Vitamin D in atherosclerosis and cardiovascular events.

Both experimental and clinical findings linking vitamin D to cardiovascular (CV) risk have prompted consideration of its supplementation to improve overall health. Yet several meta-analyses do not provide support for the clinical effectiveness of this strategy. Meanwhile, the understanding of the roles of vitamin D in the pathophysiology of CV diseases has evolved. Specifically, recent work has revealed some non-classical pleiotropic effects of vitamin D, increasing the complexity of vitamin D signalling. Within particular microenvironments (e.g. dysfunctional adipose tissue and atherosclerotic plaque), vitamin D can act locally at cellular level through intracrine/autocrine/paracrine feedforward and feedback circuits. Within atherosclerotic tissues, 'local' vitamin D levels may influence relevant systemic consequences independently of its circulating pool. Moreover, vitamin D links closely to other signalling pathways of CV relevance including those driving cellular senescence, ageing, and age-related diseases-among them CV conditions. This review updates knowledge on vitamin D biology aiming to clarify the widening gap between experimental and clinical evidence. It highlights the potential reverse causation confounding correlation between vitamin D status and CV health, and the need to consider novel pathophysiological concepts in the design of future clinical trials that explore the effects of vitamin D on atherosclerosis and risk of CV events.

Safety and Feasibility of Fasting-Mimicking Diet and Effects on Nutritional Status and Circulating Metabolic and Inflammatory Factors in Cancer Patients Undergoing Active Treatment.

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients' nutritional status. We assessed the feasibility and safety of a 5-day "Fasting-Mimicking Diet" (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients' weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

Current and emerging treatments for neonatal sepsis.

Introduction: Mortality due to sepsis is still prevalent, peaking at extreme ages of life including infancy. Despite many efforts, the peculiarity of the infant immune system has limited further advances in its treatment. Indeed, neonates experience a dramatic physiological transition from immune tolerance to the maternal antigens to functional maturity. Such a transition is extremely dynamic, as is the pathophysiology of infant sepsis, which is dependent on many infant, maternal, and environmental factors.Areas covered: In this review, the authors critically update and summarize the current paradigm of immunomodulation in infant sepsis. They confirm how exogenous stimulation of the immune system through intravenous immunoglobulin, colony stimulating factors, and granulocyte transfusion have failed to impact on the prognosis of infant sepsis. They also strongly support the beneficial effects of supplementation/replacement therapies with products naturally contained within maternal milk as well as antioxidant compounds.Expert opinion: Breastfeeding is beneficial against sepsis. Knowledge of the neonatal immune system is indeed too limited to effectively strengthen immune response by exogenous interventions, especially in preterm and low-birth-weight infants. Awareness of this limitation should pave the way for future studies (e.g. gender- and omics-based) aimed at better characterizing the infant immune system and promoting a more tailored approach.

Efficacy of Nutraceutical Combination of Monacolin K, Berberine, and Silymarin on Lipid Profile and PCSK9 Plasma Level in a Cohort of Hypercholesterolemic Patients.

The guidelines for the treatment of dyslipidemias include the use of nutraceuticals (NUTs) in association with lifestyle modifications to achieve therapeutic goals. In NUT pill, different substances may be associated; in this study we investigated a combined NUT containing monacolin K (MonK)+KA (1:1), berberine (BBR), and silymarin. The aim of the study was to evaluate low-density lipoprotein cholesterol (LDL-C) reduction in 53 patients suffering from polygenic hypercholesterolemia, characterized by a low/intermediate cardiovascular risk calculated with SCORE algorithm. The effects on lipid profile of 2-month treatment with NUT containing MonK+KA (1:1), BBR, and sylimarin, were compared with Atorvastatin (ATO) 10 mg administrated in a matched control group. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the cholesterol loading capacity (CLC) were determined at baseline and at the end of the study in NUT-treated group; variations were assessed. NUT was effective as lipid-lowering agent with a wide interindividual response variability (mean LDL-C from 170.8 ± 19.9 to 123.8 ± 20.0 with a change of -47.0 ± 21.5 mg/dL; P < .001) and the effect was similar to that induced by ATO. The use of NUT significantly modified PCSK9 levels (P < .01) and CLC (P < .001), ultimately suppressing the serum-mediated foam cell generation directly measured on human macrophages. NUT reduces LDL-C levels with an effect similar to what is induced by 10 mg of ATO and ex vivo improves the functional profile of lipoproteins with antiatherogenic action.

Update on selective treatments targeting neutrophilic inflammation in atherogenesis and atherothrombosis.

Atherosclerosis is the most common pathological process underlying cardiovascular diseases. Current therapies are largely focused on alleviating hyperlipidaemia and preventing thrombotic complications, but do not completely eliminate risk of suffering recurrent acute ischaemic events. Specifically targeting the inflammatory processes may help to reduce this residual risk of major adverse cardiovascular events in atherosclerotic patients. The involvement of neutrophils in the pathophysiology of atherosclerosis is an emerging field, where evidence for their causal contribution during various stages of atherosclerosis is accumulating. Therefore, the identification of neutrophils as a potential therapeutic target may offer new therapeutic perspective to reduce the current atherosclerotic burden. This narrative review highlights the expanding role of neutrophils in atherogenesis and discusses on the potential treatment targeting neutrophil-related inflammation and associated atherosclerotic plaque vulnerability.