Mitochondrial dysfunction is associated with the severity of liver fibrosis in patients after the Fontan operation.

The gold standard for determining the severity of liver disease in Fontan patients is now liver biopsy. Since it is an invasive procedure, this study determined the possibility of applying mitochondrial function from isolated peripheral blood mononuclear cells (PBMCs) as a non-invasive indicator of liver fibrosis. Fontan patients (n = 37) without known liver disease were analysed cross-sectionally. Patients were classified according to their histology using the METAVIR score as follows; F0/F1-no/mild fibrosis; F2-moderate fibrosis; and F3/F4-cirrhosis. Peripheral blood mononuclear cells were assessed for mitochondrial activity and apoptosis. This study did not find any significant differences in cardiac function among the groups according to liver histology. Interestingly, our findings indicated a significant decrease in maximal respiration and spare respiratory capacity, in both the moderate (F2) and cirrhosis (F3/F4) groups compared with the group without significant fibrosis (F0/F1). Moreover, the cirrhosis group exhibited higher levels of apoptosis and lower levels of live cells, compared with both the moderate and no significant fibrosis groups. In conclusion, the degree of liver fibrosis in Fontan patients is strongly correlated with mitochondrial dysfunction in PBMCs. Mitochondrial function and apoptosis could potentially serve as novel markers for tracking the progression of liver fibrosis in these patients.

Changes in blood metabolomes as potential markers for severity and prognosis in doxorubicin-induced cardiotoxicity: a study in HER2-positive and HER2-negative breast cancer patients.

BACKGROUND: We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined. METHODS: HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels. RESULTS: Cardiac injury and systolic dysfunction 2 weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment. CONCLUSIONS: The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity. TRIAL REGISTRATION: The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.

Fetal hemodynamic changes and mitochondrial dysfunction in myocardium and brain tissues in response to anemia: a lesson from hemoglobin Bart's disease.

OBJECTIVE: Whether or not the effects of anemia in the early phase, while the fetuses attempts to increase cardiac output to meet oxygen requirement in peripheral organs, is detrimental to the fetal developing vital organs is little-known. The objective of this is to compare prenatal cardiovascular changes and post-abortal cellular damages in the myocardium as a pumping organ and the brain as a perfused organ between anemic fetuses (using fetal Hb Bart's disease as a study model) in pre-hydropic phase and non-anemic fetuses. METHODS: Fetuses affected by Hb Bart's disease and non-anemic fetuses at 16-22 weeks were recruited to undergo comprehensive fetal echocardiography. Cord blood analysis was used to confirm the definite diagnosis of fetal Hb Bart's disease and normal fetuses. Fetal cardiac and brain tissues were collected shortly after pregnancy termination for the determination of oxidative stress and mitochondrial function, including mitochondrial ROS production and mitochondrial membrane changes. RESULTS: A total of 18 fetuses affected by Hb Bart's disease and 13 non-anemic fetuses were recruited. The clinical characteristics of both groups were comparable. The affected fetuses showed a significant increase in cardiac dimensions, cardiac function, cardiac output and brain circulation without deteriorating cardiac contractility and preload. However, in the affected fetuses, mitochondrial dysfunction was clearly demonstrated in brain tissues and in the myocardium, as indicated by a significant increase in the membrane potential change (p-value < 0.001), and a significant increase in ROS production in brain tissues, with a trend to increase in myocardium. The findings indicated cellular damage in spite of good clinical compensation. CONCLUSION: The new insight is that, in response to fetal anemia, fetal heart increases in size (dilatation) and function to increase cardiac output and blood flow velocity to provide adequate tissue perfusion, especially brain circulation. However, the myocardium and brain showed a significant increase in mitochondrial dysfunction, suggesting cellular damage secondary to anemic hypoxia. The compensatory increase in circulation could not completely prevent subtle brain and heart damage.

