The redox-active defensive Selenoprotein T as a novel stress sensor protein playing a key role in the pathophysiology of heart failure.

Maladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute cardiac protection. However, its action in chronic settings of cardiac dysfunction is not understood. Here, we investigated the role of SELENOT in the pathophysiology of HF: (i) by designing a small peptide (PSELT), recapitulating SELENOT activity via the redox site, and assessed its beneficial action in a preclinical model of HF [aged spontaneously hypertensive heart failure (SHHF) rats] and against isoproterenol (ISO)-induced hypertrophy in rat ventricular H9c2 and adult human AC16 cardiomyocytes; (ii) by evaluating the SELENOT intra-cardiomyocyte production and secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, and the severe ultrastructural alterations, while counteracting key mediators of cardiac fibrosis, aging, and DNA damage and restoring desmin downregulation and SELENOT upregulation in the failing hearts. In the hemodynamic assessment, PSELT improved the contractile impairment at baseline and following ischemia/reperfusion injury, and reduced infarct size in normal and failing hearts. At cellular level, PSELT counteracted ISO-mediated hypertrophy and ultrastructural alterations through its redox motif, while mitigating ISO-triggered SELENOT intracellular production and secretion, a phenomenon that presumably reflects the extent of cell damage. Altogether, these results indicate that SELENOT could represent a novel sensor of hypertrophied cardiomyocytes and a potential PSELT-based new therapeutic approach in myocardial hypertrophy and HF.

The histone methyltransferase SMYD1 is induced by thermogenic stimuli in adipose tissue.

Aim: To study the expression of histone methyltransferase SMYD1 in white adipose tissue (WAT) and brown adipose tissue and during differentiation of preadipocytes to white and beige phenotypes. Methods: C57BL/6J mice fed a high-fat diet (and exposed to cold) and 3T3-L1 cells stimulated to differentiate into white and beige adipocytes were used. Results: SMYD1 expression increased in WAT of high-fat diet fed mice and in WAT and brown adipose tissue of cold-exposed mice, suggesting its role in thermogenesis. SMYD1 expression was higher in beige adipocytes than in white adipocytes, and its silencing leads to a decrease in mitochondrial content and in Pgc-1α expression. Conclusion: These data suggest a novel role for SMYD1 as a positive regulator of energy control in adipose tissue.

In this study, a protein called SMYD1 was examined in the adipose tissue of mice to understand its role in the development of different types of fat cells. The authors used mice fed a high-fat diet or mice exposed to a cold environment. The experiments were also performed on cultured cells that were stimulated to form specific types of fat cells (white adipocytes, which store energy; or beige adipocytes, which are responsible for releasing energy in the form of heat). The study found that SMYD1 increased in white adipose tissue particularly in response to cold exposure and high-fat diet, suggesting involvement in body temperature regulation. SMYD1 was higher in beige adipocytes than in white fat cells, and when SMYD1 was reduced, there was a decrease in certain factors related to energy control. Overall, these results suggest that SMYD1 plays a novel role in energy regulation in adipose tissues.

Expanding the Frontiers of Guardian Antioxidant Selenoproteins in Cardiovascular Pathophysiology.

