Resveratrol Analogues Research Articles

Pterostilbene Suppresses Ovarian Cancer Growth via Induction of Apoptosis and Blockade of Cell Cycle Progression Involving Inhibition of the STAT3 Pathway.

A growing body of evidence has demonstrated the promising anti-tumor effects of resveratrol in ovarian cancer cells, including its inhibitory effects on STAT3 activation. Nonetheless, the low bioavailability of resveratrol has reduced its attractiveness as a potential anti-cancer treatment. In contrast, pterostilbene, a stilbenoid and resveratrol analog, has demonstrated superior bioavailability, while possessing significant antitumor activity in multiple solid tumors. In this study, the therapeutic potential of pterostilbene was evaluated in ovarian cancer cells. Pterostilbene reduces cell viability in several different ovarian cancer cell lines by suppressing cell cycle progression and inducing apoptosis. Further molecular study has shown that pterostilbene effectively suppressed phosphorylation of STAT3, as well as STAT3 downstream genes that regulate cell cycle and apoptosis, indicating that inhibition of STAT3 pathway may be involved in its anti-tumor activity. The addition of pterostilbene to the commonly used chemotherapy cisplatin demonstrated synergistic antiproliferative activity in several ovarian cancer cell lines. Pterostilbene additionally inhibited cell migration in multiple ovarian cancer cell lines. The above results suggest that pterostilbene facilitates significant anti-tumor activity in ovarian cancer via anti-proliferative and pro-apoptotic mechanisms, possibly via downregulation of JAK/STAT3 pathway. Pterostilbene thus presents as an attractive non-toxic alternative for potential adjuvant or maintenance chemotherapy in ovarian cancer.

New Resveratrol Analogues for Potential Use in Diabetes and Cancer

New Resveratrol Analogues for Potential Use in Diabetes and Cancer

Protective effects of piceatannol on methylglyoxal-induced cytotoxicity in MC3T3-E1 osteoblastic cells

Methylglyoxal (MG) is a reactive α-oxoaldehyde that increases under diabetic conditions and subsequently contributes to the complications associated with this disease. Piceatannol is a naturally occurring analogue of resveratrol that possesses multiple biological functions. The present study investigated the effects of piceatannol on MG-induced cytotoxicity in MC3T3-E1 osteoblastic cells. Piceatannol significantly restored MG-induced reductions in cell viability and reduced lactate dehydrogenase release in MG-treated MC3T3-E1 osteoblastic cells, which suggests that it suppressed MG-induced cytotoxicity. Piceatannol also increased glyoxalase I activity and glutathione levels in MG-treated cells, which indicates that it enhanced the glyoxalase system and thus cellular protection. The present study also showed that piceatannol inhibited the generation of inflammatory cytokines and reactive oxygen species and ameliorated mitochondrial dysfunction induced by MG. Furthermore, piceatannol treatment significantly reduced the levels of endoplasmic reticulum stress and autophagy induced by MG. Therefore, piceatannol could be a potent option for the development of antiglycating agents for the treatment of diabetic osteopathy.

Resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide induces G2/M cell cycle arrest through the activation of p53-p21CIP1/WAF1 in human colorectal HCT116 cells.

Resveratrol, a naturally occurring polyphenolic antioxidant, is a potential chemoprophylactic agent for various cancers, including colorectal cancer. Although emerging evidence continually suggests that a number of resveratrol derivatives may be better cancer chemopreventive candidates than resveratrol, studies on the mechanism of action of these derivatives are limited. This is the first study which investigates the mechanism underlying the cytotoxic effect of a synthesized resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide (CS) on colorectal cancer. Previously, our group reported a series of synthesized resveratrol analogues, which showed cytotoxicity against a panel of cancer cell lines, in particular on colon cancer cells. In this study, we further discovered that CS also exerts a potent suppressive effect on HCT116 colorectal cancer cells. In contrast, normal colon cells (CCD-112 Con) were not sensitive to CS up to 72h post treatment. CS caused cytotoxicity in HCT116 cells through several apoptotic events including activation of the Fas death receptor, FADD, caspase 8, caspase 3, caspase 9, and cleaved PARP, which occurred alongside cell cycle arrest from the up-regulation of p53 and p21. The results show that CS causes apoptosis via the activation of an extrinsic pathway leading to caspase activation and cell cycle arrest from activated p53. These findings suggest that CS may be a potential candidate for development as an anti-tumor agent in the future.

