Resveratrol Analogues Research Articles

Tetramethoxystilbene-Loaded Liposomes Restore Reactive-Oxygen-Species-Mediated Attenuation of Dilator Responses in Rat Aortic Vessels Ex vivo.

The methylated analogue of the polyphenol resveratrol (RV), 2,3′,4,5′-tetramethoxystilbene (TMS) displays potent antioxidant properties and is an effective cytochrome P450 (CYP) 1B1 inhibitor. The bioavailability of TMS is low. Therefore, the use of liposomes for the encapsulation of TMS is a promising delivery modality for enhanced uptake into tissues. We examined the effect of delivery of TMS in liposomes on the restoration of vasodilator responses of isolated aortic vessels after acute tension elevation ex vivo. Aortic vessels from young male Wistar rats were isolated, and endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) responses assessed. Acute tension elevation (1 h) significantly reduced ACh dilator responses, which were restored following incubation with superoxide dismutase or apocynin (an NADPH oxidase inhibitor). Incubation with TMS-loaded liposomes (mean diameter 157 ± 6 nm; PDI 0.097) significantly improved the attenuated dilator responses following tension elevation, which was sustained over a longer period (4 h) when compared to TMS solution. Endothelial denudation or co-incubation with L-NNA (Nω-nitro-l-arginine; nitric oxide synthase inhibitor) resulted in loss of dilator function. Our findings suggest that TMS-loaded liposomes can restore attenuated endothelial-dependent dilator responses induced by an oxidative environment by reducing NADPH-oxidase-derived ROS and potentiating the release of the vasodilator nitric oxide. TMS-loaded liposomes may be a promising therapeutic strategy to restore vasodilator function in vascular disease.

Synthetic Imine Resveratrol Analog 2-Methoxyl-3,6-Dihydroxyl-IRA Ameliorates Colitis by Activating Protective Nrf2 Pathway and Inhibiting NLRP3 Expression.

Resveratrol (RSV) is a naturally occurring polyphenol that exhibits pleiotropic health benefits, including anticolitis and colon cancer-protective activity. Recently, we identified the novel imine RSV analog (IRA), 2-methoxyl-3,6-dihydroxyl-IRA 3,4,5,4-tetramethoxystilbene (C33), as a putative activator of nuclear factor erythroid 2-related factor 2 (Nrf2). The present study was designed to evaluate the ability of C33 to activate the Nrf2 signaling pathway and its anticolitis effect in comparison to RSV. The anticolitis action of C33 was assessed in a mouse model of colitis induced by dextran sulfate sodium (DSS). The effect of C33 on the Nrf2 signaling pathway was examined in vitro and in vivo. Compared to RSV, C33 triggered a more dramatic increase in the expression of genes downstream of Nrf2 in LS174T cells as well as in the small intestine and colon of wild-type (WT) mice. Correlated with its superior ability to activate the cytoprotective Nrf2 pathway, C33 was significantly better in ameliorating DSS-induced colitis by improving the inflammation score, as well as downregulating the markers of inflammation in WT mice. Moreover, induction of the NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome by colitis was also significantly inhibited by the IRA. Nrf2 knockout completely abolished the effects of C33, indicating that Nrf2 is the important mechanistic target of C33 in vivo. In conclusion, the novel IRA, C33, has stronger anticolitis effects than RSV. Further studies are warranted to evaluate C33 as a potential therapeutic agent for inflammatory bowel disease and cancer chemoprevention.

PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades.

Doxorubicin (DOX) is a widely used and potent anticancer agent, but DOX dose-dependently induced cardiotoxicity greatly limits its use in clinic. Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. The present study explored the action and detailed mechanism of pterostilbene on DOX-treated cardiomyocytes. We investigated the effects of pterostilbene on established acute DOX-induced cardiotoxicity models in both H9c2 cells treated with 1 μM DOX and C57BL/6 mice with DOX (20 mg/kg cumulative dose) exposure. Pterostilbene markedly alleviated the DOX exposure-induced acute myocardial injury. Both in vitro and in vivo studies revealed that pterostilbene inhibited the acute DOX exposure-caused oxidative stress and mitochondrial morphological disorder via the PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. However, these effects were partially reversed by knockdown of AMPK or SIRT1 in vitro and treatment of Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) in vivo. Our results indicate that pterostilbene protects cardiomyocytes from acute DOX exposure-induced oxidative stress and mitochondrial damage via PGC1α upregulation and deacetylation through activating AMPK and SIRT1 cascades.

