In early diabetes, hyperglycemia and the associated metabolic dysregulation promote early changes in the functional properties of cardiomyocytes, progressively leading to the appearance of the diabetic cardiomyopathy phenotype. Recently, the interplay between histone acetyltransferases (HAT) and histone deacetylases (HDAC) has emerged as a crucial factor in the development of cardiac disorders. The present study evaluates whether HDAC inhibition can prevent the development of cardiomyocyte contractile dysfunction induced by a short period of hyperglycemia, with focus on the potential underlying mechanisms. Cell contractility and calcium dynamics were measured in unloaded ventricular myocytes isolated from the heart of control and diabetic rats. Cardiomyocytes were either untreated or exposed to the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) for 90 min. Then, a fraction of each group of cells was used to evaluate the expression levels of proteins involved in the excitation–contraction coupling, and the cardiomyocyte metabolic activity, ATP content, and reactive oxygen species levels. SAHA treatment was able to counteract the initial functional derangement in cardiomyocytes by reducing cell oxidative damage. These findings suggest that early HDAC inhibition could be a promising adjuvant approach for preventing diabetes-induced cardiomyocyte oxidative damage, which triggers the pro-inflammatory signal cascade, mitochondrial damage, and ventricular dysfunction.

Background. Green tea catechins are known to promote mitochondrial function, and to modulate gene expression and signalling pathways that are altered in the diabetic heart. We thus evaluated the effectiveness of the in vivo administration of a standardized green tea extract (GTE) in restoring cardiac performance, in a rat model of early streptozotocin-induced diabetes, with a focus on the underlying mechanisms. Methods. Twenty-five male adult Wistar rats were studied: the control (n = 9), untreated diabetic animals (n = 7) and diabetic rats subjected to daily GTE administration for 28 days (n = 9). Isolated ventricular cardiomyocytes were used for ex vivo measurements of cell mechanics and calcium transients, and molecular assays, including the analysis of functional protein and specific miRNA expression. Results. GTE treatment induced an almost complete recovery of cardiomyocyte contractility that was markedly impaired in the diabetic cells, by preserving mitochondrial function and energy availability, and modulating the expression of the sarcoplasmic reticulum calcium ATPase and phospholamban. Increased Sirtuin 1 (SIRT1) expression and activity substantially contributed to the observed cardioprotective effects. Conclusions. The data supported the hypothesis that green tea dietary polyphenols, by targeting SIRT1, can constitute an adjuvant strategy for counteracting the initial damage of the diabetic heart, before the occurrence of diabetic cardiomyopathy.

We recently showed that the long-term in vivo administration of green tea catechin extract (GTE) resulted in hyperdynamic cardiomyocyte contractility. The present study investigates the mechanisms underlying GTE action in comparison to its major component, epigallocatechin-3-gallate (EGCG), given at the equivalent amount that would be in the entirety of GTE. Twenty-six male Wistar rats were given 40 mL/day of a tap water solution with either standardized GTE or pure EGCG for 4 weeks. Cardiomyocytes were then isolated for the study. Cellular bioenergetics was found to be significantly improved in both GTE- and EGCG-fed rats compared to that in controls as shown by measuring the maximal mitochondrial respiration rate and the cellular ATP level. Notably, the improvement of mitochondrial function was associated with increased levels of oxidative phosphorylation complexes, whereas the cellular mitochondrial mass was unchanged. However, only the GTE supplement improved cardiomyocyte mechanics and intracellular calcium dynamics, by lowering the expression of total phospholamban (PLB), which led to an increase of both the phosphorylated-PLB/PLB and the sarco-endoplasmic reticulum calcium ATPase/PLB ratios. Our findings suggest that GTE might be a valuable adjuvant tool for counteracting the occurrence and/or the progression of cardiomyopathies in which mitochondrial dysfunction and alteration of intracellular calcium dynamics constitute early pathogenic factors.

