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Cachexia is a severe complication of cancer that adversely affects the course of the disease, with currently no effective treatments. It is characterized by a progressive atrophy of skeletal muscle and adipose tissue, resulting in weight loss, a reduced quality of life, and a shortened life expectancy. Although the cachectic condition primarily affects the skeletal muscle, a tissue that accounts for ~40% of total body weight, cachexia is considered a multi-organ disease that involves different tissues and organs, among which the cardiac muscle stands out for its relevance. Patients with cancer often experience severe cardiac abnormalities and manifest symptoms that are indicative of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance. Furthermore, cardiovascular complications are among the major causes of death in cancer patients who experienced cachexia. The lack of effective treatments for cancer cachexia underscores the need to improve our understanding of the underlying mechanisms. Increasing evidence links the wasting of the cardiac and skeletal muscles to metabolic alterations, primarily increased energy expenditure, and to increased proteolysis, ensuing from activation of the major proteolytic machineries of the cell, including ubiquitin-dependent proteolysis and autophagy. This review aims at providing an overview of the key mechanisms of cancer cachexia, with a major focus on those that are shared by the skeletal and cardiac muscles.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by abnormal epithelial repair, persistent inflammation, and excessive extracellular matrix deposition, leading to irreversible scarring and respiratory failure. Central to its pathogenesis is the dysregulation of the PI3K/Akt signaling pathway, which drives fibroblast activation, epithelial-mesenchymal transition, apoptosis resistance, and cellular senescence. Senescent cells contribute to fibrosis through the secretion of pro-inflammatory and profibrotic factors in the senescence-associated secretory phenotype (SASP). Current antifibrotic therapies, Nintedanib and Pirfenidone, only slow disease progression and are limited by side effects, highlighting the need for novel treatments. This review focuses on the role of PI3K/Akt signaling in IPF pathogenesis, its intersection with inflammation and fibrosis, and emerging therapeutic approaches targeting molecules along this pathway.

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

Phospholipase C (PLC) enzymes represent crucial participants in the plasma membrane of mammalian cells, including the cardiac sarcolemmal (SL) membrane of cardiomyocytes. They are responsible for the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) into 1,2-diacylglycerol (DAG) and inositol (1,4,5) trisphosphate (Ins(1,4,5)P3), both essential lipid mediators. These second messengers regulate the intracellular calcium (Ca2+) concentration, which activates signal transduction cascades involved in the regulation of cardiomyocyte activity. Of note, emerging evidence suggests that changes in cardiomyocytes’ phospholipid profiles are associated with an increased occurrence of cardiovascular diseases, but the underlying mechanisms are still poorly understood. This review aims to provide a comprehensive overview of the significant impact of PLC on the cardiovascular system, encompassing both physiological and pathological conditions. Specifically, it focuses on the relevance of PLCβ isoforms as potential cardiac biomarkers, due to their implications for pathological disorders, such as cardiac hypertrophy, diabetic cardiomyopathy, and myocardial ischemia/reperfusion injury. Gaining a deeper understanding of the mechanisms underlying PLCβ activation and regulation is crucial for unraveling the complex signaling networks involved in healthy and diseased myocardium. Ultimately, this knowledge holds significant promise for advancing the development of potential therapeutic strategies that can effectively target and address cardiac disorders by focusing on the PLCβ subfamily.

Purpose of ReviewAlong with population aging, the incidence of both heart failure (HF) and cancer is increasing. However, little is known about new-onset cancer in HF patients. This review aims at showing recent discoveries concerning this subset of patients.Recent FindingsNot only cancer and HF share similar risk factors but also HF itself can stimulate cancer development. Some cytokines produced by the failing heart induce mild inflammation promoting carcinogenesis, as it has been recently suggested by an experimental model of HF in mice.SummaryThe incidence of new-onset cancer is higher in HF patients compared to the general population, and it significantly worsens their prognosis. Moreover, the management of HF patients developing new-onset cancer is challenging, especially due to the limited therapeutic options for patients affected by both cancer and HF and the higher risk of cardiotoxicity from anticancer drugs.

Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.

Phosphodiesterase 4 (PDE4) is a key regulator of cyclic adenosine monophosphate (cAMP) signalling in cardiomyocytes, controlling contractility, calcium handling, and hypertrophic responses. PDE4 provides spatial and temporal precision to cAMP signalling, particularly under β-adrenergic stimulation, through its compartmentalised activity in subcellular nanodomains, including the sarcoplasmic reticulum, plasma membrane and nuclear envelope. This review highlights the cardiac PDE4 isoforms PDE4A, PDE4B and PDE4D, focusing on their distinct localisation and contributions to cardiac physiology and pathophysiology, particularly in heart failure and arrhythmias. Although PDE4 plays a smaller role in overall cAMP hydrolysis in human hearts than in rodents, its compartmentalised function remains critical. Recent therapeutic advances have shifted from pan-PDE4 inhibitors to isoform-specific approaches to enhance efficacy while minimising systemic toxicity. We discuss the potential of selective PDE4 modulators, gene therapies and combination strategies in restoring cAMP compartmentation and preventing maladaptive cardiac remodelling. By integrating rodent and human studies, this review underscores the translational challenges and therapeutic opportunities surrounding PDE4, positioning it as both a key regulator of cardiac signalling and a promising target for heart failure therapies.