Pterostilbene Attenuates Experimental Atherosclerosis through Restoring Catalase-Mediated Redox Balance in Vascular Smooth Muscle Cells.

Atherosclerosis, the major risk of cardiovascular events, is a chronic vascular inflammatory disease. Pterostilbene is a naturally occurring dimethylated analogue of resveratrol and has recently been demonstrated to be beneficial against cardiovascular diseases. However, the underlying mechanisms of pterostilbene on atherosclerosis remain elusive. Experimental atherosclerosis was induced by a high-fat diet (HFD) in apolipoprotein E knockout (ApoE-/-) mice. Pterostilbene was administered intragastrically for 16 weeks. We found that pterostilbene significantly attenuated thoracic and abdominal atherosclerotic plaque formation in HFD-fed ApoE-/-mice, accompanied by modulated lipid profiles and reduced production of proinflammatory cytokines (including IL-6, IFN-γ, and TNF-α). In addition, pterostilbene restored vascular redox balance in thoracic and abdominal aorta, evidenced by enhanced catalase (CAT) expression and activities, and decreased malondialdehyde and H2O2 production. Notably, pterostilbene specifically induced CAT expression and activities in the vascular smooth muscle cells (VSMCs) of thoracic and abdominal aorta. In vitro, pterostilbene markedly promoted the expression and activity of CAT and decreased ox-low-density lipoprotein (LDL)-mediated VSMC proliferation and intracellular H2O2 production, which was abolished by CAT siRNA knockdown or inhibition. Pterostilbene-induced CAT expression was associated with inhibition of Akt, PRAS40, and GSK-3β signaling activation and upregulation of PTEN. Our data clearly demonstrated that pterostilbene exerted an antiatherosclerotic effect by inducing CAT and modulating the VSMC function.

Enzyme-mediated oxidative dimerization reactions of cyano-resveratrol analogues

The synthesis and oxidative coupling reactions of two cyano-resveratrol analogues were studied. An 8-5-coupled dihydrobenzofuran-type dimer and an 8-8-coupled diastereoisomeric indane mixture were prepared. The cyano groups of the resveratrol analogues had almost no influence on the regio- or stereoselectivity of the coupling reactions of the two precursors.

Molecular modeling, simulation and principal component analysis of binding of resveratrol and its analogues with DNA

Structure-based drug designing has become a significant subject of research, and several clinically promising DNA binding compounds were evolved using this technique. The interaction of an octamer DNA sequence d(CCAATTGG)2 with a natural stilbene, resveratrol and its analogues have been studied using molecular docking method. Out of the ten compounds studied, seven compounds were found to bind to the minor groove of AATT segment of the sequence. Pterostilbene, a natural analogue of resveratrol, showed the lowest binding energy. Rhaponticin, a natural analogue of resveratrol and digalloylresveratrol, a synthetic ester of resveratrol bind to the major groove of the AATT segment while dihydroresveratrol binds to the minor groove of GC terminal base pair. ADMET (Absorption, distribution, metabolism, excretion and toxicity) study showed that all compounds obey Lipinski rule and are accepted as orally active drugs based on different physicochemical descriptors. Molecular dynamics simulations were performed for the complex with lowest binding energy and trajectory analysis were performed. Principal component analysis has been performed to underline the prominent motions in alone DNA and when it is bound to pterostilbene. Abbreviations ADMET Absorption, distribution, metabolism, excretion and toxicity DIG Digalloyl resveratrol DNA Deoxyribonucleic acid EL Electrostatic energy ENPOLAR Nonpolar solvation energy ESURF Surface area GB Generalized Born HBA Hydrogen bond acceptors HBD Hydrogen bond donors LGA Lamarckian genetic algorithm MD Molecular dynamics PB Poisson-Boltzmann PCA Principal component analysis PT Pterostilbene RMSD Root mean square deviation SA Simulated annealing TLX3 T-cell leukemia homeobox 3 VDW van der Waals Communicated by Ramaswamy H. Sarma

Design, synthesis and biological evaluation of a series of new resveratrol analogues as potential anti-cancer agents.

