Diets with an elevated content of fat, sucrose, or fructose are recognized models of diet-induced metabolic alterations, since they induce metabolic derangements, oxidative stress, and chronic low-grade inflammation associated with local and systemic accumulation of advanced glycation end-products (AGEs). This study used four-week-old C57BL/6 male mice, randomly assigned to three experimental dietary regimens: standard diet (SD), high-fat high-sucrose diet (HFHS), or high fructose diet (HFr), administered for 12 weeks. Plasma, heart, and tibialis anterior (TA) skeletal muscle were assayed for markers of metabolic conditions, inflammation, presence of AGEs, and mitochondrial involvement. The HFHS diet induced a tissue-specific differential response featuring (1) a remarkable adaptation of the heart to HFHS-induced heavy oxidative stress, demonstrated by an increased presence of AGEs and reduced mitochondrial biogenesis, and efficaciously counteracted by a conspicuous increase in mitochondrial fission and PRXIII expression; (2) the absence of TA adaptation to HFHS, revealed by a heavy reduction in mitochondrial biogenesis, not counteracted by an increase in fission and PRXIII expression. HFr-induced mild oxidative stress elicited tissue-specific responses, featuring (1) a decrease in mitochondrial biogenesis in the heart, likely counteracted by a tendency for increased fission and (2) a mild reduction in mitochondrial biogenesis in TA, likely counteracted by a tendency for increased fusion, showing the adaptability of both tissues to the diet.

Despite the development of cutting-edge treatments, coronary artery disease (CAD) morbidity and mortality rates remain present at high levels. Therefore, new cardioprotective approaches are crucial to improve the health of patients. To date, experimental investigations of acute ischemia-reperfusion injury (IRI) have generally demonstrated the efficacy of local ischemic preconditioning and postconditioning cardioprotection techniques as well as of remote conditioning. However, application in clinical settings is still highly controversial and debated. Currently, remote ischemic conditioning (RIC) seems to be the most promising method for heart repair. Protective factors are released into the bloodstream, and protection can be transferred within and across species. For a long time, the cross-function and cross-transmission mechanisms of cardioprotection were largely unknown. Recently, it has been shown that small, anuclear, bilayered lipid membrane particles, known as extracellular vesicles (EVs), are the drivers of signal transduction in cardiac IRI and RIC. EVs are related to the pathophysiological processes of cardiovascular diseases (CVDs), according to compelling evidence. In this review, we will first review the current state of knowledge on myocardial IRI and cardioprotective strategies explored over the past 37 years. Second, we will briefly discuss the role of EVs in CVD and the most recent improvements on EVs as prognostic biomarkers, diagnostic, and therapeutic agents. We will discuss how EVs can be used as a new drug delivery mechanism and how they can be employed in cardiac treatment, also from a perspective of overcoming the impasse that results from neglecting confounding factors.

Casein kinase II (CK2) has recently emerged as a pivotal mediator in the propagation of inflammation across various diseases. Nevertheless, its role in the pathogenesis of sepsis remains unexplored. Here, we investigated the involvement of CK2 in sepsis progression and the potential beneficial effects of silmitasertib, a selective and potent CK2α inhibitor, currently under clinical trials for COVID-19 and cancer. Sepsis was induced by caecal ligation and puncture (CLP) in four-month-old C57BL/6OlaHsd mice. One hour after the CLP/Sham procedure, animals were assigned to receive silmitasertib (50 mg/kg/i.v.) or vehicle. Plasma/organs were collected at 24 h for analysis. A second set of experiments was performed for survival rate over 120 h. Septic mice developed multiorgan failure, including renal dysfunction due to hypoperfusion (reduced renal blood flow) and increased plasma levels of creatinine. Renal derangements were associated with local overactivation of CK2, and downstream activation of the NF-ĸB-iNOS-NO axis, paralleled by a systemic cytokine storm. Interestingly, all markers of injury/inflammation were mitigated following silmitasertib administration. Additionally, when compared to sham-operated mice, sepsis led to vascular hyporesponsiveness due to an aberrant systemic and local release of NO. Silmitasertib restored sepsis-induced vascular abnormalities. Overall, these pharmacological effects of silmitasertib significantly reduced sepsis mortality. Our findings reveal, for the first time, the potential benefits of a selective and potent CK2 inhibitor to counteract sepsis-induced hyperinflammatory storm, vasoplegia, and ultimately prolonging the survival of septic mice, thus suggesting a pivotal role of CK2 in sepsis and silmitasertib as a novel powerful pharmacological tool for drug repurposing in sepsis.

