Int J Clin Exp Pathol.2015 Oct 1;8(10):12589-94. eCollection 2015.
Pterostilbene impact on retinal endothelial cells under high glucose environment.
Shen H1, Rong H2.
Diabetic retinopathy (DR) has complicated pathogenic factors. Studies showed that DR belongs to chronic inflammatory disease, and retinal endothelial cells oxidation by free radicals is one of its mechanisms. Pterostilbene, as the homologous derivative of resveratrol, has obvious antioxidant effect. Its influence on the DR has not been studied. This study intended to investigate the effect and mechanism of pterostilbene on human retinal endothelial cells (hRECs) under high glucose environment to illustrate pterostilbene impact on DR and provide basis for DR clinical treatment. hRECs cultured in high glucose environment were treated by 1.0 mmol/L pterostilbene. MTT assay was applied to test cell proliferation. ELISA was used to detect inflammatory factor TNF-α and IL-1β content. Real time PCR and Western blot were performed to examine NF-κB mRNA and protein expression. ROS and SOD activities were analyzed. Under high glucose environment, hRECs proliferation increased, TNF-α and IL-1β expression elevated, and NF-κB protein level upregulated significantly. On the other side, ROS production increased and SOD activity decreased obviously (P < 0.05). Pterostilbene can suppress hRECs over proliferation, decrease TNF-α and IL-1β, inhibit NF-κB protein expression, reduce ROS production, and increase SOD activity markedly compared with high glucose group (P < 0.05). Pterostilbene may delay DR progress through alleviating inflammation and antioxidation to suppress hRECs over proliferation.
KEYWORDS: Diabetic retinopathy; inflammatory factor; pterostilbene; retinal endothelial cell
PMID: 26722449 PMCID: PMC4680394
Food Funct.2015 Jun;6(6):1968-76. doi: 10.1039/c5fo00151j.
Pterostilbene improves glycaemic control in rats fed an obesogenic diet: involvement of skeletal muscle and liver.
Gómez-Zorita S1, Fernández-Quintela A, Aguirre L, Macarulla MT, Rimando AM, Portillo MP.
This study aims to determine whether pterostilbene improves glycaemic control in rats showing insulin resistance induced by an obesogenic diet. Rats were divided into 3 groups: the control group and two groups treated with either 15 mg kg(-1) d(-1) (PT15) or 30 mg kg(-1) d(-1) of pterostilbene (PT30). HOMA-IR was decreased in both pterostilbene-treated groups, but this reduction was greater in the PT15 group (-45% and -22% respectively vs. the control group). The improvement of glycaemic control was not due to a delipidating effect of pterostilbene on skeletal muscle. In contrast, GLUT4 protein expression was increased (+58% and +52% vs. the control group), suggesting an improved glucose uptake. The phosphorylated-Akt/total Akt ratio was significantly enhanced in the PT30 group (+25%), and therefore a more efficient translocation of GLUT4 is likely. Additionally, in this group the amount of cardiotrophin-1 was significantly increased (+65%). These data suggest that the effect of pterostilbene on Akt is mediated by this cytokine. In the liver, glucokinase activity was significantly increased only in the PT15 group (+34%), and no changes were observed in glucose-6-phosphatase activity. The beneficial effect of pterostilbene on glycaemic control was more evident with the lower dose, probably because in the PT15 group both the muscle and the liver were contributing to this effect, but in the PT30 group only the skeletal muscle was responsible. In conclusion, pterostilbene improves glycaemic control in rats showing insulin resistance induced by an obesogenic diet. An increase in hepatic glucokinase activity, as well as in skeletal muscle glucose uptake, seems to be involved in the anti-diabetic effect of this phenolic compound.
PMID: 25998070 DOI: 10.1039/c5fo00151j
J Agric Food Chem.2014 Aug 20;62(33):8371-8. doi: 10.1021/jf501318b. Epub 2014 Aug 8.
Pterostilbene, a dimethyl ether derivative of resveratrol, reduces fat accumulation in rats fed an obesogenic diet.
Gómez-Zorita S1, Fernández-Quintela A, Lasa A, Aguirre L, Rimando AM, Portillo MP
The current study aimed to demonstrate the effects of pterostilbene in rats fed an obesogenic diet. For this purpose, pterostilbene was administered at doses of 15 mg/kg body weight/day (PT15 group) or 30 mg/kg body weight/day (PT30 group) for 6 weeks. Pterostilbene reduced adipose tissue mass -15.1% (PT15) and -22.9% (PT30). In this tissue, it decreased malic enzyme (-39.4 and -49.5% for PT15 and PT30 groups, respectively) and fatty acid synthase (-45 and -53.4% for PT15 and PT30) activities. Acetyl-CoA carboxylase activity was reduced and AMPK activity was increased only in the PT30 group. In the liver, pterostilbene (PT30) reduced malic enzyme (-29.5%) and glucose-6-P dehydrogenase (-43.2%) activities and increased carnitine palmitoyltransferase-1a (37.5%) and acyl-coenzyme A oxidase (42.5%) activities. This increased oxidative capacity was not associated with increased mitochondriogenesis. Among biochemical serum parameters, only insulin was modified by pterostilbene (-31.6%) in the PT15 group. The amounts of pterostilbene in serum and tissues from rats in the PT30 group were in not all cases 2-fold greater than those found in the PT15 group. In conclusion, pterostilbene shows antiobesity properties due, at least in part, to reduced lipogenesis in adipose tissue and increased fatty acid oxidation in liver.
