different peptides which can potentially act on multiple mechanisms on the immune system pathways. The chemical composition showed low fat and low sugar content, saturated fatty acids-free, and the presence of 10 vitamins and 11 minerals. No mutagenic effect was observed, and the LD50 was 5000 mg kg-1 body weight. This accounts for a safe product to be used by the oral route, with potential benefits for the immune system.

Protein profile in Aspergillus nidulans recombinant strains overproducing heterologous enzymes.

Filamentous fungi are robust cell factories and have been used for the production of large quantities of industrially relevant enzymes. However, the production levels of heterologous proteins still need to be improved. Therefore, this article aimed to investigate the global proteome profiling of Aspergillus nidulans recombinant strains in order to understand the bottlenecks of heterologous enzymes production. About 250, 441 and 424 intracellular proteins were identified in the control strain Anid_pEXPYR and in the recombinant strains Anid_AbfA and Anid_Cbhl respectively. In this context, the most enriched processes in recombinant strains were energy pathway, amino acid metabolism, ribosome biogenesis, translation, endoplasmic reticulum and oxidative stress, and repression under secretion stress (RESS). The global protein profile of the recombinant strains Anid_AbfA and Anid_Cbhl was similar, although the latter strain secreted more recombinant enzyme than the former. These findings provide insights into the bottlenecks involved in the secretion of recombinant proteins in A. nidulans, as well as in regard to the rational manipulation of target genes for engineering fungal strains as microbial cell factories.

Compostos bioativos do camu-camu (Myrciaria dubia McVaugh): caracterização e atividade biológica / Bioactive compounds of camu-camu (Myrciaria dubia McVaugh): chemical characterization and biological activity

O camu-camu é considerado uma excelente fonte de vitamina C, e com capacidade antioxidante in vitro cerca de 120 vezes maior em relação às outras frutas, além do alto teor de ácido elágico. Desta forma, o objetivo deste trabalho foi caracterizar fruta e polpa comercial de camu-camu em relação ao conteúdo de fenólicos totais, flavonóides, ácido elágico livre e total, proantocianidinas e capacidade antioxidante in vitro, e verificar o efeito da ingestão de extrato bruto e frações purificadas da polpa comercial de camu-camu sobre o perfil bioquímico de ratos diabéticos e caquéticos, capacidade antioxidante do plasma, e a atividade das enzimas catalase, superóxido dismutase e glutationa peroxidase em plasma e eritrócitos. Também foi avaliado o efeito de extrato bruto e frações purificadas da polpa comercial em diferentes linhagens celulares. A polpa comercial de camu-camu apresentou maior teor de compostos bioativos que o fruto e por isso foi escolhida para continuar os estudos in vivo. Os teores de flavonóides variaram de 10 a 47 mg/ 100 g para quercetina, 4,8 a 5,0 mg/100 g para miricetina e 23 a 37 mg/100 g para rutina; os teores de ácido elágico livre variaram de 25 a 50 mg/100 g e 620 a 740 mg/100 g para ácido elágico total. Também foram identificados elagitaninos e oligômeros de proantocianidinas. Os extratos bruto e frações purificadas também foram testados em culturas celulares de miócitos (L6), macrófagos (J774), hepatócitos (FaO), beta pancreáticas (INS) e adipócitos (3T3). Os animais diabéticos e caquéticos tratados tanto com o extrato bruto quanto com a fração purificada de compostos fenólicos da polpa comercial de camu-camu apresentaram alterações do perfil lipídico plasmático, com reversão do alto colesterol total e triacilgliceróis, e ainda aumento nos níveis de HDL-colesterol. Outros efeitos como a redução da peroxidação lipídica e aumento da capacidade antioxidante plasmática também foram observados. Em linhagens celulares, os extratos bruto e...

Camu-camu fruit is considered as an excellent source of vitamin C and presented antioxidant capacity in vitro 120 times higher when compared to others fruits, in addition the high content of ellagic acid. Thus, the aim of this work was to characterize camu-camu commercial frozen pulp and fruit in relation to total phenolics, flavonoids, free and total ellagic acid content, proanthocyanidins and in vitro antioxidant capacity; besides to investigate the effect of the administration of crude and purified fractions of camu-camu commercial frozen pulp on biochemical profile of diabetic an cachetic rats, plasma antioxidant capacity and antioxidant enzymes activity of catalase, superoxide dismutase and glutathione peroxidase in plasma and erythrocytes. The effects of crude and purified fractions of camu-camu commercial frozen pulp were also evaluated. Commercial frozen pulp of camu-camu showed a higher content of bioactive compound when compared to the fruit and so was chosen for further studies in vivo. Flavonoids content varied from 10 to 47 mg/ 100 g of quercetin, 4.8 to 5.0 mg/100 g of myricetin and 23 to 37 mg/100 g of rutin; free ellagic acid content varied from 25 to 50 mg/100 g and 620 to 740 mg/100 total ellagic acid. Ellagitannins and proanthocyanidins oligomers have also been identified. The effects of camu-camu crude and purified fractions was also tested in culture cells of myocytes (L6), macrophages (J774), hepatocytes (FaO), pancreatic-beta cell (INS) and adipocytes (3T3). Animals treated with crude and purified fractions of phenolic compounds of camu-camu commercial frozen pulp showed changes in plasma lipid profile, reversing high level of total cholesterol and triacylglycerol and increase of HDL-cholesterol in diabetic and cachetic rats. Reduction on lipid peroxidation and increase on plasma antioxidant capacity was also observed. In cell line culture, crude and purified extracts of camu-camu were effective to stimulate glucose uptake in L6 cells...