Gas-loaded nanocarriers (G-LN) show promise in improving heart transplantation (HTx) outcomes. Given their success in reducing cell death during normothermic hypoxia/reoxygenation (H/R) in vitro, we tested their integration into cardioplegic solutions and static cold storage (SCS) during simulated HTx. Wistar rat hearts underwent four hours of SCS with four G-LN variants: O₂- or N₂-cyclic-nigerosyl-nigerose-nanomonomers (CNN), and O₂- or N₂-cyclic-nigerosyl-nigerose-nanosponges (CNN-NS). We monitored physiological-hemodynamic parameters and molecular markers during reperfusion to assess cell damage/protection. Hearts treated with nanomonomers (N₂-CNN or O₂-CNN) showed improvements in left ventricular developed pressure (LVDP) and a trend towards faster recovery of the rate pressure product (RPP) compared to controls. However, nanosponges (N₂-CNN-NS or O₂-CNN-NS) did not show similar improvements. None of the groups exhibited an increase in diastolic left ventricular pressure (contracture index) during reperfusion. Redox markers and apoptosis/autophagy pathways indicated an increase in Beclin 1 for O₂-CNN and in p22phox for N₂-CNN, suggesting alterations in autophagy and the redox environment during late reperfusion, which might explain the gradual decline in heart performance. The study highlights the potential of nanomonomers to improve early cardiac performance and mitigate cold/H/R-induced stunning in HTx. These early improvements suggest a promising avenue for increasing HTx success. Nevertheless, further research and optimization are needed before clinical application.

Sepsis-associated encephalopathy (SAE) is a diffuse dysfunction of the central nervous system and a major manifestation of sepsis, associated with acute clinical deterioration and poor prognosis. Despite advances in understanding its pathophysiology and sepsis-induced cerebral alterations, effective pharmacological treatments remain unavailable. Cyclin-dependent kinase 9 (CDK9) is a ubiquitous kinase implicated in several inflammatory processes, however, its role in sepsis remains poorly understood. This study investigated whether CDK9 activity contributes to SAE pathophysiology and whether its pharmacological inhibition confers protection in a clinically relevant sepsis model. Polymicrobial sepsis was induced in male C57BL/6OlaHsd mice using caecal ligation and puncture (CLP). One hour after the procedure, mice received the selective CDK9 inhibitor LDC000067 (50 mg/kg i.v.) or vehicle. At 24 h, sepsis induced marked CDK9 activation in the prefrontal cortex, accompanied by neuroinflammation, evidenced by microglial activation, and blood-brain barrier (BBB) disruption, reflected by increased plasma neurofilament light chain levels. Treatment with LDC000067 attenuated septic alterations both centrally and peripherally, reducing multiorgan dysfunction, the systemic cytokine storm, and clinical severity. In vitro, exposure of human microglial cells to a sepsis-like inflammatory stimulus increased NF-κB-related transcriptional responses, which were significantly reduced by CDK9 inhibition. Similarly, exposure of brain microvascular endothelial cells to the same stimulus resulted in endothelial barrier dysfunction, mitigated by CDK9 inhibition through preservation of claudin-5 expression and barrier integrity. Altogether, these findings identify a previously unreported role for CDK9 in SAE pathogenesis and show that its pharmacological inhibition attenuates key features of SAE, including microglial activation and BBB disruption.

Childhood, adolescent, and young adult cancer survivors (CAYACS) are at increased risk of late morbidity, potentially reflecting premature biological aging. Cellular senescence, oxidative stress, and chronic inflammation may contribute via interconnected pathways, including signaling mediated by advanced glycation end products (AGEs) and their receptor, RAGE. This study investigated biomarkers related to these pathways in CAYACS-treated Hodgkin lymphoma (HL) patients, comparing their biological profile with that of age-matched (Controls 1) and older (aged 50–65) healthy controls (Controls 2). HL survivors exhibited accumulation of AGEs, higher expression of their receptor RAGE and lower circulating levels of soluble RAGE compared to age-matched Controls 1. A similar profile of AGE-RAGE signaling was observed in Controls 2. HL survivors and Controls 2 showed an altered oxidative status. Moreover, HL survivors reported higher plasma levels of IL-6 than age-matched controls. Furthermore, HL survivors and Controls 2 showed alterations in autophagy and mitophagy. Finally, CAYACS had higher plasma MMP9 levels and higher p16 mRNA levels than age-matched Controls 1. Data show that CAYACS exhibit a biological profile consistent with premature cellular senescence, with several features resembling those observed in older healthy individuals. Alterations in AGE-RAGE signaling, oxidative stress-related pathways, and chronic inflammation may lead to the onset of this phenotype. Further longitudinal studies are needed to clarify the potential role of these biological alterations in the development of long-term treatment-related complications.