Significance: Physiological levels of reactive oxygen and nitrogen species (ROS/RNS) function as fundamental messengers for many cellular and developmental processes in the cardiovascular system. ROS/RNS involved in cardiac redox-signaling originate from diverse sources, and their levels are tightly controlled by key endogenous antioxidant systems that counteract their accumulation. However, dysregulated redox-stress resulting from inefficient removal of ROS/RNS leads to inflammation, mitochondrial dysfunction, and cell death, contributing to the development and progression of cardiovascular disease (CVD). Recent Advances: Basic and clinical studies demonstrate the critical role of selenium (Se) and selenoproteins (unique proteins that incorporate Se into their active site in the form of the 21st proteinogenic amino acid selenocysteine [Sec]), including glutathione peroxidase and thioredoxin reductase, in cardiovascular redox homeostasis, representing a first-line enzymatic antioxidant defense of the heart. Increasing attention has been paid to emerging selenoproteins in the endoplasmic reticulum (ER) (i.e., a multifunctional intracellular organelle whose disruption triggers cardiac inflammation and oxidative stress, leading to multiple CVD), which are crucially involved in redox balance, antioxidant activity, and calcium and ER homeostasis. Critical Issues: This review focuses on endogenous antioxidant strategies with therapeutic potential, particularly selenoproteins, which are very promising but deserve more detailed and clinical studies. Future Directions: The importance of selective selenoproteins in embryonic development and the consequences of their mutations and inborn errors highlight the need to improve knowledge of their biological function in myocardial redox signaling. This could facilitate the development of personalized approaches for the diagnosis, prevention, and treatment of CVD. Antioxid. Redox Signal. 40, 369-432.

Herbicide exposure alters the effect of the enthomopathogen Beauveria bassiana on immune gene expression in mealworm beetles.

Concerns have grown worldwide about the potentially far-reaching effects of herbicides on functional biodiversity in agroecosystems. Repeated applications over time can lead to accumulation of residues in soil, water, and food and may have negative impacts on non-target organisms. However, the effects of herbicide residues on interspecific relationships, such as host-pathogen interactions, are poorly studied. In this study, we evaluated the effects of two different concentrations of a commercial pendimethalin-based formulation (PND), the residual contamination (S, 13 ppm) in treated soils and the maximum residue level allowed by the European Commission in cereals (EU, 0.05 ppm). We tested the effect of PND on the biological interaction between the mealworm beetle Tenebrio molitor Linnaeus, 1758 and the entomopathogenic fungus Beauveria bassiana Vuillemin, 1912 (Bb, strain KVL 03-144) at two concentrations (LC50 5 × 105 conidia mL-1 and LC100 1 × 107 conidia mL-1). We checked the survival of beetles exposed to PND or/and inoculated with B. bassiana, the expression of four antimicrobial peptides (AMPs), and finally how PND affects in vitro germination of fungus. The exposure to PND had no significant effects on the survival of either control or Bb-exposed beetles. In the mealworm beetle, upregulation of gene expression of the inducible AMPs Tenecin 1, 2, and 4 was observed in PND-treated beetles after inoculation with Bb, while the levels of the non-inducible AMP Tenecin 3 were similar between treatments. In conclusion, our findings demonstrate that admitted residual doses of currently used herbicides modify an important component of the inducible immune response of an insect. This did not translate into an effect on the survival to B. bassiana in our system. However, residual doses of the herbicide at 13 ppm may temporarily affect fungal germination. These results raise questions about the compatibility of bioinsecticides with synthetic pesticides and the effects of herbicide residues on host-pathogen interactions.

Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer.

A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.

Emerging Molecular Determinants and Protective Strategies in Heart Disease: What's New in the Journal of Clinical Medicine? Outlook to the Future.

Cardiovascular diseases (CVD), including coronary heart disease (CHD), heart attacks, stroke, heart failure (HF), and peripheral artery disease, still represent the leading cause of death globally, taking an estimated 17 [...].

Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation.