Efficacy of the Cytokine Adsorption Therapy in Patients with Severe COVID-19-Associated Pneumonia: Lesson Learned from a Prospective Observational Study.

INTRODUCTION: Severe COVID-19 pneumonia can activate a cytokine storm. Hemoperfusion can reduce pro-inflammatory cytokines in sepsis but is still debated in the COVID-19 setting. Thus, we sought to investigate the benefits of HA-330 cytokine adsorption through clinical and laboratory outcomes. METHODS: We conducted a single-center prospective observational study in adults with severe COVID-19 pneumonia admitted to the intensive care unit at Chiang Mai University Hospital (Chiang Mai, Thailand). Those with cytokine storms indicated by organ injury, including acute respiratory distress syndrome (ARDS), and high inflammatory markers were included. Patients treated with the HA-330 device were classified as a hemoperfusion group, while those without cytokine adsorption were classified as a control group. We compared the outcomes on day 7 after treatment and evaluated the factors associated with 60-day mortality. RESULTS: A total of 112 patients were enrolled. Thirty-eight patients received hemoperfusion, while 74 patients did not. Baseline cytokine storm parameters were comparable. In univariate analysis, there was an improvement in clinical and laboratory effects from hemoperfusion therapy. In multivariate analysis, APACHE II score, SOFA score, PaO2/FiO2, the number of hemoperfusion sessions, the amount of blood purified, high-sensitivity C-reactive protein, and IL-6 were associated with mortality. Using at least 3 sessions of hemoperfusion could mitigate, the 60-day mortality (adjusted odds ratio 0.25, 95% confidence interval: 0.03-0.33, p = 0.001). By categorizing the amount of blood treated into 3 groups of <1 L/kg, 1-2 L/kg, and ≥2 L/kg, there was a linear dose-response association with survival, which was better in the higher volume purified (mortality 60% vs. 33.3% vs. 0%, respectively, p = 0.015). CONCLUSIONS: The early initiation of HA-330 hemoperfusion could improve the severity score and laboratory outcomes of COVID-19 ARDS. The optimal dose of at least three sessions or the amount of blood purified greater than 1 L/kg was associated with a reduction in 60-day mortality.

Circulating mitochondrial dysfunction as an early biomarker for contrast media-induced acute kidney injury in chronic kidney disease patients.

Contrast-induced acute kidney injury (CI-AKI) is the common hospitalized acute kidney injury (AKI). However, the diagnosis by serum creatinine might not be early enough. Currently, the roles of circulating mitochondria in CI-AKI are still unclear. Since early detection is crucial for treatment, the association between circulating mitochondrial function and CI-AKI was tested as a potential biomarker for detection of CI-AKI. Twenty patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) were enrolled. Blood and urine samples were obtained at the time of PCI, and 6, 24, 48 and 72 h after PCI. Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) were measured. Oxidative stress, inflammation, mitochondrial function, mitochondrial dynamics and cell death were determined from peripheral blood mononuclear cells. Forty percent of patients developed AKI. Plasma NGAL levels increased after 24 h after receiving contrast media. Cellular and mitochondrial oxidative stress, mitochondrial dysfunction and decreased mitochondrial fusion occurred at 6 h following contrast media exposure. Subgroup of AKI had higher %necroptosis cells and TNF-α mRNA expression than subgroup without AKI. Collectively, circulating mitochondrial dysfunction could be an early predictive biomarker for CI-AKI in CKD patients receiving contrast media. These findings provide novel strategies to prevent CI-AKI according to its pathophysiology.

Acute administration of myeloid differentiation factor 2 inhibitor and N-acetyl cysteine attenuate brain damage in rats with cardiac ischemia/reperfusion injury.