KEYWORDS: adipose tissue; bioavailability; fatty acid oxidation; lipogenesis; pterostilbene
PMID: 25083823 DOI: 10.1021/jf501318b
J Toxicol.2013;2013:463595. doi: 10.1155/2013/463595. Epub 2013 Feb 4.
Analysis of safety from a human clinical trial with pterostilbene.
Riche DM1, McEwen CL, Riche KD, Sherman JJ, Wofford MR, Deschamp D, Griswold M.
OBJECTIVES: The purpose of this trial was to evaluate the safety of long-term pterostilbene administration in humans.
METHODOLOGY: The trial was a prospective, randomized, double-blind placebo-controlled intervention trial enrolling patients with hypercholesterolemia (defined as a baseline total cholesterol ≥200 mg/dL and/or baseline low-density lipoprotein cholesterol ≥100 mg/dL). Eighty subjects were divided equally into one of four groups: (1) pterostilbene 125 mg twice daily, (2) pterostilbene 50 mg twice daily, (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, and (4) matching placebo twice daily for 6-8 weeks. Safety markers included biochemical and subjective measures. Linear mixed models were used to estimate primary safety measure treatment effects.
RESULTS: The majority of patients completed the trial (91.3%). The average age was 54 years. The majority of patients were females (71%) and Caucasians (70%). There were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. There were no statistically significant self-reported or major ADRs.
CONCLUSION: Pterostilbene is generally safe for use in humans up to 250 mg/day.
PMID: 23431291 PMCID: PMC3575612DOI: 10.1155/2013/463595
Life Sci.2006 Jul 10;79(7):641-5. Epub 2006 Apr 17.
Effect of pterostilbene on hepatic key enzymes of glucose metabolism in streptozotocin- and nicotinamide-induced diabetic rats.
Pari L1, Satheesh MA.
The purpose of this study was to investigate the effect of pterostilbene and its effect on key enzymes of glucose metabolism. Diabetic rats were orally administered with pterostilbene (10, 20, 40 mg/kg) for 2, 4 and 6 weeks on glucose was determined. Administration of pterostilbene at 40 mg/kg significantly decreases plasma glucose. Based on these data, the higher dose, 40 mg/kg pterostilbene, was selected for further evaluation. Oral administration of pterostilbene for 6 weeks on glucose, insulin levels and hepatic enzymes in normal and streptozotocin (STZ)-nicotinamide-induced diabetic rats. A significant decrease in glucose and significant increase in plasma insulin levels were observed in normal and diabetic rats treated with pterostilbene. Treatment with pterostilbene resulted in a significant reduction of glycosylated hemoglobin and an increase in total hemoglobin level. The activities of the hepatic enzymes such as hexokinase was significantly increased whereas glucose-6-phosphatase, fructose-1,6-bisphosphatase were significantly decreased by the administration of pterostilbene in diabetic rats. A comparison was made between the action of pterostilbene and the antidiabetic drug–metformin.
PMID: 16616938 DOI: 10.1016/j.lfs.2006.02.036
Chem Res Toxicol.2016 Jan 19;29(1):47-57. doi: 10.1021/acs.chemrestox.5b00378. Epub 2016 Jan 7.
Pterostilbene Ameliorates Streptozotocin-Induced Diabetes through Enhancing Antioxidant Signaling Pathways Mediated by Nrf2.
Elango B, Dornadula S, Paulmurugan R1, Ramkumar KM.
Nuclear factor erythroid 2-related factor 2 (Nrf2) remains a master regulator of cytoprotective and antioxidant genes. In this study, we investigated the antidiabetic role of pterostilbene (PTS) in streptozotocin (STZ)-induced diabetic model through Nrf2-mediated antioxidant mechanisms. The ability of PTS to activate Nrf2 in MIN6 cells was assessed by dissociation of the Nrf2-Keap1 complex at different time points and by expression of ARE-driven downstream target genes of Nrf2. Immunoblot experiments examining Nrf2 activation and phosphorylation indicated that it conferred cytoprotection against STZ-induced cellular damage. In STZ-induced diabetic mice, PTS administration significantly decreased blood glucose levels through the improvement of insulin secretion. In addition, we also observed insulin-positive cells with recovered islet architecture in the pancreas of STZ-induced diabetic mice after treatment with PTS. The activation of Nrf2 and expression of its downstream target genes were observed upon PTS treatment, thereby reducing oxidative damage to pancreas. Furthermore, PTS treatment significantly reverted the abundance of key glucose metabolism enzymes, such as hexokinase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, and fructose-1,6-bisphosphatase, to near-normal levels in liver tissue of STZ-induced diabetic mice. These results clearly indicate that PTS maintains glucose homeostasis, suggesting the possibility that it is a future candidate for use in diabetes management.