Inspired by the recent advancements in understanding the binding mode of sulfonylurea-based NLRP3 inhibitors to the NLRP3 sensor protein, we developed new NLRP3 inhibitors by replacing the central sulfonylurea moiety with different heterocycles. Computational studies evidenced that some of the designed compounds were able to maintain important interaction within the NACHT domain of the target protein similarly to the most active sulfonylurea-based NLRP3 inhibitors. Among the studied compounds, the 1,3,4-oxadiazol-2-one derivative 5 (INF200) showed the most promising results being able to prevent NLRP3-dependent pyroptosis triggered by LPS/ATP and LPS/MSU by 66.3 ± 6.6% and 61.6 ± 11.5% and to reduce IL-1ß release (35.5 ± 8.8% µM) at 10 µM in human macrophages. The selected compound INF200 (20 mg/kg/day) was then tested in an in vivo rat model of high-fat diet (HFD)-induced metaflammation to evaluate its beneficial cardiometabolic effects. INF200 significantly counteracted HFD-dependent "anthropometric" changes, improved glucose and lipid profiles, and attenuated systemic inflammation and biomarkers of cardiac dysfunction (particularly BNP). Hemodynamic evaluation on Langendorff model indicate that INF200 limited myocardial damage-dependent ischemia/reperfusion injury (IRI) by improving post-ischemic systolic recovery and attenuating cardiac contracture, infarct size, and LDH release, thus reversing the exacerbation of obesity-associated damage. Mechanistically, in post-ischemic hearts, IFN200 reduced IRI-dependent NLRP3 activation, inflammation, and oxidative stress. These results highlight the potential of the novel NLRP3 inhibitor, INF200, and its ability to reverse the unfavorable cardio-metabolic dysfunction associated with obesity.

Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+ Itpr3tf/J mice.

Autism Spectrum Disorder (ASD) is increasing, but its complete etiology is still lacking. Recently, application of ketogenic diet (KD) has shown to reduce abnormal behaviors while improving psychological/sociological status in neurodegenerative diseases. However, KD role on ASD and underlying mechanism remains unknown. In this work, KD administered to BTBR T+ Itpr3tf/J (BTBR) and C57BL/6J (C57) mice reduced social deficits (p = 0.002), repetitive behaviors (p < 0.001) and memory impairments (p = 0.001) in BTBR. Behavioral effects were related to reduced expression levels of tumor necrosis factor alpha, interleukin-1ß, and interleukin-6 in the plasma (p = 0.007; p < 0.001 and p = 0.023, respectively), prefrontal cortex (p = 0.006; p = 0.04 and p = 0.03) and hippocampus (p = 0.02; p = 0.09 and p = 0.03). Moreover, KD accounted for reduced oxidative stress by changing lipid peroxidation levels and superoxide dismutase activity in BTBR brain areas. Interestingly, KD increased relative abundances of putatively beneficial microbiota (Akkermansia and Blautia) in BTBR and C57 mice while reversing the increase of Lactobacillus in BTBR feces. Overall, our findings suggest that KD has a multifunctional role since it improved inflammatory plus oxidative stress levels together with remodeling gut-brain axis. Hence, KD may turn out be a valuable therapeutic approach for ameliorating ASD-like conditions even though more evidence is required to evaluate its effectiveness especially on a long term.

Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State.

Cardiac lipotoxicity is an important contributor to cardiovascular complications during obesity. Given the fundamental role of the endoplasmic reticulum (ER)-resident Selenoprotein T (SELENOT) for cardiomyocyte differentiation and protection and for the regulation of glucose metabolism, we took advantage of a small peptide (PSELT), derived from the SELENOT redox-active motif, to uncover the mechanisms through which PSELT could protect cardiomyocytes against lipotoxicity. To this aim, we modeled cardiac lipotoxicity by exposing H9c2 cardiomyocytes to palmitate (PA). The results showed that PSELT counteracted PA-induced cell death, lactate dehydrogenase release, and the accumulation of intracellular lipid droplets, while an inert form of the peptide (I-PSELT) lacking selenocysteine was not active against PA-induced cardiomyocyte death. Mechanistically, PSELT counteracted PA-induced cytosolic and mitochondrial oxidative stress and rescued SELENOT expression that was downregulated by PA through FAT/CD36 (cluster of differentiation 36/fatty acid translocase), the main transporter of fatty acids in the heart. Immunofluorescence analysis indicated that PSELT also relieved the PA-dependent increase in CD36 expression, while in SELENOT-deficient cardiomyocytes, PA exacerbated cell death, which was not mitigated by exogenous PSELT. On the other hand, PSELT improved mitochondrial respiration during PA treatment and regulated mitochondrial biogenesis and dynamics, preventing the PA-provoked decrease in PGC1-α and increase in DRP-1 and OPA-1. These findings were corroborated by transmission electron microscopy (TEM), revealing that PSELT improved the cardiomyocyte and mitochondrial ultrastructures and restored the ER network. Spectroscopic characterization indicated that PSELT significantly attenuated infrared spectral-related macromolecular changes (i.e., content of lipids, proteins, nucleic acids, and carbohydrates) and also prevented the decrease in membrane fluidity induced by PA. Our findings further delineate the biological significance of SELENOT in cardiomyocytes and indicate the potential of its mimetic PSELT as a protective agent for counteracting cardiac lipotoxicity.