Inflammation and oxidative stress are mechanisms which potentially underlie the brain damage that can occur after cardiac ischemic and reperfusion (I/R) injury. 2i-10 is a new anti-inflammatory agent, acting via direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 and the antioxidant N-acetylcysteine (NAC) on pathologic brain in cardiac I/R injury are unknown. We hypothesized that 2i-10 and NAC offer similar neuroprotection levels against dendritic spine reduction through attenuation of brain inflammation, loss of tight junction integrity, mitochondrial dysfunction, reactive gliosis, and suppression of AD protein expression in rats with cardiac I/R injury. Male rats were allocated to either sham or acute cardiac I/R group (30 min of cardiac ischemia and 120 min of reperfusion). Rats in cardiac I/R group were given one of following treatments intravenously at the onset of reperfusion: vehicle, 2i-10 (20 or 40 mg/kg), and NAC (75 or 150 mg/kg). The brain was then used to determine biochemical parameters. Cardiac I/R led to cardiac dysfunction with dendritic spine loss, loss of tight junction integrity, brain inflammation, and mitochondrial dysfunction. Treatment with 2i-10 (both doses) effectively reduced cardiac dysfunction, tau hyperphosphorylation, brain inflammation, mitochondrial dysfunction, dendritic spine loss, and improved tight junction integrity. Although both doses of NAC effectively reduced brain mitochondrial dysfunction, treatment using a high dose of NAC reduced cardiac dysfunction, brain inflammation, and dendritic spine loss. In conclusion, treatment with 2i-10 and a high dose of NAC at the onset of reperfusion alleviated brain inflammation and mitochondrial dysfunction, consequently reducing dendritic spine loss in rats with cardiac I/R injury.

Therapeutic potential of a single-dose melatonin in the attenuation of cardiac ischemia/reperfusion injury in prediabetic obese rats.

Although acute melatonin treatment effectively reduces cardiac ischemia/reperfusion (I/R) injury in lean rats by modulating melatonin receptor 2 (MT2), there is no information regarding the temporal effects of melatonin administration during cardiac I/R injury in prediabetic obese rats. Prediabetic obese rats induced by chronic consumption of a high-fat diet (HFD) were used. The rats underwent a cardiac I/R surgical procedure (30-min of ischemia, followed by 120-min of reperfusion) and were randomly assigned to receive either vehicle or melatonin treatment. In the melatonin group, rats were divided into 3 different subgroups: (1) pretreatment, (2) treatment during ischemic period, (3) treatment at the reperfusion onset. In the pretreatment subgroup either a nonspecific MT blocker (Luzindole) or specific MT2 blocker (4-PPDOT) was also given to the rats prior to melatonin treatment. Pretreatment with melatonin (10 mg/kg) effectively reduced cardiac I/R injury by reducing infarct size, arrhythmia, and LV dysfunction. Reduction in impaired mitochondrial function, mitochondrial dynamic balance, oxidative stress, defective autophagy, and apoptosis were observed in rats pretreated with melatonin. Unfortunately, the cardioprotective benefits were not observed when 10-mg/kg of melatonin was acutely administered to the rats after cardiac ischemia. Thus, we increased the dose of melatonin to 20 mg/kg, and it was administered to the rats during ischemia or at the onset of reperfusion. The results showed that 20-mg/kg of melatonin effectively reduced cardiac I/R injury to a similar extent to the 10-mg/kg pretreatment regimen. The MT2 blocker inhibited the protective effects of melatonin. Acute melatonin treatment during cardiac I/R injury exerted protective effects in prediabetic obese rats. However, a higher dose of melatonin is required when given after the onset of cardiac ischemia. These effects of melatonin were mainly mediated through activation of MT2.

Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways.

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

Hyperbaric oxygen therapy restores wound healing in irradiated gingiva to a similar level to that in healthy gingiva.