Rosa hybrida orcinol O-methyl transferase-mediated production of pterostilbene in metabolically engineered grapevine cell cultures

Stilbenes are naturally scarce high-added-value plant compounds with chemopreventive, pharmacological and cosmetic properties. Bioproduction strategies include engineering the metabolisms of bacterial, fungal and plant cell systems. Strikingly, one of the most effective strategies consists in the elicitation of wild grapevine cell cultures, which leads to vast stilbene resveratrol accumulation in the extracellular medium. The combination of both cell culture elicitation and metabolic engineering strategies to produce resveratrol analogs proved more efficient for the hydroxylated derivative piceatannol than for the dimethylated derivative pterostilbene, for which human hydroxylase HsCYP1B1- and grapevine O-methyltransferase VvROMT-transformed cell cultures were respectively used. Rose orcinol O-methyltransferase (OOMT) displays enzymatic properties, which makes it an appealing candidate to substitute VvROMT in the combined strategy to enhance the pterostilbene production level by engineered grapevine cells upon elicitation. Here we cloned a Rosa hybrida OOMT gene, and created a genetic construction suitable for Agrobacterium-mediated plant transformation. OOMT’s ability to catalyze the conversion of resveratrol into pterostilbene was first assessed in vitro using protein extracts of agroinfiltrated N. benthamiana leaves and transformed grapevine callus. The grapevine cell cultures transformed with RhOOMT produced about 16 mg/L culture of pterostilbene and reached an extracellular distribution of up to 34% of total production at the best, which is by far the highest production reported to date in a plant system. A bonus large resveratrol production of ca. 1500–3000 mg/L was simultaneously obtained. Our results demonstrate a viable successful metabolic engineering strategy to produce pterostilbene, a resveratrol analog with enhanced pharmacological properties.

Abstract P5-14-05: α-tocopherol succinate enhances the anti-tumor activity of pterostilbene against human breast cancer cells in vivo and in vitro

Abstract Background: The cancer preventive activity of vitamin E (α-tocopherol, α-TP) has been suggested by many epidemiologic studies. Our previous study showed that Tocopherol-Associated Protein (TAP), a major tocopherol–binding protein, is preferentially detected in normal breast tissues than in tumor regions among 93 clinical breast cancer patients, which postulate its tumor suppressive role in breast cells. Pterostilbene (3,5-dimethoxi-49-hydroxystilbene, PS) is a natural dimethylated analogue of Resveratrol found in different plants. Previous studies have shown that PS has the ability to induce apoptosis in a range of cancer cell lines. The purpose of our study was to assess the effect of TAP and Pterostilbene in tumor suppression of breast cancer cell. Methods: Cell growth, proliferation, and viability were determined using the MTT assay. TAP protein expression was ablated in MDA-MB-231 breast cancer cell with nine independent siRNA sequences. MDA-MB-231 cells were transfected with pcDNA5 plasmids expressing the firefly luciferase gene. TAP protein expressions for each plasmid transfection were measured by western-blot analysis. Synergic effects of tumor growth and metastasis inhibitions in MDA-MB-231 xenograft animal model by PS and α-tocopherol treatment were evaluated. Results: TAP served as a key molecular in responding to α-tocopheryl succinate (α-TOS) induced cell cycle regulation. PS has demonstrated the synergic decrease on breast cancer cell growth effects by the combination of α-TOS exposure. In animal model, treatment of PS and high level vitamin E diet not only induced breast tumor growth inhibition, but also suppressed tumor cell invasion by measuring circulation tumor cells in mouse blood. Conclusions: Upon the evidences showed in this study, we suggest taking vitamin E and PS as supplements may provide both breast tumor preventative and therapeutic benefits in clinic. Citation Format: Tam K-W, Lee C-H. α-tocopherol succinate enhances the anti-tumor activity of pterostilbene against human breast cancer cells in vivo and in vitro [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-14-05.

New group of azastilbene analogs of resveratrol: Synthesis, anticandidal activity and toxicity evaluation

Infections caused by microorganisms of the Candida genus represent a major cause of morbidity and mortality among the population. Therefore, this study aimed at evaluating the antifungal activity and toxicity of resveratrol-analog Schiff bases. Faced with Candida albicans ATCC 10,231, the broth microdilution method was used, along with amphotericin B as the reference drug. The toxicity was evaluated in human keratinocyte cells and against Artemia salina. All analogs were active against the microorganism and caused structural changes in the yeast. The minimum inhibitory concentration was lower for analog A (156.3 µg mL−1), followed by B (312.5 µg mL−1), C (312.5 µg mL−1) and D (625 µg mL−1); while the minimum fungicidal concentration was lower for A (1,250 µg mL−1), B (1,250 µg mL−1) and D (1,250 µg mL−1), followed by C (2,500 µg mL−1). In keratinocytes, the compounds presented cell viability between 50.9 and 93%. Against A. salina, the compounds presented moderate cytotoxic activity. The compound with the nitro group, an electron withdrawing group, in the para position presented better antifungal activity. Resveratrol analogs can be promising in the development of new antifungal agents.