Quercetin and Its Derivative Counteract Palmitate-Dependent Lipotoxicity by Inhibiting Oxidative Stress and Inflammation in Cardiomyocytes.

Cardiac lipotoxicity plays an important role in the pathogenesis of obesity-related cardiovascular disease. The flavonoid quercetin (QUE), a nutraceutical compound that is abundant in the "Mediterranean diet", has been shown to be a potential therapeutic agent in cardiac and metabolic diseases. Here, we investigated the beneficial role of QUE and its derivative Q2, which demonstrates improved bioavailability and chemical stability, in cardiac lipotoxicity. To this end, H9c2 cardiomyocytes were pre-treated with QUE or Q2 and then exposed to palmitate (PA) to recapitulate the cardiac lipotoxicity occurring in obesity. Our results showed that both QUE and Q2 significantly attenuated PA-dependent cell death, although QUE was effective at a lower concentration (50 nM) when compared with Q2 (250 nM). QUE decreased the release of lactate dehydrogenase (LDH), an important indicator of cytotoxicity, and the accumulation of intracellular lipid droplets triggered by PA. On the other hand, QUE protected cardiomyocytes from PA-induced oxidative stress by counteracting the formation of malondialdehyde (MDA) and protein carbonyl groups (which are indicators of lipid peroxidation and protein oxidation, respectively) and intracellular ROS generation, and by improving the enzymatic activities of catalase and superoxide dismutase (SOD). Pre-treatment with QUE also significantly attenuated the inflammatory response induced by PA by reducing the release of key proinflammatory cytokines (IL-1ß and TNF-α). Similar to QUE, Q2 (250 nM) also significantly counteracted the PA-provoked increase in intracellular lipid droplets, LDH, and MDA, improving SOD activity and decreasing the release of IL-1ß and TNF-α. These results suggest that QUE and Q2 could be considered potential therapeutics for the treatment of the cardiac lipotoxicity that occurs in obesity and metabolic diseases.

Chromogranin A and Its Fragments in the Critically Ill: An Expanding Domain of Interest for Better Care.

Life-threatening diseases challenge immunity with a release of chromogranins. This report focuses on Chromogranin A (CGA) and some of its derived peptides in critically ill patients, with attention paid to their potential to become biomarkers of severity and actors of defense. First, we studied whether circulating CGA may be a biomarker of outcome in non-selected critically ill patients: CGA concentrations were reliably associated with short-term death, systemic inflammation, and multiple organ failure. Additionally, when studying Vasostatin-I, the major N-terminal fragment of CGA, we noted its reliable prognostic value as early as admission if associated with age and lactate. In trauma patients, CGA concentrations heralded the occurrence of care-related infections. This was associated with an in vitro inhibitor impact of Chromofungin on both NF-kappa B- and API-transcriptional activities. Secondly, in life-threatening disease-induced oxidative stress, the multimerization of Vasostatin-I occurs with the loss of its anti-microbial properties ex vivo. In vivo, a 4%-concentration of non-oxidized albumin infusion reversed multimerization with a decrease in care-related infections. Finally, in vitro Catestatin impacted the polymorphonuclear cells-Ca++-dependent, calmodulin-regulated iPLA2 pathway by releasing immunity-related proteins. Furthermore, human Cateslytin, the active domain of Catestatin, helped destroy S. aureus: this prompted the creation of synthetic D-stereoisomer of CGA-derived peptides against superbugs for the protection of implanted devices. In conclusion, CGA consideration in the critically ill is only starting, but it offers interesting perspectives for improved outcomes.

