Mangiferin Protects against Angiotensin-II-Enhanced Hypertrophic Markers and Apoptosis in H9c2 Cardiomyocytes.

Hypertrophic cardiomyopathy accompanies numerous cardiovascular diseases, and the intervention of cardiac hypertrophy is an important issue to prevent detrimental consequences. Mangiferin (MGN) is a glucosylxanthone found in Mangifera indica, which exhibits anti-oxidant and anti-inflammatory properties. Various studies have demonstrated the cardioprotective potential of MGN, but the mechanisms behind its beneficial effects have not been fully revealed. Here, angiotensin-II (Ang-II) was used to induce cardiac hypertrophy, and we examined cell size, expression of hypertrophy markers (e.g., ANP, BNP, and [Formula: see text]-MHC), and oxidative stress (e.g., the ratio of NADPH/NADP[Formula: see text], the expression of p22phox and p67phox, and ROS and SOD production) of cardiomyocytes. Moreover, we assessed the activation of mitogen-activated protein kinase (MAPK) signaling (e.g., p38 and ERK) and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, an annexin V/PI assay was employed to evaluate whether MGN administration can attenuate Ang-II-elicited apoptosis. Lastly, the expression of Ang-II type 1 receptor (AT1) was measured to confirm its involvement in MGN-mediated protection. Our results showed that treatment with MGN attenuated the Ang-II-induced cell size, expression of hypertrophy markers, and oxidative stress in cardiomyocytes. MGN also abrogated the activation of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis. Additionally, MGN prevented apoptosis and downregulated the elevation of AT1 in cardiomyocytes that had been exposed to Ang-II. Altogether, these results demonstrated the potential of using MGN to ameliorate the Ang-II-associated cardiac hypertrophy, which may be due to its anti-oxidant and anti-inflammatory effects through suppression of MAPK signaling and the NF-[Formula: see text]Bp65/iNOS axis.

Schisanhenol Attenuates OxLDL-Induced Endothelial Dysfunction via an AMPK-Dependent Mechanism.

Atherosclerotic cardiovascular diseases, commonly known as the formation of fibrofatty lesions in the artery wall, are the leading causes of death globally. Oxidized low-density lipoprotein (oxLDL) is one of the major components of atherosclerotic plaques. It is evident that dietary supplementation containing sources of antioxidants can prevent atherogenic diseases. Schisanhenol (SAL), a dibenzocyclooctene lignin, has been shown to attenuate oxLDL-induced apoptosis and the generation of reactive oxygen species (ROS) in endothelial cells. However, the underlying molecular mechanisms are still largely unknown. In this study, human umbilical vein endothelial cells (HUVECs) were pre-treated with SAL and oxLDL. Our results showed that adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was enhanced in cells pre-treated with SAL in time-dependent and dose-dependent manners. Subsequently, oxLDL-induced AMPK dephosphorylation and protein kinase C (PKC) phosphorylation were significantly reversed in the presence of SAL. In addition, SAL treatment led to an inhibiting effect on the oxLDL-induced membrane assembly of NADPH oxidase subunits, and a similar effect was observed in ROS generation. This effect was further confirmed using knockdown AMPK with small interfering RNA (siRNA) and pharmaceutical reagents, such as the AMPK activator (AICAR), PKC inhibitor (Gö 6983), and ROS inhibitor (DPI). Furthermore, the oxLDL-induced intracellular calcium rise and the potential collapse of the mitochondrial membrane reduced the Bcl-2/Bax ratio, and released cytochrome c from the mitochondria, leading to the subsequent activation of caspase-3 in HUVECs, which were also markedly suppressed by SAL pretreatment. The results mentioned above may provide additional insights into the possible molecular mechanisms underlying the cardiovascular protective effects of SAL.

The fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate and increased respiratory muscle function in patients with upper abdominal surgery: a randomized controlled trial.

