Harnessing the power of RNA therapeutics in treating ischemic heart failure: the TRAIN-HEART story.

Ischemic heart disease (IHD) is one of the world's foremost killers, accounting for 16% of all deaths worldwide. IHD is the main cause of heart failure (HF), as it leads to pathological changes in the heart, improper pumping function and eventual death. Therapeutic interventions usually follow a systemic general strategy for all heart failure subtypes due to the lack of a deep understanding of the disease mechanisms. Hence, HF and IHD therapeutics need groundbreaking concepts to guide the development of a new therapeutics class that tackles the disease at a molecular level. The TRAIN-HEART consortium, a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN) funded by the European Commission, was established with the goal of filling that gap and developing RNA-based cardiovascular therapeutics. Created in the context of the Horizon 2020 research and innovation program, TRAIN-HEART comprises three key work packages (WPs) focusing on the pathogenesis of heart disease (WP1), the therapeutic potential of RNA therapeutics (WP2), and the development of new efficient delivery systems (WP3). Fifteen international early stage researchers (ESRs) from multiple complementary scientific disciplines were recruited to collaborate with a network of PIs from nine academic and eight non-academic partners in various disciplines to fully harness their collective potential for the betterment of HF treatment. This article provides an overview of the benefits of being part of an MSCA-ITN, with its different training and networking opportunities, maximizing ESRs' potential and broadening collaborative research possibilities. Finally, it describes what was like to do a PhD during the COVID-19 pandemic, with all the uncertainty and concern attached to it. Luckily, TRAIN-HEART stood out as a proactive network, finding new initiatives and alternatives to promote scientific and personal development. By bringing together leading academic teams, (biotech) companies, and highly motivated researchers, TRAIN-HEART is expanding scientific horizons and accelerating future development of effective RNA-based therapies to treat IHD.

The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications

Insulin resistance, the most important characteristic of the type 2 diabetes mellitus (T2DM), is mostly caused by impairment in the insulin receptor (IR) signal transduction pathway. Protein tyrosine phosphatase 1B (PTP1B), one of the main negative regulators of the IR signaling pathway, is broadly expressed in various cells and tissues. PTP1B decreases the phosphorylation of the IR resulting in insulin resistance in various tissues. The evidence for the physiological role of PTP1B in regulation of metabolic pathways came from whole-body PTP1B-knockout mice. Whole-body and tissue-specific PTP1B-knockout mice showed improvement in adiposity, insulin resistance, and glucose tolerance. In addition, the key role of PTP1B in the pathogenesis of T2DM and its complications was further investigated in mice models of PTP1B deficient/overexpression. In recent years, targeting PTP1B using PTP1B inhibitors is being considered an attractive target to treat T2DM. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. We herein summarized the biological functions of PTP1B in different tissues in vivo and in vitro. We also describe the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat T2DM. (AU)

The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications.

Insulin resistance, the most important characteristic of the type 2 diabetes mellitus (T2DM), is mostly caused by impairment in the insulin receptor (IR) signal transduction pathway. Protein tyrosine phosphatase 1B (PTP1B), one of the main negative regulators of the IR signaling pathway, is broadly expressed in various cells and tissues. PTP1B decreases the phosphorylation of the IR resulting in insulin resistance in various tissues. The evidence for the physiological role of PTP1B in regulation of metabolic pathways came from whole-body PTP1B-knockout mice. Whole-body and tissue-specific PTP1B-knockout mice showed improvement in adiposity, insulin resistance, and glucose tolerance. In addition, the key role of PTP1B in the pathogenesis of T2DM and its complications was further investigated in mice models of PTP1B deficient/overexpression. In recent years, targeting PTP1B using PTP1B inhibitors is being considered an attractive target to treat T2DM. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. We herein summarized the biological functions of PTP1B in different tissues in vivo and in vitro. We also describe the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat T2DM.

Resveratrol Reduces Lipid Accumulation through Upregulating the Expression of MicroRNAs Regulating Fatty Acid Bet Oxidation in Liver Cells: Evidence from In-vivo and In-vitro Studies.

MicroRNAs have been shown to regulate lipogenesis in liver. The aim of the present study was to investigate whether the effects of resveratrol (RSV) on lipogenesis are associated with the changes in the expression of two miRNAs (miR-107 and miR-10b) that regulate lipogenic pathways. 30 wild type C57BL/6j male mice were randomly fed three diets: a standard chow diet (ND), a high fat diet (HFD, 60% fat) and the high fat diet supplemented with 0.4% RSV (HFD-RSV) for 16 weeks. HepG2 cells were treated with high glucose (33 mM) and RSV (20 µM) for 24 h. The expression of the genes and miRNAs were measured by real-time PCR. Triglyceride level was increased in the liver of mice and HepG2 cells. In both animal and In-vitro experiments, triglyceride level was significantly decreased in groups treated with RSV. The expression of the miR-107 and miR-10b was significantly upregulated in the liver of HFD mice, whereas HFD-RSV group demonstrated a significant lower expression of both miRNAs compared to HFD group. In addition, RSV treatment significantly upregulated the expression of CPT-1a and PPARα genes in the liver of HFD mice. Moreover, treatment with RSV could reduce the expression of miR-107 and miR-10b and increase the expression of CPT-1a and PPARα in HG-treated HepG2 cells. These evidence, as a whole, suggest that RSV could exert its anti-lipogenic effect partially through alterations in the expression of miR-107 and miR-10b in liver cells.