PMID: 26700463 DOI: 10.1021/acs.chemrestox.5b00378
J Physiol Biochem.2016 Aug;73(3):457-464. doi: 10.1007/s13105-017-0556-2. Epub 2017 Feb 27.
Effects of pterostilbene in brown adipose tissue from obese rats.
Aguirre L1,2, Milton-Laskibar I1, Hijona E3,4, Bujanda L3,4, Rimando AM5, Portillo MP6,7.
Erratum to: volume 73, issue 3 of Journal of Physiology and Biochemistry.[J Physiol Biochem. 2017]
In recent years, much attention has been paid by the scientific community to phenolic compounds as active biomolecules naturally present in foods. Pterostilbene is a resveratrol dimethylether derivative which shows higher bioavailability. The aim of the present study was to analyze the effect of pterostilbene on brown adipose tissue thermogenic markers in a model of genetic obesity, which shows reduced thermogenesis. The experiment was conducted with 30 Zucker (fa/fa) rats that were distributed in three experimental groups: control and two groups orally administered with pterostilbene at 15 and 30 mg/kg body weight/day for 6 weeks. Gene expression of uncoupling protein 1 (Ucp1), peroxisome proliferator-activated receptor γ co-activator 1 α (Pgc-1α), carnitine palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor α (Pparα), nuclear respiratory factor 1 (Nfr1), and cyclooxygenase-2 (Cox-2); protein expression of PPARα, PGC-1α, p38 mitogen-activated protein kinase (p38 MAPK), UCP1 and glucose transporter (GLUT4); and enzyme activity of CPT 1b and citrate synthase (CS) were assessed in interscapular brown adipose tissue. With the exception of Pgc-1α expression, all these parameters were significantly increased by pterostilbene administration. These results show for the first time that pterostilbene increases thermogenic and oxidative capacity of brown adipose tissue in obese rats. Whether these effects effectively contribute to the antiobesity properties of these compound needs further research.
KEYWORDS: Brown adipose tissue; Fatty acid oxidation; GLUT4; Obese rats; Pterostilbene
PMID: 28243863 DOI: 10.1007/s13105-017-0556-2
J Nutr Biochem.2015 May;26(5):466-75. doi: 10.1016/j.jnutbio.2014.11.015. Epub 2015 Jan 19.
Pterostilbene suppressed irradiation-resistant glioma stem cells by modulating GRP78/miR-205 axis.
Huynh TT1, Lin CM2, Lee WH3, Wu AT4, Lin YK5, Lin YF6, Yeh CT7, Wang LS8.
Glioblastoma multiforme (GBM) is the most aggressive type characterized by relapse and resistance even with the combination of radio- and chemotherapy. The presence of glioma stem cells (GSCs) has been shown to contribute to tumorigenesis, recurrence and treatment resistance. Particularly, CD133-positive glioma cells have been shown to represent the subpopulation that confers glioma radioresistance and suggested to be the source of tumor recurrence after radiation. Thus, a better understanding and the development of agents which target GSCs could potentially lead to a significant improvement in treating GBM patients. Here, we demonstrated that GRP78 (an antistress protein) was highly expressed in GBM cells along with β-catenin and Notch and correlated to the development of GSCs. CD133+ GSCs exhibited enhanced migration/invasion and self-renewal abilities. When GRP78 was silenced, GSC properties were suppressed and the sensitivity towards irradiation increased. In addition, the level of microRNA 205 appeared to be negatively associated with GRP78 expression. Our previous study indicated that pterostilbene (PT) possessed anticancer stem cell properties in hepatocellular carcinoma. Thus, we examined whether PT is also effective against GSCs. We found that PT-treated GSCs exhibited suppressed self-renewal and irradiation-resistant abilities. PT-mediated effects were associated with an increase of miR-205. Finally, we showed that PT treatment suppressed tumorigenesis in GSC xenograft mice. In conclusion, we provided evidence that GRP78/miR-205 axis played an important role in GSC maintenance and irradiation resistance. PT treatment suppressed GSC development via negatively modulating GRP78 signaling. PT may be considered for combined therapeutic agent to enhance irradiation efficacy in GBM patients.
