Chemical Constituents of Euonymus alatus (Thunb.) Sieb. and Their PTP1B and α‐Glucosidase Inhibitory Activities

Phytochemical study on the corks of Euonymus alatus resulted in the isolation of a novel 3‐hydroxycoumarinflavanol (23), along with ten triterpenoids (1–10), ten phenolic derivatives (11–20), and two flavonoid glycosides (21 and 22). Their structures were determined by extensive 1D and 2D‐nuclear magnetic resonance spectroscopic and mass spectrometry data analysis. Furthermore, their inhibitory effects against the protein tyrosine phosphatases 1B (PTP1B) and α‐glucosidase enzyme activity were evaluated. Compounds 6, 7, 9, 15, 19, and 23 were non‐competitive inhibitors, exhibiting most potency with IC₅₀ values ranging from 5.6 ± 0.9 to 18.4 ± 0.3 µm , against PTP1B. Compound 3 (competitive), compounds 5 and 15 (mixed‐competitive) displayed potent inhibition with IC₅₀ values of 15.1 ± 0.7, 23.6 ± 0.6 and 14.8 ± 0.9 µm , respectively. Moreover, compounds 15, 20, and 23 exhibited potent inhibition on α‐glucosidase with IC₅₀ values of 10.5 ± 0.8, 9.5 ± 0.6, and 9.1 ± 0.5 µm , respectively. Thus, these active ingredients may have value as new lead compounds for the development of new antidiabetic agents. Copyright © 2015 John Wiley & Sons, Ltd.     

α‐Glucosidase Inhibitors from the Stems of Embelia ribes

From the ethyl acetate extract of the stems of Embelia ribes (Myrsinaceae), a new alkenylresorcinol, embeliphenol A (1), together with 11 known compounds have been isolated. Their structures were elucidated on the basis of spectroscopic data. All compounds possessed significant α‐glucosidase inhibitory activity in a concentration‐dependent manner, except for 2 and 9. Compounds 1, 3–6, 8, and 12 showed more potent inhibitory activity, with IC₅₀ values ranging from 10.4 to 116.7 μM, than that of a positive control acarbose (IC₅₀, 214.5 μM). Copyright © 2014 John Wiley & Sons, Ltd.     

Pheophorbide A from Gelidium amansii improves postprandial hyperglycemia in diabetic mice through α‐glucosidase inhibition

This study was designed to determine the inhibitory effects of pheophorbide A on carbohydrate digesting enzymes and its ability to improve postprandial hyperglycemia in streptozotocin (STZ)‐induced diabetic mice. Pheophorbide A caused noticeable inhibitory effects on α‐glucosidase and α‐amylase, with half‐maximal inhibitory concentrations (IC₅₀) of 80.65 ± 5.90 and 76.48 ± 6.31 μM, respectively. The pheophorbide‐mediated inhibition of α‐glucosidase and α‐amylase was significantly more effective than that of the positive control, acarbose. The increase in postprandial blood glucose levels was more significantly suppressed in the pheophorbide A group than in the control group of STZ‐induced diabetic mice. In addition, the area under the curve was decreased by pheophorbide A intake in STZ‐induced diabetic mice. Our results suggested that pheophorbide A may help to improve postprandial hyperglycemia by inhibiting the activity of carbohydrate digesting enzymes.     

Medicinal Plants Traditionally Used for Treatment of Obesity and Diabetes Mellitus – Screening for Pancreatic Lipase and α‐Amylase Inhibition

In order to find new pancreatic lipase (PL) and α‐amylase inhibitors from natural sources for the treatment of obesity and related diseases as diabetes mellitus II, 23 medicinal plants with weight‐reducing, serum glucose‐reducing or related potential were investigated. Methanolic and water extracts of the plants were evaluated by using two in vitro test systems. Our findings have shown that the methanolic extract of Hibiscus sabdariffa L. (Malvaceae) showed high inhibitory activities to PL (IC₅₀: 35.8 ± 0.8 µg/mL) and α‐amylase (IC₅₀: 29.3 ± 0.5 µg/mL). Furthermore, the methanolic extract of Tamarindus indica L. (Leguminosae) showed a high anti‐lipase (IC₅₀: 152.0 ± 7.0 µg/mL) and the aqueous extract a high anti‐amylase (IC₅₀: 139.4 ± 9.0 µg/mL) activity. This work provides a priority list of interesting plants for further study with respect to the treatment of obesity and associated diseases. Copyright © 2015 John Wiley & Sons, Ltd.     