OBJECTIVE: This study aimed to investigate the involvement of mitochondrial biogenesis, and determine the extent of fibroblast proliferation and cellular apoptosis, in the gingiva of patients who had undergone head and neck radiation, after receiving hyperbaric oxygen therapy (HBOT), in comparison with normal gingiva. METHOD: A total of 16 patients who had undergone head and neck radiation with HBOT and six healthy subjects were included in the study. After the completion of radiation therapy, patients received HBOT at 2 ATA for 90 minutes per session, and for 20 sessions per patient. Samples of gingival tissues were then taken. The levels of: transforming growth factor beta (TGF-ß); phospho-nuclear factor kappa-light-chain-enhancer of activated B cells (p-NFÏ°B); nuclear factor kappa-light-chain-enhancer of activated B cells (NFÏ°B); proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α); phospho-dynamin-related protein 1 at ser616 (p-Drp1ser616); dynamin-related protein 1 (Drp1); Bcl-2-associated X-protein (Bax); and B-cell lymphoma 2 (Bcl-2) were determined using a Western blot. Independent t-test and Chi-squared tests were used in the study. RESULTS: There were no differences in the levels of TGF-ß, p-NFÏ°B, NFÏ°B, p-Drp1ser616, Drp1, Bax and Bcl-2 between the two groups. However, the level of PGC-1α was greater in irradiated gingival tissues with HBOT than in the healthy gingiva. CONCLUSION: Radiation-induced impaired wound healing can be improved by HBOT as indicated by levels of apoptosis, mitochondrial dynamics, cell proliferation and inflammation in irradiated gingiva with HBOT to a similar level to normal healthy gingiva. These findings may occur through an increase in mitochondrial biogenesis following HBOT.

Therapeutic potentials of cell death inhibitors in rats with cardiac ischaemia/reperfusion injury.

Growing evidence demonstrated that cell death pathways including ferroptosis, apoptosis and necroptosis contribute to cardiac ischaemia/reperfusion (I/R) injury. We hypothesized that ferroptosis, apoptosis and necroptosis contribute differently to myocardial damage during acute cardiac I/R injury. Rats underwent cardiac I/R or sham operation. I/R-operated rats were divided into 4 groups: vehicle, apoptosis (Z-vad), ferroptosis (Fer-1) and necroptosis (Nec-1) inhibition. Rats in each cell death inhibitor group were subdivided into 3 different dose regimens: low, medium and high. Infarct size, left ventricular (LV) function, arrhythmias and molecular mechanism were investigated. Cardiac I/R caused myocardial infarction, LV dysfunction, arrhythmias, mitochondrial dysfunction, mitochondrial dynamic imbalance, inflammation, apoptosis and ferroptosis. Infarct size, LV dysfunction, mitochondrial dysfunction, apoptosis and ferroptosis were all reduced to a similar extent in rats treated with Z-vad (low and medium doses) or Fer-1 (medium and high doses). Fer-1 treatment also reduced mitochondrial dynamic imbalance and inflammation. No evidence of necroptosis was found in association with acute I/R injury, therefore Nec-1 treatment could not be assessed. Apoptosis and ferroptosis, not necroptosis, contributed to myocardial damage in acute I/R injury. Inhibitors of these 2 pathways provided effective cardioprotection in rats with I/R injury though modulation of mitochondrial function and attenuated apoptosis and ferroptosis.

An apoptosis inhibitor suppresses microglial and astrocytic activation after cardiac ischemia/reperfusion injury.