Modifications of Behavior and Inflammation in Mice Following Transplant with Fecal Microbiota from Children with Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder displaying the modification of complex human behaviors, characterized by social interaction impairments, stereotypical/repetitive activities and emotional dysregulation. In this study, fecal microbiota transplant (FMT) via gavage from autistic children donors to mice, led to the colonization of ASD-like microbiota and autistic behaviors compared to the offspring of pregnant females exposed to valproic acid (VPA). Such variations seemed to be tightly associated with increased populations of Tenericutes plus a notable reduction (p < 0.001) of Actinobacteria and Candidatus S. in the gastrointestinal region of FMT mice as compared to controls. Indeed altered behaviors of FMT mice was reported when evaluated in the different maze tests (light dark, novel object, three chamber tests, novel cage test). Contextually, FMT accounted for elevated expression levels of the pro-inflammatory factors IL-1ß, IL-6, COX-1 and TNF-α in both brain and small intestine. Villous atrophy and inflammatory infiltration (Caspase 3 and Ki67) were increased in the small intestine of FMT and VPA mice compared to controls. Moreover, the observed FMT-dependent alterations were linked to a decrease in the methylation status. Overall, findings of the present study corroborate a key role of gut microbiota in ASD. However, further investigations are required before any possible manipulation of gut bacteria with appropriate diets or probiotics can be conducted in ASD individuals.

Novel molecular insights and potential approaches for targeting hypertrophic cardiomyopathy: Focus on coronary modulators.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder that associates with nucleotide sequence variants in genes encoding sarcomere related proteins, and is recognized as the most common heritable cardiac diseases. Clinically, HCM can be extremely variable and this makes the diagnosis difficult until the development of serious or fatal events. Nevertheless, the main hallmark of HCM is represented by left ventricle hypertrophy that can be occasionally associated to cardiac arrhythmias, chest pain, diastolic dysfunction, obstruction of left ventricular outflow tract. The present review aims to focus on the complex interplay existing between the multifaceted non-genetic molecular mechanisms underlying HCM onset and progression, and the key pathophysiological role of abnormal coronary artery function. As the clinical course of HCM shows a mortality rate per year up to 6% the importance of innovative therapeutic strategies will be discussed, especially in regard to the use of potential endogenous coronary modulators to be enrolled as modifiers of HCM phenotype.

Targeting endothelial ion signalling to rescue cerebral blood flow in cerebral disorders.

The mechanism whereby an increase in neuronal activity (NA) leads to a local elevation in cerebral blood flow to supply the active neurons with oxygen and nutrients and remove the catabolic waste has been termed neurovascular coupling (NVC). Although it has long been thought that the vasoactive mediators involved in NVC are generated by neurons and astrocytes, recent evidence unveiled the crucial role of cerebrovascular endothelial cells in NVC. Brain capillary endothelial cells express a complement of ion channels, including inward-rectifier K+ (Kir2.1) channels, Transient Receptor Potential Ankyrin 1 channels and N-methyl-d-aspartate receptors that enable them to sense NA and thereby initiate the retrograde transmission of both electrical (via endothelium-dependent hyperpolarization) and chemical (via intercellular Ca2+ waves also sustained by TRP Vanilloid 4 channels and inositol-1,4,5-trisphosphate receptors) signals that induce vasodilation in upstream pial arteries and parenchymal arteries. Notably, a defect in the endothelial ion channel machinery (particularly, Kir2.1 channels) contributes to vascular cognitive impairment and dementia that features many cerebral disorders, including Alzheimer's disease, cerebral small vessel diseases, and traumatic brain injury. Targeting endothelial ion channels through appropriate pharmacological approaches might represent a hitherto unappreciated strategy to rescue CBF and prevent cognitive impairment and dementia in patients affected by cerebral disorders.