KEYWORDS: CD133+ glioma stem cells; Glucose-regulated protein, 78 kDa (GRP78); Irradiation resistance; Pterostilbene; miR-205
PMID: 25736407 DOI: 10.1016/j.jnutbio.2014.11.015
J Pharm Pharmacol.2006 Nov;58(11):1483-90.
The antioxidant role of pterostilbene in streptozotocin-nicotinamide-induced type 2 diabetes mellitus in Wistar rats.
Amarnath Satheesh M1, Pari L.
The antioxidant effect of pterostilbene on streptozotocin-nicotinamide-induced diabetic rats has been assessed. The activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and reduced glutathione was significantly decreased in liver and kidney of diabetic animals when compared with normal control. There were significant improvements in these activities after treatment with pterostilbene at a dose of 40 mg kg(-1) for six weeks. The increased levels of lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) in liver and kidney of diabetic rats were also normalized by treatment with pterostilbene. Chronic treatment of pterostilbene remarkably reduced the pathological changes observed in liver and kidney of diabetic rats. These results indicated the antioxidant property of pterostilbene.
PMID: 17132211 DOI: 10.1211/jpp.58.11.0009
J Agric Food Chem.2005 May 4;53(9):3403-7.
Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters.
Rimando AM1, Nagmani R, Feller DR, Yokoyama W.
Resveratrol, a stilbenoid antioxidant found in grapes, wine, peanuts and other berries, has been reported to have hypolipidemic properties. We investigated whether resveratrol and its three analogues (pterostilbene, piceatannol, and resveratrol trimethyl ether) would activate the peroxisome proliferator-activated receptor alpha (PPARalpha) isoform. This nuclear receptor is proposed to mediate the activity of lipid-lowering drugs such as the fibrates. The four stilbenes were evaluated at 1, 10, 100, and 300 microM along with ciprofibrate (positive control), for the activation of endogenous PPARalpha in H4IIEC3 cells. Cells were transfected with a peroxisome proliferator response element-AB (rat fatty acyl CoA beta-oxidase response element)-luciferase gene reporter construct. Pterostilbene demonstrated the highest induction of PPARalpha showing 8- and 14-fold increases in luciferase activity at 100 and 300 microM, respectively, relative to the control. The maximal luciferase activity responses to pterostilbene were higher than those obtained with the hypolipidemic drug, ciprofibrate (33910 and 19460 relative luciferase units, respectively), at 100 microM. Hypercholesterolemic hamsters fed with pterostilbene at 25 ppm of the diet showed 29% lower plasma low density lipoprotein (LDL) cholesterol, 7% higher plasma high density lipoprotein (HDL) cholesterol, and 14% lower plasma glucose as compared to the control group. The LDL/HDL ratio was also statistically significantly lower for pterostilbene, as compared to results for the control animals, at this diet concentration. Results from in vitro studies showed that pterostilbene acts as a PPARalpha agonist and may be a more effective PPARalpha agonist and hypolipidemic agent than resveratrol. In vivo studies demonstrate that pterostilbene possesses lipid and glucose lowering effects.
PMID: 15853379 DOI: 10.1021/jf0580364
Eur J Pharmacol.2016 Apr 15;777:9-16. doi: 10.1016/j.ejphar.2016.02.054. Epub 2016 Feb 24.
Anti-hyperlipidemic and anti-peroxidative role of pterostilbene via Nrf2 signaling in experimental diabetes.
Bhakkiyalakshmi E1, Sireesh D1, Sakthivadivel M2, Sivasubramanian S2, Gunasekaran P2, Ramkumar KM3.
Nuclear factor erythroid 2-related factor (Nrf2), a key transcription factor triggers the expression of antioxidant and detoxification genes thereby providing cellular protective functions against oxidative stress-mediated disorders. Recent research has identified that pharmacological activation of Nrf2 also regulates the largest cluster of genes associated with lipid metabolism. With this background, this paper highlights the anti-hyperlipidemic and anti-peroxidative role of pterostilbene (PTS), an Nrf2 activator, in streptozotocin (STZ)-induced diabetic model. PTS administration to diabetic mice for 5 weeks significantly regulated blood glucose levels through the elevation of insulin secretion. The circulatory and liver lipid profiles of total cholesterol (TC), triglycerides (TG) and non-esterified fatty acids (NEFA) were maintained to normal levels upon PTS treatment. Moreover, PTS administration also normalized the circulatory levels of very low-, low- and high density lipoprotein cholesterols (VLDL-, LDL-, HDL-C) and also reduced lipid peroxidation in STZ-induced diabetic mice. In addition, Nrf2 and its downstream targets, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme activities and glutathione (GSH) levels were significantly elevated in liver tissues of diabetic mice upon PTS administration. Further, H&E staining of diabetic mouse liver showed collapse in hepatic microvesicles due to altered lipid metabolism. Both structural and functional alterations were attenuated by PTS indicating its role in diabetic dyslipidemia through Nrf2-mediated mechanism that could be considered as a promising therapeutic agent.
