lignans and Insulin-Resistance

Flaxseed (Linum usitatissimum) is an oil-based seed that contains high amounts of alpha-linolenic acid, linoleic acid, lignans, fiber and many other bioactive components which is suggested for a healthier life. Nowadays, flaxseed is known as a remarkable functional food with different health benefits for humans and protects against cardiovascular disease, diabetes, dyslipidemia, obesity and altogether metabolic syndrome.. To review the bioactive components of flaxseed and their potential health effects, PubMed and Scopus were searched from commencement to July 2019. Keywords including: "flaxseed", "Linum usitatissimum", "metabolic syndrome", "obesity", "inflammation", "insulin resistance", "diabetes", "hyperlipidemia" and "menopause" were searched in the databases with varying combinations.. Consumption of flaxseed in different forms has valuable effects and protects against cardiovascular disease, hypertension, diabetes, dyslipidemia, inflammation and some other complications. Flaxseed can serve as a promising candidate for the management of metabolic syndrome to control blood lipid levels, fasting blood sugar, insulin resistance, body weight, waist circumference, body mass and blood pressure.

Topics: alpha-Linolenic Acid; Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus; Dietary Fiber; Drug Discovery; Dyslipidemias; Flax; Humans; Inflammation; Insulin Resistance; Lignans; Lipids; Metabolic Syndrome; Obesity; Plant Extracts; Seeds

The objective of the present study was to compare whole pea flour (WPF) to fractionated pea flour (FPF; hulls only) for their ability to reduce risk factors associated with CVD and diabetes in overweight hypercholesterolaemic individuals. Using a cross-over design, twenty-three hypercholesterolaemic overweight men and women received two-treatment muffins/d containing WPF, FPF or white wheat flour (WF) for 28 d, followed by 28 d washout periods. Daily doses of WPF and FPF complied with the United States Department of Agriculture's recommended level of intake of half a cup of pulses/d (approximately 50 g/d). Dietary energy requirements were calculated for each study subject, and volunteers were only permitted to eat food supplied by the study personnel. Fasting insulin, body composition, urinary enterolactone levels, postprandial glucose response, as well as fasting lipid and glucose concentrations, were assessed at the beginning and at the end of each treatment. Insulin concentrations for WPF (37·8 (SEM 3·4) pmol/ml, P = 0·021) and FPF (40·5 (SEM 3·4) pmol/ml, P = 0·037) were lower compared with WF (50·7 (SEM 3·4) pmol/ml). Insulin homeostasis modelling assessment showed that consumption of WPF and FPF decreased (P < 0·05) estimates of insulin resistance (IR) compared with WF. Android:gynoid fat ratios in women participants were lower (P = 0·027) in the WPF (1·01 (sem 0·01) group compared with the WF group (1·06 (SEM 0·01). Urinary enterolactone levels tended to be higher (P = 0·087) in WPF compared with WF. Neither treatment altered circulating fasting lipids or glucose concentrations. In conclusion, under a controlled diet paradigm, a daily consumption of whole and fractionated yellow pea flours at doses equivalent to half a cup of yellow peas/d reduced IR, while WPF reduced android adiposity in women.

Topics: 4-Butyrolactone; Adiposity; Adult; Body Composition; Cardiovascular Diseases; Cross-Over Studies; Diabetes Mellitus; Fasting; Female; Flour; Humans; Hypercholesterolemia; Insulin; Insulin Resistance; Lignans; Male; Middle Aged; Overweight; Phytotherapy; Pisum sativum; Plant Preparations; Risk Factors; Seeds

Schisandra chinensis fruit is a well-known traditional Chinese medicine (TCM) that has been used to treat various liver diseases. Our previous study revealed that its extract is effective against nonalcoholic fatty liver disease (NAFLD).. This study aimed to elucidate the active components and explore the underlying mechanisms of action of S. chinensis fruit in the treatment of NAFLD.. A HepG2 cell model was used to screen the anti-NAFLD activity of the fraction from S. chinensis fruit extract. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to determine the components of the active fraction. Active compounds, potential targets, and key pathways were predicted for the active fraction treatment of NAFLD using network pharmacology. The anti-NAFLD effects of the active fraction and core active compound 3 were further validated using a high-fat diet (HFD)-induced NAFLD mouse model, intraperitoneal glucose tolerance test (IPGTT), and intraperitoneal insulin tolerance test (IPITT). Related hepatic mRNA expression was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to preliminarily validate the mechanism.. In vitro experiments showed that the active fraction of S. chinensis fruit ethanol (EtOH) extract was mainly concentrated in the soluble fraction of petroleum ether (PET). Thirty-seven lignans were identified in this active fraction using UPLC-Q-TOF/MS. Network pharmacology studies have indicated that its anti-NAFLD effects lie in three major active lignans (3, 24, and 27) contained in PET, which may regulate the insulin resistance signaling pathway. In vivo experiments demonstrated that PET and core active compound 3 treatment significantly attenuated hepatic steatosis and reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST), insulin, malondialdehyde (MDA), hepatic triglyceride (TG), and total cholesterol (TC) in HFD-induced mice (P < 0.05). Moreover, treatment with PET and compound 3 alleviated glucose tolerance and insulin resistance. These beneficial effects can be achieved by regulating the expression of Pik3ca, Gsk3β, Jnk1, and Tnf-α.. This study identified the main active fraction and compounds responsible for the anti-NAFLD activity of S. chinensis fruit. This mechanism may be related to regulation of the resistance pathway.

