Connexin 43 modulates reverse electron transfer in cardiac mitochondria from inducible knock-out Cx43 mice by altering the coenzyme Q pool.

Succinate accumulates during myocardial ischemia and is rapidly oxidized during reperfusion, leading to reactive oxygen species (ROS) production through reverse electron transfer (RET) from mitochondrial complex II to complex I, and favoring cell death. Given that connexin 43 (Cx43) modulates mitochondrial ROS production, we investigated whether Cx43 influences RET using inducible knock-out Cx43 mice. Oxygen consumption, ROS production, membrane potential and coenzyme Q (CoQ) pool were analyzed in subsarcolemmal (SSM, expressing Cx43) and interfibrillar (IFM) cardiac mitochondria isolated from wild-type Cx43 mice and Cx43 knock-out animals treated with 4-hydroxytamoxifen (4OHT).

Targeting the Warburg Effect in Cancer: Where Do We Stand?

The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms.

Spontaneous reperfusion enhances succinate concentration in peripheral blood from stemi patients but its levels does not correlate with myocardial infarct size or area at risk.

Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab.

Diffusion MRI signal cumulants and hepatocyte microstructure at fixed diffusion time: Insights from simulations, 9.4T imaging, and histology.

Purpose: Relationships between diffusion-weighted MRI signals and hepatocyte microstructure were investigated to inform liver diffusion MRI modeling, focusing on the following question: Can cell size and diffusivity be estimated at fixed diffusion time, realistic SNR, and negligible contribution from extracellular/extravascular water and exchange?

Methods: Monte Carlo simulations were performed within synthetic hepatocytes for varying cell size/diffusivity / , and clinical protocols (single diffusion encoding; maximum b-value: {1000, 1500, 2000} s/mm ; 5 unique gradient duration/separation pairs; SNR = { , 100, 80, 40, 20}), accounting for heterogeneity in and perfusion contamination. Diffusion ( ) and kurtosis ( ) coefficients were calculated, and relationships between and were visualized. Functions mapping to were computed to predict unseen values, tested for their ability to classify discrete cell-size contrasts, and deployed on 9.

Serum Metabolomic Analysis Suggests Impairment of Myocardial Energy Production in Takotsubo Syndrome.

Introduction: Takotsubo syndrome is a complex entity that, although it usually has a good prognosis, can be life threatening. While recent advances have improved the knowledge of takotsubo syndrome, many aspects of its etiology still remain uncertain. Metabolomics, a hypothesis generating approach, could provide novel pathophysiology information about this disease.

Citric Acid Cycle Metabolites Predict Infarct Size in Submitted to Transient Coronary Artery Occlusion and Treated with Succinate Dehydrogenase Inhibitors or Remote Ischemic Perconditioning.

Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC).

Correction: PLGA protein nanocarriers with tailor-made fluorescence/MRI/PET imaging modalities.

Correction for 'PLGA protein nanocarriers with tailor-made fluorescence/MRI/PET imaging modalities' by Yajie Zhang et al., Nanoscale, 2020, 12, 4988-5002, DOI: .

Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI).

Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial.

H NMR serum metabolomic profiling of patients at risk of cardiovascular diseases performing stress test.

Cardiovascular diseases are the leading cause of death worldwide. Changes in lifestyle and/or pharmacological treatment are able to reduce the burden of coronary artery diseases (CAD) and early diagnosis is crucial for the timely and optimal management of the disease. Stress testing is a good method to measure the burden of CAD but it is time consuming and pharmacological testing may not fully mimic exercise test.

Connexin 43 Deficiency Is Associated with Reduced Myocardial Scar Size and Attenuated TGFβ1 Signaling after Transient Coronary Occlusion in Conditional Knock-Out Mice.

Previous studies demonstrated a reduction in myocardial scar size in heterozygous Cx43 mice subjected to permanent coronary occlusion. However, patients presenting with ST segment elevation myocardial infarction often undergo rapid coronary revascularization leading to prompt restoration of coronary flow. Therefore, we aimed to assess changes in scar size and left ventricular remodeling following transient myocardial ischemia (45 min) followed by 14 days of reperfusion using Cx43 (controls) and Cx43 inducible knock-out (Cx43 content: 50%) mice treated with vehicle or 4-hydroxytamoxifen (4-OHT) to induce a Cre-ER(T)-mediated global deletion of the Cx43 floxed allele.

Enhancing Glycolysis Protects against Ischemia-Reperfusion Injury by Reducing ROS Production.

After myocardial ischemia-reperfusion, fatty acid oxidation shows fast recovery while glucose oxidation rates remain depressed. A metabolic shift aimed at increasing glucose oxidation has shown to be beneficial in models of myocardial ischemia-reperfusion. However, strategies aimed at increasing glucose consumption in the clinic have provided mixed results and have not yet reached routine clinical practice.

PLGA protein nanocarriers with tailor-made fluorescence/MRI/PET imaging modalities.