KEYWORDS: Diabetes; Dyslipidemia; Lipids; Nrf2; Pterostilbene; Streptozotocin
PMID: 26921755 DOI: 10.1016/j.ejphar.2016.02.054
Biochim Biophys Acta.2017 Apr;1863(4):827-837. doi: 10.1016/j.bbadis.2017.01.005. Epub 2017 Jan 9.
Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2.
Yang Y1, Fan C2, Wang B3, Ma Z2, Wang D4, Gong B4, Di S2, Jiang S5, Li Y6, Li T6, Yang Z6, Luo E7.
In the present study, neuroblastoma (SH-SY5Y) cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene (PTE) against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy. High glucose medium (100mM) decreased cellular viability after 24h incubation which was evidenced by: (i) reduced mitochondrial complex I and III activities; (ii) reduced mitochondrial cytochrome C; (iii) increased reactive oxygen species (ROS) generation; (iv) decreased mitochondrial membrane potential (ΔΨm); and (v) increased lactate dehydrogenase (LDH) levels. PTE (2.5, 5, and 10μM for 24h) was nontoxic and induced the nuclear transition of Nrf2. Pretreatment of PTE (2.5, 5, and 10μM for 2h) displayed a dose-dependently neuroprotective effect, as indicated by significantly prevented high glucose-induced loss of cellular viability, generation of ROS, reduced mitochondrial complex I and III activities, reduced mitochondrial cytochrome C, decreased ΔΨm, and increased LDH levels. Moreover, the levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and glutathione S-transferase (GST) were elevated after PTE treatment. In addition, the elevation of nuclear Nrf2 by PTE treatment (10μM for 2h) was abolished by Nrf2 siRNA. Importantly, Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities, mitochondrial cytochrome C, reactive species generation, ΔΨm, and LDH. Overall, the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived oxidative stress.
KEYWORDS: High glucose; Neuroprotection; Nuclear factor erythroid 2-related factor 2 signaling; Oxidative stress; Pterostilbene
PMID: 28089584 DOI: 10.1016/j.bbadis.2017.01.005
Microb Cell Fact.2017 Feb 15;16(1):30. doi: 10.1186/s12934-017-0644-6.
De novo biosynthesis of pterostilbene in an Escherichia coli strain using a new resveratrol O-methyltransferase from Arabidopsis.
Heo KT1,2, Kang SY1, Hong YS3,4.
BACKGROUND: Pterostilbene, a structural analog of resveratrol, has higher oral bioavailability and bioactivity than that of the parent compound; but is far less abundant in natural sources. Thus, to efficiently obtain this bioactive resveratrol analog, it is necessary to develop new bioproduction systems.
RESULTS: We identified a resveratrol O-methyltransferase (ROMT) function from a multifunctional caffeic acid O-methyltransferase (COMT) originating from Arabidopsis, which catalyzes the transfer of a methyl group to resveratrol resulting in pterostilbene production. In addition, we constructed a biological platform to produce pterostilbene with this ROMT gene. Pterostilbene can be synthesized from intracellular L-tyrosine, which requires the activities of four enzymes: tyrosine ammonia lyase (TAL), p-coumarate:CoA ligase (CCL), stilbene synthase (STS) and resveratrol O-methyltransferase (ROMT). For the efficient production of pterostilbene in E. coli, we used an engineered E. coli strain to increase the intracellular pool of L-tyrosine, which is the initial precursor of pterostilbene. Next, we tried to produce pterostilbene in the engineered E. coli strain using L-methionine containing media, which is used to increase the intracellular pool of S-adenosyl-L-methionine (SAM). According to this result, pterostilbene production as high as 33.6 ± 4.1 mg/L was achieved, which was about 3.6-fold higher compared with that in the parental E. coli strain harboring a plasmid for pterostilbene biosynthesis.
CONCLUSION: As a potential phytonutrient, pterostilbene was successfully produced in E. coli from a glucose medium using a single vector system, and its production titer was also significantly increased using a L-methionine containing medium in combination with a strain that had an engineered metabolic pathway for L-tyrosine. Additionally, we provide insights into the dual functions of COMT from A. thaliana which was characterized as a ROMT enzyme.
KEYWORDS: De novo biosynthesis; Pterostilbene; Resveratrol O-methyltransferase
PMID: 28202018 PMCID: PMC5312575DOI: 10.1186/s12934-017-0644-6
J Nat Prod.1997 Jun;60(6):609-10.
Antihyperglycemic activity of phenolics from Pterocarpus marsupium.
Manickam M1, Ramanathan M, Jahromi MA, Chansouria JP, Ray AB.