Topics: Animals; Fruit; Insulin; Insulin Resistance; Lignans; Mice; Network Pharmacology; Non-alcoholic Fatty Liver Disease; Plant Extracts; Schisandra; Technology

Schisandra chinensis, a traditional Chinese medicinal herb, is rich in chemical constituents, including lignans, triterpenes, polysaccharides, and volatile oils. Clinically, it is commonly used to treat cardiovascular, cerebrovascular, liver, gastrointestinal, and respiratory diseases. Modern pharmacological studies have shown that S. chinensis extract and monomers have multiple pharmacological activities in lowering liver fat, alleviating insulin resistance, and resisting oxidative stress, and have good application prospects in alleviating nonalcoholic fatty liver disease(NAFLD). Therefore, this study reviewed the research progress on chemical constituents of S. chinensis and its effect on NAFLD in recent years to provide references for the research on S. chinensis in the treatment of NAFLD.

Topics: Insulin Resistance; Lignans; Non-alcoholic Fatty Liver Disease; Schisandra

Type 2 diabetes mellitus (T2DM) is a metabolic risk factor associated with non-alcoholic liver disease (NAFLD). Schisandrin B (Sch B) is a promising agent for NAFLD. However, the actions of Sch B on diabetes-associated NAFLD and the underlying mechanisms are not characterized. This study aimed to assess whether Sch B has beneficial effects on T2DM-associated NAFLD. Sch B (50 mg/kg, gavage) was administrated to C57BL/KSJ db/db mice for 2 weeks. Body weight, liver weight, blood glucose, and insulin resistance were measured. Serum lipid level and liver function were detected using the biochemistry analyzer. Quantitative Real-Time PCR assay was used to evaluate mRNA levers of lipid metabolism genes. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was performed to measure apoptosis in the liver. Pathological analysis and immunohistochemistry assessment were used to analyze hepatic steatosis and inflammatory infiltration. Sch B supplementation significantly decrease body weight, related liver weight, blood glucose, and serum insulin, and improved insulin resistance in db/db mice. Sch B obviously corrected NAFLD phenotypes including lipid deposition, steatohepatitis, and high levels of hepatic enzymes and serum lipid. In addition, mRNA levels of Sterol response element-bind protein 1c (SREBP-1c), fatty acid synthetase (Fasn), and acetyl-CoA carboxylase (ACC) were markedly downregulated by Sch B treatment. TUNEL-positive cells were also decreased by Sch B. Furthermore, Sch B inhibited the Kupffer cells, IL-1β, and TNF-α infiltration to the liver. Sch B ameliorated insulin resistance and lipid accumulation under high glucose conditions, which was partly associated with its inhibition of apoptosis and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Cyclooctanes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Insulin Resistance; Lignans; Lipid Metabolism; Lipids; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Polycyclic Compounds; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

In this study, we aimed to investigate the effect of Magnolol on Alzheimer's disease (AD). After the model of streptozotocin-induced AD mice with brain insulin resistance was established, the mice were treated with Magnolol or miR-200c antagomiR. The abilities of ambulations, rearings, discrimination, spatial learning, and memory were evaluated by open-field test (OFT), novel object recognition (NOR), and morris water maze (MWM) tests. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and miR-200c in the mice hippocampus were evaluated by enzyme-linked immunosorbent assay, Western blot, or Quantitative real-time Polymerase Chain Reaction. In AD mice model, streptozotocin induced the locomotor impairment and cognitive deficit, up-regulated levels of MDA, TNF-α, IL-6, and CRP, while down-regulated levels of GSH, SOD, and miR-200c. Magnolol increased the rearings numbers and discrimination index of AD mice in OFT and NOR tests. Magnolol increased the number of entries in the target quadrant and time spent in the target quadrant and decreased the escape latency of AD mice in the MWM test. Magnolol also down-regulated the levels of MDA, TNF-α, IL-6, and CRP, and up-regulated the levels of GSH, SOD, and miR-200c in the hippocampus tissues of AD mice. However, miR-200c antagomiR did the opposite and further offset the effects of the Magnolol on AD mice. Magnolol attenuated the locomotor impairment, cognitive deficit, and neuroinflammatory in AD mice with brain insulin resistance via up-regulating miR-200c.

Topics: Alzheimer Disease; Animals; Antagomirs; Biphenyl Compounds; Brain; Disease Models, Animal; Insulin Resistance; Lignans; Locomotion; Male; Malondialdehyde; Mice; Morris Water Maze Test; Spatial Learning; Streptozocin

We aimed to examine the effect of Honokiol (HKL) on endothelial dysfunction in type 2 diabetic rats and its possible mechanism. A high-fat diet and streptozotocin (STZ) were used to establish the type 2 diabetic model in rats. Part of these rats were intraperitoneally injected with HKL 10 mg/kg daily. Then the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), eNOS, and CD31, vasodilation function, insulin signaling, indicators of oxidative stress and relative signaling pathway were measured. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanism of the effect of HKL on high glucose-related endothelial injury in vitro. The data showed that HKL could reverse the decline of the expression of p-eNOS and CD31, endothelium-related vasodilation dysfunction, insulin resistance and activation of oxidative stress induced by type 2 diabetes in vivo. The similar results were obtained in vitro. In summary, our study demonstrates that HKL improves endothelial function and diminishes insulin resistance and oxidative stress, suggesting that HKL could be used as a treatment option for diabetes in the future.

