Nicotinamide Mononucleotide improves oocyte maturation of mice with type 1 diabetes.

BACKGROUND: The number of patients with type 1 diabetes rises rapidly around the world in recent years. Maternal diabetes has a detrimental effect on reproductive outcomes due to decreased oocyte quality. However, the strategies to improve the oocyte quality and artificial reproductive technology (ART) efficiency of infertile females suffering from diabetes have not been fully studied. In this study, we aimed to examine the effects of nicotinamide mononucleotide (NMN) on oocyte maturation of mouse with type 1 diabetes mouse and explore the underlying mechanisms of NMN's effect. METHODS: Streptozotocin (STZ) was used to establish the mouse models with type 1 diabetes. The successful establishment of the models was confirmed by the results of body weight test, fasting blood glucose test and haematoxylin and eosin (H&E) staining. The in vitro maturation (IVM) rate of oocytes from diabetic mice was examined. Immunofluorescence staining (IF) was performed to examine the reactive oxygen species (ROS) level, spindle/chromosome structure, mitochondrial function, actin dynamics, DNA damage and histone modification of oocytes, which are potential factors affecting the oocyte quality. The quantitative reverse transcription PCR (RT-qPCR) was used to detect the mRNA levels of Sod1, Opa1, Mfn2, Drp1, Sirt1 and Sirt3 in oocytes. RESULTS: The NMN supplementation increased the oocyte maturation rate of the mice with diabetes. Furthermore, NMN supplementation improved the oocyte quality by rescuing the actin dynamics, reversing meiotic defects, improving the mitochondrial function, reducing ROS level, suppressing DNA damage and restoring changes in histone modifications of oocytes collected from the mice with diabetes. CONCLUSION: NMN could improve the maturation rate and quality of oocytes in STZ-induced diabetic mice, which provides a significant clue for the treatment of infertility of the patients with diabetes.

Natural Deep Eutectic Solvent-Based Microwave-Assisted Extraction of Total Flavonoid Compounds from Spent Sweet Potato (Ipomoea batatas L.) Leaves: Optimization and Antioxidant and Bacteriostatic Activity.

Natural deep eutectic solvents (NADESs) coupled with microwave-assisted extraction (MAE) were applied to extract total flavonoid compounds from spent sweet potato (Ipomoea batatas L.) leaves. In this study, ten different NADESs were successfully synthesized for the MAE. Based on single-factor experiments, the response surface methodology (RSM) was applied, and the microwave power, extraction temperature, extraction time, and solid−liquid ratio were further evaluated in order to optimize the yields of total flavonoid compounds. Besides, the extracts were recovered by macroporous resin for the biological activity detection of flavonoid compounds. As a result, NADES-2, synthesized by choline chloride and malic acid (molar ratio 1:2), exhibited the highest extraction yield. After that, the NADES-2-based MAE process was optimized and the optimal conditions were as follows: microwave power of 470 W, extraction temperature of 54 °C, extraction time of 21 min, and solid−liquid ratio of 70 mg/mL. The extraction yield (40.21 ± 0.23 mg rutin equivalents/g sweet potato leaves) of the model validation experiment was demonstrated to be in accordance with the predicted value (40.49 mg rutin equivalents/g sweet potato leaves). In addition, flavonoid compounds were efficiently recovered from NADES-extracts with a high recovery yield (>85%) using AB-8 macroporous resin. The bioactivity experiments in vitro confirmed that total flavonoid compounds had good DPPH and O2−· radical-scavenging activity, as well as inhibitory effects on E. coli, S. aureus, E. carotovora, and B. subtilis. In conclusion, this study provides a green and efficient method to extract flavonoid compounds from spent sweet potato leaves, providing technical support for the development and utilization of sweet potato leaves' waste.

Identification of higenamine as a novel α1 -adrenergic receptor antagonist.