Dolichandroside A,a new α‐glucosidase inhibitor and DPPH free‐radical Scavenger from Dolichandrone falcata seem

A new phenylpropanoid glycoside, dolichandroside‐A, together with seven known compounds α‐lapachone, lapachol, aloesaponarin II, 8‐hydroxydehydroiso‐α‐lapachone, β‐sitosterol, 3,8‐dihydroxydehydroiso‐α‐lapachone and verbascoside were isolated from the active ethyl acetate soluble extract of heartwood of Dolichandrone falcata. All except for dolichandroside‐A are known compounds, but have been isolated for the first time from this plant. The structure of all these compounds was determined on the basis of 1D‐ and 2D‐NMR spectral data. All the isolates were tested for α‐glucosidase inhibitory and DPPH radical scavenging activity. This is the first report identifying DPPH scavenging activity and α‐glucosidase inhibitory activity in D. falcata. Furthermore, along with a new compound, dolichandroside‐A, this study also assigns for the first time α‐glucosidase inhibitory activity to verbascoside and aloe saponarin‐II. Copyright © 2008 John Wiley & Sons, Ltd.     

A Polyphenol‐rich Pomegranate Fruit Extract Suppresses NF‐κB and IL‐6 Expression by Blocking the Activation of IKKβ and NIK in Primary Human Chondrocytes

Pomegranate fruit extract (PE) rich in polyphenols has been shown to exert chondroprotective effects, but the mechanism is not established. Here, we used an in vitro model of inflammation in osteoarthritis (OA) to investigate the potential of PE to suppress interleukin 1 beta (IL‐1β)‐stimulated expression of inflammatory cytokine IL‐6, generation of reactive oxygen species (ROS) levels, and investigated the mechanism of NF‐κB inhibition by analyzing the activation of the kinases upstream of IκBα in primary human chondrocytes. Total and phosphorylated forms of kinases and expression of IL‐6 were determined at protein and mRNA levels by western immunoblotting and Taqman assay, respectively. Dihydrorhodamine 123 staining estimated ROS generation. Pomegranate fruit extract inhibited the mRNA and protein expression of IL‐6, generation of ROS, and inhibited the IL‐1β‐mediated phosphorylation of inhibitor of nuclear factor kappa‐B kinase subunit beta (IKKβ), expression of IKKβ mRNA, degradation of IκBα, and activation and nuclear translocation of NF‐κB/p65 in human chondrocytes. Importantly, phosphorylation of NF‐κB‐inducing kinase was blocked by PE in IL‐1β‐treated human OA chondrocytes. Taken together, these data suggest that PE exerts the chondroprotective effect(s) by suppressing the production of IL‐6 and ROS levels. Inhibition of NF‐κB activation by PE was blocked via modulation of activation of upstream kinases in human OA chondrocytes. Copyright © 2017 John Wiley & Sons, Ltd.     

Effect of Natural β‐Glucosidase Inhibitors in Reducing Toxicity of Amygdalin in Persicae Semen

Amygdalin can be decomposed into hydrocyanic acid, which is the primary source of Persicae Semen toxicity, by gut flora. Here, the inhibitory activity of β‐glucosidase for test herb extracts was first determined and compared. In turn, optimization of the ratio of substrate and inhibitor in vitro and LD₅₀ values of extracts, serum and liver contents of amygdalin in vivo was measured. Lycii Cortex was found to be the best inhibitory activity for β‐glucosidase. The ratio of amygdalin‐to‐Lycii Cortex extract of 7.19:8.18 (mmol L^?1/mg mL^?1) can be relatively suitable for inhibiting β‐glucosidase activity in test in vitro reaction system. After mixed with Lycii Cortex extract, the toxicity of Persicae Semen ethanol extract in mice is significantly reduced and more amygdalin can be absorbed into the bloodstream. The study provides useful information for reducing toxicity of Persicae Semen and suggests how to better use these natural β‐glucosidase inhibitors in the utilization of glycosides and aglycones. Copyright © 2017 John Wiley & Sons, Ltd.     