Topics: Animals; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Insulin Resistance; Lignans; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Vascular Diseases; Vasodilation

Menopausal women are susceptible to have high risk of cardiovascular diseases, type II diabetes and osteoporosis due to the metabolic disorder caused by estrogen deficiency. Accumulating evidence supports that gut microbiota is a key regulator of metabolic diseases. Our previous metabolomics study interestingly demonstrated that the anti-osteoporotic effects of lignan-rich fraction (SWCA) from Sambucus wialliamsii Hance were related to the restoration of a series of lipid and glucose metabolites. This study aims to investigate how SWCA modulates lipid and glucose metabolism and the underlying mechanism. Our results show that oral administration of SWCA (140 mg/kg and 280 mg/kg) for 10 weeks alleviated dyslipidemia, improved liver functions, prevented glucose tolerance and insulin actions, attenuated system inflammation and improved intestinal barrier in OVX rats. It also induced a high abundance of Actinobacteria, and restored microbial composition. We are the first to report the protective effects of the lignan-rich fraction from S. williamsii on dyslipidemia and insulin resistance. Our findings provide strong evidence for the application of this lignan-rich fraction to treat menopausal lipid disorder and insulin resistance-related diseases.

Topics: Administration, Oral; Animals; Cytokines; Dyslipidemias; Female; Gastrointestinal Microbiome; Glucose; Glucose Tolerance Test; Hypolipidemic Agents; Insulin Resistance; Lignans; Liver; Ovariectomy; Plant Extracts; Plant Stems; Rats; Rats, Sprague-Dawley; Sambucus

Sesamin (SES) has the ameliorating effect on L02 hepatocyte model of insulin resistance induced by high glucose and high insulin, based on insulin receptor signaling pathway IRS/PI3K/Akt. Treatment with SES (200, 100μg/ml) increased glucose consumption, glucose uptake and the intracellular glycogen synthesis of L02 hepatocyte model of insulin resistance significantly. Moreover, treatment with SES promoted the gene and protein expression levels of insulin receptor (InsR) and the post-receptor associated proteins, such as insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), PI3K (phosphatidylinositol 3-kinase), GLUT4 (glucose transporter 4) significantly, which were determined by RT-PCR and immunoblot analysis. In conclusion, SES has the ameliorating effect on L02 hepatocyte model of insulin resistance induced by high glucose/high insulin, which might be related to its effect on promoting expression of insulin receptor and its associated proteins of IRS-PI3K-Akt passway, and thus promoting insulin sensitivity.

Topics: Antigens, CD; Cell Line; Chromatography, High Pressure Liquid; Dioxoles; Glucose; Glucose Transporter Type 4; Glycogen; Hepatocytes; Humans; Immunoblotting; Insulin Receptor Substrate Proteins; Insulin Resistance; Lignans; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction

Obesity and type 2 diabetes mellitus, correlate with increased tissue concentration of sphingolipids, which directly interfere with insulin signaling pathway. Phytoestrogens are a group of plant-derived compounds that have been studied in the case of metabolic disorders treatment. Therefore, the aim of this study was to ascertain whether enterolactone (ENL), a commonly known phytoestrogen, may affect sphingolipid metabolism and decrease hepatic insulin resistance development in a lipid overload state.. The study was conducted on HepG2 cells incubated with ENL and/or palmitic acid (PA) for 16 h. Intra- and extracellular sphingolipid concentrations were assessed by high performance liquid chromatography. The expression of sphingolipid pathway enzymes, apoptosis and insulin signaling pathway proteins and glucose metabolism regulators were evaluated by Western Blot.. In HepG2 cells, a considerable augmentation of intracellular ceramide and sphingosine concentration in ENL with PA group were indicated with simultaneous increase in extracellular ceramide concentration. The ENL treatment increased expression of selected enzymes from de novo ceramide synthesis pathway with lower expression of ceramide transfer protein. We also observed a decreased expression of insulin-stimulated phosphorylation of AKT and AMPK after exposure to ENL with PA. Our research demonstrated that ENL with PA resulted in an increased expression of caspase-3.. Enterolactone, in a higher fatty acids availability, led to the development of hepatic IR in HepG2 cells. This phenomenon may be the result of elevated intracellular ceramide accumulation caused by increased de novo synthesis pathway what led to enhanced apoptosis of HepG2 cells.