A series of novel resveratrol derivatives were designed, synthesized and evaluated as anti-cancer agents. Most of the compounds showed significant anti-proliferative activities against three human cancer cell lines (HepG2, A549 and Hela). Among these compounds, compound r displayed the most potent inhibitory activity and showed low cytotoxic activity. Cell apoptosis and cell cycle assays demonstrated that compound r significantly induced apoptosis (p < 0.001) and arrested cell cycle at S phase. Immunofluorescence microscopy analysis showed compound r disrupted the tubulin network. Docking simulations supported the pharmacological results of compound r. It is believed that this work would be very useful for designing a new series of tubulin inhibitors.

Emerging therapeutic potentials of dual‐acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases

No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson's disease (PD) or Alzheimer's disease (AD); despite increased comprehension of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the "one protein, one target" philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A2A A receptors, in conjunction with strategies to counter oxidative stress and beta-amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual-acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A2A A receptors, and describes the structure-activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil-propargylamine conjugates, homoisoflavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling pathways and numerous drug targets.

Application of linear solvation energy relationships and principal component analysis methods for the prediction of the retention behaviour of E-resveratrol analogues with substituted silica hydride stationary phases

In this investigation, application of linear solvent energy relationships (LSERs) and principal component analysis (PCA) methods have been employed to investigate the structure-retention dependencies of E-resveratrol analogues separated under different stationary and mobile phase conditions. To this end, the retention of 22 analogues have been determined with phenyl, diol, bidentate anchored C18 (BDC18) and Diamond Hydride™ C18 (DHC18) substituted silica hydride stationary phases under isocratic chromatographic conditions using mobile phases containing 0.1 (% v/v) formic acid and different acetonitrile or methanol contents from 10 to 90% (v/v) in 10% increments. In general, these compounds showed decreasing retention with increased acetonitrile or methanol content in the mobile phase with all the stationary phases. The retention order generally followed their log P values, although some unique selectivity variations were apparent depending on the nature of the selected stationary and mobile phases. These 22 compounds contained different backbone functionalities linking the phenyl ring A to phenyl ring B and different numbers of hydroxyl groups in the phenyl ring A/phenyl ring B. Structure-retention descriptors, derived according to LSER concepts, were analysed by PCA methods to provide group classification of these resveratrol analogues from the associated PC1 versus PC2 score plots. These results revealed that the selectivity of these compounds was dominated by hydrophobic and steric interactions. Based on the number and position of hydroxyl groups in a specific resveratrol analogue, a reliable curve fitting approach (indicated by R2 > 0.99 for the correlation between experimental and predicted log k values) was derived for prediction of the retention of these analytes under different mobile phase isocratic separation conditions. The application of similar methods are anticipated to find general utility for the analysis of diverse classes of other low molecular mass compounds in the different modes of liquid chromatography, permitting enhanced levels of prediction and evaluation of the retention attributes of polar and non-polar compounds.

Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85 μM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100 μM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50 > 100 μM) but inhibited collagen induced platelet aggregation at 50 μM and 100 μM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100 μM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85 μM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor.

A Novel Quinolyl-Substituted Analogue of Resveratrol Inhibits LPS-Induced Inflammatory Responses in Microglial Cells by Blocking the NF-κB/MAPK Signaling Pathways.

The anti-neuroinflammatory effect of a novel quinolyl-substituted analogue of resveratrol (RV01) on lipopolysaccharide (LPS)-induced microglial activation is investigated, as well as the possible underlying mechanisms. Cell viability is measured using an MTT assay. Nitric oxide (NO) release is determined by nitrite assay. The interaction between RV01 and inducible nitric oxide synthase (iNOS) is studied using molecular docking. Free radical scavenging activity and reactive oxygen species (ROS) production are determined by DPPH reduction assay and DCFH-DA assay. Pretreatment with RV01 (1-30µm) prior to LPS (1µgmL-1 ) stimulation decreased NO release and iNOS expression without observable cytotoxicity. RV01 reduced the mRNA levels and secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RV01 also inhibited LPS-induced ROS production and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Furthermore, RV01 decreases the protein expression of toll-like receptor 4 (TLR4) and inhibits the LPS-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear transcription factor-κB (NF-κB) signaling pathways. Additionally, conditioned medium from microglia co-treated with LPS and RV01 alleviates the death of SH-SY5Y cells induced by conditioned medium from activated N9 microglial cells. Lastly, a mouse neuroinflammation model is further used to confirm the effect of RV01 in vivo. These results show that RV01 suppresses microglia-mediated neuroinflammation and protects neurons from inflammatory damage, which indicates that RV01 has great potential as a nutritional preventive strategy for neuroinflammation-related diseases.

