The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and plays a role in mitochondrial biogenesis and oxidative function, in gain- and loss-of function studies. Rev-erb-α-deficiency in skeletal muscle leads to reduced mitochondrial content and oxidative function, resulting in compromised exercise capacity. This phenotype was recapitulated in isolated fibers and in muscle cells upon Rev-erbα knock-down, while Rev-erb-α over-expression increased the number of mitochondria with improved respiratory capacity. Rev-erb-α-deficiency resulted in deactivation of the Stk11–Ampk–Sirt1–Ppargc1-α signaling pathway, whereas autophagy was up-regulated, resulting in both impaired mitochondrial biogenesis and increased clearance. Muscle over-expression or pharmacological activation of Rev-erb-α increased respiration and exercise capacity. This study identifies Rev-erb-α as a pharmacological target which improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

Wound healing is a well-tuned biological process, which is achieved via consecutive and overlapping phases including hemostasis, inflammatory-related events, cell proliferation and tissue remodeling. Several factors can impair wound healing such as oxygenation defects, aging, and stress as well as deleterious health conditions such as infection, diabetes, alcohol overuse, smoking and impaired nutritional status. Growing evidence suggests that reactive oxygen species (ROS) are crucial regulators of several phases of healing processes. ROS are centrally involved in all wound healing processes as low concentrations of ROS generation are required for the fight against invading microorganisms and cell survival signaling. Excessive production of ROS or impaired ROS detoxification causes oxidative damage, which is the main cause of non-healing chronic wounds. In this context, experimental and clinical studies have revealed that antioxidant and anti-inflammatory strategies have proven beneficial in the non-healing state. Among available antioxidant strategies, treatments using mitochondrial-targeted antioxidants are of particular interest. Specifically, mitochondrial-targeted peptides such as elamipretide have the potential to mitigate mitochondrial dysfunction and aberrant inflammatory response through activation of nucleotide-binding oligomerization domain (NOD)-like family receptors, such as the pyrin domain containing 3 (NLRP3) inflammasome, nuclear factor-kappa B (NF-κB) signaling pathway inhibition, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2).

O besity and type 2 diabetes mellitus (DM) have reached epidemic levels worldwide. These 2 metabolic disorders are independent risk factors for the development of heart failure. [1][2][3] Epidemiological and clinical studies strongly support the existence of obesity and diabetic cardiomyopathies unrelated to coronary artery disease, hypertension, and other comorbidities. 4,5 Clinical Perspective on p 564Studies in rodent models of obesity and DM have identified intrinsic cardiomyocyte dysfunctions secondary to alterations in energy substrate utilization, mitochondrial dysfunction, increased oxidative stress, and intracellular accumulation of lipotoxic byproducts. Similarly, human studies have shown that dysregulation of the energy conversion process is one of the major characteristics of the failing heart of subjects with cardiomyopathy related to DM or obesity. 6,7Background-Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Methods and Results-Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A 1C , but neither body mass index nor the insulin resistance index (homeostasis model assessment-insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A 1C . Conclusion-Worsening

The diagnostic accuracy of protected-specimen brush (PSB), bronchoalveolar lavage (BAL), and endotracheal aspirates (EA) was prospectively evaluated in a series of 28 mechanically ventilated patients (MV patients) who died within 3 d of the bronchoscopic procedure, using postmortem lung examination as the gold standard for establishing the diagnosis of pneumonia. The entire fixed lungs were carefully dissected along the bronchovascular axes and each segment was cut into 5- to 10-mm thick sections, enabling gross examination of the lung parenchyma. Two tissue blocks were taken from each segment, including grossly abnormal areas whenever present. In several cases, two peripheral (subpleural) lung-tissue blocks were also taken from each lobe prior to systematic dissection of the lungs. Quantitative cultures (QC) and direct cytologic and microbiologic examination (DE) was performed on respiratory samples obtained within 72 h before death. Values of 10(3) cfu/ml of Ringer's solution, 10(4) cfu/ml of retrieved fluid, and 10(6) cfu/ml of respiratory secretions were used as cutoff points for quantitative PSB, BAL, and EA cultures, respectively. The main findings in this study were that: (1) Pneumonia was present in 67% of the patients. (2) Histologic lesions of pneumonia were mainly bilateral and predominated in the dependent lung segments. (3) Coexistence of a variety of noninfectious processes was a common finding in patients with pneumonia. (4) In several cases pneumonia was absent from peripheral lung samples while more central areas of the same segment displayed typical foci of pneumonia. (5) The sensitivity of quantitative cultures was 55%, 57%, and 47% for EA, PSB, and BAL, respectively, and the specificity was 85%, 88%, and 100%, respectively. Reducing the diagnostic threshold of EA to 10(5) cfu/ml of respiratory secretions instead of 10(6) cfu/ml resulted in a sensitivity of 63.1% and a specificity of 75% for EA. The sensitivity of direct examination (DE) was 50%, 47%, and 47%, respectively, and the specificity was 75%, 88%, and 87%. (6) The presence of intracellular organisms (ICO) in BAL had a 36.8% sensitivity and 100% specificity in establishing the diagnosis of pneumonia regardless of their percentage. (7) Although 15 patients (53%) were not on antibiotics or were off antibiotics for more than 48 h before testing, no relationship could be established between the patients' antibiotic status and the result of any diagnostic test. By using a recommended methodology for respiratory sampling techniques together with complete postmortem lung examination as a diagnostic "gold standard," this study provides a realistic insight into the diagnostic values of EA, PSB, and BAL in MV patients with suspected pneumonia.

