The Treatment of Rhodiola Mimics Exercise to Resist High-Fat Diet-Induced Muscle Dysfunction via Sirtuin1-Dependent Mechanisms.

Muscle dysfunction is a complication of high-fat diet (HFD)-induced obesity that could be prevented by exercise, but patients did not get enough therapeutic efficacy from exercise due to multiple reasons. To explore alternative or supplementary approaches to prevent or treat muscle dysfunction in individuals with obesity, we investigated the effects of Rhodiola on muscle dysfunction as exercise pills. SIRT1 might suppress atrogenes expression and improve mitochondrial quality control, which could be a therapeutic target stimulated by exercise and Rhodiola, but further mechanisms remain unclear. We verified the lipid metabolism disorders and skeletal muscle dysfunction in HFD feeding mice. Moreover, exercise and Rhodiola were used to intervene mice with a HFD. Our results showed that exercise and Rhodiola prevented muscle atrophy and dysfunction in obese mice and activating the SIRT1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved. EX-527, SIRT1 inhibitor, was used to validate the essential role of SIRT1 in salidroside benefit. Results of cell culture experiment showed that salidroside alleviated high palmitate-induced atrophy and mitochondrial quality control impairments, but these improvements of salidroside were inhibited by EX-527 in C2C12 myotubes. Overall, Rhodiola mimics exercise that activates SIRT1 signaling leading to improvement of HFD-induced muscle dysfunction.

Yiqi-Huoxue Granule (YQHX) Downregulates Prothrombotic Factors by Modulating KLF2 and NF-κB in HUVECs following LPS Stimulation.

The Yiqi-Huoxue granule (YQHX) is a traditional Chinese medication widely used in the therapy of the traditional Chinese medicine diagnosis "Qi deficiency" or "blood stasis" in China. Both these symptoms are related to inflammation, but the mechanisms of YQHX against inflammation are largely unknown. Thus, our present study investigated the effects of YQHX on regulating inflammatory responses induced by lipopolysaccharides (LPS) in HUVECs. Our data found that YQHX remarkably inhibits the production of prothrombotic factors, plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF), while it upregulates the protein expression of Kruppel-like factor 2 (KLF2). The increase in PAI-1 and TF was significantly attenuated through a transgenic knockdown in KLF2 with a Lenti-shKLF2 vector. YQHX also decreases the phosphorylation of nuclear factor-κB (NF-κB) p65 and IκB following LPS stimulation, and it effectively suppresses PAI-1 and TF via a NF-κB-dependent mechanism. Taken together, our results suggest that YQHX provides a notable antithrombotic activity via regulating the KLF2 expression and NF-κB signaling pathway in HUVECs. The KLF2 and NF-κB may be potential therapeutic targets for interventions of inflammation associated with atherosclerosis.

Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy.

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.

Bupleurum chinense polysaccharide inhibit adhesion of human melanoma cells via blocking ß1 integrin function.

Adhesive interaction contributes toward tumor metastasis and the transmembrane glycoprotein receptor, integrin has been recognized to mediate the adhesion to extracellular matrix thus upregulating tumor metastasis. In the current study, we evaluated the anti-adhesive mechanisms of a water-soluble polysaccharide (BCP) extracted from Bupleurum chinense. BCP inhibited integrin-mediated adhesion of human melanoma A375 cells to fibronectin but had no effects on nonspecific adhesion to poly-l-lysine. BCP also reduced ß1 integrin ligand affinity for GST-FNIII9-10 proteins. The adhesion-dependent formation of F-actin stress fiber and focal adhesion (FA) was also inhibited by BCP treatment. The inhibition of BCP on integrin-mediated signaling is probably through inhibiting phosphorylation of focal adhesion kinase (FAK) and paxillin. Collectively, our current findings indicated that BCP may be a potential therapy for melanoma metastasis due to its inhibitory effects on integrin function.

Induction of mitochondrial nitrative damage and cardiac dysfunction by chronic provision of dietary omega-6 polyunsaturated fatty acids.