Abstract 304: Pgc1a Activation by Pterostilbene Ameliorates Acute Doxorubicin Cardiotoxicity via Reducing Mitochondrial Oxidative Stress Through Enhancing Ampk and Sirt1 Cascades

Background: Doxorubicin (DOX) is a widely used and potent anticancer agent, but DOX dose-dependently induced cardiotoxicity greatly limits its use in clinic. Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. The present study explored the actions and detailed mechanisms of pterostilbene on DOX-treated cardiomyocytes. Experimental Approach: We investigated the effects of pterostilbene on established acute DOX-induced cardiotoxicity models in both H9c2 cells treated with 1 μM DOX and C57BL/6 mice with DOX (20 mg/kg cumulative dose) exposure. Cell viability, ATP content, oxidative parameters, transmission electron microscopy, western blot analyses were respective performed. AMPK and SIRT1 siRNA, Compound C and EX527 treatment were further conducted to elucidate the underlying mechanism about the involvement of AMPK, SIRT1 and PGC1α cascades. Key Results: Pterostilbene markedly upregulated the cell viability and ATP content in DOX-treated H9c2 cells. Both in vitro and in vivo studies revealed that pterostilbene inhibited the acute DOX exposure-caused oxidative stress and mitochondrial morphological disorder via the PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. However, these effects were partially reversed by knockdown of AMPK or SIRT1 in vitro and treatment of Compound C or EX527 in vivo . Conclusion and Implications: Our results indicate that pterostilbene protects cardiomyocytes from acute DOX exposure-induced oxidative stress and mitochondrial damage via PGC1α upregulation and deacetylation through activating AMPK and SIRT1 cascades.

Repurposing mosloflavone/5,6,7-trimethoxyflavone-resveratrol hybrids: Discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators

Herein, we address repurposing hybrids of mosloflavone or 5,6,7-trimethoxyflavone with amide analogs of resveratrol from anticancer leads to novel potent anti-inflammatory chemical entities. To unveil the potent anti-inflammatory molecules, biological evaluations were initiated in LPS-induced RAW 264.7 macrophages at 1 μM concentration. Promising compounds were further evaluated at various concentrations. Multiple proinflammatory mediators were assessed including NO, PGE2, IL-6, TNF-α and IL-1β. Compound 5z inhibited the induced production of NO, PGE2, IL-6, TNF-α and IL-1β at the low 1 μM concentration by 44.76, 35.71, 53.48, 29.39 and 41.02%, respectively. Compound 5z elicited IC50 values as low as 2.11 and 0.98 μM against NO and PGE2 production respectively. Compounds 5q and 5g showed potent submicromolar IC50 values of 0.31 and 0.59 μM respectively against PGE2 production. Reverse docking of compound 5z suggested p38-α MAPK, which is a key signaling molecule within the pathways controlling the transcription of proinflammatory mediators, as the molecular target. Biochemical testing confirmed these compounds as p38-α MAPK inhibitors explaining its potent inhibition of proinflammatory mediators’ production. Collectively, the results presented 5z as a promising compound for further development of anti-inflammatory agents for treatment of macrophages-and/or immune mediated inflammatory diseases.

Antidiabetic effects of pterostilbene through PI3K/Akt signal pathway in high fat diet and STZ-induced diabetic rats

Pterostilbene (PTE) is a natural dimethylated analog of resveratrol, which exerts antioxidative, hypolipidemic and hypoglycemic effects; however, the underlying mechanism is not yet clear. In this study, we evaluated the effects of PTE on diabetic rats and clarified the underlying mechanism. Diabetes was induced in rats by streptozotocin (STZ) and a high-sugar and high-fat diet. Rats were then treated with PTE (20, 40 and 80 mg/kg/d) for 8 weeks. Oral glucose tolerance test (OGTT) was performed to measure the glycometabolism of the diabetic rats at the end of the treatment. Fasting blood glucose (FBG), fasting insulin (FINS) and lipid profile were determined using an automatic biochemistry analyzer and serum inflammatory factors were analyzed by enzyme-linked immunosorbent assay. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were also analyzed by spectrophotometry to evaluate the anti-oxidant effects. The expression of proteins of PPARγ and PI3K/Akt signaling pathway related proteins in adipose tissue of the diabetic rats was analyzed by Western blotting. PTE treatment significantly reduced weight loss, FBG, insulin resistance, serum lipid levels and inflammatory factors. PTE treatment also inhibited oxidative stress by decreasing MDA expression and increasing SOD expression. Simultaneously, PTE treatment significantly ameliorated morphological impairment of the pancreas in diabetic rats. Furthermore, PTE treatment significantly increased the protein expression of PPARγ, PI3K, p-Akt, GLUT4 and IRS-1 in adipose tissues of diabetic rats. This study suggests that PTE can exert antidiabetic effects via the PI3K/Akt signaling pathway.