Glucose levels in rats with hyperglycemia induced by streptozotocin were determined after i.p. administration of marsupsin (1), pterosupin (2), and pterostilbene (3), three important phenolic constituents of the heartwood of Pterocarpus marsupium. Marsupsin and pterostilbene significantly lowered the blood glucose level of hyperglycemic rats, and the effect was comparable to that of 1,1-dimethylbiguanide (metformin).
PMID: 9214733 DOI: 10.1021/np9607013
Sci Rep.2016 Nov 11;6:36827. doi: 10.1038/srep36827.
Engineering yeast for high-level production of stilbenoid antioxidants.
Li M1, Schneider K1, Kristensen M1, Borodina I1, Nielsen J1,2,3.
Stilbenoids, including resveratrol and its methylated derivatives, are natural potent antioxidants, produced by some plants in trace amounts as defense compounds. Extraction of stilbenoids from natural sources is costly due to their low abundance and often limited availability of the plant. Here we engineered the yeast Saccharomyces cerevisiae for production of stilbenoids on a simple mineral medium typically used for industrial production. We applied a pull-push-block strain engineering strategy that included overexpression of the resveratrol biosynthesis pathway, optimization of the electron transfer to the cytochrome P450 monooxygenase, increase of the precursors supply, and decrease of the pathway intermediates degradation. Fed-batch fermentation of the final strain resulted in a final titer of 800 mg l-1 resveratrol, which is by far the highest titer reported to date for production of resveratrol from glucose. We further integrated heterologous methyltransferases into the resveratrol platform strain and hereby demonstrated for the first time de novo biosynthesis of pinostilbene and pterostilbene, which have better stability and uptake in the human body, from glucose.
PMID: 27833117 PMCID: PMC5105057DOI: 10.1038/srep36827
Phytother Res.2017 Aug;31(8):1273-1282. doi: 10.1002/ptr.5852. Epub 2017 Jun 19.
Pterostilbene Inhibits Lipogenic Activity similar to Resveratrol or Caffeine but Differently Modulates Lipolysis in Adipocytes.
Gomez-Zorita S1,2,3, Belles C1,4, Briot A1, Fernández-Quintela A2,3, Portillo MP2,3, Carpéné C1.
The anti-obesity effects of resveratrol shown in rodents are not transposed into an efficient therapy of human obesity. Consequently, the search for molecules mimicking or surpassing resveratrol actions is ongoing. The natural phenolic compound pterostilbene exhibits beneficial health effects and has the capacity to limit fat mass in animal models. In this study, we tested whether pterostilbene modulates triacylglycerol accumulation/breakdown. Prolonged exposure to pterostilbene or resveratrol inhibited adipocyte differentiation in 3T3-F442A preadipocytes. Acute effects on lipolysis, antilipolysis and lipogenesis were determined for pterostilbene in mouse adipocytes, and compared with resveratrol. Pterostilbene was also tested on glycerol release and glucose uptake in subcutaneous human adipocytes. Dose-response analyses did not reveal a clear lipolytic effect in both species. The antilipolytic effect of insulin was improved by pterostilbene at 1-10 μM in mouse fat cells only, while at 1 mM, the phenolic compound was antilipolytic in human fat cells in a manner not additive to insulin. Pterostilbene dose-dependently inhibited glucose incorporation into lipids similarly to resveratrol and caffeine. However, only the former did not inhibit insulin-stimulated glucose uptake. Indeed, pterostilbene abolished the insulin lipogenic effect without inhibiting its antilipolytic action and rapid activation of glucose uptake. Pterostilbene therefore exhibits a unique panel of direct interactions with adipocytes that relies on its reported anti-obesity and antidiabetic properties.
Copyright © 2017 John Wiley & Sons, Ltd.
KEYWORDS: adipogenesis; adipose tissue; glucose transport; human; insulin; polyphenol
PMID: 28627722 DOI: 10.1002/ptr.5852
Oxid Med Cell Longev.2016;2016:2427618. doi: 10.1155/2016/2427618. Epub 2016 Jan 5.
Dietary Phenolic Compounds Interfere with the Fate of Hydrogen Peroxide in Human Adipose Tissue but Do Not Directly Inhibit Primary Amine Oxidase Activity.
Carpéné C1, Hasnaoui M1, Balogh B2, Matyus P2, Fernández-Quintela A3, Rodríguez V3, Mercader J4, Portillo MP3.
