This study was designed to investigate the effects of cAMP on immune regulation and apoptosis during acute rat cardiac allograft rejection. We found that the production of immune markers such as inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), iNOS expression, and nitric oxide (NO) production, was significantly increased in the blood and transplanted hearts of allograft recipients, but not of isograft controls. These increases were effectively suppressed by the administration of the membrane permeable cAMP analog dibutyryl cAMP (db-cAMP). Administration of db-cAMP reduced allograft-induced elevation of several biochemical markers, such as adhesion molecule expression, iron-nitrosyl complex formation, caspase-3 activation, and apoptotic DNA fragmentation in an animal model. Furthermore, treatment of allograft recipients with db-cAMP prolonged median graft survival to 11 days compared with a median graft survival time of 8 days in saline-treated allograft recipients. These results suggest that db-cAMP exerts a beneficial effect on murine cardiac allograft survival by modulating allogeneic immune response and cytotoxicity.
Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cyclic AMP/analogs & derivatives/*pharmacology/*therapeutic use ; Electron Spin Resonance Spectroscopy ; Graft Rejection/*drug therapy ; Graft Survival/*drug effects ; Heart Transplantation/*adverse effects ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Male ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/genetics ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha/metabolism

Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.
Acetylation ; Amino Acids ; Citric Acid Cycle ; Diabetes Mellitus, Type 2 ; Fatty Acids ; Glucose ; Glycolysis ; Metabolic Diseases ; Metabolic Networks and Pathways ; Metabolism* ; Mitochondria ; Neurodegenerative Diseases ; Obesity ; Oxidative Phosphorylation ; Oxidoreductases ; Phosphoric Monoester Hydrolases ; Phosphorylation ; Phosphotransferases ; Protein Processing, Post-Translational ; Pyruvate Dehydrogenase Complex* ; Pyruvic Acid*

Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca²⁺ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca²⁺ release and thereby deplete ER Ca²⁺ stores. The resulting ER Ca²⁺ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca²⁺ release, cytosolic and mitochondrial matrix Ca²⁺ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca²⁺ depletion mediate persistent Ca²⁺ influx, further impairing cytosolic and mitochondrial Ca²⁺ homeostasis. Mitochondrial Ca²⁺ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications.
Adenosine Triphosphate ; Apoptosis ; Calcium* ; Cytosol ; Diabetes Complications ; Endoplasmic Reticulum ; Fatty Acids, Nonesterified ; Homeostasis ; Insulin Resistance ; Ion Channels ; Metabolic Diseases ; Metabolism ; Oxidative Stress* ; Protein Folding ; Reactive Oxygen Species ; Superoxides

BACKGROUNDCentral blood pressure (BP) is pathophysiologically more important than peripheral BP for the pathogenesis of cardiovascular disease. Arterial stiffness is also a good predictor of cardiovascular morbidity and mortality. The effects of benidipine, a unique dual L-/T-type calcium channel blocker, on central BP have not been reported. This study aimed to compare the effect of benidipine and losartan on the central BP and arterial stiffness in mild to moderate essential hypertensives.

METHODSThis 24 weeks, multi-center, open label, randomized, active drug comparative, parallel group study was designed as a non-inferiority study. The eligible patients (n = 200) were randomly assigned to receive benidipine (n = 101) or losartan (n = 99). Radial artery applanation tonometry and pulse wave analysis were used to measure the central BP, pulse wave velocity (PWV) and augmentation index (AIx). We also measured the metabolic and inflammatory markers.

RESULTSAfter 24 weeks, the central BP decreased significantly from baseline by (16.8 ± 14.0/10.5 ± 9.2) mmHg (1 mmHg = 0.133 kPa) (systolic/diastolic BP; P < 0.001) in benidipine group and (18.9 ± 14.7/12.1 ± 10.2) mmHg (P < 0.001) in losartan group respectively. Both benidipine and losartan groups significantly lowered peripheral BP (P < 0.001) and AIx (P < 0.05), but there were no significant differences between the two groups. The mean aortic, brachial and femoral PWV did not change in both groups after 24-week treatment. There were no significant changes of the blood metabolic and inflammatory biomarkers in each group.

CONCLUSIONBenidipine is as effective as losartan in lowering the central and peripheral BP, and improving arterial stiffness.

Adolescent ; Adult ; Aged ; Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Blood Pressure ; drug effects ; Calcium Channel Blockers ; therapeutic use ; Dihydropyridines ; adverse effects ; therapeutic use ; Essential Hypertension ; Female ; Humans ; Hypertension ; drug therapy ; physiopathology ; Losartan ; adverse effects ; therapeutic use ; Male ; Middle Aged ; Vascular Stiffness ; drug effects

Background: Current international guidelines recommend against deep sedation as it is associated with worse outcomes in the intensive care unit (ICU). However, in Korea the prevalence of deep sedation and its impact on patients in the ICU are not well known. Methods: From April 2020 to July 2021, a multicenter, prospective, longitudinal, noninterventional cohort study was performed in 20 Korean ICUs. Sedation depth extent was divided into light and deep using a mean Richmond Agitation–Sedation Scale value within the first 48 hours. Propensity score matching was used to balance covariables; the outcomes were compared between the two groups. Results: Overall, 631 patients (418 [66.2%] and 213 [33.8%] in the deep and light sedation groups, respectively) were included. Mortality rates were 14.1% and 8.4% in the deep and light sedation groups (P = 0.039), respectively. Kaplan-Meier estimates showed that time to extubation (P < 0.001), ICU length of stay (P = 0.005), and death P = 0.041) differed between the groups. After adjusting for confounders, early deep sedation was only associated with delayed time to extubation (hazard ratio [HR], 0.66; 95% confidence inter val [CI], 0.55– 0.80; P < 0.001). In the matched cohort, deep sedation remained significantly associated with delayed time to extubation (HR, 0.68; 95% 0.56–0.83; P < 0.001) but was not associated with ICU length of stay (HR, 0.94; 95% CI, 0.79–1.13; P = 0.500) and in-hospital mortality (HR, 1.19; 95% CI, 0.65–2.17; P = 0.582). Conclusion In many Korean ICUs, early deep sedation was highly prevalent in mechanically ventilated patients and was associated with delayed extubation, but not prolonged ICU stay or in-hospital death.