Topics: 4-Butyrolactone; Ceramides; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Lignans; Lipid Metabolism; Liver; Phytoestrogens; Signal Transduction; Sphingolipids

Diabetic nephropathy (DN) is one of the most serious long-term complications of type 2 diabetes (T2D). 4-O-methylhonokiol (MH) is one of the biologically active ingredients extracted from the Magnolia stem bark. In this study, we aim to elucidate whether treatment with MH can ameliorate or slow-down progression of DN in a T2D murine model and, if so, whether the protective response of MH correlates with AMPK-associated anti-oxidant and anti-inflammatory effects. To induce T2D, mice were fed normal diet (ND) or high fat diet (HFD) for 3 months to induce insulin resistance, followed by an intraperitoneal injection of STZ to induce hyperglycemia. Both T2D and control mice received gavage containing vehicle or MH once diabetes onset for 3 months. Once completing 3-month MH treatment, five mice from each group were sacrificed as 3 month time-point. The rest mice in each group were sacrificed 3 months later as 6 month time-point. In T2D mice, the typical DN symptoms were induced as expected, reflected by increased proteinuria, renal lipid accumulation and lipotoxic effects inducing oxidative stress, and inflammatory reactions, and final fibrosis. However, these typical DN changes were significantly prevented by MH treatment for 3 months and even at 3 months post-MH withdrawal. Mechanistically, MH renal-protection from DN may be related to lipid metabolic improvement and oxidative stress attenuation along with increases in AMPK/PGC-1α/CPT1B-mediated fatty acid oxidation and Nrf2/SOD2-mediated anti-oxidative stress. Results showed the preventive effect of MH on the renal oxidative stress and inflammation in DN.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, High-Fat; Enzyme Activation; Fatty Acids; Insulin Resistance; Kidney; Lignans; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Phytotherapy

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with glucose intolerance, insulin resistance and type 2 diabetes mellitus (T2DM). Although several studies have revealed that intermittent hypoxia (IH) in OSAHS may further aggravate pancreatic β cell damage and promote the evolution of type 2 diabetes (T2DM) by increasing oxidative stress, the underlying mechanisms are unclear. Honokiol, a potent radical scavenger, has been demonstrated to ameliorate oxidative stress in many cases. The present study aimed to explore the potential mechanism of IH and diabetes synergistically damage and destruct the pancreatic β cell, examine the effects of honokiol on ameliorating pancreatic β cell injury in this context and explore the mechanism of such effects. High glucose (HG) cultured INS-1 cells were exposed to 50 μM of honokiol for 24, 48 and 72 h with or without IH intervention. T2DM rats were treated with honokiol and exposed to 80 s of IH followed by 160 s of normoxia for 8 weeks. The cell proliferation, apoptosis and oxidative stress were measured. Blood glucose, insulin, glucagon and HOMA-IR (Homeostasis model assessment -insulin resistence) were also detected, and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by immunofluorescence staining and western blotting. Honokiol can reduce oxidative stress, cytotoxicity and apoptosis in the INS-1 cells of rats receiving HG treatment or both HG and IH treatment. IH can further aggravate pancreas dysfunction, cause a marked elevation in fasting blood glucose, glucagon, HOMA-IR and oxidative stress levels in DM rats. In addition, honokiol can effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in vivo and in vitro. These findings indicate that honokiol acts as a potent ROS scavenger via Nrf2/ARE pathway and effectively attenuates oxidative stress and improves pancreatic β cell function of DM rats under IH treatment.

Topics: Animals; Apoptosis; Biphenyl Compounds; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Free Radical Scavengers; Glucagon; Hypoxia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lignans; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sleep Apnea, Obstructive

7-Hydroxymatairesinol (7-HMR) is a plant lignan abundant in various concentrations in plant foods. The objective of this study was to test HMRLignan™, a purified form of 7-HMR, and the corresponding Picea abies extract (total extract P. abies; TEP) as dietary supplements on a background of a high-fat diet (HFD)-induced metabolic syndrome in mice and in the 3T3-L1 adipogenesis model. Mice, 3 weeks old, were fed a HFD for 60 d. Subgroups were treated with 3 mg/kg body weight 7-HMR (HMRLignan™) or 10 mg/kg body weight TEP by oral administration. 7-HMR and TEP limited the increase in body weight (-11 and -13 %) and fat mass (-11 and -18 %) in the HFD-fed mice. Epididymal adipocytes were 19 and -12 % smaller and the liver was less steatotic (-62 and -65 %). Serum lipids decreased in TEP-treated mice (-11 % cholesterol, -23 % LDL and -15 % TAG) and sugar metabolism was ameliorated by both lignan preparations, as shown by a more than 70 % decrease in insulin secretion and insulin resistance. The expression of several metabolic genes was modulated by the HFD with an effect that was reversed by lignan. In 3T3-L1 cells, the 7-HMR metabolites enterolactone (ENL) and enterodiol (END) showed a 40 % inhibition of cell differentiation accompanied by the inhibited expression of the adipogenic genes PPARγ, C/EBPα and aP2. Furthermore, END and ENL caused a 10 % reduction in TAG uptake in HEPA 1-6 hepatoma cells. In conclusion, 7-HMR and TEP reduce metabolic imbalances typical of the metabolic syndrome and obesity in male mice, whereas their metabolites inhibit adipogenesis and lipid uptake in vitro.