Antioxidant and Anti‐α‐glucosidase Compounds from the Rhizome of Peltiphyllum peltatum (Torr.) Engl

The antioxidant, anti‐α‐glucosidase and anticholinesterase effects of the alcohol extract of fresh underground rhizomes of Peltiphyllum peltatum were studied. A potent antioxidant activity accompanied by a selective α‐glucosidase effect was observed for the crude extract. Further activity‐guided fractionation (petroleum ether, chloroform, ethyl acetate, n‐butanol and water) resulted in the identification of the ethyl acetate fraction with the highest antioxidant effect. Gallic acid, methyl‐3‐O‐methyl gallate, catechin, gallocatechin, bergenin and 11‐O‐galloylbergenin were isolated from the ethyl acetate fraction. While all the isolated compounds did show a variable degree of radical scavenging effect, 11‐O‐galloylbergenin was identified as the selective α‐glucosidase inhibitor. The isolation, structural elucidation and biological effects of these compounds are discussed. Copyright © 2012 John Wiley & Sons, Ltd.     

Triterpene acids isolated from Lagerstroemia speciosa leaves as α‐glucosidase inhibitors

The potential antidiabetic activity of ethyl acetate extract of the leaves of Lagerstroemia speciosa (LSL) was investigated by α‐amylase and α‐glucosidase inhibition assay. Six pentacyclic triterpenes (oleanolic acid, arjunolic acid, asiatic acid, maslinic acid, corosolic acid and 23‐hydroxyursolic acid) were isolated from LSL. Their structures were determined by spectroscopic analysis and their α‐glycosidase and α‐amylase inhibitory activities were investigated. They exhibited no or weak inhibitory activity against α‐amylase and middle α‐glucosidase inhibitory activities. Corosolic acid, which shows best bioactivity against α‐glucosidase (IC₅₀ = 3.53 µg/mL), contributes most to the α‐glucosidase inhibitory activity of EtOAc extract. The kinetics of inhibition of corosolic acid was also discussed. Results from this study might provide the scientific evidence for LSL for the treatment of diabetes in traditional medicine. Copyright © 2008 John Wiley & Sons, Ltd.     

Daily Inhalation of α‐Pinene in Mice: Effects on Behavior and Organ Accumulation

In phytotherapy, essential oils tend to be used daily for a period of days or weeks, rather than in a single application. However, the literature contains very little information on repeated use of essential oils. In this study, we investigated the effects on behavior and the accumulation in the brain and liver of α‐pinene, an essential oil component, when inhaled by mice. Animals were individually housed in cages for 1 week. Mice inhaled α‐pinene or water vapor (negative control) for 90 min/day for 1 day, 3 days, or 5 days, and they were then submitted to the elevated plus maze test for 10 min. We used gas chromatography with flame ionization detection to quantify concentrations of α‐pinene in the brain and liver. There was significant anxiolytic‐like activity, which remained constant for the 5 days' inhalation of α‐pinene. On the other hand, the accumulation of α‐pinene in the brain and liver peaked on the third day of inhalation. The existence of stress related to the new environment appears to have affected the change in the accumulation of α‐pinene in the internal organs, keeping the anxiolytic‐like action constant. Copyright © 2013 John Wiley & Sons, Ltd.     

Sour Cherry Seed Kernel Extract Increases Heme Oxygenase‐1 Expression and Decreases Representation of CD3+ TNF‐α + and CD3 + IL‐8+ Subpopulations in Peripheral Blood Leukocyte Cultures from Type 2 Diabetes Patients