The α1 -adrenoceptor (α1 -AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α1 -AR antagonist. In this study, we investigated the effects of HG in HEK293A cells transfected with α1A -, α1B -, and α1D -AR in vitro, rat mesenteric artery ex vivo, Wistar-Kyoto rats and spontaneously hypertensive rats in vivo. The radioligand binding assay showed that HG competitively inhibited the binding of [3 H]-prazosin to α1 -AR in a concentration-dependent manner. The affinities (pKi) of HG for the cloned α1A -, α1B -, and α1D -AR were 6.57, 6.48, and 6.35, respectively, indicating that HG displayed no selectivity for the three α1 -AR subtypes. In in vitro studies, HG was able to blunt inositol monophosphate production. It also displayed an inhibitory effect on the influx and entry of calcium ions and phosphorylation of extracellular signal-regulated kinase 1 and 2 induced by phenylephrine (PE). In ex vivo studies, PE caused a dose-dependent inotropic response curve, and the pA2 value for HG was 6.86 ± 0.29. In addition, the in vivo results showed that HG could decrease the blood pressure in normotension, spontaneous hypertension, and PE-induced hypertension models. These results indicate that HG can directly bind to α1 -AR and it appears to be a novel antagonist for α1 -AR, which may contribute to its hypotensive effect.

Preparation and in vivo evaluation of a silicate-based composite bone cement.

Silicate-based cements have been developed as a class of bioactive and biodegradable bone cements owing to their good in vitro bioactivity and ability to dissolve in a simulated body fluid. Until recently, however, the in vivo evidence of their ability to support bone regeneration is still scarce. In the present study, a pilot in vivo evaluation of a silicate-based composite bone cement (CSC) was carried out in a rabbit femur defect model. The cement was composed of tricalcium silicate, 45S5 bioglass and calcium sulfate, and the self-setting properties of the material were established. The in vivo bone integration and biodegradability of CSC were investigated and compared with those of bioactive glass particulates, and a calcium phosphate cement. The results showed that CSC underwent a relatively slower in vivo degradation as compared with bioactive glass and calcium phosphate cement. Histological observation demonstrated that bone contact area at the interface between the surrounding bone and CSC gradually increased with time proceeding. CSC kept its structural integrity during implantation in vivo because of its acceptable mechanical strength. These results provide evidence of effectiveness in vivo and suggest potential clinical applications of the silicate-based composite bone cements.

The Protective Effect of Cordycepin on D-Galactosamine/Lipopolysaccharide-Induced Acute Liver Injury.

As the major active ingredient of Cordyceps militaris, cordycepin (3'-deoxyadenosine) has been well documented to alleviate inflammation and oxidative stress both in vitro and in vivo. To explore the potential protective effect of cordycepin in fulminant hepatic failure, mice were pretreated with cordycepin for 3 weeks followed by D-galactosamine (GalN)/lipopolysaccharide (LPS) injection. Then we found cordycepin (200 mg/kg) administration elevated survival rate, improved liver function, and suppressed hepatocyte apoptosis and necrosis in mice with severe hepatic damage by GalN/LPS treatment. Further, cordycepin inhibited hepatic neutrophil and macrophage infiltration and prevented proinflammatory cytokine production possibly through suppressing TLR4 and NF-κB signaling transduction. The blockade of reactive oxygen species (ROS) and lipid peroxidation production by cordycepin was associated with the decrease of NAD(P)H oxidase (NOX) activity. Besides, cordycepin significantly prevented excessive autophagy induced by GalN/LPS in the liver. These data suggested that cordycepin could be a promising therapeutic agent for GalN/LPS-induced hepatotoxicity.