Effects of Piceatannol and Resveratrol on Sirtuins and Hepatic Inflammation in High-Fat Diet-Fed Mice.

Piceatannol (PIC) is a natural hydroxylated analog of resveratrol (RSV) and considered as a potential metabolic regulator. The purpose of this study was to compare the effects of PIC and RSV on parameters affecting inflammation, oxidative stress, and sirtuins (Sirt). Male C57BL/6J mice, 20 weeks old, were assigned to the following groups; (1) lean control, (2) high-fat diet control (HF), (3) HF_PIC, and (4) HF_RSV. Oral administration of PIC and RSV (10 mg/kg/day) for 4 weeks improved glucose control as shown by decreasing levels of area under the curve (AUC) during the oral glucose tolerance test compared with HF group. PIC improved glycemic control by increasing hepatic levels of insulin receptor and AMP-activated protein kinase. PIC increased the levels of Sirt1, Sirt3, and Sirt6 and also increased two downstream targets of Sirt, peroxisome proliferator-activated receptor gamma coactivator 1-alpha and forkhead box O1, in the liver. The inflammatory markers, interleukin (IL)-1 and IL-6, in the liver were downregulated by RSV treatment. Exposure to PIC and RSV significantly lowered hepatic levels of tumor necrosis factor-alpha. However, PIC and RSV treatments showed minimal effects on hepatic markers of oxidative stress. The levels of antioxidant enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), were only increased in livers of RSV-treated mice compared with HF control mice. In conclusion, PIC was superior to an equal concentration of RSV in the regulation of Sirt and its downstream targets as well as insulin signaling-related parameters, while RSV potentially suppressed levels of proinflammatory markers and increased NQO1 protein levels.

Pterostilbene reverses palmitic acid mediated insulin resistance in HepG2 cells by reducing oxidative stress and triglyceride accumulation

Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we evaluated ability of pterostilbene (PTS), a methoxylated analogue of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated IR in HepG2 cells. PTS prevented reactive oxygen species (ROS) formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 (NOX3) in PA treated HepG2 cells. Hepatic glucose production was used as a measure of IR and PTS reversed PA-mediated increase in hepatic glucose production by reducing expression of genes coding for gluconeogenic enzymes namely glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC); and their transcription factors cAMP response element binding protein (CREB) and fork head class Box O (FOXO1) along with its coactivator peroxisome proliferator-activated receptor gamma co-activator-1 α (PGC1α). PTS reversed PA-mediated activation of c-Jun N-terminal kinase (JNK), which in turn altered insulin signalling pathway by phosphorylating IRS-1 at Ser 307, leading to inhibition of phosphorylation of Akt and GSK-3β. PTS also reduced PA-mediated lipid accumulation by reducing expression of transcription factors SREBP1c and PPARα. SREBP1c activates genes involved in fatty acid and triglyceride synthesis while PPARα activates CPT1, a rate limiting enzyme for controlling entry and oxidation of fatty acids into mitochondria. PTS, however, did not influence PA uptake confirmed by using BODIPY-labelled fluorescent C16 fatty acid analogue. Thus, our data provides a possible mechanistic explanation for reversal of PA-mediated IR in HepG2 cells.

Pterostilbene inhibits lung squamous cell carcinoma growth in vitro and in vivo by inducing S phase arrest and apoptosis.

