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Reactive oxygen species (ROS) are important signaling molecules, physiologically synthesized by oxygen metabolism [...].Reactive oxygen species (ROS) are important signaling molecules, physiologically synthesized by oxygen metabolism [...].

The series of reactive biological events that we identify as inflammation has been investigated in recent years and unveiled as an important mechanism for regeneration. The study of the underlying complexity has been boosted by new technological innovation in research and allowed the identification of inflammatory responses as the basis of diseases that were considered degenerative rather than regenerative in nature. This is the case for cardiovascular diseases, from the organ damage that follows an acute event to the damage of target organs exposed to chronic risk factors. This editorial explores innovative aspects of inflammation in the setup of cardiovascular risk factors and diseases.

Inflammation is a key mechanism of cardiovascular diseases. It is an essential component of atherosclerosis and a significant risk factor for the development of cardiovascular events. In the crosstalk between inflammation and cardiovascular diseases, the transcription factor NFκB seems to be a key player since it is involved in the development and progression of both inflammation and cardiac and vascular damage. In this review, we deal with the recent findings of the role of inflammation in cardiac diseases, focusing, in particular, on NFκB as a functional link. We describe strategies for the therapeutic targeting of NFκB as a potential strategy for the failing heart.

The beneficial effects of physical activity on the cardiovascular system nowadays have achieved the relevance of clinical evidence. In fact, several studies have documented the benefits of exercise training in the prevention of the cardiovascular risk. Abnormalities of insulin signaling transduction account for the impairment of insulin sensitivity and development of insulin resistance, which, in turn, is responsible for the enhancement of cardiovascular risk. Insulin sensitivity is related to the degree of physical activity, and physical training has been shown to ameliorate insulin action in insulin-resistant subjects. This effect is mediated by the improvement of the molecular abnormalities that are responsible of the insulin resistance, contributing in this way to restore the physiological insulin sensitivity. However, it should be underlined that mechanisms that account for this phenomenon are extremely complex and still unclear. Further studies are required to better clarify the molecular basis of the exercise-evoked improvement of insulin signal.[Images not available. See PDF.]Graphical abstract

A tight association between inflammation and cardiac damage has been extensively recognized. In this review, we will focus on macrophages as key players in the physiology and pathology of the heart and on their role in the functional crosstalk between inflammation and heart disease. In the steady state, macrophages contribute to the homeostasis of cardiac tissue. Indeed, cardiac resident macrophages promote coronary development and tissue homeostasis, favor electric conduction in cardiomyocytes, and contribute to mitochondrial quality control. However, macrophages also take part in adverse cardiac events contributing to the development or the progression of several pathologic conditions. Infiltrating cells derived from circulating monocytes contribute to tissue injury through the release of inflammatory cytokines and catecholamines. In particular, the present review will discuss the role of macrophages in heart failure, atherosclerosis, and anthracycline-dependent cardiotoxicity. Prolonged inflammatory response and increased apoptotic cell death sustained by chronic activation of the transcription factor NFκB are the basis of heart failure pathogenesis. Here, we will discuss the involvement of NFκB signaling in macrophage-dependent cardiac damage and its use as a therapeutic target in the treatment of cardiovascular pathologies.

Background The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC). Methods PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice. Results Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation. Conclusions PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.