Applications of Higenamine in pharmacology and medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum has been used as local and traditional medicines in many asian regions for the treatment of various diseases such as collapse, syncope, painful joints, oedema, bronchial asthma et al. Higenamine, a plant-based alkaloid, was initially isolated from Aconitum and identified as the active cardiotonic component of Aconitum. It has been tested as a candidate of pharmacologic stress agent in the detection of coronary artery diseases (CADs) and now researchers have just accomplished the phase III clinical studies successfully in China. Besides, a large number of studies have revealed the various pharmacological properties and potentially multi-spectral medical applications of higenamine. However, to date, no comprehensive review on higenamine has been published. AIM OF THE REVIEW: This present paper aims to compile a comprehensive update regarding the biochemistry, pharmacokinetic features, pharmacological activities, clinical and potential clinical uses and toxicities on higenamine with the ultimate objective of providing a guide for future research on this drug. MATERIALS AND METHODS: The selection of relevant data was made through a search using the keyword "higenamine" in "Web of science", "Pubmed", and "China Knowledge Resource Integrated (CNKI)". Information was also acquired from local classic herbal literature, government reports and conference papers. RESULTS: In addition to Aconitum, higenamine also exists in many other plants including Tinospora crispa, Nandina domestica THUNBERG, Gnetum Parvifolium C.Y. Cheng, sarum Heterotropoides,Nelumbo nucifera,N.nucifera. The pharmacokinetic studies conducted in animals and humans showed that higenamine conformed to a two-compartment pharmacokinetic model. Studies over the last four decades on higenamine have revealed its various pharmacological properties such as positive inotropic and chronotropic effect, activating slow channel effect, vascular and tracheal relaxation effect, anti-thrombotic, anti-apoptotic and anti-oxidative effect, anti-inflammatory and immunomodulatory effect. This phytochemical constituent has shown its potential therapeutic effects for diseases like heart failure, disseminated intravascular coagulation (DIC), shock, arthritis, asthma, ischemia/reperfusion (I/R) injuries and erectile dysfunction. CONCLUSIONS: Extensive basic and clinical studies on higenamine showed valuable therapeutic effects on different disorders. However, the underlying mechanisms of higenamine have not been established. Therefore, the safety, tolerability and efficacy of higenamine are as yet, not fully understood. Additionally, some of the studies were small sample-sized and unreliable. To sum up, there is a need for deeper investigation in the mechanisms of higenamine action, as well as well-designed preclinical and clinical trials studies to test the safety and clinical value of the drug.

Quantitative Metabolomic Profiling of Plasma, Urine, and Liver Extracts by 1H NMR Spectroscopy Characterizes Different Stages of Atherosclerosis in Hamsters.

Atherosclerosis (AS) is a progressive disease that contributes to cardiovascular disease and shows a complex etiology, including genetic and environmental factors. To understand systemic metabolic changes and to identify potential biomarkers correlated with the occurrence and perpetuation of diet-induced AS, we applied 1H NMR-based metabolomics to detect the time-related metabolic profiles of plasma, urine, and liver extracts from male hamsters fed a high fat and high cholesterol (HFHC) diet. Conventional biochemical assays and histopathological examinations as well as protein expression analyses were performed to provide complementary information. We found that diet treatment caused obvious aortic lesions, lipid accumulation, and inflammatory infiltration in hamsters. Downregulation of proteins related to cholesterol metabolism, including hepatic SREBP2, LDL-R, CYP7A1, SR-BI, HMGCR, LCAT, and SOAT1 was detected, which elucidated the perturbation of cholesterol homeostasis during the HFHC diet challenge. Using "targeted analysis", we quantified 40 plasma, 80 urine, and 60 liver hydrophilic extract metabolites. Multivariate analyses of the identified metabolites elucidated sophisticated metabolic disturbances in multiple matrices, including energy homeostasis, intestinal microbiota functions, inflammation, and oxidative stress coupled with the metabolisms of cholesterol, fatty acids, saccharides, choline, amino acids, and nucleotides. For the first time, our results demonstrate a time-dependent metabolic progression of multiple biological matrices in hamsters from physiological status to early AS and further to late-stage AS, demonstrating that 1H NMR-based metabolomics is a reliable tool for early diagnosis and monitoring of the process of AS.