Increased awareness of obesity has led to a dietary shift toward "heart-friendly" vegetable oils containing omega-6 polyunsaturated fatty acid (omega-6 PUFA). In addition to its beneficial effects, omega-6 PUFA also exhibits proinflammatory and prooxidative properties. We hypothesized that chronic dietary omega-6 PUFA can induce free radical generation, predisposing the cardiac mitochondria to oxidative damage. Male Wistar rats were fed a diet supplemented with 20% w/w sunflower oil, rich in omega-6 PUFA (HP) or normal laboratory chow (LP) for 4 weeks. HP feeding augmented phospholipase A(2) activity and breakdown of cardiolipin, a mitochondrial phospholipid. HP hearts also demonstrated elevated inducible nitric oxide synthase expression, loss of Mn superoxide dismutase, and increased mitochondrial nitrotyrosine levels. In these hearts, oxidative damage to mitochondrial DNA (mDNA) was demonstrated by 8-hydroxyguanosine immunopositivity, overexpression of DNA repair enzymes, and a decrease in the mRNA expression of specific respiratory subunits encoded by the mDNA. Functionally, at higher workloads, HP hearts also demonstrated a greater decline in cardiac work than LP, suggesting a compromised mitochondrial reserve. Our study, for the first time, demonstrates that consumption of a high fat diet rich in omega-6 PUFA for only 4 weeks instigates mitochondrial nitrosative damage and causes cardiac dysfunction at high afterloads.

Role of dietary fatty acids and acute hyperglycemia in modulating cardiac cell death.

OBJECTIVE: We examined the effect of dietary manipulation of palmitic acid (20% [w/w] palm oil [PO]) on cardiomyocyte apoptosis in the rat heart under normoglycemic and hyperglycemic conditions in vivo. We used 20% (w/w) sunflower oil (SO; a diet rich in omega-6 polyunsaturated fatty acids) as an isocaloric control. METHODS: Adult male Wistar rats were fed experimental diets containing normal laboratory chow (5% corn oil) or a high fat diet (AIN-76A with PO or SO) for 4 wk. Subsequently, to induce diabetes, rats were injected with streptozotocin (55 mg/kg, intravenously). After 4 d of diabetes, hearts were tested for evidence of lipotoxicity and cell death, and the serum for its related markers. RESULTS: Feeding PO and SO magnified palmitic and linoleic acid contents within lipoproteins and hearts respectively. Compared with SO, PO diabetic hearts demonstrated significantly higher levels of apoptosis, with an altered Bax:Bcl-2 ratio, augmented lipid peroxidation, and protein modification by formation of nitrotyrosine. Interestingly, SO-fed diabetic animals demonstrated an increase in serum lactate dehydrogenase and myocardial necrotic changes. CONCLUSION: In marked contrast to results obtained in vitro, PO feeding led to only a minor fraction of cardiomyocytes undergoing apoptosis and suggests that, in the intact heart, protective mechanisms could be triggered that dampen excessive apoptosis. Of greater clinical significance was the observation that "heart-friendly" vegetable oils such as SO, rich in omega-6 polyunsaturated fatty acids, could precipitate cardiac necrosis, and questions its beneficial role in the cardiovascular system, especially following diabetes.

Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA.

Diabetic patients are particularly susceptible to cardiomyopathy independent of vascular disease, and recent evidence implicates cell death as a contributing factor. Given its protective role against apoptosis, we hypothesized that dietary n-6 polyunsaturated fatty acid (PUFA) may well decrease the incidence of this mode of cardiac cell death after diabetes. Male Wistar rats were first fed a diet rich in n-6 PUFA [20% (wt/wt) sunflower oil] for 4 wk followed by streptozotocin (STZ, 55 mg/kg) to induce diabetes. After a brief period of hyperglycemia (4 days), hearts were excised for functional, morphological, and biochemical analysis. In diabetic rats, n-6 PUFA decreased caspase-3 activity, crucial for myocardial apoptosis. However, cardiac necrosis, an alternative mode of cell death, increased. In these hearts, a rise in linoleic acid and depleted cardiac glutathione could explain this "switch" to necrotic cell death. Additionally, mitochondrial abnormalities, impaired substrate utilization, and enhanced triglyceride accumulation could have also contributed to a decline in cardiac function in these animals. Our study provides evidence that, in contrast to other models of diabetic cardiomyopathy that exhibit cardiac dysfunction only after chronic hyperglycemia, n-6 PUFA feeding coupled with only 4 days of diabetes precipitated metabolic and contractile abnormalities in the heart. Thus, although promoted as being beneficial, excess n-6 PUFA, with its predisposition to induce obesity, insulin resistance, and ultimately diabetes, could accelerate myocardial abnormalities in diabetic patients.