The antihypertensive effect of the soluble fraction of wine lees (WL) from Cabernet variety grapes was recently reported by our group. This blood pressure (BP)-lowering effect was attributed to the presence of flavanols and anthocyanins. In this context, phenolic-enriched wine lees (PWL) could potentially exhibit a stronger bioactivity. Therefore, the aim of this study was to obtain a soluble fraction of WL with increased phenolic content and evaluate its functionality. The PWL were obtained using an enzyme-assisted extraction based on the hydrolysis of WL proteins with Flavourzyme^®. They contained 57.20% more total phenolic compounds than WL, with anthocyanins and flavanols being the largest families present. In addition, PWL also showed greater angiotensin-converting enzyme inhibitory and antioxidant activities. Finally, the antihypertensive activity of the PWL was evaluated in spontaneously hypertensive rats. A single dose of 5 mL/kg body weight of PWL showed a greater BP-lowering effect than the one shown by WL. Moreover, this antihypertensive effect was more prolonged than the one produced by the antihypertensive drug Captopril. These results demonstrate that enzymatic protein hydrolysis is a useful method to maximize the extraction of phenolic compounds from WL and to obtain extracts with enhanced functionalities.

Wine lees (WL) are by-products generated in the winemaking process. The aim of this study was to investigate the angiotensin-converting enzyme inhibitory (ACEi) activity, and the blood pressure (BP) lowering effect of WL from individual grape varieties. The relationship among their activities and phenolic profiles was also studied. Three WL, from Cabernet, Mazuela, and Garnacha grape varieties, were firstly selected based on their ACEi properties. Their phenolic profiles were fully characterized by UHPLC-ESI-Q-TOF-MS. Then, their potential antihypertensive effects were evaluated in spontaneously hypertensive rats (SHR). BP was recorded before and after their oral administrations (2, 4, 6, 8, 24, and 48 h) at a dose of 5 mL/kg bw. Cabernet WL (CWL) exhibited a potent antihypertensive activity, similar to that obtained with the drug Captopril. This BP-lowering effect was related to the high amount of anthocyanins and flavanols present in these lees. In addition, a potential hypotensive effect of CWL was discarded in normotensive Wistar–Kyoto rats. Finally, the ACEi and antihypertensive activities of CWL coming from a different harvest were confirmed. Our results suggest the potential of CWL for controlling arterial BP, opening the door to commercial use within the wine industry.

The antihypertensive effect of wine lees powder (WLPW) from a Cabernet grape variety was related to its high content in flavanols and anthocyanins compounds. This study investigates the involvement of endothelial-derived factors and SIRT1 in its bioactivity. Spontaneously hypertensive rats (SHR) were orally administered water or WLPW (125 mg/kg bw). Posteriorly, both groups were intraperitoneally administered saline, Nω-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, indomethacin, a prostacyclin synthesis inhibitor, or sirtinol, an inhibitor of sirtuins. Blood pressure (BP) was recorded before and 6 h after WLPW administration. In an additional experiment, SHR were administered water or WLPW and endothelial expressions of eNos, Sirt1, Nox4, and Et1 were determined. The BP-lowering properties of WLPW were abolished by L-NAME and partially reduced by indomethacin, demonstrating that WLPW antihypertensive effect was mediated by changes in NO availability, although prostacyclin also contributed to this activity. Moreover, BP-lowering effect was reduced by sirtinol, indicating that WLPW decreased BP in a SIRT1-dependent manner. Furthermore, WLPW upregulated eNos and Sirt1 and downregulated Nox4 and Et1 endothelial gene expression. These results evidence the vasoprotective effect of WLPW and show that its antihypertensive effect in SHR is endothelium dependent and mediated by SIRT1.

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

Background: The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross‐talk between the immune system and insulin‐producing beta cells, has hindered the development of effective disease‐modifying therapies. The discovery that the pharmacological activation of LRH‐1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH‐1/NR5A2 activation and improve islet survival.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH‐1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T‐cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001‐target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co‐cultures of PBMCs and iPSCs‐derived islet organoids were performed to assess the impact of BL001 on beta cell viability.Results: LRH‐1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro‐inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro‐inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro‐inflammatory to an anti‐inflammatory/tolerogenic state, resulting in the inhibition of CD4⁺ and CD8⁺ T‐cell proliferation. BL001 treatment also increased CD4⁺/CD25⁺/FoxP3⁺ regulatory T‐cells and Th2 cells within PBMCs while decreasing CD8+ T‐cell proliferation. Additionally, BL001 alleviated PBMC‐induced apoptosis and maintained insulin expression in human iPSC‐derived islet organoids.Conclusion: These findings demonstrate the potential of LRH‐1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach.Key Points: LRH‐1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro‐inflammatory cell surface markers and cytokine release. LRH‐1/NR5A2 promotes a mitohormesis‐induced immuno‐resistant phenotype to pro‐inflammatory macrophages. Mature dendritic cells acquire a tolerogenic phenotype via LRH‐1/NR5A2‐stimulated mitochondria turnover. LRH‐1/NR5A2 agonistic activation expands a CD4⁺/CD25⁺/FoxP3⁺ T‐cell subpopulation. Pharmacological activation of LRH‐1/NR5A2 improves the survival iPSC‐islets‐like organoids co‐cultured with PBMCs from individuals with T1D.