BACKGROUND: Upper abdominal surgical treatment may reduce respiratory muscle function and mucociliary clearance, which might be a cause of postoperative pulmonary complications (PPCs). Threshold inspiratory muscle training (IMT) may serve as an effective modality to improve respiratory muscle strength and endurance in patients. However, whether this training could help patients with upper abdominal surgery remains to be determined. The aim of the present investigation was to determine the effect of a fully engaged IMT on PPCs and respiratory function in patients undergoing upper abdominal surgery. We hypothesized that the fully engaged IMT could reduce PPCs and improve respiratory muscle function in patients with upper abdominal surgery. METHODS: This is a randomized controlled trial (RCT) with 28 patients who underwent upper abdominal surgery. Patients were randomly assigned to the control (CLT) group or the IMT group. The CTL group received regular health care. The IMT group received 3 weeks of IMT with 50% of MIP as the initial intensity before the operation. The intensity of MIP increased by 5-10% per week. The IMT was continued for 4 weeks after the operation. The study investigated the outcomes including PPCs, respiratory muscle strength, diaphragmatic function, cardiopulmonary function, and quality of life (QoL). RESULTS: We found that IMT improved respiratory muscle strength and diaphragmatic excursion. IMT also had a beneficial effect on the incidence of postoperative pulmonary complications (PPCs) compared to CLT care. CONCLUSION: The results from this study revealed that IMT provided positive effects on parameters associated with the respiratory muscle function and reduced the incidence of PPCs. We propose that fully engaged IMT should be a part of clinical management in patients with upper abdominal surgery.KEY MESSAGESThe fully engaged inspiratory muscle training reduces postoperative pulmonary complications rate in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases maximal inspiratory pressure in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases diaphragm function in patients with upper abdominal surgery.The fully engaged inspiratory muscle training increases the quality of life in patients with upper abdominal surgery.

Quercetin Mitigates Cisplatin-Induced Oxidative Damage and Apoptosis in Cardiomyocytes through Nrf2/HO-1 Signaling Pathway.

Cisplatin is massively used to treat solid tumors. However, several severe adverse effects, such as cardiotoxicity, are obstacles to its clinical application. Cardiotoxicity may lead to congestive heart failure and even sudden cardiac death in patients receiving cisplatin. Therefore, finding a novel therapeutic strategy for the prevention of cisplatin-induced cardiotoxicity is urgent. Quercetin is a flavonol compound that can be found in dietary fruits and vegetables. The antioxidant function and anti-inflammatory capacity of quercetin have been reported. However, whether quercetin could protect against cisplatin-caused apoptosis and cellular damage in cardiomyocytes is still unclear. H9c2 cardiomyocytes were treated with cisplatin (40 µM) for 24 h to induce cellular damage with or without quercetin pretreatment. We found that quercetin activates Nrf2 and HO-1 expression, thereby mitigating cisplatin-caused cytotoxicity in H9c2 cells. Quercetin also increases SOD levels, maintains mitochondrial function, and reduces oxidative stress under cisplatin stimulation. Quercetin attenuates cisplatin-induced apoptosis and inflammation in H9c2 cardiomyocytes; however, these cytoprotective effects were diminished by silencing Nrf2 and HO-1. In conclusion, this study reports that quercetin has the potential to antagonize cisplatin-caused cardiotoxicity by reducing ROS-mediated mitochondrial damage and inflammation via the Nrf2/HO-1 and p38MAPK/NF-[Formula: see text]Bp65/IL-8 signaling pathway. This study provided the theoretical basis and experimental proof for the clinical application of quercetin as a new effective strategy to relieve chemotherapy-induced cardiotoxicity.

Epigallocatechin Gallate Reduces Homocysteine-Caused Oxidative Damages through Modulation SIRT1/AMPK Pathway in Endothelial Cells.

