The direct effect of lipopolysaccharide on an isolated heart is different from the effect on cardiac myocytes in vitro.

Introduction: Lipopolysaccharide (LPS) is widely used to induce experimental animals. However, its effects on cardiac contraction is controversial. Although LPS probably induces its influence in vivo both directly and indirectly, we focused on the direct effects of LPS in this report. Material and methods: Isolated ventricular myocytes mounted on a Langendorff apparatus were perfused with LPS. The changes in cultured H9c2 cells incubated with LPS over a 3-h exposure were compared with the changes after a 24-h incubation. Apoptosis was identified using flow cytometry and Western blotting. The mRNA levels were also determined. Results: LPS directly stimulated cardiac contractility at low doses, although it produced inhibition at higher doses. The TLR4-coupled JAK2/STAT3 pathway was identified in H9c2 cells after LPS treatment, with an increase in intracellular calcium levels. LPS dose-dependently activated hypertrophic signals in H9c2 cells and induced apoptosis at the high dose. However, apoptosis was observed in H9c2 cells after a 24-h exposure to LPS, even at low doses. This observation appears to be associated with the level of paracrine cytokines. Changes in H9c2 cells by LPS were diminished by NPS2390, an inhibitor of the calcium-sensing receptor (CaSR). LPS also promoted CaSR mRNA expression in H9c2 cells, which may be unrelated to the changes in cytokine expression influenced by an inflammasome inhibitor. Conclusions: In contrast to the isolated hearts, LPS activated hypertrophic signals prior to apoptotic signals in cardiac cells. Thus, LPS injury appears to be associated with CaSR, which was not markedly influenced by an inflammasome inhibitor.

Thymoquinone activates imidazoline receptor to enhance glucagon-like peptide-1 secretion in diabetic rats.

Introduction: Thymoquinone (TQ) is one of the principal bioactive ingredients proven to exhibit anti-diabetic effects. Recently, glucagon-like peptide-1 (GLP-1) has been found to be involved in antidiabetic effects in rats. The aim of this study was to evaluate the mediation of GLP-1 in the antidiabetic effect of TQ and to understand the possible mechanisms. Material and methods: NCI-H716 cells and CHO-K1 cells were used to investigate the effects of TQ on GLP-1 secretion in vitro. In type 1 diabetic rats, the changes in plasma glucose and GLP-1 levels were evaluated with TQ treatment. Results: The direct effect of TQ on imidazoline receptors (I-Rs) was identified in CHO-K1 cells overexpressing I-Rs. Additionally, in the intestinal NCI-H716 cells that may secrete GLP-1, TQ treatment enhanced GLP-1 secretion in a dose-dependent manner. However, these effects of TQ were reduced by ablation of I-Rs with siRNA in NCI-H716 cells. Moreover, these effects were inhibited by BU224, the imidazoline I2 receptor (I-2R) antagonist. In diabetic rats, TQ increased plasma GLP-1 levels, which were inhibited by BU-224 treatment. Functionally, TQ-attenuated hyperglycemia is also evidenced through GLP-1 using pharmacological manipulations. Conclusions: This report demonstrates that TQ may promote GLP-1 secretion through I-R activation to reduce hyperglycemia in type-1 diabetic rats.

Impact of statin on long-term outcome among patients with end-stage renal disease with acute myocardial infarction (AMI): a nationwide case-control study.

BACKGROUND: Use of statin has been associated with reduced risk of cardiovascular diseases events and mortality. However, in patients with end-stage renal disease (ESRD), the protective effects of statin are controversial. To evaluate the impact of chronic statin use on clinical outcomes of patients with acute myocardial infarction (AMI) with ESRD. METHODS: We enrolled 8056 patients with ESRD who were initially diagnosed and admitted for first AMI from Taiwan's National Health Insurance Research Database. Of which, 2134 patients underwent statin therapy. We randomly selected and use age, sex, hypertension, diabetes mellitus (DM), peripheral vascular diseases (PVD), heart failure (HF), cerebrovascular accidents (CVA), chronic obstructive pulmonary disease, matched with the study group as controls (non-stain user). We compared the effects of statin use in term of all-cause death among patients with AMI with ESRD. RESULTS: Statin use resulted in a significantly higher survival rate in patients ith AMI with ESRD compared with non-statin users. After adjusted the comorbidities the male patients and patients with DM, PVD, HF and CVA had lower long-term survival rate (all p<0.001). Patients who underwent percutaneous coronary intervention (p<0.001), ACE inhibitors/angiotensin II receptor blockers (p<0.001), ß receptor blockers (p<0.001) and statin therapy (p=0.007) had better long-term survival rate. Patients with AMI with ESRD on statin therapy exhibited a significantly lower risk of mortality compared with non-statin users (p<0.0001). CONCLUSION: Among patients with ESRD with AMI, statin therapy was associated with reduced all-cause mortality.