[Suppression effect of Mai Shu on formation of atherosclerotic plaque of apolipoprotein E knock-out mice].

The research aimed to investigate the suppression effect of Mai Shu which contains hawthorn, hippophae, medlar, phytosterols（ß-sitosterol, stigmasterol and campesterol）, ß-glucan and lycopeneon formation of atherosclerotic plaque in apolipoprotein E knock-out (ApoE-/-) mice. Liquid chromatography-ultravioletmass spectrometry（LC-UV-MC） methods were used to analyze the main chemical composition of Mai Shu. Atherosclerotic mice models were established by high-fat diet. The mice were administrated with Mai Shu (1, 2, 4 g·kg-1·d-1) or other contrast materials by intragastric route for 10 weeks continuously. At the end of administration, the blood of mice was collected for tests of the serum total cholesterol（TC）, total triglyceride（TG） and high density lipoprotein cholesterol（HDL-C） level. Atherosclerotic lesions in aorta and aortic root were assessed by calculating the relative area of lesions（oil red O stained）. Intravital fluorescence microscopic system was used to evaluate the leukocyte-endothelial adhesion in mesenteric artery of mice by detecting the rolling velocity of white blood cells（WBC）. Collagenous fibers and macrophages in lesions were detected by sirius red staining and immunological histological chemistry to evaluate the atherosclerotic plaque stability. Results showed that Mai Shu contains various flavonoids（9.5%）, phytosterols（23.8%） and polysaccharides（8.9%）. The serum lipid level of model animals was significantly higher than the control animals. Serum TC level was decreased by Mai Shu (4 g·kg-1, P < 0.001) compared to the untreated model. Serum TG level was reduced by Mai Shu (1, 2, 4 g·kg-1) compared to model（P < 0.01）. Area of atherosclerotic lesions in aorta and aortic root was decreased in Mai Shu group (aorta: 1 g·kg-1, P < 0.05; 2 g·kg-1, P < 0.01; 4 g·kg-1, P < 0.001; aortic root: 2, 4 g·kg-1, P < 0.01). Rolling velocity of white blood cells of Mai Shu (4 g·kg-1, P < 0.001) group was increased over the untreated model. Collagenous fibers in lesions were observationally increased by Mai Shu (1, 2 g·kg-1) and macrophages were decreased (2, 4 g·kg-1) compared to model. These results demonstrate that Mai Shu can obviously decrease the serum lipid levels and the risk of leukocyte-endothelial adhesion in ApoE-/- mice. The effect of Mai Shu may be associated with the decrease of macrophages in plaque.

Inhibition of Lon blocks cell proliferation, enhances chemosensitivity by promoting apoptosis and decreases cellular bioenergetics of bladder cancer: potential roles of Lon as a prognostic marker and therapeutic target in baldder cancer.

ATP-dependent Lon protease within mitochondrial matrix contributes to the degradation of abnormal proteins. The oxidative or hypoxic stress which represents the stress phenotype of cancer leads to up-regulation of Lon. However, the role of Lon in bladder cancer remains undefined. Here, we found that Lon expression in bladder cancer tissues was significantly higher than those in noncancerous tissues; down-regulation of Lon in bladder cancer cells significantly blocked cancer cell proliferation via suppression c-Jun N-terminal kinase (JNK) phosphorylation due to decreased reactive oxygen species (ROS) production and enhanced the sensitivity of bladder cancer cells to chemotherapeutic agents by promoting apoptosis. We further found that Lon down-regulation in bladder cancer cells decreased cellular bioenergetics as determined by measuring aerobic respiration and glycolysis using extracellular flux analyzer. The tissue microarray (TMA) results showed that high expression of Lon was related to the T and TNM stage, as well as histological grade of bladder cancer patients. We also demonstrated that Lon was an independent prognostic factor for overall survival of bladder cancer. Taken together, our data suggest that Lon could serve as a potential diagnostic biomarker and therapeutic target for treatment of bladder cancer, as well as for prediction of the effectiveness of chemotherapy.