The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress.

Oxidative stress and endoplasmic reticulum stress (ERS) are strictly involved in myocardial ischemia/reperfusion (MI/R). Selenoprotein T (SELENOT), a vital thioredoxin-like selenoprotein, is crucial for ER homeostasis and cardiomyocyte differentiation and protection, likely acting as a redox-sensing protein during MI/R. Here, we designed a small peptide (PSELT), encompassing the redox site of SELENOT, and investigated whether its pre-conditioning cardioprotective effect resulted from modulating ERS during I/R. The Langendorff rat heart model was employed for hemodynamic analysis, while mechanistic studies were performed in perfused hearts and H9c2 cardiomyoblasts. PSELT improved the post-ischemic contractile recovery, reducing infarct size and LDH release with and without the ERS inducer tunicamycin (TM). Mechanistically, I/R and TM upregulated SELENOT expression, which was further enhanced by PSELT. PSELT also prevented the expression of the ERS markers CHOP and ATF6, reduced cardiac lipid peroxidation and protein oxidation, and increased SOD and catalase activities. An inert PSELT (I-PSELT) lacking selenocysteine was ineffective. In H9c2 cells, H2O2 decreased cell viability and SELENOT expression, while PSELT rescued protein levels protecting against cell death. In SELENOT-deficient H9c2 cells, H2O2 exacerbated cell death, that was partially mitigated by PSELT. Microscopy analysis revealed that a fluorescent form of PSELT was internalized into cardiomyocytes with a perinuclear distribution. Conclusions: The cell-permeable PSELT is able to induce pharmacological preconditioning cardioprotection by mitigating ERS and oxidative stress, and by regulating endogenous SELENOT.

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity.

Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it is not surprising that structural and functional impairments of mitochondria can lead to contractile dysfunction, and have been widely implicated in the onset of diverse cardiovascular diseases, including ischemic cardiomyopathy, heart failure, and stroke. Several studies support mitochondrial targets as major determinants of the cardiotoxic effects triggered by an increasing number of chemotherapeutic agents used for both solid and hematological tumors. Mitochondrial toxicity induced by such anticancer therapeutics is due to different mechanisms, generally altering the mitochondrial respiratory chain, energy production, and mitochondrial dynamics, or inducing mitochondrial oxidative/nitrative stress, eventually culminating in cell death. The present review summarizes key mitochondrial processes mediating the cardiotoxic effects of anti-neoplastic drugs, with a specific focus on anthracyclines (ANTs), receptor tyrosine kinase inhibitors (RTKIs) and proteasome inhibitors (PIs).

Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction.

Metabolic syndrome and its associated disorders such as obesity, insulin resistance, atherosclerosis and type 2 diabetes mellitus are globally prevalent. Different molecules showing therapeutic potential are currently available for the management of metabolic syndrome, although their efficacy has often been compromised by their poor bioavailability and side effects. Studies have been carried out on medicinal plant extracts for the treatment and prevention of metabolic syndrome. In this regard, isolated pure compounds have shown promising efficacy for the management of metabolic syndrome, both in preclinical and clinical settings. Apigenin, a natural bioactive flavonoid widely present in medicinal plants, functional foods, vegetables and fruits, exerts protective effects in models of neurological disorders and cardiovascular diseases and most of these effects are attributed to its antioxidant action. Various preclinical and clinical studies carried out so far show a protective effect of apigenin against metabolic syndrome. Herein, we provide a comprehensive review on both in vitro and in vivo evidence related to the promising antioxidant role of apigenin in cardioprotection, neuroprotection and renoprotection, and to its beneficial action in metabolic-syndrome-dependent organ dysfunction. We also provide evidence on the potential of apigenin in the prevention and/or treatment of metabolic syndrome, analysing the potential and limitation of its therapeutic use.

Understanding the heart-brain axis response in COVID-19 patients: A suggestive perspective for therapeutic development.