Slicing Ceramics on Material Removed by a Single Abrasive Particle.

Multi-wire saw machining (MWSM) used for slicing hard-brittle materials in the semiconductor and photovoltaic industries is an important and efficient material removal process that uses free abrasives. The cutting model of single-wire saw machining (SWSM) is the basis of MWSM. The material removal mechanism of SWSM is more easily understood than MWSM. A mathematical model (includes brittle fracture and plastic deformation) is presented in this paper for SWSM ceramic with abrasives. This paper determines the effect of various machining parameters on the removal of hard-brittle materials. For brittle fracture of SWSM ceramics, the minimum strain energy density is used as a fracture criterion. For plastic deformation of SWSM ceramics, the material removal is calculated using equations of motion. Actual wire-sawing experiments are conducted to verify the results of the developed mathematical model. The theoretical results agree with experimental data and practical experience. From the developed mathematical model, brittle fracture plays a major role in material removal of SWSM ceramics. Wire speed (S) and working load (P) are positively correlated with material removal of SWSM ceramics. The coefficient of friction is low, a lateral crack, which propagates almost parallel to the working surface, leads to more brittle fracture and material removal is increased.

Effects of Saccharomyces cerevisiae in association with Torulaspora delbrueckii on the aroma and amino acids in longan wines.

This study investigated the effects of monocultures of Saccharomyces cerevisiae and Torulaspora delbrueckii as well as simultaneous and sequential cultures of S. cerevisiae and T. delbrueckii on the nonvolatile and volatile compounds in longan wines. The four cultures had similar characteristics in longan wines. The main amino acids in all the fermentations were glutamic acid, arginine, alanine, leucine, proline, and GABA. The main volatile compounds in longan wines were ethanol, isoamyl alcohol, isobutanol, 2-phenylethanol, isoamyl acetate, ethyl decanoate, ethyl octanoate, ethyl hexanoate, and ethyl acetate, which can contribute more desired aroma compounds in wines. Among the four treatments, the longan wine fermented with the simultaneous culture produced the highest total volatile aroma content (345.26 mg/L). The simultaneous culture also had a better ability to generate a high level of the main volatile compounds in longan wines and also could achieve a noticeable intensity of floral and fruity aromas of wine as evaluated by calculation of the odor activity values.

The isolation, structural characterization, and anticancer activity from the aerial parts of Cymbopogon flexuosus.

This study investigated bioactive secondary metabolites from the aerial parts of Cymbopogon flexuosus (CF). Total phenolic and total flavonoid contents, the antioxidant activities including 2, 2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS+ ) and 2, 2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging systems, and cytotoxic effects were determined. 1, 3-O-di-E-caffeoylglycerol (SA3) and 1-O-p-coumaroyl-3-O-caffeoylglycerol (SA4) were firstly isolated from an ethanol extract of CF. Their chemical structures were elucidated by extensive spectroscopic analyses, including MS and NMR spectra as well as by comparison to the data reported in the literature. DPPH and ABTS+ radical scavenging tests showed that the highest antioxidant potent was detected for compound SA3 with IC50 of 4.42 ± 0.18 and 21.84 ± 0.22 µg/ml, respectively. The compound SA3 stimulated the apoptotic factors of caspase-3, bax, and bcl-2 in HepG2 and caspase-3, caspase-9, P53 in A549. PRACTICAL APPLICATIONS: CF has been widely used as both a herbal drink and as a spice in diets. In the food processing industry, CF was used to process candy. In addition, it is used for the treatment of sore throat, cough, skin diseases, and other diseases in traditional oriental medicine. Recently, in Vietnam, CF has also been used to treat liver and lung cancer and consumed daily to process many dishes.