Topics: 3T3-L1 Cells; 4-Butyrolactone; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Diet, High-Fat; Dietary Supplements; Fatty Liver; Gene Expression; Insulin Resistance; Lignans; Lipid Metabolism; Lipids; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Picea; Plant Extracts

The novel target products were synthesized in the formation of a triazine ring from berberine, magnolol, and metformin catalyzed by sodium methylate. The structures of products

Topics: Anti-Inflammatory Agents; Berberine; Biphenyl Compounds; Cyclization; Humans; Inflammation; Insulin Resistance; Lignans; Metformin; Molecular Structure; Sodium; Structure-Activity Relationship; Triazines

Gomisin N (GN) is a lignan derived from Schisandra chinensis. AMP-activated kinase (AMPK) has gained attention as a therapeutic target for the treatment of metabolic syndrome. Previously, we reported that GN activated the AMPK pathway and ameliorated high-fat diet (HFD)-induced hepatic steatosis. In this study, we investigated the anti-diabetic effects of GN in C2C12 myotubes and HFD obese mice. GN enhanced the phosphorylation of AMPK/acetyl-CoA carboxylase (ACC) and Akt. In addition, GN promoted glucose uptake in C2C12 myotubes, which was accompanied by the translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Treatment with compound C, an AMPK inhibitor, suppressed GN-mediated stimulation of glucose uptake. Furthermore, GN increased the expression of mitochondria biogenesis and fatty acid oxidation genes in C2C12 myotubes. In the in vivo study, administration of GN to HFD mice decreased the levels of fasting blood glucose and insulin, and improved glucose tolerance in HFD obese mice. GN administration rescued the decreased phosphorylation of AMPK and Akt and stimulated the expression of mitochondria biogenesis genes in the skeletal muscle of HFD mice. These findings suggested that GN exerted anti-hyperglycemic effects through AMPK activation.

Topics: AMP-Activated Protein Kinases; Animals; Blood Glucose; Cyclooctanes; Diabetes Mellitus; Dose-Response Relationship, Drug; Enzyme Activation; Female; Hypoglycemic Agents; Insulin; Insulin Resistance; Lignans; Mice; Mice, Inbred C57BL; Mitochondria, Muscle; Muscle, Skeletal; Organelle Biogenesis; Polycyclic Compounds

Patients with prehypertension are more likely to progress to manifest hypertension than those with optimal or normal blood pressure. However, the mechanisms underlying the development from prehypertension to hypertension still remain largely elusive and the drugs for antihypertensive treatment in prehypertension are absent. Here we determined the effects of magnolol (MAG) on blood pressure and aortic vasodilatation to insulin, and investigated the underlying mechanisms. Four-week-old male spontaneous hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) control rats were used. Our results shown that treatment of young SHRs with MAG (100 mg/kg/day, o.g.) for 3 weeks decreased blood pressure, improved insulin-induced aorta vasodilation, restored Akt and eNOS activation stimulated by insulin, and increased PPARγ and decreased TRB3 expressions. In cultured human umbilical vein endothelial cells (HUVECs), MAG incubation increased PPARγ, decreased TRB3 expressions, and restored insulin-induced phosphorylated Akt and eNOS levels and NO production, which was blocked by both PPARγ antagonist and siRNA targeting PPARγ. Improved insulin signaling in HUVECs by MAG was abolished by upregulating TRB3 expression. In conclusion, treatment of young SHRs with MAG beginning at the prehypertensive stage decreases blood pressure via improving vascular insulin resistance that is at least partly attributable to upregulated PPARγ, downregulated TRB3 and consequently increased Akt and eNOS activations in blood vessels in SHRs.

Topics: Animals; Aorta; Biphenyl Compounds; Blood Pressure; Blood Vessels; Densitometry; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Insulin; Insulin Resistance; Lignans; Nitric Oxide Synthase Type III; PPAR gamma; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Up-Regulation; Vasodilation

The focus was directed to the study of two of the most lignan-rich food sources: sesame and flaxseeds. Recent epidemiological and experimental evidences suggesting that these foods may improve metabolic functions underlying metabolic syndrome (MetS).. To characterize the effect of these oilseeds on metabolic functions, we conducted an experimental study aimed at preventing adiposity and metabolic imbalance in a mouse model of high-fat diet (HFD)-induced MetS. Statistical analysis was performed by two-way analysis of variance test followed by post hoc Bonferroni analysis.. We studied the effect of the oilseeds sesame and flaxseed on metabolic parameters in mice on a HFD. When the HFD was integrated with 20% of sesame or flaxseed flours, the mice showed a decrease in body fat, already at day 15, from time 0. The size of the adipocytes was smaller in epididymal fat, liver steatosis was inhibited, and insulin sensitivity was higher in mice on the supplemented diets. The supplemented diets also resulted in a significant increase in the serum levels of the lignan metabolites enterodiol and enterolactone compared with the controls. The expression of genes associated with the inflammatory response, glucose metabolism, adipose metabolism and nuclear receptor were altered by the oilseed-supplemented diets. Some of the most abundant lignans in these oilseeds were studied in 3T3-L1 preadipocyte cells and were effective in inhibiting adipocyte differentiation at the minimal dose of 1 nM.. The consumption of sesame and flaxseed may be beneficial to decrease metabolic parameters that are generally altered in MetS.

