Resveratrol Analogues Research Articles

CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues.

Naturally occurring stilbenoids, such as the (E)-stilbenoid resveratrol and the (Z)-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines. Breast tumour cell lines that express CYP1 were significantly more strongly affected by the resveratrol analogues than the cell lines that did not have CYP1 activity. Metabolism studies using isolated CYP1 enzymes provided further evidence that (E)-stilbenoids can be substrates for these enzymes. Structures of metabolic products were confirmed by comparison with synthetic standards and LC-MS co-elution studies. The most promising stilbenoid was (E)-4,3',4',5'-tetramethoxystilbene (DMU212). The compound itself showed low to moderate cytotoxicity, but upon CYP1-catalysed dealkylation, some highly cytotoxic metabolites were formed. Thus, DMU212 selectively affects proliferation of cells that express CYP1 enzymes.

Anti-inflammatory effects of quinolinyl analog of resveratrol targeting TLR4 in MCAO/R ischemic stroke rat model

BackgroundAmong adults, stroke is the main causes of mortality and permanent disability. Neuroinflammation is one of the main causes of stoke-mediated neuronal death. Our previous study revealed that (E)-5-(2-(Quinolin-4-yl) vinyl) benzene-1, 3-diol (RV01), a quinolinyl analog of resveratrol, inhibits microglia-induced neuroinflammation and safeguards neurons from inflammatory harm. The preventive role of RV01 in ischemic stroke and its underlying cellular mechanisms and molecular targets remain poorly understood. PurposeTo investigate whether RV01 alleviates ischemia-reperfusion (I/R) injury by inhibiting microglia-mediated neuroinflammation and determine the potential molecular mechanisms and targets by which RV01 inhibits the I/R-mediated microglia activation. MethodsRat middle cerebral artery occlusion and reperfusion (MCAO/R) and BV-2 or primary microglial cells oxygen-glucose deprivation and reperfusion (OGD/R) models were established. The neurological behavior scores, 2, 3, 5-triphenyl tetrazolium chloride staining and immunofluorescence were used to detect the neuroprotective effect of RV01 in the MCAO/R rats. In addition, the mRNA expression levels of IL-6, TNF-α, and IL-1β were detected to reveal the antineuroinflammatory effect of RV01. Moreover, a western blot assay was performed to explore the protein expression changes in NF-κB-mediated neuroinflammation. Finally, we identified TLR4 as an RV01 target through molecular docking, drug sensitivity target stability analysis, cellular thermal shift analysis, and surface plasmon resonance techniques. ResultsRV01 reduced the infarct volume and neurological deficits, increased the rotarod duration, and decreased the number of rightward deflections in the MCAO/R rats. RV01 inhibited the NF-κB signaling pathway in vitro and in vivo, as demonstrated by the reduction in the transcription factor p65-mediated expression of several inflammatory factors including IL-6, TNF-α, and IL-1β. Further studies showed that its protective effect was associated with targeting the TLR4 protein. Notably, the anti-inflammatory effect of RV01 was markedly reinforced by the TLR4 knockdown, but inhibited by the overexpression of TLR4. Results revealed that the conditioned medium derived from the RV01-treated BV-2 cells significantly decreased the OGD/R-mediated neuronal damage. ConclusionOur results are the first to reveal the protective effects of RV01 on cerebral ischemia, depending on its inhibitory effect on the NF-κB pathway by targeting TLR4. RV01 could be a potential protective agent in ischemic stroke treatment.

Pterostilbene in the treatment of inflammatory and oncological diseases.

Pterostilbene (PTS), a naturally occurring analog of resveratrol (RSV), has garnered significant attention due to its potential therapeutic effects in treating inflammatory and oncological diseases. This comprehensive review elucidates the pharmacological properties, mechanisms of action, and therapeutic potential of PTS. Various studies indicate that PTS exhibits anti-inflammatory, antioxidant, and antitumour properties, potentially making it a promising candidate for clinical applications. Its influence on regulatory pathways like NF-κB and PI3K/Akt underscores its diverse strategies in addressing diseases. Additionally, PTS showcases a favorable pharmacokinetic profile with better oral bioavailability compared to other stilbenoids, thus enhancing its therapeutic potential. Given these findings, there is an increased interest in incorporating PTS into treatment regimens for inflammatory and cancer-related conditions. However, more extensive clinical trials are imperative to establish its safety and efficacy in diverse patient populations.

Suppressive effect of resveratrol, catechin and their conformationally constrained analogs on neutrophil extracellular trap formation by HL-60-derived neutrophils.