GLP-1 mediates the modulating effect of thymoquinone on feeding behaviors in diabetic rats.

Background: Thymoquinone (TQ) is a safe nutrient isolated from the seeds or volatile oil extract of Nigella sativa. In addition to its benefits in glucose regulation, TQ improves feeding disorders in diabetic animals. Glucagon-like peptide-1 (GLP-1) analogs improve glycemic control and ameliorate obesity or hyperphagia. Therefore, the present study aimed to investigate the role of GLP-1 in TQ-induced anorexia. Method: Type 2 diabetes was induced in rats by nicotinamide and streptozotocin injection. TQ was orally administered to diabetic rats at different doses for 45 days. Following TQ treatment, changes in serum glucose levels, GLP-1 concentration, body weight, food intake, and water intake were determined. To further explore the interaction between GLP-1 and TQ, the inhibitor of dipeptidyl peptidase 4, sitagliptin and the GLP-1 receptor antagonist exendin 9-39 (Ex 9-39) were separately administered to TQ- or vehicle-treated diabetic rats. Results: TQ treatment attenuated hyperglycemia and reduced hyperphagy and water intake in streptozotocin-induced diabetic rats in a dose-dependent manner. Moreover, TQ treatment elevated plasma GLP-1 levels compared to those in control rats. The effects of TQ were enhanced by treatment with sitagliptin and reduced by the injection of Ex 9-39 into the brain. In contrast, similar treatment with another antioxidant (either ascorbic acid or N-acetylcysteine) produced the same anorexic effect as TQ without changing the plasma GLP-1 levels in diabetic rats. Therefore, TQ attenuated hyperphagy while increasing plasma GLP-1 levels and had antioxidant-like effects. Conclusion: TQ increased endogenous GLP-1 levels to reduce hyperphagy in diabetic rats.

Effects of Tempeh Fermentation with Lactobacillus plantarum and Rhizopus oligosporus on Streptozotocin-Induced Type II Diabetes Mellitus in Rats.

The increased consumption of high fat-containing foods has been linked to the prevalence of obesity and abnormal metabolic syndromes. Rhizopus oligosporus, a fungus in the family Mucoraceae, is widely used as a starter for homemade tempeh. Although R. oligosporus can prevent the growth of other microorganisms, it grows well with lactic acid bacteria (LAB). Lactobacillus plantarum can produce ß-glucosidase, which catalyzes the hydrolysis of glucoside isoflavones into aglycones (with greater bioavailability). Therefore, the development of a soybean-based functional food by the co-inoculation of R. oligosporus and L. plantarum is a promising approach to increase the bioactivity of tempeh. In this study, the ameliorative effect of L. plantarum in soy tempeh on abnormal carbohydrate metabolism in high-fat diet (HFD)-induced hyperglycemic rats was evaluated. The co-incubation of L. plantarum with R. oligosporus during soy tempeh fermentation reduced the homeostatic model assessment of insulin resistance, HbA1c, serum glucose, total cholesterol, triglyceride, free fatty acid, insulin, and low-density lipoprotein contents, and significantly increased the high-density lipoprotein content in HFD rats. It also increased the LAB counts, as well as the bile acid, cholesterol, triglyceride, and short-chain fatty acid contents in the feces of HFD rats. Our results suggested that the modulation of serum glucose and lipid levels by LAB occurs via alterations in the internal microbiota, leading to the inhibition of cholesterol synthesis and promotion of lipolysis. Tempeh, which was produced with both L. plantarum and R. oligosporus, might be a beneficial dietary supplement for individuals with abnormal carbohydrate metabolism.

Synergistic Antitumor Effect of Oligogalacturonides and Cisplatin on Human Lung Cancer A549 Cells.