Elevated plasma concentration of total homocysteine is a pathological condition that causes vascular endothelial injury and subsequently leads to the progression of endothelial apoptosis in atherosclerosis. Epigallocatechin gallate (EGCG), a well-known anti-oxidant in green tea, has been reported with benefits on metabolic and cardiovascular diseases. This study aimed to explore that EGCG ameliorates homocysteine-induced endothelial cell apoptosis through enhancing the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) survival signaling pathway. Human umbilical endothelial cells were treated with homocysteine in the presence or absence of EGCG. We found that EGCG significantly increased the activities of SIRT1 and AMPK. EGCG diminished homocysteine-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation by inhibiting protein kinase C activation as well as reactive oxygen species (ROS) generation and recovered the activity of the endogenous antioxidant enzyme, superoxidase dismutase (SOD). Besides, EGCG also restores homocysteine-mediated dephosphorylation of Akt and decreases endothelial NO synthase (eNOS) expression. Furthermore, EGCG ameliorates homocysteine-activated pro-apoptotic events. The present study shows that EGCG prevents homocysteine-induced endothelial cell apoptosis via enhancing SIRT1/AMPK as well as Akt/eNOS signaling pathways. Results from this study indicated that EGCG might have some benefits for hyperhomocysteinemia.

The effects of threshold inspiratory muscle training in patients with obstructive sleep apnea: a randomized experimental study.

OBJECTIVES: Patients with obstructive sleep apnea (OSA) (an obstructed airway and intermittent hypoxia) negatively affect their respiratory muscles. We evaluated the effects of a 12-week threshold inspiratory muscle training (TIMT) program on OSA severity, daytime sleepiness, and pulmonary function in newly diagnosed OSA. METHODS: Sixteen patients with moderate-to-severe OSA were randomly assigned to a TIMT group and 6 to a control group. The home-based TIMT program was 30-45 min/day, 5 days/week, for 12 weeks using a TIMT training device. Their apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), and forced vital capacity (FVC) scores were evaluated pre- and post-treatment. Polysomnographic (PSG) analysis showed that 9 TIMT-group patients had positively responded (TIMT-responder group: post-treatment AHI < pre-treatment) and that 7 had not (TIMT non-responder group: post-treatment AHI > pre-treatment). RESULTS: Post-treatment AHI and ESS scores were significantly (both P < 0.05) lower 6% and 20.2%, respectively. A baseline AHI ≤ 29.0/h predicted TIMT-responder group patients (sensitivity 77.8%; specificity 85.7%). FVC was also significantly (P < 0.05) higher 7.2%. Baseline AHI and FEV6.0 were significant predictors of successful TIMT-responder group intervention. OSA severity and daytime sleepiness were also significantly attenuated. CONCLUSIONS: Home-based TIMT training is simple, efficacious, and cost-effective.

Neural Mobilization Attenuates Mechanical Allodynia and Decreases Proinflammatory Cytokine Concentrations in Rats With Painful Diabetic Neuropathy.

Background: Painful diabetic neuropathy (PDN) is a common complication in patients with diabetes. It is related to ischemic nerve damage and the increase in the levels of proinflammatory mediators, such as tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß). Neural mobilization may have the potential to alleviate PDN, but it has not yet been tested. Also, the physiological mechanism of neural mobilization is unclear. Objective: The objective of this study was to investigate treatment effect and physiological mechanism of neural mobilization. Design: This was an experimental study using rats with streptozocin (or streptozotocin)-induced type 1 diabetes. Methods: Three groups were used in the study, the control group (vehicle), the diabetes group (PDN group), and the neural mobilization treatment group (PDN-NM group) (n = 6). Rats in the vehicle group were healthy rats. Rats in the PDN and PDN-NM groups were rats with diabetes. Rats in the PDN-NM group received treatment in the right sciatic nerve, whereas rats in the PDN group did not. Mechanical pain sensitivity and the levels of IL-1ß and TNF-α in the sciatic nerve branches and trunk, the L4 to L6 dorsal horn ganglion, and the spinal cord dorsal horn were measured. Results: Techanical allodynia was alleviated after treatment, but the effect was limited to the treatment side. The concentrations of proinflammatory cytokines were decreased in the nerves that received treatment compared with those on the other side, indicating that neural mobilization may reduce mechanical sensitivity by decreasing the concentrations of local sensitizing agents. Limitations: A limitation of this study was that no direct measurement of nerve blood flow was done. Conclusions: The results of this study showed that neural mobilization effectively alleviated mechanical allodynia in rats with PDN. The side that received treatment had lower concentrations of TNF-α and IL-1ß in the sciatic nerve branches and sciatic nerve trunk; this result may have been related to the alleviation of mechanical allodynia.