The present study evaluates a hypothesis that sour cherry (Prunus cerasus) seed extracts (SCE) modulate CD3+ T lymphocyte activity in ways predictive of potential for uses of SCE in management of inflammatory diseases. Peripheral blood mononuclear cells (PBMC) from 12 type 2 diabetes (T2DM) patients and eight healthy control subjects were cultured 24 h with 100 ng/ml lipopolysaccharide (LPS) to increase inflammatory signaling and co‐incubated with 0.5–100 µg/ml SCE. Cultures were evaluated by two‐color flow cytometry for percent representation of CD3+ IL8+ and CD3 + TNF‐α + cells which express interleukin‐8 (IL‐8), and tumor necrosis factor‐α, (TNF‐α+) respectively, and by enzyme‐linked immunoassay for lymphocyte‐associated heme oxygenase‐1 (HO‐1, known to be induced by SCE). SCE dosage ranges of 0.5–100 µg/ml in cell cultures significantly suppressed LPS‐increased CD3 + TNF‐α + and CD3 + IL8+ representation from all participants (p < 0.05), with greater pharmacological effect noted in suppression of CD3 + TNF‐α + noted in cells from T2DM patients versus healthy control subjects. These effects correlated with increased HO‐1 expression in SCE‐treated PBMC from all subjects (p < 0.05). Since TNF‐α and IL‐8 are diagnostic/prognostic biomarkers for many inflammatory syndromes, the capacity of SCE to down‐regulate representation of cells that express them suggests potential for therapeutic use of SCE in T2DM and other diseases. Copyright © 2012 John Wiley & Sons, Ltd.     

Hydroxy‐Safflower Yellow A inhibits the TNFR1‐Mediated Classical NF‐κB Pathway by Inducing Shedding of TNFR1

Hydroxy‐safflower yellow A (HSYA) is the major active component of safflower, a traditional Asia herbal medicine well known for its cardiovascular protective activities. The purpose of this study was to investigate the effect of HSYA on TNF‐α‐induced inflammatory responses in arterial endothelial cells (AECs) and to explore the mechanisms involved. The results showed that HSYA suppressed the up‐regulation of ICAM‐1 expression in TNF‐α‐stimulated AECs in a dose‐dependent manner. High concentration (120 μM) HSYA significantly inhibited the TNF‐α‐induced adhesion of RAW264.7 cells to AECs. HSYA blocked the TNFR1‐mediated phosphorylation and degradation of IκBα and also prevented the nuclear translocation of NF‐κB p65. Moreover, HSYA reduced the cell surface level of TNFR1 and increased the content of sTNFR1 in the culture media. TNF‐α processing inhibitor‐0 (TAPI‐0) prevented the HSYA inhibition of TNFR1‐induced IκBα degradation, implying the occurrence of TNFR1 shedding. Furthermore, HSYA induced phosphorylation of TNF‐α converting enzyme (TACE) at threonine 735, which is thought to be required for its activation. Conclusively, HSYA suppressed TNF‐α‐induced inflammatory responses in AECs, at least in part by inhibiting the TNFR1‐mediated classical NF‐κB pathway. TACE‐mediated TNFR1 shedding can be involved in this effect. Our study provides new evidence for the antiinflammatory and anti‐atherosclerotic effects of HSYA. Copyright © 2016 John Wiley & Sons, Ltd.     

Phloroglucinol Protects INS‐1 Pancreatic β‐cells Against Glucotoxicity‐Induced Apoptosis

Decreasing numbers, and impaired function, of pancreatic β‐cells are key factors in the development of type 2 diabetes. This study was designed to investigate whether phloroglucinol protected pancreatic β‐cells against glucotoxicity‐induced apoptosis using a rat insulinoma cell line (INS‐1). High glucose treatment (30 mM) induced INS‐1 cell death; however, the level of glucose‐induced apoptosis was significantly reduced in cells treated with 100‐μM phloroglucinol. Treatment with 10–100‐μM phloroglucinol increased cell viability and decreased intracellular levels of reactive oxygen species, nitric oxide, and lipid peroxidation dose‐dependently in INS‐1 cells pretreated with high glucose. Furthermore, phloroglucinol treatment markedly reduced the protein expression of Bax, cytochrome c, and caspase 9, while increasing anti‐apoptotic Bcl‐2 protein expression. Cell death type was examined using annexin V/propidium iodide staining, revealing that phloroglucinol markedly reduced high glucose‐induced apoptosis. These results demonstrated that phloroglucinol could be useful as a potential therapeutic agent for the protection of pancreatic β‐cells against glucose‐induced apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.     