Protective effects of sulphonated formononetin in a rat model of cerebral ischemia and reperfusion injury.

Sodium formononetin-3'-sulphonate is a derivative of the plant isoflavone formononetin. The present study aimed to investigate the neuroprotective and angiogenesis effects of sodium formononetin-3'-sulphonate in vivo and in vitro. Treatment with sodium formononetin-3'-sulphonate (3, 7.5, 15, and 30 mg/kg, intravenous injection) could protect the brain from ischemia and reperfusion injury by improving neurological function, suppressing cell apoptosis, and increasing expression levels of vascular endothelial growth factor and platelet endothelial cell adhesion molecule 1 by middle cerebral artery occlusion. Treatment with sodium formononetin-3'-sulphonate (10 and 20 µg/mL) significantly increased cell migration, tube formation, and vascular endothelial growth factor and platelet endothelial cell adhesion molecule levels in human umbilical vein endothelial cells. Our results suggest that sodium formononetin-3'-sulphonate provides significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improves cerebrovascular angiogenesis in human umbilical vein endothelial cells. The protective mechanisms of sodium formononetin-3'-sulphonate may be attributed to the suppression of cell apoptosis and improved cerebrovascular angiogenesis by promoting vascular endothelial growth factor and platelet endothelial cell adhesion molecule expression.

A Systematic, Integrated Study on the Neuroprotective Effects of Hydroxysafflor Yellow A Revealed by (1)H NMR-Based Metabonomics and the NF-κB Pathway.

Hydroxysafflor yellow A (HSYA) is the main active component of the Chinese herb Carthamus tinctorius L.. Purified HSYA is used as a neuroprotective agent to prevent cerebral ischemia. Injectable safflor yellow (50 mg, containing 35 mg HSYA) is widely used to treat patients with ischemic cardiocerebrovascular disease. However, it is unknown how HSYA exerts a protective effect on cerebral ischemia at the molecular level. A systematical integrated study, including histopathological examination, neurological evaluation, blood-brain barrier (BBB), metabonomics, and the nuclear factor-κB (NF-κB) pathway, was applied to elucidate the pathophysiological mechanisms of HSYA neuroprotection at the molecular level. HSYA could travel across the BBB, significantly reducing the infarct volume and improving the neurological functions of rats with ischemia. Treatment with HSYA could lead to relative corrections of the impaired metabolic pathways through energy metabolism disruption, excitatory amino acid toxicity, oxidative stress, and membrane disruption revealed by (1)H NMR-based metabonomics. Meanwhile, HSYA treatment inhibits the NF-κB pathway via suppressing proinflammatory cytokine expression and p65 translocation and binding activity while upregulating an anti-inflammatory cytokine.

Production of sulfate radical from peroxymonosulfate induced by a magnetically separable CuFe2O4 spinel in water: efficiency, stability, and mechanism.

A simple, nonhazardous, efficient and low energy-consuming process is desirable to generate powerful radicals from peroxymonosulfate (PMS) for recalcitrant pollutant removal. In this work, the production of radical species from PMS induced by a magnetic CuFe(2)O(4) spinel was studied. Iopromide, a recalcitrant model pollutant, was used to investigate the efficiency of this process. CuFe(2)O(4) showed higher activity and 30 times lower Cu(2+) leaching (1.5 µg L(-1) per 100 mg L(-1)) than a well-crystallized CuO at the same dosage. CuFe(2)O(4) maintained its activity and crystallinity during repeated batch experiments. In comparison, the activity of CuO declined significantly, which was ascribed to the deterioration in its degree of crystallinity. The efficiency of the PMS/CuFe(2)O(4) was highest at neutral pH and decreased at acidic and alkaline pHs. Sulfate radical was the primary radical species responsible for the iopromide degradation. On the basis of the stoichiometry of oxalate degradation in the PMS/CuFe(2)O(4), the radical production yield from PMS was determined to be near 1 mol/mol. The PMS decomposition involved an inner-sphere complexation with the oxide's surface Cu(II) sites. In situ characterization of the oxide surface with ATR-FTIR and Raman during the PMS decomposition suggested that surface Cu(II)-Cu(III)-Cu(II) redox cycle was responsible for the efficient sulfate radical generation from PMS.