Cisplatin (DPP), a clinically potent antineoplastic agent, is limited by its severe adverse effects. The aim of this study was to investigate the effect of oligogalacturonides (OGA) and DDP on human lung cancer A549 cells. The combined use of OGA and DDP had a synergistic effect on the growth inhibition of A549 cells, changed the cell cycle distribution, and enhanced apoptotic response, especially in sequential combination treatment group of DDP 12 h + OGA 12 h. Western blot analyses showed that the combination treatment of OGA and DDP upregulated Bax, p53, and Caspase-3 and downregulated Bcl-2 proteins. More importantly, DDP-induced toxicity was attenuated by OGA and DDP combination treatment in normal HEK293 cells. Our data suggests that the combined use of OGA from natural sources and DDP could be an important new adjuvant therapy for lung cancer as well as offer important insights for reducing kidney toxicity of DDP and delaying the development of DDP resistance.

Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] are widely recommended for health promotion. Over the last decade, prescription omega-3 fatty acid products (RxOME3FAs) have been approved for medical indications. Nonetheless, there is no comprehensive analysis of safety and tolerability of RxOME3FAs so far. METHODS: A systematic review of randomized controlled trials (RCTs) was carried out based on searches in six electronic databases. The studies involving marketed RxOME3FA products were included, and adverse-effect data were extracted for meta-analysis. Subgroup analysis and meta-regression were conducted to explore the sources of potential heterogeneity. RESULTS: Among the 21 included RCTs (total 24,460 participants; 12,750 from RxOME3FA treatment cohort and 11,710 from control cohort), there was no definite evidence of any RxOME3FA-emerging serious adverse event. Compared with the control group, RxOME3FAs were associated with more treatment-related dysgeusia (fishy taste; p = 0.011) and skin abnormalities (eruption, itching, exanthema, or eczema; p < 0.001). Besides, RxOME3FAs had mild adverse effects upon some non-lipid laboratory measurements [elevated fasting blood sugar (p = 0.005); elevated alanine transaminase (p = 0.022); elevated blood urea nitrogen (p = 0.047); decreased hemoglobin (p = 0.002); decreased hematocrit (p = 0.009)]. Subgroup analysis revealed that EPA/DHA combination products were associated with more treatment-related gastrointestinal adverse events [eructation (belching; p = 0.010); nausea (p = 0.044)] and low-density lipoprotein cholesterol elevation (p = 0.009; difference in means = 4.106mg/dL). CONCLUSION: RxOME3FAs are generally safe and well tolerated but not free of adverse effects. Post-marketing surveillance and observational studies are still necessary to identify long-term adverse effects and to confirm the safety and tolerability profiles of RxOME3FAs.

The stimulating effects of polyphenol and protein fractions from jelly fig (Ficus awkeotsang Makino) achenes against proliferation of leukemia cells.

This study aimed to investigate the direct and immune-stimulated antiproliferative activities of jelly fig achenes fractions including pectinesterase inhibitors, crude polyphenols extract, and purified polyphenols extract (PP). Beside the measurement of cell viability of U937, the quantity of cytokines in conditioned medium and morphologic changes in leukemia were observed. After surveying all fractions in jelly fig, the obtained fractions of polyphenol exhibited the highest stimulating effects and directly cytotoxic effects against leukemia with the lowest effect found in protein fractions. The leukemia treated by our PP fraction showed dose-dependent response between the concentration and G2/M cell numbers of the U937 cells. The PP fraction had more pronounced effect on immune-stimulated than direct antiproliferative activities. The finding was also supported by morphological analysis by showing the formation of apoptotic bodies and differentiation from immature U937 cells into mature monocytes/macrophages on cells cultured with PP-conditioned medium. In conclusion, polyphenol fraction of pectinesterase inhibitors from jelly fig showed the immune-stimulated antiproliferative activities against U937 cell.

Evaluation of the prebiotic effects of citrus pectin hydrolysate.