The small-GTPase Rac1 is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics. Loss-of-function mutations in RAC1 and other genes of the Rac signaling pathway have been implicated in the pathogenesis of Intellectual Disability (ID). The Rac1 activity is negatively controlled by GAP proteins, however the effect of Rac1 hyperactivity on neuronal networking in vivo has been poorly studied. ArhGAP15 is a Rac-specific negative regulator, expressed in the main subtypes of pyramidal cortical neurons. In the absence of ArhGAP15 , cortical pyramidal neurons show defective neuritogenesis, delayed axonal elongation, reduced dendritic branching, both in vitro and in vivo . These phenotypes are associated with altered actin dynamics at the growth cone due to increased activity of the PAK-LIMK pathway and hyperphosphorylation of ADF/cofilin. These results can be explained by shootin1 hypo-phosphorylation and uncoupling with the adhesion system. Functionally, ArhGAP15 −/− mice exhibit decreased synaptic density, altered electroencephalographic rhythms and cognitive deficits. These data suggest that both hypo- and hyperactivation of the Rac pathway due to mutations in Rac1 regulators can result in conditions of ID, and that a tight regulation of Rac1 activity is required to attain the full complexity of the cortical networks.

Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress. Synopsis FAO is catalyzed by the mitochondrial trifunctional protein (MTP) and, if overloaded, generates ROS. ROS are boosted during stressful events, favoring cardiac maladaptive remodeling. Melusin is a muscle-specific chaperone able to sustain heart resilience during a wide variety of stressful insults. Melusin interacts and inhibits the MTP, restraining FAO and ROS generation in the myocardium. Heart resilience depends on the rate of FAO during stressful events occurrence. Inhibiting lipid metabolism in a timely manner during stress protects the heart from dysfunction and prolongs the survival in preclinical models. FAO is catalyzed by the mitochondrial trifunctional protein (MTP) and, if overloaded, generates ROS. ROS are boosted during stressful events, favoring cardiac maladaptive remodeling. Melusin is a muscle-specific chaperone able to sustain heart resilience during a wide variety of stressful insults.

Although PI3Kγ has been extensively investigated in inflammatory and cardiovascular diseases, the exploration of its functions in the brain is just at dawning. It is known that PI3Kγ is present in neurons and that the lack of PI3Kγ in mice leads to impaired synaptic plasticity, suggestive of a role in behavioral flexibility. Several neuropsychiatric disorders, such as attention‐deficit/hyperactivity disorder (ADHD), involve an impairment of behavioral flexibility. Here, we found a previously unreported expression of PI3Kγ throughout the noradrenergic neurons of the locus coeruleus (LC) in the brainstem, serving as a mechanism that regulates its activity of control on attention, locomotion and sociality. In particular, we show an unprecedented phenotype of PI3Kγ KO mice resembling ADHD symptoms. PI3Kγ KO mice exhibit deficits in the attentive and mnemonic domains, typical hyperactivity, as well as social dysfunctions. Moreover, we demonstrate that the ADHD phenotype depends on a dysregulation of CREB signaling exerted by a kinase‐independent PI3Kγ‐PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD. Synopsis PI3K regulates synaptic plasticity and behavioral flexibility via a kinase‐independent but CREB‐dependent mechanism in noradrenergic neurons of the locus coeruleus. PI3Kγ‐deficient mice model main features of attention‐deficit/hyperactivity disorders (ADHD). PI3Kγ KO mice exhibit symptomatic traits of the attention‐deficit/hyperactivity disorder (ADHD), displaying deficits in the attentive and mnemonic domains, coupled with typical hyperactivity, as well as social dysfunctions. PI3Kγ controls locus coeruleus (LC) functions in the modulations of these behavioral domains by kinase‐independent mechanisms; the PI3Kγ KD (kinase‐defective) mice are not affected. PI3Kγ physically interacts with phosphodiesterase 4D (PDE4D) in the LC and controls cAMP–CREB signaling, which is constitutively increased in PI3Kγ KO mice. Selective genetic targeting of increased CREB signaling in the LC by stereotactic approach rescues the ADHD phenotype of PI3Kγ KO mice. Graphical Abstract PI3K regulates synaptic plasticity and behavioral flexibility via a kinase‐independent but CREB‐dependent mechanism in noradrenergic neurons of the locus coeruleus. PI3Kγ‐deficient mice model main features of attention‐deficit/hyperactivity disorders (ADHD).