ROS-driven and preferential killing of HepG2 over L-02 cells by a short-term cooperation of Cu(II) and a catechol-type resveratrol analog

This study was aimed at understanding why dietary polyphenols with a catechol skeleton tend to exhibit cancer chemopreventive activity by using a catechol-type stilbene (3,4-DHS) as a model molecule. Only a short-term cooperation of 3,4-DHS and exogenous Cu(II) exhibited a strong preferential ability to kill HepG2 cells over normal L02 cells. Mechanism studies reveal that this 3,4-DHS/Cu(II) system could produce extracellularly reactive oxygen species (ROS) and o-quinone through two sequential proton loss electron transfer followed by diffusion of ROS into cells, leading to higher intracellular accumulation of ROS, preferential disruption of redox homeostasis and more effective mitochondria-dependent apoptosis as well as necrosis of HepG2 cells than L-02 cells. This work provides further evidence that dietary catechol-type molecules show chemopreventive activity by virtue of their copper-dependent prooxidant action.

Selective synthesis of the resveratrol analogue 4,4′-dihydroxy-trans-stilbene and stilbenoids modification by fungal peroxygenases

Different unspecific peroxygenases (UPOs) catalyze the hydroxylation or epoxidation of trans-stilbene and other stilbenoids yielding resveratrol analogs and other compounds.

Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway

Background/Aims: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. Methods: C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. Results: In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H₂O₂) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H₂O₂-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. Conclusion: Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.

Metabolism and pharmacokinetics of resveratrol and pterostilbene.

Beneficial properties of resveratrol and pterostilbene, a dimethyl ether analog of resveratrol, have attracted increasing interest in recent years. Resveratrol and pterostilbene exhibit many pharmacological similarities and both of them are generally considered to be safe for human consumption. Beyond the structural and general bioactivity similarities between them, large amounts of data are now available to reveal the metabolic fate and pharmacological differences between them. Pterostilbene was found to be more metabolically stable and usually exhibited stronger pharmacological activities than that of resveratrol. As a contribution to clarify and compare aspects like metabolic stability and pharmacokinetics of resveratrol and pterostilbene, as well as explain the pharmacological similarities and differences between them, this review presents and compares recent data on the metabolism and pharmacokinetics of resveratrol and pterostilbene. © 2018 BioFactors, 44(1):16-25, 2018.

Pterostilbene Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors and Downregulation of Cell Survival Proteins in TRAIL-Resistance Triple Negative Breast Cancer Cells

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is nontoxic to normal cells and preferentially cytotoxic to cancer cells. Recent data suggest that malignant breast cancer cells often become resistant to TRAIL. Pterostilbene (PTER), a naturally occurring analogue of resveratrol found in blueberries, is known to induce cancer cells to undergo apoptosis. In the present study, we examined whether PTER affects TRAIL-induced apoptosis and its mechanism in TRAIL-resistant triple negative breast cancer (TNBC) cells. Our data indicated that PTER induced apoptosis (14.68 ± 3.78% for 40 μM PTER vs 1.98 ± 0.25% for control, p < 0.01) in TNBC cells and enhanced TRAIL-induced apoptosis in TRAIL-resistant TNBC cells (18.45 ± 4.65% for 40 μM PTER vs 29.38 ± 6.35% for combination of 40 μM PTER and 100 ng/mL TRAIL, p < 0.01). We demonstrated that PTER induced death receptors DR5 and DR4 as well as decreased decoy receptor DcR-1 and DcR-2 expression. PTER also decreased the antiapoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, survivin, and XIAP. PTER induced the cleavage of bid protein and caused proapoptotic Bax accumulation. Moreover, we found that PTER induced the expression of DR4 and DR5 through the reactive oxygen species (ROS)/ endoplasmic reticulum (ER) stress/ERK 1/2 and p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results showed that PTER potentiated TRAIL-induced apoptosis via ROS-mediated CHOP activation leading to the expression of DR4 and DR5.

The Role of Resveratrol in Cancer Therapy.

Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. A significant amount of research, including preclinical, clinical, and epidemiological studies, has indicated that dietary consumption of polyphenols, found at high levels in cereals, pulses, vegetables, and fruits, may prevent the evolution of an array of diseases, including cancer. Cancer development is a carefully orchestrated progression where normal cells acquires mutations in their genetic makeup, which cause the cells to continuously grow, colonize, and metastasize to other organs such as the liver, lungs, colon, and brain. Compounds that modulate these oncogenic processes can be considered as potential anti-cancer agents that may ultimately make it to clinical application. Resveratrol, a natural stilbene and a non-flavonoid polyphenol, is a phytoestrogen that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. It has been reported that resveratrol can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents. Several novel analogs of resveratrol have been developed with improved anti-cancer activity, bioavailability, and pharmacokinetic profile. The current focus of this review is resveratrol’s in vivo and in vitro effects in a variety of cancers, and intracellular molecular targets modulated by this polyphenol. This is also accompanied by a comprehensive update of the various clinical trials that have demonstrated it to be a promising therapeutic and chemopreventive agent.

Differential Anticancer Activity of Pterostilbene Against Three Subtypes of Human Breast Cancer Cells.

Although pterostilbene, a natural analog of resveratrol, has potent antitumor activity against several human cancer types, the possible inhibitory mechanisms against subtypes of human breast cancer with different hormone receptor and human epidermal growth factor receptor 2 (HER2) status remain unknown. We investigated the anticancer activity of pterostilbene using three subtypes of breast cancer cell lines. Pterostilbene treatment exhibited a dose-dependent antiproliferative activity, with the greatest growth inhibition observed in triple-negative MDA-MB-468 cells. Although pterostilbene arrested cell-cycle progression at the G0/G1 phase regardless of breast cancer subtype, its apoptosis-inducing activity was highly apparent in MDA-MB-468 cells. Pterostilbene induced strong and sustained activation of extracellular signal-regulated kinase (ERK) 1/2, with concomitant cyclin D1 suppression and p21 up-regulation, and inhibited the phosphorylation of AKT and mammalian target of rapamycin (mTOR), followed by subsequent up-regulation of BAX without affecting B-cell lymphoma-extra large (BCL-xL). Oral administration of pterostilbene significantly suppressed tumor growth in nude mice xenotransplanted with MDA-MB-468 cells. These data suggest a potential role of pterostilbene for prevention and treatment of human breast cancer, especially of triple-negative breast cancer.

Resveratrol analogues like piceatannol are potent antioxidants as quantitatively demonstrated through the high scavenging ability against reactive oxygen species and methyl radical

Resveratrol (RSV) analogues have attracted much attention because of the expected health functions including antioxidant activities. We have carried out a quantitative determination of the scavenging abilities of six trans-RSV analogues against various reactive oxygen species and methyl radical (hydroxyl radical, superoxide, alkoxyl radical, peroxyl radical, methyl radical, and singlet oxygen). RSV analogues are in general more potent scavenger than the parent RSV. Furthermore, piceatannol (PIC) having two OH groups in the ortho position of resveratrol was found to show 11 times higher scavenging ability against peroxyl radical than parent resveratrol. With the aid of previous theoretical studies, the enhanced antioxidant ability was interpreted based on the effects of substituent that modifies the original resveratrol structure and function.

Protective effects of the resveratrol analog piceid in dopaminergic SH-SY5Y cells

Age-related motor deficits, such as loss of balance and coordination, are caused, in part, by loss of dopaminergic neurons. Oxidative stress is known to play a role in this neuronal loss. Resveratrol, a natural antioxidant with anticancer and anti-inflammatory potential, has been shown to protect dopaminergic-like cells (SH-SY5Y) against oxidative stress. However, the low bioavailability of resveratrol makes it worthwhile to explore newer compounds with similar properties. Piceid (RV8), an analog of resveratrol, has greater bioavailability than resveratrol, and our studies found that piceid (10, 20, 30µM) protects SH-SY5Y cells against oxidative stress. Our investigations also found that the neuroprotection afforded by piceid was decreased when the MAP kinases, ERK1/2 and ERK5, were independently inhibited. Since oxidative stress is considered a master operator of apoptosis, our study also scrutinized dopamine-induced apoptosis and whether caspase-3/7 and Bcl-2 are involved, following piceid pretreatment followed by dopamine exposure. Our findings suggested that piceid pretreatment inhibited the dopamine-induced increase in caspase-3/7 activity and dopamine-induced loss of Bcl-2 expression. Overall, these findings suggest that the neuroprotective effects of piceid are mediated via the activation of ERK1/2, ERK5, and inhibition of apoptosis caused by oxidative stress.

Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor

Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations ≥1μM and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations ≤5μM for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations ≥10μM. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation.

Identification of Polyphenol-Specific Innate Epitopes That Originated from a Resveratrol Analogue.

Polyphenols have received a significant amount of attention in disease prevention because of their unique chemical and biological properties. However, the underlying molecular mechanism for their beneficial effects remains unclear. We have now identified a polyphenol as a source of innate epitopes detected in natural IgM and established a unique gain-of-function mechanism in the formation of innate epitopes by polyphenol via the polymerization of proteins. Upon incubation with bovine serum albumin (BSA) under physiological conditions, several polyphenols converted the protein into the innate epitopes recognized by the IgM Abs. Interestingly, piceatannol, a naturally occurring hydroxylated analogue of a red wine polyphenol, resveratrol, mediated the modification of BSA, whose polymerized form was specifically recognized by the IgMs. The piceatannol-mediated polymerization of the protein was associated with the formation of a lysine-derived cross-link, dehydrolysinonorleucine. In addition, an oxidatively deaminated product, α-aminoadipic semialdehyde, was detected as a potential precursor for the cross-link in the piceatannol-treated BSA, suggesting that the polymerization of the protein might be mediated by the oxidation of a lysine residue by piceatannol followed by a Schiff base reaction with the ε-amino group of an unoxidized lysine residue. The results of this study established a novel mechanism for the formation of innate epitopes by small dietary molecules and support the notion that many of the beneficial effects of polyphenols could be attributed, at least in part, to their lysyl oxidase-like activity. They also suggest that resveratrol may have beneficial effects on human health because of its conversion to piceatannol.

4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) suppresses HIV1-gp120 mediated production of IL6 and IL8 but not CCL5

Human immunodeficiency virus (HIV) has been associated with inflammatory effects that may potentially result in neurodegenerative changes and a number of newer chemotherapeutic agents are being tested to ameliorate these effects. In this study, we investigated the anti-neuroinflammatory activity of a novel resveratrol analog 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) against HIV1-gp120 induced neuroinflammation in SVG astrocytes. SVG astrocytic cells were pretreated with TIMBD or resveratrol (RES) and then transfected with a plasmid encoding HIV1-gp120. The mRNA and protein expression levels of proinflammatory cytokines IL6, IL8 and CCL5 were determined. Protein expression levels of NF-κB, AP1, p-STAT3, p-AKT, p-IKKs and p-p38 MAPK were also determined. TIMBD inhibited gp120-induced RNA and protein expression levels of IL6 and IL8, but not that of CCL5 in SVG astrocytes. Moreover, TIMBD attenuated gp120-induced phosphorylation of cJUN, cFOS, STAT3, p38-MAPK, AKT and IKKs, and the nuclear translocation of NF-κB p-65 subunit whereas RES mostly affected NF-κB protein expression levels. Our results suggest that TIMBD exerts anti-inflammatory effects better than that of RES in SVG astrocytes in vitro. These effects seem to be regulated by AP1, STAT-3 and NF-κB signaling pathways. TIMBD may thus have a potential of being a novel agent for treating HIV1-gp120-mediated neuroinflammatory diseases.

Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress

Pterostilbene (PT), the natural dimethylated analog of resveratrol (RSV), is a potent anticarcinogen for non-small-cell lung cancer (NSCLC), but its anti-NSCLC mechanisms remain unclear. In this study, we show that PT treatment time- and dose-dependently enhanced the endoplasmic reticulum stress (ERS) signaling (i.e., p-PERK, IRE1, ATF4, CHOP), thus decreasing the cell viability and inducing apoptosis in human PC9 and A549 NSCLC cell lines. Moreover, the decreased migratory and adhesive abilities, downregulation of intracellular glutathione (GSH) level, enhanced reactive oxygen species (ROS) generation, Caspase 3 activity and mitochondrial membrane depolarization were observed in NSCLC cells treated with PT. These effects were reversed by CHOP siRNA which inhibited the ERS signaling pathway, but were promoted by thapsigargin (a classical ERS inducer) in vitro. Besides, in vivo studies also verify that PT exerted anticancer activity by mobilizing ERS signaling and apoptosis-related proteins, and these effects were enhanced by thapsigargin. Therefore, ERS activation may represent a new mechanism of anti-NSCLC action by PT, and a novel therapeutic intervention for lung cancer.