In-depth characterization of heart-brain communication in critically ill patients with severe acute respiratory failure is attracting significant interest in the COronaVIrus Disease 19 (COVID-19) pandemic era during intensive care unit (ICU) stay and after ICU or hospital discharge. Emerging research has provided new insights into pathogenic role of the deregulation of the heart-brain axis (HBA), a bidirectional flow of information, in leading to severe multiorgan disease syndrome (MODS) in patients with confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Noteworthy, HBA dysfunction may worsen the outcome of the COVID-19 patients. In this review, we discuss the critical role HBA plays in both promoting and limiting MODS in COVID-19. We also highlight the role of HBA as new target for novel therapeutic strategies in COVID-19 in order to open new translational frontiers of care. This is a translational perspective from the Italian Society of Cardiovascular Researches.

Cardiometabolism as an Interlocking Puzzle between the Healthy and Diseased Heart: New Frontiers in Therapeutic Applications.

Cardiac metabolism represents a crucial and essential connecting bridge between the healthy and diseased heart. The cardiac muscle, which may be considered an omnivore organ with regard to the energy substrate utilization, under physiological conditions mainly draws energy by fatty acids oxidation. Within cardiomyocytes and their mitochondria, through well-concerted enzymatic reactions, substrates converge on the production of ATP, the basic chemical energy that cardiac muscle converts into mechanical energy, i.e., contraction. When a perturbation of homeostasis occurs, such as an ischemic event, the heart is forced to switch its fatty acid-based metabolism to the carbohydrate utilization as a protective mechanism that allows the maintenance of its key role within the whole organism. Consequently, the flexibility of the cardiac metabolic networks deeply influences the ability of the heart to respond, by adapting to pathophysiological changes. The aim of the present review is to summarize the main metabolic changes detectable in the heart under acute and chronic cardiac pathologies, analyzing possible therapeutic targets to be used. On this basis, cardiometabolism can be described as a crucial mechanism in keeping the physiological structure and function of the heart; furthermore, it can be considered a promising goal for future pharmacological agents able to appropriately modulate the rate-limiting steps of heart metabolic pathways.

Cateslytin abrogates lipopolysaccharide-induced cardiomyocyte injury by reducing inflammation and oxidative stress through toll like receptor 4 interaction.

Global public health is threatened by new pathogens, antimicrobial resistant microorganisms and a rapid decline of conventional antimicrobials efficacy. Thus, numerous medical procedures become life-threating. Sepsis can lead to tissue damage such as myocardium inflammation, associated with reduction of contractility and diastolic dysfunction, which may cause death. In this perspective, growing interest and attention are paid on host defence peptides considered as new potential antimicrobials. In the present study, we investigated the physiological and biochemical properties of Cateslytin (Ctl), an endogenous antimicrobial chromogranin A-derived peptide, in H9c2 cardiomyocytes exposed to lipopolysaccharide (LPS) infection. We showed that both Ctl (L and D) enantiomers, but not their scrambled counterparts, significantly increased cardiomyocytes viability following LPS, even if L-Ctl was effective at lower concentration (1 nM) compared to D-Ctl (10 nM). L-Ctl mitigated LPS-induced LDH release and oxidative stress, as visible by a reduction of MDA and protein carbonyl groups content, and by an increase of SOD activity. Molecular docking simulations strongly suggested that L-Ctl modulates TLR4 through a direct binding to the partner protein MD-2. Molecular analyses indicated that the protection mediated by L-Ctl against LPS-evoked sepsis targeted the TLR4/ERK/JNK/p38-MAPK pathway, regulating NFkB p65, NFkB p52 and COX2 expression and repressing the mRNA expression levels of the LPS-induced proinflammatory factors IL-1ß, IL-6, TNF-α and NOS2. These findings indicate that Ctl could be considered as a possible candidate for the development of new antimicrobials strategies in the treatment of myocarditis. Interestingly, L-enantiomeric Ctl showed remarkable properties in strengthening the anti-inflammatory and anti-oxidant effects on cardiomyocytes.