Van Hoan Tran

Gingerols: A novel class of vanilloid receptor (VR1) agonists

Gingerols, the pungent constituents of ginger, were synthesized and assessed as agonists of the capsaicin‐activated VR1 (vanilloid) receptor. [6]‐Gingerol and [8]‐gingerol evoked capsaicin‐like intracellular Ca2+ transients and ion currents in cultured DRG neurones. These effects of gingerols were blocked by capsazepine, the VR1 receptor antagonist. The potency of gingerols increased with increasing size of the side chain and with the overall hydrophobicity in the series. We conclude that gingerols represent a novel class of naturally occurring VR1 receptor agonists that may contribute to the medicinal properties of ginger, which have been known for centuries. The gingerol structure may be used as a template for the development of drugs acting as moderately potent activators of the VR1 receptor.

Gingerols and Related Analogues Inhibit Arachidonic Acid-Induced Human Platelet Serotonin Release and Aggregation

Gingerols, the active components of ginger (the rhizome of Zingiber officinale, Roscoe), represent a potential new class of platelet activation inhibitors. In this study, we examined the ability of a series of synthetic gingerols and related phenylalkanol analogues (G1-G7) to inhibit human platelet activation, compared to aspirin, by measuring their effects on arachidonic acid (AA)-induced platelet serotonin release and aggregation in vitro. The IC(50) for inhibition of AA-induced (at EC(50)=0.75 mM) serotonin release by aspirin was 23.4+/-3.6 microM. Gingerols and related analogues (G1-G7) inhibited the AA-induced platelet release reaction in a similar dose range as aspirin, with IC(50) values between 45.3 and 82.6 microM. G1-G7 were also effective inhibitors of AA-induced human platelet aggregation. Maximum inhibitory (IC(max)) values of 10.5+/-3.9 and 10.4+/-3.2 microM for G3 and G4, respectively, were approximately 2-fold greater than aspirin (IC(max)=6.0+/-1.0 microM). The remaining gingerols and related analogues maximally inhibited AA-induced platelet aggregation at approximately 20-25 microM. The mechanism underlying inhibition of the AA-induced platelet release reaction and aggregation by G1-G7 may be via an effect on cyclooxygenase (COX) activity in platelets because representative gingerols and related analogues (G3-G6) potently inhibited COX activity in rat basophilic leukemia (RBL-2H3) cells. These results provide a basis for the design of more potent synthetic gingerol analogues, with similar potencies to aspirin, as platelet activation inhibitors with potential value in cardiovascular disease.

Chemistry and pharmacology of Gynostemma pentaphyllum

In traditional Chinese medicine, Gynostemma pentaphyllum (Thunb.) Makino is a herbal drug of extreme versatility and has been extensively researched in China. The dammarane saponins isolated from Gynostemma pentaphyllum, namely gypenosides or gynosaponins, are believed to be the active components responsible for its various biological activities and reported clinical effects. This review attempts to encompass the available literature on Gynostemma pentaphyllum, from its cultivation to the isolation of its chemical entities and a summary of its diverse pharmacological properties attributed to its gypenoside content. Other aspects such as toxicology and pharmacokinetics are also discussed. In vitro and in vivo evidence suggests that Gynostemma pentaphyllum may complement the popular herbal medicine, Panax ginseng, as it also contains a high ginsenoside content and exhibits similar biological activities.

Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review

Zingiber officinale (ginger) has been used as herbal medicine to treat various ailments worldwide since antiquity. Recent evidence revealed the potential of ginger for treatment of diabetes mellitus. Data from in vitro, in vivo, and clinical trials has demonstrated the antihyperglycaemic effect of ginger. The mechanisms underlying these actions are associated with insulin release and action, and improved carbohydrate and lipid metabolism. The most active ingredients in ginger are the pungent principles, gingerols, and shogaol. Ginger has shown prominent protective effects on diabetic liver, kidney, eye, and neural system complications. The pharmacokinetics, bioavailability, and the safety issues of ginger are also discussed in this update.

Prenylated cinnamate and stilbenes from Kangaroo Island propolis and their antioxidant activity

A prenylated cinnamic acid derivative as well as six prenylated tetrahydroxystilbenes were isolated from the ethyl acetate extract of propolis that originated from Kangaroo Island, Australia. Furthermore, six known stilbenes and two known flavanones were also identified from the same sample. Stilbenes are not common in propolis; therefore, Kangaroo Island propolis is considered a unique type of propolis that is rich in prenylated stilbenes. Stilbene propolis from Kangaroo Island showed a stronger scavenging activity towards DPPH free radical than Brazilian green propolis. This strong activity can be explained by the presence of large number of stilbenes, most of them showed strong free radical scavenging activity.