Use of metal carbonyl-based compounds capable of releasing carbon monoxide (CO) in biological systems have emerged as a potential adjunctive therapy for sepsis via their antioxidant, anti-inflammatory, and antiapoptotic effects. The role of CO in regulation of mitochondrial dysfunction and biogenesis associated with sepsis has not been investigated. In the present study, we employed a ruthenium-based water-soluble CO carrier, tricarbonylchoro(glycinato)ruthenium (II) (CORM-3), one of the novel CO-releasing molecules (CO-RMs), to test whether CO can improve cardiac mitochondrial dysfunction and survival in peritonitis-induced sepsis. Peritonitis was performed in mice by cecal ligation and perforation. Tumor necrosis factor-␣, interleukin-10, and nitrite/nitrate plasma levels were tested to evaluate the systemic inflammatory response. Functional mitochondrial studies included determination of membrane potential, respiration, and redox status. Oxidative stress was evaluated by measurements of mitochondrial hydrogen peroxide, carbonyl protein and GSH levels. Mitochondrial biogenesis was assessed by peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ protein expression and mitochondrial DNA (mtDNA) copy number. The systemic inflammatory response elicited by peritonitis was accompanied by mitochondrial energetic metabolism deterioration and reduced PGC-1␣ protein expression. CORM-3 treatment in septic mice restored the deleterious effects of sepsis on mitochondrial membrane potential, respiratory control ratio, and energetics. It is interesting that administration of CORM-3 during sepsis elicited a mild oxidative stress response that stimulated mitochondrial biogenesis with PGC-1␣ protein expression and mtDNA copy number increases. Our results reveal that delivery of controlled amounts of CO dramatically reduced mortality in septic mice, indicating that CO-RMs could be used therapeutically to prevent organ dysfunction and death in sepsis.

No abstract

The glycocalyx constitutes the first line of the blood tissue interface and is thus involved in many physiological processes, deregulation of which may lead to microvascular dysfunction. Because administration of LPS is accompanied by severe microvascular dysfunction, the purpose of the study was to investigate microvascular glycocalyx function during endotoxemia. Bolus infusion of LPS (10 mg kg(-1)) to male Sprague-Dawley rats elicited the development of hyporeactivity to vasoactive agents and microvascular derangements, including decreased capillary density and significant increases in intermittent and stopped flow capillaries in the small intestine muscularis layer compared with controls. LPS elicited plasma hyluronan release and reduction in endothelial surface thickness, indicative of glycocalyx degradation. Because endothelial glycocalyx is extremely sensitive to free radicals, oxidative stress was evaluated by oxidation of dihydrorhodamine in microvascular beds and levels of heart malondialdehyde and plasma carbonyl proteins, which were all increased in LPS-treated rats. Activated protein C (240 microg kg(-1) h(-1)) enhanced systemic arterial pressure response to norepinephrine in LPS-treated rats. Activated protein C (240 microg kg(-1) h(-1)) prevented capillary perfusion deficit in the septic microvasculature that were associated with reduced oxidative stress and preservation of glycocalyx. Our findings support the conclusion that LPS induces major microcirculation dysfunction accompanied by microvascular oxidative stress and glycocalyx degradation that may be limited by activated protein C treatment.

Peak VO2 is severely impaired in candidates for LT and affects survival and post-LT course. Perioperative respiratory rehabilitation programs validated in lung and heart transplantation must be tested.