Objective: Sex disparities in the association between psychosocial stress and cardiovascular risk have been reported, yet the extent to which social stress impacts cardiovascular function in a sex-specific manner remains unclear. The objectives of this study were to investigate sex differences in the electromechanical remodeling of the heart of socially stressed rats, and to explore potential epigenetic mechanisms (cardiac microRNAs). Methods: Adult wild-type Groningen rats of both sexes vicariously experienced the social defeat bout between 2 males for 9 consecutive days [“witness stress” (WS) paradigm] or were exposed to a control condition ( n =8/sex/group). After repeated WS exposure, arrhythmic vulnerability was evaluated via beta-adrenergic stimulation with isoproterenol in conscious rats, while cardiac contractile properties were assessed via hemodynamic analyses under anesthesia. Cardiac tissue was collected to measure expression levels of several miRNAs (including miR-22 and miR-34a) and their molecular targets (eg, SIRT1) involved in the regulation of cardiac electromechanical function. Results: An increased vulnerability to isoproterenol-induced arrhythmias was found in male, but not female, rats with a history of WS. Signs of contractile dysfunction were found in both sexes after WS, but to a greater extent in males. In addition, only male WS rats exhibited a significantly higher cardiac expression of miR-34a and miR-22, which were associated with a reduced expression of their common molecular target (SIRT-1). Conclusion: These findings suggest an epigenetic mechanism underlying the larger vulnerability to adverse cardiac electromechanical remodeling in socially stressed male rats, informing our understanding of the sex-specific impact of social stress on cardiac function.

Non-Hodgkin lymphomas (NHLs) are the most common hematological malignancies worldwide. Among these, B-cell lymphomas (B-NHLs) are the second leading cause of death in hematologic neoplasms. In this study, a detailed immunophenotypic analysis of lymphocytes in the bone marrow aspirate (BMA) of 75 patients with four different subtypes of B-NHLs was performed at diagnosis. The samples were analyzed by flow cytometry (FC) using a stain-lyse-no wash technique and a comprehensive six-color antibody panel. Our data showed a different trend in the percentage values of the distinct lymphocyte subsets, which did not seem to correlate with a worse prognosis, except for B cells in diffuse large B-cell lymphoma (DLBCL), which were significantly higher in stage IV than in stages II and III. ROC curve analysis showed that the B-cell percentage value could be used to predict the stage of the disease. Total lymphocytes and B cells were greater in lymphomas that presented a lower percentage of disease progression, specifically mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). In contrast, natural killer (NK) and T cells showed higher values in DLBCL and follicular lymphoma (FL), which progressed more frequently. Interestingly, in DLBCL patients with higher percentage values of double positive (DPT) and helper T cells (Th), we observed a good prognosis. Specifically, univariate Cox regression analyses indicated that a higher value of Th cells at diagnosis was a better prognostic predictor in patients with DLBCL. These preliminary findings encourage us to further investigate the role of lymphocyte subpopulations in B-cell NHL.

Background: In this study, we retrospectively analyzed clinical and toxicity outcomes of 67 prostate cancer (PCa) patients undergoing moderately hypofractionated radiotherapy (RT) after prostatectomy, with adjuvant or salvage intent. Methods: Irradiation was delivered by volumetric modulated arc therapy. The median follow-up was 48 months. The 3- and 5-year biochemical relapse-free survival rates were 80% and 69%. The RT schedule consisted of a median total dose of 67.5 Gy with a median number of 25 fractions and a median fraction dose of 2.7 Gy to the prostate bed (PB) and 60% of patients simultaneously received whole pelvis irradiation (WP; fraction dose: 1.8 Gy, median total dose of 46.8 Gy). Results: The rate of acute toxicity was 54% for gastrointestinal (GI) and 36% for genitourinary (GU). No grade 3 acute toxicity was observed. Late toxicity was as follows: G1, G2, and G3 GI events in 25.5%, 3.6%, and 1.8% of the cases, respectively; G1, G2, and G3 GU events in 37.1%, 11.1%, and 7.4%, respectively. The toxicity-free survival (TFS) curves showed a different trend for acute and late toxicity. TFS was significantly associated with RT volume, except for acute GI toxicity. Specifically, the concomitant irradiation of PB and WP appeared to be a significant risk factor for late GI and GU toxicity (p = 0.029 and p = 0.012, respectively). Conclusions: At the 48-month median timepoint considered by our study, postoperative hypofractionated RT achieved promising results in terms of clinical outcomes with acceptable toxicity. Only the irradiated volume seems to be an important predictor for toxicity.