Designing theranostic nanocarriers with high protein payload and multimodality tracking without cross interferences between the different imaging probes and the delicate protein cargo is challenging. Here, chemical modifications of poly(lactic-co-glycolic acid) (PLGA) to produce nanocapsules (NCs) that incorporate several imaging moieties are reported. The biocompatible and biodegradable PLGA-NCs can be endowed with a magnetic resonance imaging (MRI) reporter, two fluorescence imaging probes (blue/NIR) and a positron emission tomography (PET) reporter.

H-NMR Urinary Metabolic Profile, A Promising Tool for the Management of Infants with Human Cytomegalovirus-Infection.

Congenital human cytomegalovirus (HCMV) infection is the most common mother-to-child transmitted infection in the developed world. Certain aspects of its management remain a challenge. Urinary metabolic profiling is a promising tool for use in pediatric conditions.

High-fat diet improves tolerance to myocardial ischemia by delaying normalization of intracellular PH at reperfusion.

Reports on the effect of obesity on the myocardial tolerance to ischemia are contradictory. We have described that obesity induced by high-fat diet (HFD) reduces infarct size in B6D2F1 mice submitted to transient coronary occlusion. In this study, we analysed the mechanism by which dietary obesity modifies the susceptibility to myocardial ischemia and the robustness of this effect.

Author Correction: Selective Inhibition of Succinate Dehydrogenase in Reperfused Myocardium with Intracoronary Malonate Reduces Infarct Size.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Sex differences in the H NMR metabolic profile of serum in cardiovascular risk patients.

Personalized diagnosis and risk stratification of cardiovascular diseases would allow optimizing therapeutic strategies and lifestyle changes. Metabolomics is a promising technique for personalized diagnosis and prognosis; however, various physiological parameters, including sex, influence the metabolic profile thus hampering its translation to the clinic. Knowledge of the variation in the metabolic profile associated with sex would facilitate metabolomic translation to the clinic.

Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires reactive oxygen radicals accumulation and is inhibitable by the micropeptide humanin.

The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the link between ENDOG activity and cardiomyocyte growth.

Selective Inhibition of Succinate Dehydrogenase in Reperfused Myocardium with Intracoronary Malonate Reduces Infarct Size.

Inhibition of succinate dehydrogenase (SDH) with malonate during reperfusion reduces infarct size in isolated mice hearts submitted to global ischemia. However, malonate has toxic effects that preclude its systemic administration in animals. Here we investigated the effect of intracoronary malonate on infarct size in pigs submitted to transient coronary occlusion.

Metabolomics and Heart Diseases: From Basic to Clinical Approach.

Background: The field of metabolomics has been steadily increasing in size for the last 15 years. Advances in analytical and statistical methods have allowed metabolomics to flourish in various areas of medicine. Cardiovascular diseases are some of the main research targets in metabolomics, due to their social and medical relevance, and also to the important role metabolic alterations play in their pathogenesis and evolution.

Glycative and oxidative stress are associated with altered thrombus composition in diabetic patients with ST-elevation myocardial infarction.

Background: The role of type 2 diabetes (T2DM) on composition of thrombus has not been fully characterized in patients with ST-elevation myocardial infarction (STEMI).

Aims: To elucidate the differences between diabetic and non-diabetic patients with STEMI in relation to the composition of coronary thrombus, and the potential association of these differences with glycated haemoglobin levels and markers of oxidative stress.

Methods: Intracoronary thrombi from consecutive thrombus aspiration procedures in STEMI patients, 25 diabetic and 28 non-diabetic, were analyzed by immunofluorescence with confocal microscopy.

Remote ischemic conditioning provides humoural cross-species cardioprotection through glycine receptor activation.

Aims: Remote ischaemic conditioning (RIC) releases a humoural factor able to exert cross-species cardioprotection when plasma dialysate is applied to isolated hearts. However, the exact chemical nature of this factor is currently unknown.

Methods And Results: RIC (4 × 5min femoral occlusion/5min reperfusion) was applied to 10 male pigs, and blood was taken before and after the manoeuvre.

Measuring Water Distribution in the Heart: Preventing Edema Reduces Ischemia-Reperfusion Injury.

Background: Edema is present in many heart diseases, and differentiation between intracellular (ICW) and extracellular (ECW) myocardial water compartments would be clinically relevant. In this work we developed a magnetic resonance imaging-based method to differentiate ICW and ECW and applied it to analyze ischemia-reperfusion-induced edema.

Methods And Results: Isolated rat hearts were perfused with gadolinium chelates as a marker of extracellular space.

High-fat diet induces metabolic changes and reduces oxidative stress in female mouse hearts.

After an acute myocardial infarction, obese patients generally have a better prognosis than their leaner counterparts, known as the "obesity paradox". In addition, female sex is associated with a lower risk of cardiac ischemic events and smaller infarct size compared to males. The objective of the present work was to study the metabolic phenotype and mitochondrial function associated to female sex and short-term high-fat diet.