Modulation of P-glycoprotein-mediated anticancer drug accumulation, cytotoxicity, and ATPase activity by flavonoid interactions

Flavonoids are components of plant foods and of many herbal medicines taken in combination with anticancer drugs. We have examined the potential of flavonoids to affect the accumulation and cytotoxicity of 3 cytotoxic drugs [vinblastine (VLB), daunorubicin (DNR), and colchicine (COL)] that are substrates for the ABC transporter, P-glycoprotein in a vinblastine-resistant T-cell leukemia, CEM/VBL100, that overexpresses P-glycoprotein. The effects of the flavonoids on accumulation and cytotoxicity of these drugs were different depending on the P-gp substrate used. Most of the 30 flavonoids tested decreased DNR accumulation in the VBL-resistant, but not sensitive, leukemia cells. By contrast, flavonoids that inhibited DNR accumulation enhanced the accumulation of fluorescently labeled vinblastine. None of these flavonoids affected COL accumulation. The effects of the flavonoids on the cytotoxicities of these drugs paralleled their effects on accumulation; the same flavonoids decreased DNR cytotoxicity but increased VLB cytotoxicity and had no effect on COL. Verapamil reversed the accumulation deficit and cytotoxicity of all three P-gp substrates. These effects correlated with the effects of flavonoids on P-gp-ATPase activity. Flavonoids that decreased DNR accumulation stimulated DNR-activated P-gp ATPase, whereas flavonoids that increased fluorescently labeled VLB accumulation inhibited VBL-stimulated P-gp ATPase activity, thereby accounting for the decrease or increase in cancer drug accumulation in resistant cells. We conclude that flavonoids often ingested by cancer patients may have different effects on anticancer drugs and that these findings should be considered in designing future combination treatments for cancer patients.

Attenuation of Proinflammatory Responses by S-[6]-Gingerol via Inhibition of ROS/NF-Kappa B/COX2 Activation in HuH7 Cells

Introduction. Hepatic inflammation underlies the pathogenesis of chronic diseases such as insulin resistance and type 2 diabetes mellitus. S-[6]-Gingerol has been shown to have anti-inflammatory properties. Important inflammatory mediators of interleukins include nuclear factor κB (NFκB) and cyclooxygenase 2 (COX2). We now explore the mechanism of anti-inflammatory effects of S-[6]-gingerol in liver cells. Methods. HuH7 cells were stimulated with IL1β to establish an in vitro hepatic inflammatory model. Results. S-[6]-Gingerol attenuated IL1β-induced inflammation and oxidative stress in HuH7 cells, as evidenced by decreasing mRNA levels of inflammatory factor IL6, IL8, and SAA1, suppression of ROS generation, and increasing mRNA levels of DHCR24. In addition, S-[6]-gingerol reduced IL1β-induced COX2 upregulation as well as NFκB activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NFκB inhibitor) suppressed mRNA levels of IL6, IL8, and SAA1. Importantly, PDTC attenuated IL1β-induced overexpression of COX2. Of particular note, the protective effect of S-[6]-gingerol against the IL1β-induced inflammatory response was similar to that of BHT, an ROS scavenger. Conclusions. The findings of this study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1β-induced inflammatory insults through inhibition of the ROS/NFκB/COX2 pathway.

Characterization of PXR mediated P-glycoprotein regulation in intestinal LS174T cells

Intestinal P-glycoprotein (P-gp) is an important target in drug-drug interactions. Pregnane X receptor (PXR) mediates the induction of intestinal P-gp. The LS174T intestinal cell line has been used in several studies as an in vitro tool to identify the effect of PXR inducers on intestinal P-gp expression. In this study we aimed to further characterize this cell line by focusing on the time dependence of P-gp expression, localization and function in the presence of rifampicin, a P-gp inducer. P-gp protein expression was increased in a time and dose dependent manner following exposure of cells to rifampicin (5-50 μM). The induction of P-gp by rifampicin and its inhibition by ketoconazole (an inhibitor of PXR mediated P-gp induction) confirms the suitability of these cells for PXR induction studies. Confocal microscopy showed that P-gp translocated from intracellular compartments to plasma membrane over 7 days in LS174T cells. P-gp function, as established by rhodamine 123 (Rh123) intracellular accumulation, correlated with increasing P-gp expression and plasma membrane localization over this period. Our data demonstrates that LS174T cells provide a suitable in vitro model to test for the effect of PXR inducers/inhibitors on P-gp induction, localization and function over this culture period. This model also has application for the screening of drug candidates for effects on oral bioavailability via effects on the subcellular distribution and trafficking of P-gp.