Neutrophil extracellular trap (NET) formation is a unique self-defense mechanism of neutrophils; however, it is also involved in many diseases, including atherosclerosis. Resveratrol and catechin are antioxidants with anti-atherosclerotic properties. Here, we examined the effects of resveratrol, catechin, and other related compounds on NET formation. HL-60-derived neutrophils were pretreated with resveratrol and other compounds before stimulation with phorbol-myristate acetate (PMA). DNA and myeloperoxidase released from neutrophils were determined. Resveratrol suppressed the DNA release from neutrophils in a dose-dependent manner. NET formation was enhanced by 1-palmitoyl-2-oxovaleroyl phosphatidylcholine (POVPC), a truncated form of oxidized phospholipid, and resveratrol suppressed NET formation induced by POVPC and PMA. Furthermore, we designed several analogs of resveratrol or catechin whose conformation was restricted by the inhibition of the free rotation of aromatic rings. The conformationally constrained analogs were more effective at inhibiting NET formation; however, their inhibitory function decreased when compound was a large, hydrophobic analog. The most potent compounds, planar catechin and resveratrol, suppressed myeloperoxidase release from activated neutrophils. In addition, these compounds suppressed DNA release from neutrophils stimulated with calcium ionophore. These results suggest that resveratrol, catechin and their analogs exert anti-NET effects, and that constraining the geometry of these compounds enhanced their inhibitory effects.

In silico approach in the development of structural analogues of resveratrol with improved distribution in the central nervous system

Resveratrol exerts neuroprotective effects that are not only due to anti-inflammatory and antioxidant activity but also by launched biogenesis via sirtuin-1 (SIRT1) protein that protects cells from oxidative stress. Resveratrol has low bioavailability due to low aqueous solubility and rapid metabolism. To improve the pharmacological profile, one of the strategies is the structural modification and selecting an analogue that would activate SIRT1 and improve pharmacokinetics. The aim was to examine the neuroprotective potential of resveratrol analogues through the analysis of the binding affinity to the sirtuin-1 receptor and with improved permeability through the blood-brain barrier. 15 of them have a higher affinity for the target. Four analogues are characterized by better properties including both higher permeability and higher binding affinity for SIRT1 compared to resveratrol. The selected compounds are assumed to have better bioavailability and CNS distribution, and further studies are proposed to confirm their effects and use as neuroprotective agents.

A SIRT1-independent mechanism mediates protection against steroid-induced senescence by resveralogues in equine tenocytes.

Tendinopathy is a common age-related disease which causes significant morbidity for both human athletes and performance horses. In the latter, the superficial digital flexor tendon is an excellent model for human tendinopathies because it is a functional homologue of the human Achilles tendon and a primary site of injuries with strong similarities to the human disease. Corticosteroids have been previously used clinically to treat tendinopathic inflammation, but they upregulate the p53-p21 axis with concomitant reductions in cell proliferation and collagen synthesis in human tenocytes. This phenotype is consistent with the induction of cellular senescence in vitro and in vivo and probably represents an important clinical barrier to their effective use. Because of the many differences in senescence mechanisms between species, this study aimed to evaluate these mechanisms after corticosteroid treatment in equine tenocytes. Exposure to clinically reflective levels of dexamethasone for 48 hours drove equine tenocytes into steroid induced senescence (SIS). This was characterised by permanent growth arrest and upregulation of p53, the cyclin dependent kinase inhibitors p21waf and p16ink4a as well as the matrix degrading enzymes MMP1, MMP2 and MMP13. SIS also induced a distinctive equine senescence associated secretory phenotype (eSASP) characterised by enhanced secretion of IL-8 and MCP-1. Preincubation with resveratrol or the potent SIRT1 activator SRT1720 prevented SIS in equine tenocytes, while treatment with the non-SIRT1 activating resveratrol analogue V29 was equally protective against SIS, consistent with a novel, as yet uncharacterised SIRT1-indendent mechanism which has relevance for the development of future preventative and therapeutic strategies.

Photochemical Transformations of Diverse Biologically Active Resveratrol Analogs in Batch and Flow Reactors.