Citrus pectin enzyme hydrolysate (PEH) of different hydrolysis time intervals (6 hours, PEH-6; 12 hours, PEH-12; 24 hours, PEH-24; or 48 hours, PEH-48) or concentrations (1%, 2%, and 4%) was tested for its growth stimulation effect on two probiotics, Bifidobacterium bifidum and Lactobacillus acidophilus. Higher monosaccharide concentrations and smaller molecular weights of PEHs were obtained by prolonging the hydrolysis time. In addition, higher PEH concentrations resulted in significantly higher (p < 0.05) probiotic populations, pH reduction, and increase in total titratable acidity than the glucose-free MRS negative control. Furthermore, significantly higher populations in the low pH environment and longer survival time in nonfat milk (p < 0.05) were observed when the two probiotics were incubated in media supplemented with 2% PEH-24, than in glucose and the negative control. In comparison with other prebiotics, addition of 2% PEH-24 resulted in a more significant increase in the probiotic population (p < 0.05) than in the commercial prebiotics. This study demonstrated that PEH derived from citrus pectin could be an effective prebiotic to enhance the growth, fermentation, acid tolerance, and survival in nonfat milk for the tested probiotics.

Effects of Davallia formosana Hayata Water and Alcohol Extracts on Osteoblastic MC3T3-E1 Cells.

The Taiwanese native fern Davallia formosana Hayata (DFH) is used to treat bone diseases in classical Chinese medicine. We analyzed MC3T3E1 osteoblasts treated with different concentrations of water and ethanol extracts (10, 25, and 50 [both], and 100 µg/mL [DFE only]) using cell viability, expression of osteoblast differentiation markers [bone morphogenetic protein 2 (BMP-2), collagen 1 (CoL-1), alkaline phosphatase (ALP), and Runt-related transcription factor 2 (Runx 2)], and mineralization. These were significantly increased by DFW or DFE after 24-h incubation compared with the untreated controls. Compared with other treatments, DFW 50 and DFE 100 µg/mL significantly increased MC3T3E1 cell survival. DFW 25 and 50 µg/mL increased bone BMP-2, CoL-1, ALP, and Runx2 protein expression, ALP activity, and mineralization more than DFE did. Repeated chromatographic separation of DFW yielded compound (-)-epicatechin-3-O-d-allipyranoside (ECAP), which was characterized using 1 H and 13 C nuclear magnetic resonance spectroscopy. (-)-Epicatechin-3-O-d-allipyranoside (0.01 µg/mL) significantly increased cell survival (118.9%) and mineralization (218.7%) compared with that of the control treatment. We inferred that ECAP could mediate the main activity of DFW in bone formation, likely through BMP-2-induced Runx2 transcription, which increased bone cell differentiation factors ALP and CoL-1 and promoted mineralization. (-)-Epicatechin-3-O-d-allipyranoside could be an anti-osteoporotic agent. Copyright © 2017 John Wiley & Sons, Ltd.

Identification of morin as an agonist of imidazoline I-3 receptor for insulin secretion in diabetic rats.

Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetics. Morin has been demonstrated to increase plasma insulin. However, the mechanism(s) remains unknown. The present study is designed to investigate the effect of morin on the imidazoline receptor (I-R) that regulates insulin secretion. We used Chinese hamster ovary (CHO) cells transfected with an I-R expression construct (NISCH-CHO-K1 cells) to identify the direct effect of morin on the I-R. Moreover, the imidazoline I3 receptor (I-3R) is known to be present in pancreatic ß cells and involved in insulin secretion. Therefore, we applied a specific antagonist (KU14R) to block I-3R in diabetic rats. Additionally, the effect of morin on insulin secretion was characterized in isolated pancreatic islets. Morin decreased blood glucose levels by increasing plasma insulin levels in diabetic rats. In CHO cells expressing an I-R, morin increased calcium influx in a dose-dependent manner. Additionally, KU14R dose-dependently inhibited the morin-induced effects, including hypoglycemia and the increase in insulin secretion and plasma C-peptide levels, in diabetic rats. Furthermore, morin enhanced insulin secretion from isolated pancreatic islets, and this effect was also dose-dependently inhibited by KU14R. Phospholipase C (PLC) is known to couple with the I-R, and a PLC inhibitor dose-dependently attenuated the insulin secretion induced by morin in isolated pancreatic islets. Taken together, these data suggest that morin can activate I-3R to enhance insulin secretion. Therefore, it would be useful to develop morin into a treatment for diabetic disorders.

Effects of Myricetin-Containing Ethanol Solution on High-Fat Diet Induced Obese Rats.