Resveratrol has been reported to inhibit monoamine oxidases (MAO). Many substrates or inhibitors of neuronal MAO interact also with other amine oxidases (AO) in peripheral organs, such as semicarbazide-sensitive AO (SSAO), known as primary amine oxidase, absent in neurones, but abundant in adipocytes. We asked whether phenolic compounds (resveratrol, pterostilbene, quercetin, and caffeic acid) behave as MAO and SSAO inhibitors. AO activity was determined in human adipose tissue. Computational docking and glucose uptake assays were performed in 3D models of human AO proteins and in adipocytes, respectively. Phenolic compounds fully inhibited the fluorescent detection of H2O2 generated during MAO and SSAO activation by tyramine and benzylamine. They also quenched H2O2-induced fluorescence in absence of biological material and were unable to abolish the oxidation of radiolabelled tyramine and benzylamine. Thus, phenolic compounds hampered H2O2 detection but did not block AO activity. Only resveratrol and quercetin partially impaired MAO-dependent [(14)C]-tyramine oxidation and behaved as MAO inhibitors. Phenolic compounds counteracted the H2O2-dependent benzylamine-stimulated glucose transport. This indicates that various phenolic compounds block downstream effects of H2O2 produced by biogenic or exogenous amine oxidation without directly inhibiting AO. Phenolic compounds remain of interest regarding their capacity to limit oxidative stress rather than inhibiting AO.
PMID: 26881018 PMCID: PMC4736399DOI: 10.1155/2016/2427618
Diabetes Obes Metab.2005 Jul;7(4):414-20.
Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate.
Grover JK1, Vats V, Yadav SS.
Insulin resistance (hyperinsulinaemia) is now recognized as a major contributor to the development of glucose intolerance, dyslipidaemia and hypertension in non-insulin-dependent diabetes mellitus (NIDDM) patients. Sedentary lifestyle, consumption of energy-rich diet, obesity, longer lifespan, etc., are important reasons for this rise (J. R. Turtle, Int J Clin Prac 2000; 113: 23). Aqueous extracts of Pterocarpus marsupium Linn bark (PM), Ocimum sanctum Linn leaves (OS) and Trigonella foenumgraecum Linn seeds (FG) have been shown to exert hypoglycaemic/antihyperglycaemic effect in experimental as well as clinical setting. As no work has been carried out so far to assess the effect of PM, OS and FG on fructose-induced hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia, we undertook this study to assess whether these extracts attenuate the metabolic alteration induced by fructose-rich diet in rats. Five groups of rats (eight each) were fed chow diet, 66% fructose diet, 66% fructose diet + PM leaves extract (1 g/kg/day), 66% fructose diet + OS leaves extract (200 mg/kg/day) and 66% fructose diet + FG seeds extract (2 g/kg/day) for 30 days. Fructose feeding to normal rats for 30 days significantly increased serum glucose, insulin and triglyceride levels in comparison with control. Treatment with all the three plants extract for 30 days significantly lowered the serum glucose levels in comparison with control group. However, only PM extract substantially prevented hypertriglyceridaemia and hyperinsulinaemia, while OS and FG had no significant effect on these parameters. Results of this study, in addition to previous clinical benefits of PM seen in NIDDM subjects, are suggestive of usefulness of PM bark (Vijayasar) in insulin resistance, the associated disorder of type 2 diabetes; however, OS and FG may not be useful. Though several antidiabetic principles (-epicatechin, pterosupin, marsupin and pterostilbene) have been identified in the PM, yet future studies are required to certify their efficacy and safety before clinical scenario.
PMID: 15955128 DOI: 10.1111/j.1463-1326.2005.00414.x
Life Sci.2017 Aug 1;182:112-121. doi: 10.1016/j.lfs.2017.06.015. Epub 2017 Jun 16.
Pterostilbene ameliorates insulin sensitivity, glycemic control and oxidative stress in fructose-fed diabetic rats.
Kosuru R1, Singh S2.
AIMS: The present investigation was designed to explore the effectiveness of pterostilbene (PT) on insulin resistance, metabolic syndrome and oxidative stress in fructose-fed insulin resistant rats.
MAIN METHODS: Age-matched, male Sprague-Dawley rats (330±30g body weight) were allocated into five groups (n=10). Control (C) group received 65% cornstarch, and the diabetic (D) group received 65% fructose for eight weeks. The third group (D+PT20) received 65% fructose and PT 20mg/kg/day for eight weeks. The fourth group (D+PT40) received 65% fructose and PT 40mg/kg/day for eight weeks. The fifth group (D+M) received 65% fructose and metformin (M) 100mg/kg/day for eight weeks. PT was dissolved in 10% β-cyclodextrin and given orally to rats. Several biochemical parameters were determined to assess the PT efficacy against insulin resistance, metabolic complications, and hepatic oxidative stress.
KEY FINDINGS: Significantly high HOMA-IR (p<0.001) values in D group compared to C group indicate the presence of insulin resistance. Significantly high levels of TBARS (p<0.001) and decreased levels of SOD (p<0.001) and GSH (p<0.001) in hepatic tissues of D group indicate oxidative stress associated with insulin resistance. Pterostilbene treatment to fructose-fed diabetic rats significantly decreased HOMA-IR (p<0.001) values. Furthermore, PT treatment significantly decreased hepatic TBARS (p<0.001) and increased SOD (p<0.001) and GSH (p<0.001) levels in fructose-fed diabetic rats.
