Cells can shift their metabolism between glycolysis and oxidative phosphorylation to enact their cell fate program in response to external signals. Widely distributed α1-adrenergic receptors (ARs) are physiologically stimulated during exercise, were reported to associate with the activating energetic AMPK pathway, and are expected to have biological effects beyond their hemodynamic effects. To investigate the effects and mechanism of AR stimulation on the physiology of the whole body, various in vitro and in vivo experiments were conducted using the AR agonist midodrine, 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]-acetamide. The expression of various biomarkers involved in ATP production was estimated through Western blotting, reverse transcription polymerase chain reaction, oxygen consumption rate, enzyme-linked immunosorbent assay (ELISA), fluorescence staining, and Oil red O staining in several cell lines (skeletal muscle, cardiac muscle, liver, macrophage, vascular endothelial, and adipose cells). In spontaneously hypertensive rats, blood pressure, blood analysis, organ-specific biomarkers, and general biomolecules related to ATP production were measured with Western blot analysis, immunohistochemistry, ELISA, and echocardiography. Pharmacological activation of α1-adrenergic receptors in C2C12 skeletal muscle cells promoted mitochondrial oxidative phosphorylation and ATP production by increasing the expression of catabolic molecules, including PPARδ, AMPK, and PGC-1α, through cytosolic calcium signaling and increased GLUT4 expression, as seen in exercise. It also activated those energetic molecules and mitochondrial oxidative phosphorylation with cardiomyocytes, endothelial cells, adipocytes, macrophages, and hepatic cells and affected their relevant cell-specific biological functions. All of those effects occurred around 3 h (and peaked 6 h) after midodrine treatment. In spontaneously hypertensive rats, α1-adrenergic receptor stimulation affected mitochondrial oxidative phosphorylation and ATP production by activating PPARδ, AMPK, and PGC-1α and the relevant biologic functions of multiple organs, suggesting organ crosstalk. The treatment lowered blood pressure, fat and body weight, cholesterol levels, and inflammatory activity; increased ATP content and insulin sensitivity in skeletal muscles; and increased cardiac contractile function without exercise training. These results suggest that the activation of α1-adrenergic receptor stimulates energetic reprogramming via PPARδ that increases mitochondrial oxidative phosphorylation and has healthy and organ-specific biological effects in multiple organs, including skeletal muscle, beyond its vasomotion effect. In addition, the action mechanism of α1-adrenergic receptor may be mainly exerted via PPARδ.
This study is aimed at elucidating how aspirin could systemically and simultaneously normalize nonalcoholic fatty liver disease (NAFLD) and atherosclerosis through both in vitro and in vivo studies in hyperlipidemic conditions. We evaluated the effects and mechanism of aspirin on the levels of various biomarkers related to NAFLD, atherosclerosis, and oxidative phosphorylation in cells and animals of hyperlipidemic conditions. The protein levels of biomarkers (PPARδ, AMPK, and PGC-1α) involved in oxidative phosphorylation in both the vascular endothelial and liver cells were elevated by the aspirin in hyperlipidemic condition. Also in the stimulation pathway of oxidative phosphorylation by aspirin, PPARδ was a superior regulator than AMPK and PGC-1α in HepG2 cells. In the vascular endothelial cells, the phosphorylated endothelial nitric oxide synthase level was increased by the treatment. The protein levels of biomarkers related to lipid synthesis were decreased by the treatment in the liver cells. In rabbits administered with cholesterol diet, the levels of triglyceride, HDLcholesterol, and alanine amino transferase in serums were ameliorated by the aspirin treatment, the levels of ATP and TNFα were increased or decreased, respectively, by the aspirin in liver and aorta tissues, and mannose receptor and C-C chemokine receptor type 2 levels were increased or decreased by the aspirin in spleen, respectively. The elevated levels of macrophage antigen, angiotensin II type1 receptor, and lipid accumulation were decreased in both the liver and aorta tissues in the aspirintreated group. In conclusion, aspirin can systemically and simultaneously ameliorate NAFLD and atherosclerosis by inhibiting lipid biosynthesis and inflammation and by elevating catabolic metabolism through the activation of the PPARδ-AMPK-PGC-1α pathway. Furthermore, aspirin may normalize atherosclerosis and NAFLD by modulating the mannose receptor and CCR2 in macrophages.
Hypertension is a disease with a high prevalence and high mortality rates worldwide. In addition, various factors, such as genetic predisposition, lifestyle factors, and the abnormality of organs related to blood pressure, are involved in the development of hypertension. However, at present, there are few available drugs for hypertension that do not induce side effects. Although the therapeutic effects of ginger on hypertension are well established, the precise mechanism has not been elucidated. Therefore, this study was designed to evaluate the antihypertensive mechanism of 6-gingerol, one of the main ingredients of ginger, and to assist in the development of new drugs for hypertension without side effects. The antihypertensive effects and mechanism of 6-gingerol were identified through reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunocytochemical staining for biomarkers involved in hypertension in human umbilical vein endothelial cells (HUVECs), human embryonal kidney cells (HEK293 cells), and mouse preadipocytes (3T3-L1 cells). The lipid accumulation in differentiated 3T3-L1 cells was evaluated by using Oil Red O staining. 6- Gingerol increased the level of phosphorylated endothelial nitric oxide synthase (eNOS) protein but decreased that of vascular cell adhesion protein 1 (VCAM1) and tumor necrosis factor alpha (TNFα) in HUVECs. In HEK293 cells, the expression of the epithelial sodium channel (ENaC) protein was reduced by 6-gingerol. Lipid accumulation was attenuated by 6-gingerol treatment in differentiated 3T3-L1 cells. These effects were regulated via peroxisome proliferator-activated receptor delta (PPARδ). 6-Gingerol ameliorated the expression of biomarkers involved in the development of hypertension through PPARδ in HUVECs, HEK293, and differentiated 3T3-L1 cells.
HA (Hyaluronic acid) filler, the most commonly used dermal filler, causes several side effects. HA-PN (Hyaluronic acid-Polynucleotide), a new composite filler, has excellent biocompatibility and induces tissue regeneration. In this study, we compare the efficacies and safety profiles of these fillers. The characteristics of HA and HA-PN fillers were compared using scanning electron microscopy and rheometry. No morphological difference was noted between the fillers. However, the latter had higher viscosity and elasticity values. The HA-PN filler induced higher cell migration than the HA filler in a wound healing assay. It was also found to stimulate better collagen synthesis in human and mouse fibroblasts. The HA and HA-PN fillers were injected into SKH1 hairless mice to determine changes in their volume for up to 24 weeks. Increased cell migration and collagen synthesis were observed in mice injected with the HA-PN complex filler. Although the safety and durability of the HA and HA-PN fillers were similar, the latter induced a lower transient receptor potential vanilloid 4 expression and caused less stimulation upon injection. In conclusion, HA-PN complex fillers can stimulate fibroblast growth and facilitate volume growth and skin regeneration.
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