Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8+ and CD4+ T cells. A differential compartmentalization was detected between Helioshigh and Helioslow Treg subsets (thymus-derived versus peripherally induced): while Helioslow Tregs were enriched in both sites, only Helioshigh Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

Immunological backbone of uveal melanoma: is there a rationale for immunotherapy?

No standard treatment has been established for metastatic uveal melanoma (mUM). Immunotherapy is commonly used for this disease even though UM has not been included in phase III clinical trials with checkpoint inhibitors. Unfortunately, only a minority of patients obtain a clinical benefit with immunotherapy. The immunological features of mUM were reviewed in order to understand if immunotherapy could still play a role for this disease

Anti-Inflammatory and Proliferative Properties of Luteolin-7-O-Glucoside

Flavonoids display a broad range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages. Recent data showed their activity, and in particular of luteolin-7-O-glucoside (LUT-7G), in reduction of oxidative stress and inflammatory mechanisms in different physiological systems. In this paper, we tried to elucidate how LUT-7G could exert both antioxidant and anti-inflammatory effects in endothelial cells cultured in vitro. Here, we showed that LUT-7G is able to inhibit the STAT3 pathway, to have an antiproliferative action, and an important antioxidant property in HUVEC cells. These properties are exerted by the flavone in endothelial through the transcriptional repression of a number of inflammatory cytokines and their receptors, and by the inhibition of ROS generation. ROS and STAT3 activation has been correlated with the production of oxysterols and other hydroxylated fatty acids, and they have been recognized important as players of atherogenesis and cardiocirculatory system diseases. The analysis of the general production pathway of these hydroxylated species, showed a strong decrease of cholesterol hydroxylated species such as 7-alpha-hydroxicholesterol, 7-beta-hydroxicholesterol by the treatment with LUT-7G. This confirms the anti-inflammatory properties of LUT-7G also in the endothelial district, showing for the first time the molecular pathway that verify previous postulated cardiovascular benefits of this flavone

Lp-PLA2, a new biomarker of vascular disorders in metabolic diseases

Metabolic diseases are chronic disorders correlated to a greater risk of cardiovascular event and death. Recently, many data have sustained the biological link between microvascular dysfunction, oxidative stress, vascular inflammation, and metabolic diseases. The determination of new and specific blood biomarkers of vascular inflammation associated with obesity-related metabolic syndrome (MetS) and diabetes such as lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) could be useful to identify subject with high risk of cardiovascular events. Lp-PLA 2 participates by a crucial role in microvascular dysfunction and oxidative stress showing positive association with metabolic disorders. In this review, we will argue the evolving role of Lp-PLA 2 in predicting cardiovascular events in metabolic disease patients

Obesity-related changes in the vascular actions of insulin

Ingles

10th Anniversary of Biomedicines - Advances in Endothelial Dysfunction

N/

increased endothelin 1 mediated vasoconstrictor tone in human obesity effects of gut hormones

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome

Emerging pharmacological approaches for the treatment of arterial hypertension

Despite the availability of several drug classes for the treatment of hypertension, the current approaches to high blood pressure (BP) are not fully satisfying the needs of this patient population. As a result, in recent years, many clinical trials have investigated novel pharmacological approaches for lowering high BP. As overactivity of the renin-angiotensin-aldosterone system is often present in hypertensive patients, especially those with resistant hypertension, several studies have focused on novel strategies to counteract this phenomenon by the use of non-steroidal inhibitors of the mineralocorticoid receptors, aldosterone synthase inhibitors or RNA-targeting therapies to inhibit the hepatic synthesis of angiotensinogen. The latter approach in particular might offer the additional advantage of reducing the daily pill burden of these patients, hence mitigating the common occurrence of non-adherence to treatment. Because obesity and diabetes are common risk factors for hypertension (a high percentage of individuals with resistant hypertension being obese), numerous investigations have analyzed the BP-lowering effects of those agents, such as glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors, which have been shown to reduce body weight and improve cardiovascular outcomes in these patients. Available evidence suggests that these drug classes can indeed afford a clinically meaningful BP decrease and, potentially, reduce the treatment burden. In conclusion, even though the rates of uncontrolled hypertension remain high, several novel therapeutic options are in the offing. As these emerging treatments will compound with many already available agents, future efforts should be directed at better phenotyping patients to tailor the most suitable approach for each one

Metabolic and Cardiovascular Effects of Ghrelin

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is synthesized as a preprohormone and then proteolytically processed to yield a 28-amino acid peptide. This peptide was originally reported to induce growth hormone release; large evidence, however, has indicated many other physiological activities of ghrelin, including regulation of food intake and energy balance, as well as of lipid and glucose metabolism. Ghrelin receptors have been detected in the hypothalamus and the pituitary, but also in the cardiovascular system, where ghrelin exerts beneficial hemodynamic activities. Ghrelin administration acutely improves endothelial dysfunction by increasing nitric oxide bioavailability and normalizes the altered balance between endothelin-1 and nitric oxide within the vasculature of patients with metabolic syndrome. Other cardiovascular effects of ghrelin include improvement of left ventricular contractility and cardiac output, as well as reduction of arterial pressure and systemic vascular resistance. In addition, antinflammatory and antiapoptotic actions of ghrelin have been reported both in vivo and in vitro. This review summarizes the most recent findings on the metabolic and cardiovascular effects of ghrelin through GH-dependent and -independent mechanisms and the possible role of ghrelin as a therapeutic molecule for treating cardiovascular diseases