[Primary study of skin wound healing in rats for Loropetalum chinens].

OBJECTIVE: Cutaneous wound is a common health problem of humans. Loropetalum chinens, a medicinal plant, is widely used to treat wounds among the people. The research aims to observe whether L. chinens can promote the rats' wounds healing process, isolate the extracts primarily and commit the wound healing selection, which provide work basis for wound healing research of L. chinens. METHOD: First we analyzed the possible components with HC-MS/MS, then committed our wound healing experiments for L. chinens in the rat incision wound model and excision wound model, which are commonly used worldwide. After that, we carried on the preliminary isolation of the L. chinens and we screened the heal-promoting effects of the isolations in incision wound model. RESULT: L. chinens significantly accelerates the wound healing of rat's skin, shortens the healing period, enhances the healing intensity and promotes the cell proliferation and blood vessels formation around the wounds. The isolations, which are petroleum ether layer, ethyl acetate layer and n-butyl alcohol layer, exert heal-promoting effects. It indicates that the possible morphon that promotes wound healing may exist in these three components, with small polar. CONCLUSIONS: L. chinens possesses strong wound healing promoting effects, and the active constituent, with small polar, exists in petroleum ether layer, ethyl acetate layer and n-butyl alcohol layer, and we should focus on these three layers when carrying on further studies.

Gossypium herbaceam L. extracts ameliorate disequilibrium of IL-1RA/IL-1ß ratio to attenuate inflammatory process induced by amyloid ß in rats.

A chronic inflammatory response possibly mediated by Amyloid ß (Aß) is believed to be a major factor in the pathology of Alzheimer's disease (AD). Studies suggest that the mediators of the inflammatory response, which might contribute to brain damage, involve cytokines, such as IL-1ß. IL-1ß could play an important part in the development of pathologic conditions. There is also an endogenous interleukin-1 receptor antagonist (IL-1RA) in IL-1 family, which could prevent the actions of IL-1ß by competing for receptor binding without inducing any signal transduction. Therefore, the balance of IL-1ß vs IL-1RA is a critical parameter in determining not only whether excessive host inflammation will occur, but also the degree of subsequent host cell damage and associated toxicity. In our previous study, it has been determined that the anti-inflammatory action of Gossypium herbaceam L. extracts (GHE) was involved in its neuroprotection. However, the effects of GHE on IL-1ß and IL-1RA have not been clearly defined in the experimental rat model of AD induced by Aß. Therefore, the current study is performed to evaluate whether GHE could affect the disequilibrium of IL-1RA/IL-1ß ratio in the hippocampus of rats after Aß treatment. Subsequently, we further identify that GHE could efficaciously promote Akt and GSK3ß phosphorylation, and thereby contribute to IL-1ß release decrease as well as a concurrent increase in the level of IL-1RA through NF-κB and MAPK pathways. As a consequence, GHE is potentially beneficial to maintain the endogenous IL-1RA/ IL-1ß balance in the hippocampus of rats and it might be a potential agent to ameliorate inflammatory process in AD.

Effects of Gossypium herbaceam extract administration on the learning and memory function in the naturally aged rats: neuronal niche improvement.