OBJECTIVE: Microglial hyperactivation and apoptosis were observed following myocardial infarction and ischemia reperfusion (I/R) injury. This study aimed to test the hypothesis that the apoptosis inhibitor, Z-VAD, attenuates microglial and astrocytic hyperactivation and brain inflammation in rats with cardiac I/R injury. MATERIALS AND METHODS: Rats were subjected to either sham or cardiac I/R operation (30 min-ischemia followed by 120-min reperfusion), rats in the cardiac I/R group were given either normal saline solution or Z-VAD at 3.3 mg/kg via intravenous injection 15 min prior to cardiac ischemia. Left ventricular ejection fraction (% LVEF) was determined during the cardiac I/R protocol. The brain tissues were removed and used to determine brain apoptosis, brain inflammation, microglial and astrocyte morphology. RESULTS: Cardiac dysfunction was observed in rats with cardiac I/R injury as indicated by decreased %LVEF. In the brain, we found brain apoptosis, brain inflammation, microglia hyperactivation, and reactive astrogliosis occurred following cardiac I/R injury. Pretreatment with Z-VAD effectively increased %LVEF, reduced brain apoptosis, attenuated brain inflammation by decreasing IL-1ß mRNA levels, suppressed microglial and astrocytic hyperactivation and proliferation after cardiac I/R injury. CONCLUSION: Z-VAD exerts neuroprotective effects against cardiac I/R injury not only targeting apoptosis but also microglial and astrocyte activation.

The temporal impact of erythropoietin administration on mitochondrial function and dynamics in cardiac ischemia/reperfusion injury.

Erythropoietin (EPO) has been shown to provide protection against ischemia/reperfusion (I/R) injury in various experimental models. However, clinical trials revealed unsatisfactory results when EPO was given to patients with myocardial infarction following reperfusion. The timing of EPO administration and its relation to mitochondrial function may largely involve in this controversy. We hypothesized that EPO given at different time points exert varying cardioprotective effects in terms of myocardial infarct size, left ventricular (LV) function, arrhythmia, apoptosis, mitochondrial function, and mitochondrial dynamics in rats with cardiac I/R injury. Male Wistar rats were subjected to either sham (n = 6) or cardiac I/R operation (n = 48). Rats undergoing cardiac I/R operation (30-min ischemia, followed by 120-min reperfusion) were allotted into 4 subgroups (n = 12/group): vehicle, EPO pretreatment, EPO given during ischemia, and EPO given at reperfusion. EPO was administered intravenously at 5000 unit/kg. Arrhythmia and LV function were monitored throughout the protocol. Next, the hearts were collected to determine infarct size, mitochondrial function, mitochondrial dynamics, gap junction protein, and apoptosis. Cardiac I/R promoted arrhythmias, LV dysfunction, infarct size expansion, apoptosis, mitochondrial dysfunction and increased mitochondrial fission. EPO given either before or during ischemia, but not at reperfusion, attenuated arrhythmia scores, LV dysfunction, infarct size, and apoptosis. Only EPO given either before or during ischemia alleviated mitochondrial swelling, mitochondrial depolarization, and reduced the levels of p-Drp1ser616/Drp1. Data from in vitro study also confirmed that EPO directly attenuated mitochondrial dysfunction in H9c2 cells subjected to hypoxia/reoxygenation. In conclusion, the EPO administration, either before or during ischemia, exerted cardioprotection against I/R injury by attenuating mitochondrial dynamic imbalance, mitochondrial dysfunction, and apoptosis, leading to reduced infarct size and improved LV function.

The Protective and Reparative Role of Colony-Stimulating Factors in the Brain with Cerebral Ischemia/Reperfusion Injury.

Stroke is a debilitating disease and has the ability to culminate in devastating clinical outcomes. Ischemic stroke followed by reperfusion entrains cerebral ischemia/reperfusion (I/R) injury, which is a complex pathological process and is associated with serious clinical manifestations. Therefore, the development of a robust and effective poststroke therapy is crucial. Granulocyte colony-stimulating factor (GCSF) and erythropoietin (EPO), originally discovered as hematopoietic growth factors, are versatile and have transcended beyond their traditional role of orchestrating the proliferation, differentiation, and survival of hematopoietic progenitors to one that fosters brain protection/neuroregeneration. The clinical indication regarding GCSF and EPO as an auspicious therapeutic strategy is conferred in a plethora of illnesses, including anemia and neutropenia. EPO and GCSF alleviate cerebral I/R injury through a multitude of mechanisms, involving antiapoptotic, anti-inflammatory, antioxidant, neurogenic, and angiogenic effects. Despite bolstering evidence from preclinical studies, the multiple brain protective modalities of GCSF and EPO failed to translate in clinical trials and thereby raises several questions. The present review comprehensively compiles and discusses key findings from in vitro, in vivo, and clinical data pertaining to the administration of EPO, GCSF, and other drugs, which alter levels of colony-stimulating factor (CSF) in the brain following cerebral I/R injury, and elaborates on the contributing factors, which led to the lost in translation of CSFs from bench to bedside. Any controversial findings are discussed to enable a clear overview of the role of EPO and GCSF as robust and effective candidates for poststroke therapy.