Topics: 3T3-L1 Cells; 4-Butyrolactone; Adipocytes; Adipose Tissue; Adiposity; Animals; Cell Differentiation; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Insulin Resistance; Lignans; Linseed Oil; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Sesame Oil

Obesity is caused by a combination of both genetic and environmental risks. Disruption in energy balance is one of these risk factors. In the present study, the preventive effect on high-fat diet- (HFD-) induced obesity and insulin resistance in mice by Magnolia bioactive constituent 4-O-methylhonokiol (MH) was compared with Magnolia officinalis extract BL153. C57BL/6J mice were fed by normal diet or by HFD with gavage-administered vehicle, BL153, low-dose MH, and high-dose MH simultaneously for 24 weeks, respectively. Either MH or BL153 slightly inhibited body-weight gain of mice by HFD feeding although the food intake had no obvious difference. Body fat mass and the epididymal white adipose tissue weight were also mildly decreased by MH or BL153. Moreover, MH significantly lowered HFD-induced plasma triglyceride, cholesterol levels and activity of alanine transaminase (ALT), liver weight and hepatic triglyceride level, and ameliorated hepatic steatosis. BL153 only significantly reduced ALT and liver triglyceride level. Concurrently, low-dose MH improved HFD-induced hyperinsulinemia and insulin resistance. Furthermore, the infiltration of mast cells in adipose tissue was decreased in MH or in BL153 treatment. These results suggested that Magnolia bioactive constituent MH might exhibit potential benefits for HFD-induced obesity by improvement of lipid metabolism and insulin resistance.

Topics: Adipose Tissue; Adiposity; Animals; Biphenyl Compounds; Blood Glucose; Body Weight; Cholesterol; Diet, High-Fat; Fatty Liver; Feeding Behavior; Glucose Tolerance Test; Inflammation; Insulin; Insulin Resistance; Lignans; Lipid Metabolism; Magnolia; Male; Mice, Inbred C57BL; Obesity; Protective Agents; Triglycerides

In obese adipose tissue, tumor necrosis factor-α secreted from macrophages plays an important role in the adipocyte dysfunctions, including insulin resistance, lipolytic acceleration, and changes of adipokines, which promote the development of obesity-related complications. Phillyrin, an active ingredient found in many medicinal plants and certain functional foods, elicits anti-obesity and anti-inflammatory properties in vivo. The aim of the current study was to investigate the role of phillyrin in preventing tumor necrosis factor α-induced insulin resistance or lipolytic acceleration in 3T3-L1 adipocytes. Our results showed that phillyrin partially restored insulin-stimulated 2-DOG uptake, which was reduced by tumor necrosis factor-α, with concomitant restoration in serine phosphorylation of insulin receptor substrate-1 and insulin-stimulated Glut4 translocation to plasma membrane. Phillyrin also dose-dependently prevented tumor necrosis factor α-stimulated adipocyte lipolysis with preserved downregulation of perilipin. The mitogen-activated protein kinases and I kappaB kinase activation was promoted in tumor necrosis factor α-stimulated adipocytes, but pretreatment with 40 µM phillyrin inhibited the phosphorylation of extracellular signal-regulated kinases1/2, stress-activated protein kinase/Jun N-terminal kinase and I kappaB kinase (p<0.05). Moreover, phillyrin could inhibit the expressions of interleukin-6 and monocyte chemoattractant protein-1 induced by tumor necrosis factor-α. Using transwell coculture method with 3T3-L1 adipocytes and RAW 264.7 macrophages, the enhanced productions of tumor necrosis factor-α and free fatty acids in the medium were significantly reduced by phillyrin (p<0.05). These results indicate that phillyrin exerts a beneficial effect on adipocyte dysfunctions induced by tumor necrosis factor-α through suppression of the activation of I kappaB kinase and N-terminal kinase. Phillyrin may have the potential to ameliorate the inflammatory changes and insulin resistance in obese adipose tissue.

Topics: 3T3-L1 Cells; Animals; Anti-Inflammatory Agents; Cell Survival; Glucose; Glucosides; I-kappa B Kinase; Insulin Resistance; Lignans; Lipolysis; Mice; Obesity; Tumor Necrosis Factor-alpha

This study investigated the effect of honokiol (HON) and magnolol (MAG), phenolic compounds in Magnolia plants, on adiposity and adiposity-related metabolic disturbances in mice fed high-fat diet (HFD), and the potential underlying mechanisms focusing on the lipid metabolism and inflammatory response.. C57BL/6J mice were fed HFD (45 kcal% fat) with or without HON (0.02%, w/w) or MAG (0.02%, w/w) for 16 wk. Despite no changes in body weight, food intake, and hepatic fat accumulation, HON and MAG significantly lowered the weight of white adipose tissue (WAT) as well as adipocyte size and protected against insulin resistance induced by HFD. These effects were associated with increases in energy expenditure and adipose fatty acid oxidation and decreases in fatty acid synthase activity and expression of genes related to fatty acid synthesis, desaturation, and uptake, as well as adipocyte differentiation in WAT. Moreover, HON and MAG significantly lowered the expression of proinflammatory genes in WAT and elevated the plasma IL-10 level. Particularly, HON significantly decreased the plasma resistin level and increased the plasma adiponectin level compared to the control group.. HON and MAG have potential as novel agents for amelioration of adiposity and associated insulin resistance and inflammation.