Aging-associated cognitive impairment is an important health care issue since individuals with mild cognitive impairment are more likely to develop Alzheimer's disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment associated with aging were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70, and 140 mg/kg exerted an improved effect on the learning and memory impairment in aged rats. Subsequently, GHE afforded a beneficial action on eradication of free radicals without influence on the activity of glutathione peroxidase and superoxide dismutase. GHE treatment enhanced the expression levels of nerve growth factor. Meanwhile, proliferation of neural progenitor cells was elevated in hippocampus after treatment with GHE. Taken together, neurogenic niche improvement could be involved in the mechanism underlying neuroprotection of GHE against aging-associated cognitive impairment. These findings suggested that GHE might be a potential agent as cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease or treatment of aging-associated cognitive impairment.

Novel LDL-oriented pharmacotherapeutical strategies.

Elevated levels of low-density cholesterol (LDL-C) are highly correlated with increased risk of cardiovascular diseases (CVD). Thus, current guidelines have recommended progressively lower LDL-C for cholesterol treatment and CVD prevention as the primary goal of therapy. Even so, some patients in the high risk category fail to achieve recommended LDL-C targets with currently available medications. Thereby, additional pharmaceutical strategies are urgently required. In the review, we aim to provide an overview of both current and emerging LDL-C lowering drugs. As for current available LDL-C lowering agents, attentions are mainly focused on statins, niacin, bile acid sequestrants, ezetimibe, fibrates and omega-3 fatty acids. On the other hand, the emerging drugs differ from mechanisms are including: intervention of cholesterol biosynthesis downstream enzyme (squalene synthase inhibitors), inhibition of lipoprotein assembly (antisense mRNA inhibitors of apolipoprotein B and microsomal transfer protein inhibitors), enhanced lipoprotein clearance (proprotein convertase subtilisin kexin type 9, thyroid hormone analogues), inhibition of intestinal cholesterol absorption (Niemann-Pick C1-like 1 protein and acyl coenzyme A:cholesterol acyltransferase inhibitors) and interrupting enterohepatic circulation (apical sodium-dependent bile acid transporter inhibitors). Several ongoing agents are in their different stages of clinical trials, in expectation of promising antihyperlipidemic drugs. Therefore, alternative drugs monotherapy or in combination with statins will be sufficient to reduce LDL-C concentrations to optimal levels, and a new era for better LDL-C managements is plausible.

Cardioprotection of Asperosaponin X on experimental myocardial ischemia injury.

BACKGROUND: Asperosaponin X was isolated from the roots of Dipsacus asper. In this study, we investigated the anti-myocardial ischemia and reperfusion (I/R) injury effects of Asperosaponin X in vivo and elucidated the potential mechanism in vitro. RESULTS: Asperosaponin X significantly attenuated hypoxia-induced cytotoxicity in a concentration-dependent manner in H9c2 cells. Treatment of H9c2 cells with Asperosaponin X 5 µM or 10 µM blocked TNF-α-induced nuclear factor kappaB (NF-κB) phosphorylation by blocking HMGB1 expression. Treatment of rats with Asperosaponin X 10mg/kg, (i.v.) protected the animals from myocardial I/R injury as indicated by a decrease in infarct volume, improvement in hemodynamics and reduction of myocardial damage severity. Treatment with Asperosaponin X also lowered serum levels of pro-inflammatory factors and reduced High mobility group box-1 protein (HMGB1), phosphorylated IκB-α and NF-κB expression in ischemic myocardial tissue. Additionally, continuous i.v. of Asperosaponin X 14 days attenuated cardiac remodeling. CONCLUSIONS: These protective effects suggested that Asperosaponin X may be due to block of myocardial inflammatory cascades through an HMGB1-dependent NF-κB signaling pathway.

Effect of loganin on experimental diabetic nephropathy.