Myeloid differentiation factor 2 in the heart: Bench to bedside evidence for potential clinical benefits?

Cardiac inflammation has been involved in many pathological processes in the heart including cardiac hypertrophy, fibrosis, adverse remodeling, and dysfunction. Myeloid differentiation factor 2 (MD2) is a key mediating protein that has been shown to contribute to the inflammatory process. MD2 is required for the activation of TLR4 in the form of dimerization complex. Upon activation of TLR4, the signal can be sent through either myeloid differentiation primary response protein 88 (Myd88) or toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing IFN-ß (TRIF) proteins to activate the inflammatory response in cardiac tissue, after which the inflammatory cytokines and genes are produced. In patients with dilated cardiomyopathy, a positive correlation was demonstrated between the serum MD2 levels and mortality rate. Therefore, MD2 inhibition should provide beneficial effects in inflammation related to cardiac diseases such as obesity and heart failure. Multiple inhibitors of TLR4/MD2 interaction reportedly attenuated cardiac dysfunction and remodeling in animals with obesity and heart failure. In this review, we comprehensively summarized the reports from in vitro, in vivo, and clinical studies regarding the role of MD2 and the effects of MD2 inhibitors on cardiac inflammation, dysfunction, fibrosis, and remodeling. The information regarding the beneficial effects of MD2 inhibitors will be used to encourage future clinical use as a novel anti-inflammatory agent.

The roles of resveratrol on cardiac mitochondrial function in cardiac diseases.

Left ventricular (LV) dysfunction is commonly associated with a variety of health conditions including acute myocardial infarction and obesity/diabetes. In addition, administration of several pharmacological agents such as anticancer, antiviral, and immunosuppressive drugs has been shown to be related with LV dysfunction. The molecular mechanism responsible for LV dysfunction has been extensively studied, and it has been proposed that the overproduction of reactive oxygen species (ROS) plays a crucial role in the regulation of this function. Mitochondria require the balance between ROS production and antioxidants to maintain their appropriate function and to prevent excessive ROS production. Thus, the excessive production of ROS and the reduced scavenging process under any pathological conditions could disrupt mitochondrial function, leading to energy depletion with subsequent cell death. Therefore, maintenance of the balance between oxidative stress and antioxidants is essential. Resveratrol, a stilbene, has been investigated extensively, and potentially used to treat or prevent various cardiovascular diseases. Resveratrol directly upregulates antioxidative capacity by increasing antioxidant genes such as heme oxygenase-1, superoxide dismutase, catalase, and glutathione. In this review, accumulated data from in vitro, ex vivo, and in vivo studies regarding the effects of resveratrol on cardiac mitochondrial function in cardiac pathologies are comprehensively summarized and discussed. Since there is no conclusive available clinical study regarding the effects of resveratrol on cardiac mitochondrial function, this review also aims to encourage more clinical investigations to confirm findings from basic research. This comprehensive review will provide insight regarding the potential mechanistic roles of resveratrol in preventing and/or treating patients with cardiovascular diseases to improve LV function and their health status.

High central venous oxygen saturation is associated with mitochondrial dysfunction in septic shock: A prospective observational study.