SIGNIFICANCE: Current study reveals that PT is successful in ameliorating glycemic control, insulin sensitivity while diminishing metabolic disturbances and hepatic oxidative stress in a fructose-induced T2DM rat model.
Copyright © 2017 Elsevier Inc. All rights reserved.
KEYWORDS: HbA1c; Hepatic oxidative stress; Insulin resistance; Pterostilbene; Type 2 diabetes
PMID: 28629731 DOI: 10.1016/j.lfs.2017.06.015
J Nutr Biochem.2017 Jun;44:11-21. doi: 10.1016/j.jnutbio.2017.02.015. Epub 2017 Mar 6.
Role of pterostilbene in attenuating immune mediated devastation of pancreatic beta cells via Nrf2 signaling cascade.
Sireesh D1, Ganesh MR2, Dhamodharan U1, Sakthivadivel M3, Sivasubramanian S3, Gunasekaran P3, Ramkumar KM4.
Nrf2 (nuclear factor erythroid 2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress response and also suppress inflammation. Nrf2 signaling is associated with an increased susceptibility to various kinds of stress. Nrf2 has been shown as a promising therapeutic target in various human diseases including diabetes. Our earlier studies showed Pterostilbene (PTS) as a potent Nrf2 activator, and it protects the pancreatic β-cells against oxidative stress. In this study, we investigated PTS confer protection against cytokine-induced β-cell apoptosis and its role on insulin secretion in streptozotocin (STZ)-induced diabetic mice. The Nrf2 activation potential of PTS was assessed by dissociation of the Nrf2-Keap1 complex and by expression of ARE-driven downstream target genes in MIN6 cells. Further, the nuclear Nrf2 translocation and blockage of apoptotic signaling as demonstrated by the reduction of BAX/Bcl-2 ratio, Annexin-V positive cells and caspase-3 activity conferred the cyto-protection of PTS against cytokine-induced cellular damage. In addition, PTS treatment markedly improved glucose homeostasis and abated inflammatory response evidenced by the reduction of proinflammatory cytokines in diabetic mice. The inhibition of β-cell apoptosis by PTS as assessed by BAX/Bcl-2 ratio and caspase-3 activity in the pancreas was associated with the activation of Nrf2 and the expression of its downstream target genes. PTS also inhibited the activation of iNOS and decreased nitric oxide (NO) formation in the pancreas of diabetic animals. The results obtained from both in vitro and in vivo experiments showed that PTS improves β-cell function and survival against cytokine stress and also prevents STZ-induced diabetes.
KEYWORDS: Cytokine cocktail; Diabetes; MIN6; Nrf2; Streptozotocin
PMID: 28343084 DOI: 10.1016/j.jnutbio.2017.02.015
J Biotechnol.2017 Apr 20;248:69-76. doi: 10.1016/j.jbiotec.2017.03.009. Epub 2017 Mar 16.
Exploiting the aglycon promiscuity of glycosyltransferase Bs-YjiC from Bacillus subtilis and its application in synthesis of glycosides.
Dai L1, Li J1, Yao P1, Zhu Y1, Men Y1, Zeng Y1, Yang J1, Sun Y2.
Glycosylation is a prominent biological mechanism for structural and functional diversity of natural products. Uridine diphosphate-dependent glycosyltransferases with aglycon promiscuity are generally recognised as effective biocatalysts for glycodiversification of natural products for practical applications. In this study, the aglycon promiscuity of glycosyltransferase Bs-YjiC from Bacillus subtilis 168 was explored. Bs-YjiC, with uridine diphosphate glucose (UDPG) as sugar donor, exhibited robust capabilities to glycosylate 19 structurally diverse types of drug-like scaffolds with regio- and stereospecificities and form O-, N- and S-linkage glycosides. Twenty-four glycosides of 17 aglycons were purified from scale-up reactions using Bs-YjiC as a biocatalyst, and their structures were confirmed by nuclear magnetic resonance spectra. Furthermore, a one-pot reaction by coupling Bs-YjiC to sucrose synthase from Arabidopsis thaliana was applied to glycosylate pterostilbene. Without adding the costly UDPG as sugar donor, 9mM (3.8g/L) pterostilbene 4′-O-β-glucoside was obtained by periodic feeding of pterostilbene. These results suggest the aglycon promiscuity of Bs-YjiC and demonstrate its significant application prospect in biosynthesis of valuable natural products.
KEYWORDS: Aglycon promiscuity; Bacillus subtilis 168; Glycosylation; Glycosyltransferase sucrose synthase; Natural products
PMID: 28315700 DOI: 10.1016/j.jbiotec.2017.03.009