Topics: Adipogenesis; Adiponectin; Adipose Tissue, White; Adiposity; Animals; Biphenyl Compounds; Blood Glucose; Body Weight; Chemokine CCL2; Cholesterol; Diet, High-Fat; Dietary Supplements; Energy Metabolism; Glucose Tolerance Test; Inflammation; Insulin Resistance; Interleukin-10; Interleukin-6; Lignans; Liver; Male; Mice; Mice, Inbred C57BL; Triglycerides; Tumor Necrosis Factor-alpha

The ability of sesamin from sesame meal to ameliorate insulin resistance in KK-Ay mice (an animal model of type 2 diabetes) was evaluated.. Treatment with sesamin (100 or 50 mg kg(-1)) significantly decreased the level of fasting plasma glucose, glycosylated serum protein, serum insulin, triglycerides, cholesterol, free fatty acid and malondialdehyde content of livers. Treatment with sesamin significantly increased the content of hepatic glycogen, reduced glutathione and the activity of superoxide dismutase and glutathione peroxidase. Moreover, the insulin-binding capacity to liver crude plasma membranes increased and histopathological changes of the pancreas were ameliorated in the treatment group.. Sesamin has hypoglycaemic, hypolipidaemic and the ability to ameliorate insulin resistance in KK-Ay mice, which might be related to its effect on insulin receptors, and thus increases insulin sensitivity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dioxoles; Female; Glutathione; Glutathione Peroxidase; Hypoglycemic Agents; Insulin Resistance; Lignans; Lipids; Mice; Mice, Inbred C57BL; Sesamum; Superoxide Dismutase

Five new dibenzocyclooctadiene lignans, schisphenlignans A-E (1-5), together with eight known ones, were isolated from the stems of Schisandra sphenanthera. The structures of 1-5 were elucidated based on the analysis of their NMR, MS and circular dichroism (CD) spectra. Some isolates were tested for their acute activities on insulin sensitivity in 3T3-L1 differentiated adipocytes, but none of them showed significant bioactivity with 10 µM administration of the tested compounds.

Topics: 3T3-L1 Cells; Animals; Cyclooctanes; Insulin; Insulin Resistance; Lignans; Mice; Plant Stems; Schisandra

The inhibition of protein tyrosine phosphatase 1B (PTP1B) is considered a valid strategy to combat insulin resistance and type II diabetes. We show here that a dichloromethane extract of Ratanhiae radix ( RR_EX) dose-dependently inhibits human recombinant PTP1B in vitro and enhances insulin-stimulated glucose uptake in murine myocytes. By determination of the PTP1B inhibiting potential of 11 recently isolated lignan derivatives from RR_EX, the observed activity of the extract could be partly assigned to ratanhiaphenol III. This compound inhibited PTP1B in vitro with an IC (50) of 20.2 µM and dose-dependently increased insulin receptor phosphorylation as well as insulin-stimulated glucose uptake in cultured myotubes. This is the first report to reveal an antidiabetic potential for a constituent of rhatany root, traditionally used against inflammatory disorders, by showing its capability of inhibiting PTP1B.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Krameriaceae; Lignans; Metabolic Syndrome; Mice; Muscle Cells; Muscle Fibers, Skeletal; Phytotherapy; Plant Preparations; Plant Roots; Protein Tyrosine Phosphatase, Non-Receptor Type 1

This study is to observe anti-lipotoxic effect of sesamin on renovascular hypertensive rats fed with a high-fat, high-sucrose diet. Thirty-four complex model rats were induced by two-kidney, one-clip method and on high-fat and refined-carbohydrate diet for thirteen weeks. From the fifth week, intragastric administration of sesamin (120, 60 and 30 mg x kg(-1) x d(-1)) lasted for eight weeks. Blood pressure (BP), blood fat (BF), blood glucose (BG), free fatty acids (FFA), insulin (Ins), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were determined. Pathological changes of pancreas, perirenal fat and liver were semiquantitatively analyzed. In sesamin (120 and 60 mg x kg(-1) x d(-1)) group, it was found that there were decrease of levels of BP, BF, BG, TNF-alpha, IL-6 and FFA, improvement of insulin resistance and glucose tolerance, alleviation of body weight, humid weight of fat, liver and pancreas and their organ index, and reduction of islet cell hyperplasia and amount of lipid droplet vacuoles in lipocyte and hepatocyte. It is implied that sesamin had anti-lipotoxic effect and its mechanism may be closely associated with the amelioration of insulin resistance via reducing lipidoses in hepatocyte and inflammatory adipokines such as TNF-alpha and IL-6.

Topics: Adipocytes; Animals; Anticholesteremic Agents; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Diet, High-Fat; Dioxoles; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Glucose Tolerance Test; Hypertension, Renovascular; Insulin; Insulin Resistance; Interleukin-6; Islets of Langerhans; Lignans; Liver; Male; Pancreas; Rats; Rats, Sprague-Dawley; Sucrose; Triglycerides; Tumor Necrosis Factor-alpha