Investigation of plant‐derived phenolic compounds as plasma membrane Ca2+‐ATPase inhibitors with potential cardiovascular activity

Various flavonoids and alkylphenols have been reported to inhibit the Ca2+‐ATPase of plasma membrane (PM) and sarcoplasmic reticulum Ca2+‐ATPase. This article describes the development of phenolic inhibitors of PM Ca2+‐ATPase as potential cardiovascular agents. The new inhibitors were obtained from the screening of alkylphenols, alkylresorcinols, and phenolic constituents of medicinal plants, followed by synthesis of analogues and analysis of their structure–activity relationships. Alkylphenols were found to inhibit the PM Ca2+‐ATPase, with 2‐nonylphenol being the most potent compound (IC50 = 30 μM) among a series of synthetic phenols. Several bis‐resorcinols were isolated from the Australian plants Grevillea robusta and Grevillea striata, including two novel compounds which were identified as 1‐(1,3‐dihydroxy‐4‐methylphenyl)‐14‐(1,3‐dihydroxyphenyl)tetradec‐8‐Z‐ene (grebustol‐A) and norstriatol‐B. Among these bis‐resorcinols, striatol was found to be the most potent inhibitor of PM Ca2+‐ATPase, with an IC50 value of 16 μM. Analogues of bis‐phenols and bis‐resorcinols were synthesised and investigated for Ca2+‐ATPase inhibitory activity. It was found that 2,2′‐(decane‐1,10‐diyl)bisphenol (decanediyl‐bisphenol) was the most potent inhibitor (IC50 = 10 μM). The synthetic bis‐phenols and alkylphenols were shown to inhibit the PM Ca2+‐ATPase in a concentration‐ and structure‐dependent fashion. The inhibitory activity of decanediyl‐bisphenol was also demonstrated in reconstituted purified Ca2+‐ATPase from human erythrocyte plasma membrane and in intact red blood cells and smooth muscle cells. The mechanism of action of these inhibitors, however, is not fully understood but presumably, due to their high lipophilic nature, they would interact with the hydrophobic interior or at the lipid–protein interface, thereby perturbing the Ca2+‐ATPase enzyme function. The inhibition was independent of calmodulin stimulation. The inhibition of Ca2+‐ATPase was selective relative to the Na+,K+‐ATPase and Mg2+‐ATPase in the same membrane preparations. These results indicate that bis‐phenolic compounds may be useful in studying the function of PM Ca2+‐ATPase and regulation of intracellular Ca2+, and may have potential cardiovascular activities. Drug Dev. Res. 46:235–249, 1999.© 1999 Wiley‐Liss, Inc.

Preventative effect of Zingiber officinale on insulin resistance in a high-fat high-carbohydrate diet-fed rat model and its mechanism of action.

Insulin resistance is a core component of metabolic syndrome and usually precedes the development of type 2 diabetes mellitus. We have examined the preventative effect of an ethanol extract of ginger (Zingiber officinale, Zingiberaceae) on insulin resistance in a high‐fat high‐carbohydrate (HFHC) diet‐fed rat model of metabolic syndrome. The HFHC control rats displayed severe insulin resistance, whilst rats treated with ginger extract (200 mg/kg) during HFHC diet feeding showed a significant improvement of insulin sensitivity using the homeostatic model assessment of insulin resistance (HOMA‐IR) after 10 weeks (p < 0.01). An in vitro mechanistic study showed that (S)‐[6]‐gingerol, the major pungent phenolic principle in ginger, dose‐dependently (from 50 to 150 μM) increased AMPK α‐subunit phosphorylation in L6 skeletal muscle cells. This was accompanied by a time‐dependent marked increment of PGC‐1α mRNA expression and mitochondrial content in L6 skeletal muscle cells. These results suggest that the protection from HFHC diet‐induced insulin resistance by ginger is likely associated with the increased capacity of energy metabolism by its major active component (S)‐[6]‐gingerol.