Natural dietary components have become the subject of an increasing amount of interest due to the side effects of anticancer treatment. Pterostilbene, an analog of resveratrol, is primarily found in grapes, and has been suggested to exert antioxidant and anticancer effects in different tumor types. The present study aimed to investigate the antitumor effects and molecular mechanisms of pterostilbene in the human lung squamous cell carcinoma (SqCC) cell line, H520. The results of the present study indicate that pterostilbene significantly reduced cell viability and induced S phase arrest, and that treatment with pterostilbene was associated with the downregulation of cyclin A and cyclin E, as with the upregulation of p21 and p27 expression in H520 cells. In the apoptosis analysis, pterostilbene induced S phase accumulation and the activation of caspase-3, −8 and −9 in H520 cells, potentially through the activation of extrinsic and intrinsic apoptotic pathways. Additionally, the in vivo study demonstrated that pterostilbene effectively inhibited lung SqCC growth in a H520 ×enograft model. Given the in vitro and in vivo antitumor effects of pterostilbene demonstrated in the present study, pterostilbene may serve a novel and effective therapeutic agent to for patients with SqCC.

Effect of Piceatannol on Cell Cycle Progression in Prostate Cancer Cells (P05-005-19)

ObjectivesPiceatannol (PIC) is a polyphenolic and resveratrol analog that is found in many vegetables consumed by humans. Like resveratrol, PIC has beneficial effects on health due to its anti-inflammatory, anti-oxidative and anti-proliferative features. However, the molecular targets of PIC in prostate cancer (PCa), which is the second most common cancer in men worldwide, are still poorly understood. Preventing cancer through dietary sources is a promising strategy to control diseases. Therefore, the aim of present study was to investigate the molecular mechanistic of actions of PIC in PCa cell lines with different genetic background common to human prostate cancer. MethodsHuman PCa cell lines (PC-3, 22Rv1, LNCaP, and VCaP) were treated with different doses of PIC (5–40 μM) and used for cell viability assay, measurement of total free fatty acids (FFA) and lactate, and cell cycle distribution. ResultsPIC treatment dose- and time-dependently reduced viability in PC-3 (androgen-independent, PTEN null, p53 null) and VCaP cells (androgen-responsive, wild-type PTEN, mutant p53). Because metabolic alterations, such as increased glucose and lipid metabolism are implicated in pathogenesis of in PCa, we tested if PIC could affect these pathways. Results from lactate and total free fatty acid assays in VCaP, 22Rv1 (castration-resistant, wild-type PTEN, mutant p53), and LNCaP (androgen-responsive, PTEN null, wild-type p53) revealed no effect of PIC on these metabolisms. However, PIC treatment delayed cell cycle progression in G0/G1 phase concomitant with the induction of apoptosis in both LNCaP and 22Rv1 cells, suggesting that growth inhibitory effect of PIC in PCa is associated with cell cycle arrest and apoptotic cell death at least LNCaP and 22Rv1 cells. ConclusionsWhile PIC treatment does not alter lipid or glucose metabolism, cell cycle arrest and apoptosis induction are likely important in anti-cancer effects of PIC. Funding SourcesSão Paulo Research Foundation (2018/09793-7).

Derivatives and Analogues of Resveratrol: Recent Advances in Structural Modification.

Resveratrol is a non-flavonoid polyphenol containing a terpenoid backbone. It has been intensively studied because of its various promising biological properties, such as anticancer, antioxidant, antibacterial, neuroprotective and anti-inflammatory activities. However, the medicinal application of resveratrol is constrained by its poor bioavailability and stability. In the past decade, more attention has been focused on making resveratrol derivatives to improve its pharmacological activities and pharmacokinetics. This review covers the literature published over the past 15 years on synthetic analogues of resveratrol. The emphasis is on the chemistry of new compounds and relevant biological activities along with structure-activity relationship. This review aims to provide a scientific and reliable basis for the development of resveratrol-based clinical drugs.

Inhibition of eIF2\u03b1 dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner

Hepatocellular carcinoma (HCC) is the one of the most common cancers worldwide. Because the side effects of current treatments are severe, new effective therapeutic strategies are urgently required. Pterostilbene (PT), a natural analogue of resveratrol, has diverse pharmacologic activities, including antioxidative, anti-inflammatory and antiproliferative activities. Here we demonstrated that PT inhibits HCC cell growth without the induction of apoptosis in an endoplasmic reticulum (ER) stress- and autophagy-dependent manner. Mechanistic studies indicated that the combination of salubrinal and PT modulates ER stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. An in vivo xenograft analysis revealed that PT significantly reduced tumour growth in mice with a SK-Hep-1 tumour xenograft. Taken together, our results yield novel insights into the pivotal roles of PT in ER stress- and autophagy-dependent cell death in HCC cells.