Fructus Schisandrae, the fruit of Schisandra chinensis (Turcz.) Baillon, has been traditionally used as a hypoglycemic agent in Asia and its extracts have been shown to improve insulin-stimulated glucose uptake in cell-based assays in previous studies.. We set out to determine which fractions of Fructus Schisandrae improved peroxisome proliferator-activated receptor (PPAR)-γ activity and glucose-stimulated insulin secretion in cell-based experiments. The fractions that enhance glucose homeostasis were then tested for their hypoglycemic effects and mechanism was examined.. The fractions (FS-0, FS-20, FS-40, FS-60, FS-80, FS-100) were made by extracting Fructus Schisandrae with 70% ethanol followed by its fractionation with a XDA column with a different ratio of methanol and water. The insulin-stimulated glucose uptake and PPAR-γ agonistic actions of each fraction were investigated in 3T3-L1 adipocytes and glucose-stimulated insulin secretion was determined in Min6 cells. The fraction(s) that were efficacious (200mg/kg bw) were orally given to 90% pancreatectomized (Px) diabetic rats for 8 weeks to evaluate insulin sensitivity in euglycemic hyperinsulinemic clamp and insulin secretion at hyperglycemic clamp.. FS-60 contains schizandrin, gomisin A and angeloylgomisin H while FS-80 contains deoxyschizandrin, γ-schizandrin, and gomisin N. A PPAR-γ agonistic action was greater in the ascending order of the control, FS-80 and FS-60 in 3T3-L1 adipocytes. FS-60 increased the glucose disposal rates of Px rats as much as rosiglitazone during euglycemic hyperinsulinemic clamp while hepatic glucose output at hyperinsulinemic clamped states decreased in the descending order of the control, FS-80, FS-60 with potentiating insulin signaling. At hyperglycemic clamp only FS-60 potentiated first phase insulin secretion in diabetic animals; the second phase was not increased.. FS-60, a lignan-rich fraction, improves glucose homeostasis by increasing glucose disposal rates and enhancing hepatic insulin sensitivity by working as a PPAR-γ agonist in type-2 diabetic rats.

Topics: 3T3-L1 Cells; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Insulin; Insulin Resistance; Lignans; Mice; Plant Extracts; PPAR gamma; Rats; Schisandra; Triglycerides

Hepatic lipid accumulation is a major risk factor for dyslipidemia, nonalcoholic fatty liver disease, and insulin resistance. The present study was conducted to evaluate hypolipidemic effects of meso-dihydroguaiaretic acid (MDA), anti-oxidative and anti-inflammatory compound isolated from the Myristica fragrans HOUTT., by oil red O staining, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot. MDA significantly inhibited insulin-induced hepatic lipid accumulation in a dose-dependent manner. The lipid-lowering effect of MDA was accompanied by increased expression of proteins involved in fatty acid oxidation and decreased expression of lipid synthetic proteins. In addition, MDA activated AMP-activated protein kinase (AMPK) as determined by phosphorylation of acetyl-CoA carboxylase (ACC), a downstream target of AMPK. The effects of MDA on lipogenic protein expression were suppressed by pretreatment with compound C, an AMPK inhibitor. Taken together, these findings show that MDA inhibits insulin-induced lipid accumulation in human HepG2 cells by suppressing expression of lipogenic proteins through AMPK signaling, suggesting a potent lipid-lowering agent.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Cell Culture Techniques; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Dyslipidemias; Enzyme Activation; Enzyme Inhibitors; Fatty Liver; Guaiacol; Hep G2 Cells; Humans; Hypolipidemic Agents; Insulin Resistance; Lignans; Lipid Metabolism; Liver; Molecular Targeted Therapy; Myristica; Non-alcoholic Fatty Liver Disease; Phosphorylation; Phytotherapy; Plant Extracts; Pyrazoles; Pyrimidines

There has been a growing interest in lignans, a class of phyto-oestrogens, because of their potentially favourable effects on human health. The aim of the present study was to compare the metabolic profile of post-menopausal women consuming various amounts of dietary lignans. Phyto-oestrogen intake was assessed using a 3-d dietary record analysed with a Canadian food phyto-oestrogen content data table in 115 post-menopausal women (age 56.8 (SD 4.4) years and BMI 28.5 (SD 5.9) kg/m(2)). Plasma enterolactone (ENL), the major biologically active metabolite of dietary lignans, was determined by time-resolved fluoroimmunoassay. Anthropometrics, abdominal adipose tissue areas (computed tomography), body composition (hydrostatic weighing) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) were measured in all women. Women in the high dietary lignan intake subgroup (n 29) had a significantly lower BMI and total body fat mass, as well as a better glucose disposal rate (GDR; P < 0.05), compared with women in the low lignan intake subgroup (n 28). The majority of women with the highest dietary lignan intake were also in the highest quartile of plasma ENL (59 %). Women in the highest ENL quartile had a significantly lower BMI (26.1 (SD 4.4) v. 30.4 (SD 6.9) kg/m(2), P < 0.05), total body fat mass (24.8 (SD 9.8) v. 33.3 (SD 13.3) kg, P < 0.05), 2 h postload glycaemia (5.5 (SD 0.9) v. 5.7 (sd 0.8) nmol/l, P < 0.05) and a higher GDR (8.3 (SD 2.7) v. 5.5 (SD 2.8), P < 0.01) compared with women in the lowest ENL quartile. In conclusion, women with the highest ENL concentrations had a better metabolic profile including higher insulin sensitivity and lower adiposity measures.

Topics: 4-Butyrolactone; Adiposity; Aged; Analysis of Variance; Biomarkers; Body Composition; Body Mass Index; Diet; Diet Records; Female; Fluoroimmunoassay; Humans; Insulin Resistance; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Statistics, Nonparametric