Resveratrol alleviates obesity-induced skeletal muscle inflammation via decreasing M1 macrophage polarization and increasing the regulatory T cell population.

Resveratrol was reported to inhibit inflammatory responses; however, the role of this polyphenol in obesity-induced skeletal muscle inflammation remains unknown. Mice fed a high fat diet (HFD) were treated with resveratrol for 16 weeks. Resveratrol treatment decreased macrophage infiltration into skeletal muscle of HFD-fed mice. Resveratrol also led to the polarization of macrophages to the M2 direction, as well as decreasing the expression of a number of M1 pro-inflammatory cytokines [tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß) and interleukin 6 (IL-6)]. In addition, increased infiltration of regulatory T cells (Treg cells) was found following resveratrol treatment in skeletal muscle of mice. Decreased intramyocellular lipid deposition was associated with reduced expression levels of toll-like receptors 2 (TLR2) and TLR4 in resveratrol treated mice. We also found that diminished inflammation in skeletal muscle following resveratrol treatment was accompanied by increasing phosphorylation of 5'-adenosine monophosphate-activated protein kinase (AMPK) and decreasing phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Taken together, these findings suggest that resveratrol ameliorates inflammation in skeletal muscle of HFD-induced model of obesity. Therefore, resveratrol might represent a potential treatment for attenuation of inflammation in skeletal muscle tissue.

Resveratrol alleviates non-alcoholic fatty liver disease through epigenetic modification of the Nrf2 signaling pathway.

Recent findings have demonstrated the aberrant DNA methylation of the Nrf2-Keap1 genes in human cancers; however, the epigenetic control of this pathway in non-alcoholic fatty liver disease (NAFLD) is unknown. Resveratrol can modify epigenetic mechanisms. Our objectives in this study were to explore the correlation between promoter methylation of the Nrf2-Keap1 genes and NAFLD, and that investigate the effect of resveratrol on the epigenetic regulation Nrf2-Keap1 in vitro and in vivo models of NAFLD. Resveratrol attenuated high fat-diet (HFD)-induced methylation of the Nrf2 promoter in the liver of mice, and this effect was correlated with reduction in triglyceride level and decrease in the expression of lipogenesis-related genes such as FAS and SREBP-1c. In addition, treatment of HepG2 cells with high glucose (HG) enhanced methylation level of the Nrf2 promoter, whereas resveratrol reversed this effect. Treatment of the cells with resveratrol or 5-aza, a demethylating agent, could prevent HG-induced reactive oxygen species production and expression of Nrf2-controlled antioxidant genes. Moreover, resveratrol or 5-aza could significantly attenuate HG-induced triglyceride accumulation in HepG2 cells. These findings indicate that resveratrol attenuates NAFLD through the epigenetic modification the Nrf2 signaling.

In-vitro Synergistic Effect of Metformin and Berberine on High Glucose-induced Lipogenesis.

Metformin and berberine have been reported to have lipid lowering effects. This study aims to investigate lipid lowering effects of berberine and Metformin, alone and in combination, in HepG2 cells to determine whether berberine and Metformin work synergistically and elucidate their mechanisms. HepG2 cells were treated with 33 mM glucose in the presence of various concentrations of berberine and Metformin, alone and in combination, for 24 h. The cytotoxic effects of these compounds were determined by MTT assay. Oil red O staining, triglyceride measurement, and gene expression analyses were performed to evaluate the effects of these compounds on hepatocytes lipogenesis. Berberine at doses 20 µM and 40 µM and Metformin at doses 1 mM and 2 mM reduced total lipid content and triglyceride level in HepG2 cells. Metformin (mM) and berberine (µM) at combination ratios of 2:40, 1:20, 0.5:10, and 0.25:5 exhibited a synergistic lipid-lowering effect on HepG2 cells. These ratios could significantly decrease total lipid content and triglyceride level in HepG2 cells. The lowest dose of the combination [Metformin (0.25 mM) and berberine (5 µM)] also synergistically reduced the expression of the FAS and SREBP-1c genes in HepG2 cells treated with high glucose. The combination of Metformin and berberine exerted synergistic lipid-lowering effects on HepG2 cells by reducing total lipid content, triglyceride level, and the expression of the genes involved in lipogenesis.