Ameliorative Effects of Pine Bark Extract on Spermatotoxicity by α‐Chlorohydrin in Rats

We investigated the protective effects of pine bark extract (Pycnogenol®, PYC, Horphag Research Ltd., Route de Belis, France) against α‐chlorohydrin (ACH)‐induced spermatotoxicity in rats. Rats were orally administered ACH (30 mg/kg/day) with or without PYC (20 mg/kg/day) for 7 days. Administration of ACH significantly decreased sperm motility. α‐Chlorohydrin also caused histopathological alterations and apoptotic changes in caput epididymides. An increased malondialdehyde concentration and decreased glutathione content, as well as catalase and glutathione peroxidase activities were also found. In contrast, PYC treatment significantly prevented ACH‐induced spermatotoxicity, including decreased sperm motility, histopathological lesions, and apoptotic changes in the caput epididymis. Pycnogenol® also had an antioxidant benefit by decreasing malondialdehyde and increasing levels of the antioxidant glutathione and the activities of the antioxidant enzymes catalase and peroxidase in epididymal tissues. These results indicate that PYC treatment attenuated ACH‐induced spermatotoxicity through antioxidant and antiapoptotic effects. Copyright © 2013 John Wiley & Sons, Ltd.     

Identification of higenamine as a novel α1‐adrenergic receptor antagonist

The α₁‐adrenoceptor (α₁‐AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α₁‐AR antagonist. In this study, we investigated the effects of HG in HEK293A cells transfected with α_1A‐, α_1B‐, and α_1D‐AR in vitro, rat mesenteric artery ex vivo, Wistar–Kyoto rats and spontaneously hypertensive rats in vivo. The radioligand binding assay showed that HG competitively inhibited the binding of [³H]‐prazosin to α₁‐AR in a concentration‐dependent manner. The affinities (pKi) of HG for the cloned α_1A‐, α_1B‐, and α_1D‐AR were 6.57, 6.48, and 6.35, respectively, indicating that HG displayed no selectivity for the three α₁‐AR subtypes. In in vitro studies, HG was able to blunt inositol monophosphate production. It also displayed an inhibitory effect on the influx and entry of calcium ions and phosphorylation of extracellular signal‐regulated kinase 1 and 2 induced by phenylephrine (PE). In ex vivo studies, PE caused a dose‐dependent inotropic response curve, and the pA₂ value for HG was 6.86 ± 0.29. In addition, the in vivo results showed that HG could decrease the blood pressure in normotension, spontaneous hypertension, and PE‐induced hypertension models. These results indicate that HG can directly bind to α₁‐AR and it appears to be a novel antagonist for α₁‐AR, which may contribute to its hypotensive effect.     

Chelidonine inhibits TNF‐α‐induced inflammation by suppressing the NF‐κB pathways in HCT116 cells

Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) is a complex that regulates several hundreds of genes, including those involved in immunity and inflammation, survival, proliferation, and the negative feedback of NF‐κB signaling. Chelidonine, a major bioactive, isoquinoline alkaloid ingredient in Chelidonium majus, exhibits antiinflammatory pharmacological properties. However, its antiinflammatory molecular mechanisms remain unclear. In this work, we explored the effect of chelidonine on TNF‐induced NF‐κB activation in HCT116 cells. We found chelidonine inhibited the phosphorylation and degradation of the inhibitor of NF‐κB alpha and nuclear translocation of RELA. Furthermore, by inhibiting the activation of NF‐κB, chelidonine downregulated target genes involved in inflammation, proliferation, and apoptosis. Chelidonine also inhibited mitogen‐activated protein kinase pathway activation by blocking c‐Jun N‐terminal kinase and p38 phosphorylation. These results suggest that chelidonine may be a potential therapeutic agent against inflammatory diseases in which inhibition of NF‐κB activity plays an important role.     

Analgesic and diuretic properties of α‐santalone from Polygonum flaccidum

Polygonum flaccidum Meissn. is an annual herb, native to Bangladesh, and well known for its analgesic, anti‐inflammatory, diuretic, purgative and insecticidal properties, and also for its use against snake‐bites. The analgesic and the diuretic properties of α‐santalone (1), isolated from the aerial parts of Polygonum flaccidum, were assessed by the acetic‐acid‐induced writhing method and the Lipschitz test, respectively. Complete ¹H and ¹³C NMR data of 1 are also presented. Copyright © 2010 John Wiley & Sons, Ltd.     