To test the hypothesis that an impaired mitochondrial function is associated with altered central venous oxygen saturation (ScvO2 ), venous-to-arterial carbon dioxide tension difference (delta PCO2 ) or serum lactate in sepsis patients. This prospective cohort study was conducted in a single tertiary emergency department between April 2017 and March 2019. Patients with suspected sepsis were included in the study. Serum lactate was obtained in sepsis, ScvO2 and delta PCO2 were evaluated in septic shock patients. Mitochondrial function was determined from the peripheral blood mononuclear cells. Forty-six patients with suspected sepsis were included. Of these, twenty patients were septic shock. Mitochondrial oxidative stress levels were increased in the high ScvO2 group (ScvO2  > 80%, n = 6), compared with the normal (70%-80%, n = 9) and low ScvO2 (<70%, n = 5) groups. A strong linear relationship was observed between the mitochondrial oxidative stress and ScvO2 (r = .75; P = .01). However, mitochondrial respiration was increased in the low ScvO2 group. In addition, mitochondrial complex II protein levels were significantly decreased in the high ScvO2 group (P < .05). Additionally, there was no correlation between serum lactate, delta PCO2 , and mitochondria oxidative stress or mitochondria function. ScvO2 can be potentially useful for developing new therapeutics to reduce mitochondrial dysfunction in septic shock patient.

Acute dapagliflozin administration exerts cardioprotective effects in rats with cardiac ischemia/reperfusion injury.

BACKGROUND: A sodium-glucose co-transporter 2 (SGLT-2) inhibitor had favorable impact on the attenuation of hyperglycemia together with the severity of heart failure. However, the effects of acute dapagliflozin administration at the time of cardiac ischemia/reperfusion (I/R) injury are not established. METHODS: The effects of dapagliflozin on cardiac function were investigated by treating cardiac I/R injury at different time points. Cardiac I/R was instigated in forty-eight Wistar rats. These rats were then split into 4 interventional groups: control, dapagliflozin (SGLT2 inhibitor, 1 mg/kg) given pre-ischemia, at the time of ischemia and at the beginning of reperfusion. Left ventricular (LV) function and arrhythmia score were evaluated. The hearts were used to evaluate size of myocardial infarction, cardiomyocyte apoptosis, cardiac mitochondrial dynamics and function. RESULTS: Dapagliflozin given pre-ischemia conferred the maximum level of cardioprotection quantified through the decrease in arrhythmia, attenuated infarct size, decreased cardiac apoptosis and improved cardiac mitochondrial function, biogenesis and dynamics, leading to LV function improvement during cardiac I/R injury. Dapagliflozin given during ischemia also showed cardioprotection, but at a lower level of efficacy. CONCLUSIONS: Acute dapagliflozin administration during cardiac I/R injury exerted cardioprotective effects by attenuating cardiac infarct size, increasing LV function and reducing arrhythmias. These benefits indicate its potential clinical usefulness.

The possible roles of necroptosis during cerebral ischemia and ischemia / reperfusion injury.

Cell death is a process consequential to cerebral ischemia and cerebral ischemia/reperfusion (I/R) injury. Recent evidence suggest that necroptosis has been involved in the pathogenesis of ischemic brain injury. The mechanism of necroptosis is initiated by an activation of inflammatory receptors including tumor necrosis factor, toll like receptor, and fas ligands. The signals activate the receptor-interacting protein kinase (RIPK) 1, 3, and a mixed-lineage kinase domain-like pseudokinase (MLKL) to instigate necroptosis. RIPK1 inhibitor, necrostatin-1, was developed, and dramatically reduced brain injury following cerebral ischemia in mice. Consequently, necroptosis could be a novel therapeutic target for stroke, which aims to reduce long-term adverse outcomes after cerebral ischemia. Several studies have been conducted to test the roles of necroptosis on cerebral ischemia and cerebral I/R injury, and the efficacy of necrostatin-1 has been tested in those models. Evidence regarding the roles of necroptosis and the effects of necrostatin-1, from in vitro and in vivo studies, has been summarized and discussed. In addition, other therapeutic managements, involving in necroptosis, are also included in this review. We believe that the insights from this review might clarify the clinical perspective and challenges involved in future stroke treatment by targeting the necroptosis pathway.