Myricetin is a natural flavonol widely occurring in wines. Many beneficial effects of myricetin in alcoholic beverages have been reported before, but never including anti-obesity. In the present study, we fed obese male Sprague-Dawley rats with ethanol solutions containing various concentrations of myricetin and found that myricetin may maintain the food intake while reduce the weight-gain, feed efficiency, level of blood lipids, adipocyte size, and weight and size of the perirenal and epididymal adipose tissues (P < 0.01). Our experiment data also show that the anti-obesity effect may be associated with the upregulation of adropin and ß-endorphin levels. Based on the above-described findings, we propose the potential for myricetin-containing alcoholic beverages to be developed into anti-obesity health food.

Investigation of morin-induced insulin secretion in cultured pancreatic cells.

Morin is a flavonoid contained in guava that is known to reduce hyperglycemia in diabetes. Insulin secretion has been demonstrated to increase following the administration of morin. The present study is designed to investigate the potential mechanism(s) of morin-induced insulin secretion in the MIN6 cell line. First, we identified that morin induced a dose-dependent increase in insulin secretion and intracellular calcium content in MIN6 cells. Morin potentiated glucose-stimulated insulin secretion (GSIS). Additionally, we used siRNA for the ablation of imidazoline receptor protein (NISCH) expression in MIN6 cells. Interestingly, the effects of increased insulin secretion by morin and canavanine were markedly reduced in Si-NISCH cells. Moreover, we used KU14R to block imidazoline I3 receptor (I-3R) that is known to enhance insulin release from the pancreatic ß-cells. Without influence on the basal insulin secretion, KU14R dose-dependently inhibited the increased insulin secretion induced by morin or efaroxan in MIN6 cells. Additionally, effects of increased insulin secretion by morin or efaroxan were reduced by diazoxide at the dose sufficient to open KATP channels and attenuated by nifedipine at the dose used to inhibit L-type calcium channels. Otherwise, phospholipase C (PLC) is introduced to couple with imidazoline receptor (I-R). The PLC inhibitor dose-dependently inhibited the effects of morin in MIN6 cells. Similar blockade was also observed in protein kinase C (PKC) inhibitor-treated cells. Taken together, we found that morin increases insulin secretion via the activation of I-R in pancreatic cells. Therefore, morin would be useful to develop in the research and treatment of diabetic disorders.

Diosmin, a Citrus Nutrient, Activates Imidazoline Receptors to Alleviate Blood Glucose and Lipids in Type 1-Like Diabetic Rats.

Diosmin is a nutrient that is widely contained in citrus and that has been indicated to improve glucose metabolism in diabetic disorders. Recently, we demonstrated that diosmin induces ß-endorphin to lower hyperglycemia in diabetic rats. However, the mechanisms of diosmin in opioid secretion were unclear. Therefore, we focused on the secretion of opioids from isolated adrenal glands induced by diosmin. The changes in the released ß-endorphin-like immunoreactivity (BER) were determined using ELISA. Diosmin increased the BER level in a dose-dependent manner, and this effect was markedly reduced in the absence of calcium ions. Activation of the imidazoline I-2 receptor (I-2R) has been introduced to induce opioid secretion. Interestingly, we observed that diosmin activates CHO cells expressing I-R. Additionally, diosmin-increased BER was inhibited by the blockade of I-2R in isolated adrenal glands. Additionally, an antagonist of I-2R blocked diosmin-induced effects, including the reduction in hyperglycemia and the increase in plasma BER in streptozotocin-induced diabetic rats (STZ-diabetic rats). Repeated treatment of STZ-diabetic rats with diosmin for one week induced changes in hepatic glycogen, lipid levels, and the expression of phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, an antagonist of I-2R blocked the diosmin-induced changes. Additionally, plasma lipids modified by diosmin were also reversed by the blockade of I-2R in STZ-diabetic rats. Taken together, we suggest that diosmin may activate I-2R to enhance the secretion of ß-endorphin from adrenal glands and to influence metabolic homeostasis, resulting in alleviation of blood glucose and lipids in STZ-diabetic rats.

Antihyperglycaemic action of diosmin, a citrus flavonoid, is induced through endogenous ß-endorphin in type I-like diabetic rats.