In patients with type II diabetes, the development of diabetic cardiomyopathy (DC) is associated with a high risk of mortality. Left ventricular hypertrophy, diastolic dysfunction, and exercise intolerance are the first signs of DC. The underlying mechanisms are not fully elucidated, and there is an urgent need for specific biomarkers and molecular targets for early diagnosis and treatment. Mitochondrial alterations play a key role in the development of DC, and microRNAs regulating mitochondrial function are emerging as potential biomarkers of metabolic stress in DC. L-Arginine (Arg) supplementation has been shown to be an effective strategy for improving mitochondrial function and energetics, with a significant impact on physical performance. The aim of the current study was to evaluate the effects of Arg supplementation on cardiac mitochondrial function, DC development, and relative phenotypes including exercise intolerance. We used db/db mice as a model of type II diabetes, chronically treated with Arg (1 mg/kg/day) for 12 weeks. Arg-treated db/db mice showed preserved diastolic function and left ventricular morphology compared with untreated diabetic mice. Arg supplementation also improved exercise tolerance and the propensity to physical activity. Mitochondrial respiration was significantly increased in cardiomyocytes isolated from treated db/db mice, as well as in diabetic cardiomyocytes treated with Arg in vitro. The improvement of cardiac mitochondrial function in db/db + Arg mice was associated with an increase in PGC-1-alpha levels, mitochondrial biogenesis, recycling, and antioxidant capacity. Arg treatment prevented the accumulation of circulating and cardiac miR-143 in db/db mice, which is an index of metabolic stress and activation of mitochondrial damage mechanisms. In conclusion, Arg supplementation is effective in preventing the development of DC, preserving diastolic function and exercise tolerance by improving mitochondrial fitness and homeostasis. Additionally, miR-143 could potentially be employed to monitor cardiac metabolic stress and the effects of Arg treatment in diabetes.

Formyl peptide receptors (FPR1, FPR2 and FPR3) are innate immune sensors of pathogen and commensal bacteria and have a role in colonic mucosa homeostasis. We identified FPR1 as a tumour suppressor in gastric cancer cells due to its ability to sustain an inflammation resolution response with antiangiogenic potential. Here, we investigate whether FPR1 exerts similar functions in colorectal carcinoma (CRC) cells. Since it has been shown that the commensal bacterium Lactobacillus rhamnosus GG (LGG) can promote intestinal epithelial homeostasis through FPR1, we explored the possibility that it could induce proresolving and antiangiogenic effects in CRC cells. We demonstrated that pharmacologic inhibition or genetic deletion of FPR1 in CRC cells caused a reduction of proresolving mediators and a consequent upregulation of angiogenic factors. The activation of FPR1 mediates opposite effects. Proresolving, antiangiogenic and homeostatic functions were also observed upon treatment of CRC cells with supernatant of LGG culture, but not of other lactic acid or nonprobiotic bacteria (i.e. Bifidobacterium bifidum or Escherichia coli). These activities of LGG are dependent on FPR1 expression and on the subsequent MAPK signalling activation. Thus, the innate immune receptor FPR1 could be a regulator of the balance between microbiota, inflammation and cancer in CRC models. The commensal probiotic bacteria Lactobacillus rhamnosus GG (LGG), by activating the innate immune receptor formyl peptide receptor 1 (FPR1), influence normal intestinal epithelial homeostasis and sustain wound restitution. We demonstrated that LGG, but not other lactic acid or nonprobiotic bacteria, activate an inflammation resolution program that dampens the angiogenic response of colorectal carcinoma cells.

Sirolimus (rapamycin) is an immunosuppressive drug used in transplantation. One of its major side effects is the increased risk of diabetes mellitus; however, the exact mechanisms underlying such association have not been elucidated. Here we show that sirolimus impairs glucose-stimulated insulin secretion both in human and murine pancreatic islets and in clonal β cells in a dose- and time-dependent manner. Importantly, we demonstrate that sirolimus markedly depletes calcium (Ca 2+ ) content in the endoplasmic reticulum and significantly decreases glucose-stimulated mitochondrial Ca 2+ uptake. Crucially, the reduced mitochondrial Ca 2+ uptake is mirrored by a significant impairment in mitochondrial respiration. Taken together, our findings indicate that sirolimus causes depletion of intracellular Ca 2+ stores and alters mitochondrial fitness, eventually leading to decreased insulin release. Our results provide a novel molecular mechanism underlying the increased incidence of diabetes mellitus in patients treated with this drug.