Parthenolide Inhibits the LPS‐induced Secretion of IL‐6 and TNF‐α and NF‐κB Nuclear Translocation in BV‐2 Microglia

Feverfew (Tanacetum parthenium [L.] Sch. Bip. [Asteraceae]) is a popular herbal treatment used to prevent and treat headache and migraine. Parthenolide (PTN), the sesquiterpene lactonic derivative that is the plant's major component, might be one of the ingredients that act on mediators of inflammation. In the present study, in cultured lipopolysaccharide (LPS)‐stimulated BV‐2 microglia pretreatment with PTN caused a dose‐dependent reduction of interleukin‐6 (IL‐6) secretion (29% by 200 nm, p < 0.001; 45% by 1 µm, p < 0.001; 98% by 5 µm, p < 0.001); at 5 µm, the highest concentration tested, it also reduced the secretion of TNF‐α (54%, p < 0.001). Western blotting analysis on separate cytoplasmic and nuclear extracts showed that PTN strongly reduced the translocation of nuclear factor (NF)‐κB to the cell nucleus. The reduction of microglial activation by inhibition of proinflammatory agents may help attenuate the onset and intensity of acute migraine attacks. These in vitro results provide an additional explanation for the efficacy of orally administered T. parthenium as an antimigraine agent. Copyright © 2012 John Wiley & Sons, Ltd.     

The Protective Effect of α‐Hederin,the Active Constituent of Nigella sativa,on Lung Inflammation and Blood Cytokines in Ovalbumin Sensitized Guinea Pigs

In the present study, the preventive effect of two different concentrations of α‐hederin, the active constituent of Nigella sativa, on lung inflammation and blood cytokines in ovalbumin sensitized guinea pigs was examined. Forty eight male adult guinea pigs were divided into control (C), sensitized (S) and sensitized pretreated groups; with thymoquinone (S+TQ), low dose (S+LAH) and high dose of α‐hederin (S+HAH) and inhaled fluticasone propionate (S+FP). The lung histopathology and blood levels of IL‐4, IFN‐γ and IL‐17 were assessed. Compared to sensitized animals, all pathological changes improved significantly in pretreated groups (p < 0.001 to p < 0.05). These improvements in α‐hederin pretreated groups were similar to S+TQ and S+FP groups except cellular infiltration in S+LAH and S+HAH groups which was lower than S+TQ group (p < 0.05). The blood IL‐4 and IL‐17 levels in S+HAH groups showed a significant decrease compared to S group (p < 0.05) which were similar to S+TQ and S+FP groups. The level of IFN‐γ in S+LAH and S+HAH groups increased significantly compared to S group (p < 0.05) which was higher than S+FP group (p < 0.05). Blood IL‐4 in S+HAH group was significantly lower than S+LAH group (p < 0.05). In conclusion, α‐hederin could attenuate the lung inflammation and improve the changes of cytokines like thymoquinone and fluticasone in used dosages. Copyright © 2015 John Wiley & Sons, Ltd.     

Effects of Lonicera japonica Thunb. on Type 2 Diabetes via PPAR‐γ Activation in Rats

Lonicera japonica Thunb. (Caprifoliaceae) is a traditional herbal medicine and has been used to treat diabetic symptoms. Notwithstanding its use, the scientific basis on anti‐diabetic properties of L. japonica is not yet established. This study is designed to investigate anti‐diabetic effects of L. japonica in type 2 diabetic rats. L. japonica was orally administered at the dose of 100 mg/kg in high‐fat diet‐fed and low‐dose streptozotocin‐induced rats. After the treatment of 4 weeks, L. japonica reduced high blood glucose level and homeostatic model assessment of insulin resistance in diabetic rats. In addition, body weight and food intake were restored by the L. japonica treatment. In the histopathologic examination, the amelioration of damaged β‐islet in pancreas was observed in L. japonica‐treated diabetic rats. The administration of L. japonica elevated peroxisome proliferator‐activated receptor gamma and insulin receptor subunit‐1 protein expressions. The results demonstrated that L. japonica had anti‐diabetic effects in type 2 diabetic rats via the peroxisome proliferator‐activated receptor gamma regulatory action of L. japonica as a potential mechanism. Copyright © 2015 John Wiley & Sons, Ltd.