A combination of an antioxidant with a prebiotic exerts greater efficacy than either as a monotherapy on cognitive improvement in castrated-obese male rats.

Previous studies by ourselves and others have demonstrated that both obesity and testosterone deprivation have been related to cognitive decline. We have also shown that a prebiotic and n-acetyl cysteine (NAC) improved cognitive dysfunction in obese rats and castrated-male rats. However, the effects of NAC, a prebiotic (inulin), and a combination of the two on cognition in castrated-obese rats has never been investigated. The hypothesis was that NAC and inulin attenuated cognitive decline in castrated-obese rats by improving gut dysbiosis, and decreasing oxidative stress, glial activation and apoptosis. Male Wistar rats (n = 36) were fed with either a normal diet (ND: n = 6) or a high-fat diet (HFD: n = 30) for twenty-eight weeks. The resultant obese rats had a bilateral orchiectomy (ORX) and were randomly divided into five subgroups (n = 6/ subgroup). Each subgroup was treated with one of five therapies: a vehicle; testosterone replacement (2 mg/kg/day); NAC (100 mg/kg); inulin (10%, w/w), or a combination of the NAC and inulin for four weeks. The results demonstrated that castrated-obese rats developed gut dysbiosis, metabolic disturbance, brain pathologies, and cognitive decline. All of the pathological conditions in the brain were ameliorated to an equal extent by testosterone replacement, NAC, and inulin supplementation. Interestingly, a combination of NAC and inulin had the greatest beneficial effect on cognitive function by synergistically reducing hippocampal inflammation and ameliorating glial dysmorphology. These findings suggest that a combination of NAC and inulin may confer the greatest benefits in improving cognitive function in castrated-obese male rats.

The comparative effects of high dose atorvastatin and proprotein convertase subtilisin/kexin type 9 inhibitor on the mitochondria of oxidative muscle fibers in obese-insulin resistant female rats.

The present study aimed to compare the effects of high dose atorvastatin and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor on the mitochondrial function in oxidative muscle fibers in obese female rats. Female Wistar rats were fed with either a normal diet (ND: n = 12) or a high-fat diet (HFD: n = 36) for a total of 15 weeks. At week 13, ND-fed rats received a vehicle, and HFD-fed rats were divided to three groups to receive either a vehicle, 40 mg/kg/day of atorvastatin, or 4 mg/kg/day of PCSK9 inhibitor (SBC-115076) for 3 weeks. Soleus muscles were investigated to assess mitochondrial ROS, membrane potential, swelling, mitochondrial-related protein expression, and level of malondialdehyde (MDA). The results showed that HFD-fed rats with vehicle developed obese-insulin resistance and dyslipidemia. Both atorvastatin and PCSK9 inhibitor reduced obesity and dyslipidemia, as well as improved insulin sensitivity in HFD-fed rats. However, the efficacy of PCSK9 inhibitor to increase weight loss and reduce dyslipidemia in HFD-fed rats was greater than those of atorvastatin. An increase in MDA level, ratio of p-Drp1ser616/total Drp1 protein, CPT1 protein, mitochondrial ROS, and membrane depolarization in the soleus muscle were observed in HFD-fed rats with vehicle. PCSK9 inhibitor enabled the restoration of all these parameters to normal levels. However, atorvastatin facilitated restoration of some parameters, including MDA level, p-Drp1ser616/total Drp1 ratio, and CPT1 protein expression. These findings suggest that PCSK9 inhibitor is superior to atorvastatin in instigating weight loss, cholesterol reduction, and attenuation of mitochondrial oxidative stress in oxidative muscle fibers of obese female rats.