Ginkgo biloba extract inhibits oxidized low-density lipoprotein (oxLDL)-induced matrix metalloproteinase activation by the modulation of the lectin-like oxLDL receptor 1-regulated signaling pathway in human umbilical vein endothelial cells.

BACKGROUND: The overexpression of matrix metalloproteinases (MMPs) induced by oxidized low-density lipoprotein (oxLDL) has been found in atherosclerotic lesions. Previous reports have identified that oxLDL, via the upregulation of lectin-like ox-LDL receptor 1 (LOX-1), modulates the expression of MMPs in endothelial cells. Ginkgo biloba extract (GbE), from Ginkgo biloba leaves, has often been considered as a therapeutic compound for cardiovascular and neurologic diseases. However, further investigation is needed to ascertain the probable molecular mechanisms underlying the antiatherogenic effects of GbE. The aim of this study was to investigate the effects of GbE on oxLDL-activated MMPs of human endothelial cells and to test the involvement of LOX-1 and protein kinase C (PKC)-α, extracellular signal-regulated kinase (ERK), and peroxisome proliferator-activated receptor-γ (PPAR-γ). METHODS: Human umbilical vein endothelial cells were stimulated with oxLDL, with or without GbE treatment. LOX-1 signaling and MMPs expression were tested by Western blotting or activity assay. Further, protein expression levels of PKC-α, ERK, nuclear factor-κB, and PPAR-γ were investigated by Western blotting. RESULTS: GbE inhibited the oxLDL-caused upregulation of MMP-1, MMP-2, and MMP-3. Pretreating with GbE reduced oxLDL-activated LOX-1 expression. Furthermore, pharmacologic inhibitors of free radicals, Ca(++), PKC, and GbE, inhibited the oxLDL-induced ERK and nuclear factor-κB activation. Lastly, GbE ameliorated the oxLDL-inhibited PPAR-γ function. CONCLUSIONS: Data obtained in this study indicate that GbE actives its protective effects by regulating the LOX-1-mediated PKC-α/ERK/PPAR-γ/MMP pathway, resulting in the suppression of reactive oxygen species formation and, ultimately, the reduction of MMPs expression in endothelial cells treated with oxLDL.

Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism.

Atherosclerosis is a complex inflammatory arterial disease, and oxidized low-density lipoprotein (oxLDL) is directly associated with chronic vascular inflammation. Previous studies have shown that Ginkgo biloba extract (GbE) acts as a therapeutic agent for neurological and cardiovascular disorders. However, the mechanisms mediating the actions of GbE are still largely unknown. In the present study, we tested the hypothesis that GbE protects against oxLDL-induced endothelial dysfunction via an AMP-activated protein kinase (AMPK)-dependent mechanism. Human umbilical vein endothelial cells were treated with GbE, followed by oxLDL, for indicated time periods. Results from Western blot showed that GbE inhibited the membrane translocation of the NADPH oxidase subunits p47(phox) and Rac-1 and attenuated the increase in protein expression of membrane subunits gp91 and p22(phox) caused by oxLDL-induced AMPK dephosphorylation and subsequent PKC activation. AMPK-α(1)-specific small interfering RNA-transfected cells that had been exposed to GbE followed by oxLDL revealed elevated levels of PKC and p47(phox). In addition, exposure to oxLDL resulted in reduced AMPK-mediated Akt/endothelial nitric oxide (NO) synthase signaling and the induction of phosphorylation of p38 mitogen-activated protein kinase, which, in turn, activated NF-κB-mediated inflammatory responses, such as the release of interleukin-8, the expression of the adhesion molecule, and the adherence of monocytic cells to human umbilical vein endothelial cells. Furthermore, oxLDL upregulated the expression of inducible NO synthase, thereby augmenting the formation of NO and protein nitrosylation. Pretreatment with GbE, however, exerted significant cytoprotective effects in a dose-dependent manner. Results from this study may provide insight into a possible molecular mechanism by which GbE protects against oxLDL-induced endothelial dysfunction.