Connective tissue growth factor (CTGF) plays a pathogenic role in diabetic nephropathy (DN). Loganin, an iridoid glucoside compound was isolated from Cornus officinalis Sieb. et Zucc. This study was conducted to investigate the efficacy of loganin on DN and to elucidate the potential mechanism. High glucose (HG) stimulated cultured human renal proximal tubular epithelial cells (HK-2) analyzed CTGF expression by Western blotting and investigated whether extracellular signal-regulated kinase (ERK) signaling pathway was involved. Streptozotocin (STZ)-induced experimental DN, randomized to receive intragastric (i.g.) of loganin. Renal tissue, blood and urine samples were collected to determine and analyze. In vitro study, loganin reduced CTGF excretion in HG-induced HK-2 cells through the ERK signaling pathway. In vivo study, I.g. of loganin 5 mg/kg or 10 mg/kg significantly ameliorated renal function and increased body weight. Meanwhile, loganin reduced renal CTGF expression by immunohistochemical staining, reduced serum levels of CTGF. Besides, there were no significant differences in blood sugar levels between the loganin groups compared to the STZ-treated group. Furthermore, loganin ameliorated renal pathology. These results suggested that loganin exerts an early renal protective role to DN. Inhibition of CTGF may be a potential target in DN therapy, which highlights the possibility of using loganin to treat DN.

Cardioprotective effects of salvianolic Acid a on myocardial ischemia-reperfusion injury in vivo and in vitro.

Salvianolic acid A (SAA), one of the major active components of Danshen that is a traditional Chinese medicine, has been reported to possess protective effect in cardiac diseases and antioxidative activity. This study aims to investigate the cardioprotection of SAA in vivo and in vitro using the model of myocardial ischemia-reperfusion in rat and hydrogen peroxide (H(2)O(2))-induced H9c2 rat cardiomyoblasts apoptosis. It was found that SAA significantly limited infarct size of ischemic myocardium when given immediately prior to reperfusion. SAA also significantly suppressed cellular injury and apoptotic cell death. Additionally, the results of western blot and phospho-specific antibody microarray analysis showed that SAA could up-regulate Bcl-2 expression and increase the phosphorylation of proteins such as Akt, p42/p44 extracellular signal-related kinases (Erk1/2), and their related effectors. The phosphorylation of those points was related to suppress apoptosis. In summary, SAA possesses marked protective effect on myocardial ischemia-reperfusion injury, which is related to its ability to reduce myocardial cell apoptosis and damage induced by oxidative stress. The protection is achieved via up-regulation of Bcl-2 expression and affecting protein phosphorylation. These findings indicate that SAA may be of value in cardioprotection during myocardial ischemia-reperfusion injury, which provide pharmacological evidence for clinical application.

Forsythoside B protects against experimental sepsis by modulating inflammatory factors.

The present study investigated the effects of Forsythoside B on an experimental model of sepsis induced by caecal ligation and puncture (CLP) in rats and elucidated the potential mechanism in cultured RAW 264.7 cells. Results showed that Forsythoside B concentration-dependently down-regulated the levels of TNF-α, IL-6 and high-mobility group-box 1 protein (HMGB1) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, inhibited the IκB kinase (IKK) pathway and modulated nuclear factor (NF)- κB. Intravenous injection (i.v.) of Forsythoside B alone or plus Imipenem reduced serum levels of TNF-α, IL-6, HMGB1, triggering receptor expressed on myeloid cells (TREM-1) and endotoxin, while the serum level of IL-10 was up-regulated and myeloperoxidase (MPO) in lung, liver and small intestine was reduced. Meanwhile, i.v. of Forsythoside B alone or plus Imipenem reduced CLP-induced lethality in rats. These data indicated that the antisepsis effect of Forsythoside B is mediated by decreasing local and systemic levels of a wide spectrum of inflammatory mediators. Its antisepsis mechanism may be that Forsythoside B binds to LPS and reduces the biological activity of serum LPS, and inhibits NF-κB activition. Our studies enhance the case for the use of Forsythoside B in sepsis. Forsythoside B itself has promise as a therapy for the treatment of sepsis in humans.