Diosmin is one of the flavonoids contained in citrus and has been demonstrated to improve glucose metabolism in diabetic disorders. However, the mechanism(s) of diosmin in glucose regulation remain obscure. Therefore, we investigated the potential mechanism(s) for the antihyperglycaemic action of diosmin in streptozotocin-induced diabetic rats (STZ-diabetic rats). Diosmin lowered hyperglycaemia in a dose-dependent manner in STZ-diabetic rats. This action was inhibited by naloxone at a dose sufficient to block opioid receptors. Additionally, we determined the changes in plasma ß-endorphin-like immunoreactivity (BER) using enzyme-linked immunosorbent assay (ELISA). Diosmin also increased BER dose-dependently in the same manner. Repeated treatment of STZ-diabetic rats with diosmin for 1 week resulted in an increase in the expression of the glucose transporter subtype 4 (GLUT 4) in the soleus muscle and a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) in the liver. These effects were also inhibited by naloxone at a dose sufficient to block opioid receptors. Bilateral adrenalectomy in STZ-diabetic rats eliminated the actions of diosmin, including both the reduction in hyperglycemia and the elevation of plasma BER. In conclusion, our results suggest that diosmin may act on the adrenal glands to enhance the secretion of ß-endorphin, which can stimulate the opioid receptors to attenuate hepatic gluconeogenesis and increase glucose uptake in soleus muscle, resulting in reduced hyperglycemia in STZ-diabetic rats.

Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study.

Dopamine (DA) is commonly used to maintain the hemodynamic stability of brain-dead donors despite its controversial effects on organ functions. This study aimed at examining the hemodynamic effect of DA in a rat brain-dead model in vivo, alteration of hepatocyte integrity in liver grafts after ex vivo preservation, and changes in cultured clone-9 hepatocytes including cellular viability, cell cycle, apoptotic regulators, and lipopolysaccharide (LPS)-stimulated nuclear factor kappa B (NF-κB) signaling machinery. Although in vivo findings demonstrated enhanced portal venous blood flow and hepatic microcirculatory perfusion after DA infusion, no apparent advantage was noted in preserving hepatocyte integrity ex vivo. In vitro, prolonged exposure to high-dose DA reduced proliferation and induced G1 growth arrest of clone-9 hepatocytes with concomitant decreases in B cell lymphoma 2 (BCL2)/B cell lymphoma 2-associated X protein (BAX) and heat shock protein 70/BAX protein ratios and intracellular NF-κB p65. Moreover, DA pretreatment suppressed LPS-elicited inhibitor of κBα phosphorylation and subsequent NF-κB nuclear translocation, suggesting that DA may down-regulate NF-κB signaling, thereby reducing expression of antiapoptotic regulators, such as BCL2. In conclusion, despite augmentation of hepatic perfusion, DA infusion failed to preserve hepatocyte integrity both in vivo and ex vivo. In vitro findings demonstrated that high-dose DA may hamper the function of NF-κB signaling machinery and eventually undermine functional integrity of hepatocytes in liver grafts.

Ruscogenin protects against high-fat diet-induced nonalcoholic steatohepatitis in hamsters.

The protective effects of ruscogenin on nonalcoholic steatohepatitis in hamsters fed a high-fat diet were investigated. Ruscogenin (0.3, 1.0, or 3.0 mg/kg/day) was orally administered by gavage once daily for eight weeks. A high-fat diet induced increases in plasma levels of total cholesterol, triglycerides, and free fatty acids, while the degree of insulin resistance was lowered by ruscogenin. High-fat diet-induced hepatic steatosis and necroinflammation were improved by ruscogenin. Gene expression of inflammatory cytokines and activity of nuclear transcription factor-κB were also increased in the high-fat diet group, which were attenuted by ruscogenin. Ruscogenin decreased hepatic mRNA levels of sterol regulatory element-binding protein-1c and its lipogenic target genes. The hepatic mRNA expression of peroxisome proliferator-activated receptor α, together with its target genes responsible for fatty acid ß-oxidation were upregulated by ruscogenin. In conclusion, these findings suggest that ruscogenin may attenuate high-fat diet-induced steatohepatitis through anti-inflammatory mechanisms, reducing hepatic lipogenic gene expression, and upregulating proteins in the fatty acid oxidation process.