Crude extracts of Solanum lyratum protect endothelial cells against oxidized low-density lipoprotein-induced injury by direct antioxidant action.

BACKGROUND: Oxidized low-density lipoprotein (oxLDL) is a proatherogenic molecule that accumulates in the vascular wall and contributes to the pathogenesis of vascular dysfunction early in the development of atherosclerosis. The whole plant of Solanum lyratum is a traditional Chinese medicine that has been used for centuries to treat cancer, tumors, and herpes. However, the cellular and molecular mechanisms of its antioxidant effects are still largely unknown. This study tested the hypothesis that Solanum lyratum Thunberg extract (SLE) could block oxLDL-induced endothelial dysfunction in cultured human umbilical vein endothelial cells (HUVECs). Possible mechanisms were explored. METHODS: Antioxidative activities of SLE were assayed by measuring the scavenging of 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical and the inhibition of copper-mediated or cell-mediated LDL oxidation. Production of reactive oxygen species (ROS) and the expression of adhesion molecules were evaluated in HUVECs after exposure to oxLDL and treatment with SLE. Several apoptotic signaling pathways were investigated. RESULTS: SLE scavenged DPPH and also delayed the kinetics of LDL oxidation in a dose-dependent manner. SLE attenuated the level of oxLDL-induced ROS generation, diminished the expression of endothelial NO synthase (eNOS), and enhanced the expression of adhesion molecules (vascular cellular adhesion molecule-1, E-selectin, and monocyte chemotactic protein-1) and the adherence of monocytic THP-1 cells to HUVECs. OxLDL increased the concentration of intracellular calcium, disturbed the balance of the Bcl-2 protein family, destabilized the mitochondrial membrane potential, increased the amount of cytochrome c released into the cytosol, and increased the activation of caspase 3. These detrimental effects were ameliorated dose-dependently by SLE (P < .05). CONCLUSION: Crude extracts of Solanum lyratum protect against oxLDL-induced injury in endothelial cells by direct antioxidant action. CLINICAL RELEVANCE: Atherosclerosis is a chronic inflammatory disease characterized by lipid-laden lesions within arterialblood vessel walls. Inhibiting the oxidation of low-density lipoprotein may be an effective way to prevent or delay theprogression of atherosclerosis. This study underscores the potential clinical benefits and application of Solanum lyratumextract in controlling oxidized low-density lipoprotein-associated vascular injury and cardiovascular disease.

Ginkgo biloba extract attenuates oxLDL-induced oxidative functional damages in endothelial cells.

Atherosclerosis is a chronic inflammatory process with increased oxidative stress in vascular endothelium. Ginkgo biloba extract (GbE), extracted from Ginkgo biloba leaves, has commonly been used as a therapeutic agent for cardiovascular and neurological disorders. The aim of this study was to investigate how GbE protects vascular endothelial cells against the proatherosclerotic stressor oxidized low-density lipoprotein (oxLDL) in vitro. Human umbilical vein endothelial cells (HUVECs) were incubated with GbE (12.5-100 microg/ml) for 2 h and then incubated with oxLDL (150 microg/ml) for an additional 24 h. Subsequently, reactive oxygen species (ROS) generation, antioxidant enzyme activities, adhesion to monocytes, cell morphology, viability, and several apoptotic indexes were assessed. Our data show that ROS generation is an upstream signal in oxLDL-treated HUVECs. Cu,Zn-SOD, but not Mn-SOD, was inactivated by oxLDL. In addition, oxLDL diminished expression of endothelial NO synthase and enhanced expression of adhesion molecules (ICAM, VCAM, and E-selectin) and the adherence of monocytic THP-1 cells to HUVECs. Furthermore, oxLDL increased intracellular calcium, disturbed the balance of Bcl-2 family proteins, destabilized mitochondrial membrane potential, and triggered subsequent cytochrome c release into the cytosol and activation of caspase-3. These detrimental effects were ameliorated dose dependently by GbE (P < 0.05). Results from this study may provide insight into a possible molecular mechanism underlying GbE suppression of the oxLDL-mediated vascular endothelial dysfunction.