Previous biological tests have shown that some resveratrol analogs exhibited significant antioxidative and cholinesterase inhibitory potential, as evidenced by lower IC50 values compared to the established standards, resveratrol and galantamine, respectively. Photochemical transformations were made in parallel on these compounds in the presence of porphyrin photocatalysts in batch and microreactor, showing the significant advantage of flow photochemistry concerning productivity, selectivity, and yields. In this research, the products of photocatalysis and direct irradiation (photolysis) of resveratrol analogs were compared to elucidate how the types and ratios of the products depend on the excitation energy, to reveal the effects of the substituent on the photoinduced reactions and to rationalize experimentally and computationally the nature and ratio of the obtained products. Thus, two main paths were computed in agreement with the experimental results: isomerization with the participation of triplet state intermediates to yield the experimentally detected cis-isomers and subsequent cyclization following a pathway not available for the trans-isomers. The investigation of five model compounds confirmed the advantages of the flow photoreactor in the photochemical reactions of heterocyclic resveratrol analogs.

New resveratrol analogs as improved biologically active structures: Design, synthesis and computational modeling

New analogs of the well-known bioactive trihydroxy-stilbene resveratrol were synthesized to investigate their potential biological activity. The focus was on assessing their ability to inhibit cholinesterase enzymes (ChEs) and their antioxidative properties, which were thoroughly examined. New resveratrol analogs were synthesized through Wittig or McMurry reaction in moderate-to-good yields. In all synthetic pathways, mixtures of cis- and trans-isomers were obtained, then separated by chromatography, and trans-isomers were isolated as targeted structures. The stilbene derivatives underwent evaluation for antioxidant activity (AOA) using DPPH and CUPRAC assay, and their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) was also measured. The biological tests have shown that the same compounds exhibited significant antioxidative and butyrylcholinesterase inhibitory potential, as evidenced by lower IC50 values compared to the established standards, trans-resveratrol, and galantamine, respectively. Additionally, molecular docking of the selected synthesized potential inhibitors to the enzyme's active site was performed, followed by assessing the complex stability using molecular dynamics simulation lasting 100 ns. Lastly, the new compounds underwent examination to determine their potential mutagenicity.

Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways.

Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 μM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1β and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.

Resveratrol: biology, metabolism, and detrimental role on the tumor microenvironment of colorectal cancer.

A substantial increase in colorectal cancer (CRC)-associated fatalities can be attributed to tumor recurrence and multidrug resistance. Traditional treatment options, including radio- and chemotherapy, also exhibit adverse side effects. Ancient treatment strategies that include phytochemicals like resveratrol are now widely encouraged as an alternative therapeutic option. Resveratrol is the natural polyphenolic stilbene in vegetables and fruits like grapes and apples. It inhibits CRC progression via targeting dysregulated cancer-promoting pathways, including PI3K/Akt/Kras, targeting transcription factors like NF-κB and STAT3, and an immunosuppressive tumor microenvironment. In addition, combination therapies for cancer include resveratrol as an adjuvant to decrease multidrug resistance that develops in CRC cells. The current review discusses the biology of resveratrol and explores different mechanisms of action of resveratrol in inhibiting CRC progression. Further, the detrimental role of resveratrol on the immunosuppressive tumor microenvironment of CRC has been discussed. This review illustrates clinical trials on resveratrol in different cancers, including resveratrol analogs, and their efficiency in promoting CRC inhibition.

Phytogenic One-pot Synthesis and Spectroscopic Characterization of Novel Mono Benzylated Resveratrol Hybrid Molecule Using Extracted Resveratrol from Green Grape Peels: In Silico ADMET Study and In Vitro Antitumor Activities Against Breast Cancer Cells

Background: Despite the development of numerous customized techniques for treating breast cancer, cancer patients' clinical results revealed adverse consequences in addition to chemotherapeutic drug resistance. Hence, finding therapeutic compounds with little or no side effects becomes essential in the fight against cancer. Resveratrol, a naturally occurring non-flavonoid polyphenol present in plants as a phytoalexin, is a promising therapeutic agent that has garnered the interest of several researchers due to its prodigious pharmacological and biological activities, but its unfavourable pharmacokinetic properties complicated its clinical studies. Along with several structural modifications, substitutions, etc., that have already been reported, this is the first time that a novel resveratrol analogue comprising an aromatic hetero moiety (ResD1) was synthesized using resveratrol isolated from grape (Vitis vinifera) peels as a precursor. Methods: ResD1 was synthesized by one-pot reaction using extracted and isolated resveratrol from grape peels. Structure confirmation of the isolated resveratrol and synthesized resveratrol derivative was elucidated by 1H-NMR, 13C-NMR, FTIR, and LC-MS. In silico molecular docking and ADMET study of ResD1 were carried out using AutoDock 4.2 and ADMETLab 2.0. ResD1 was evaluated for in vitro antioxidant, antimicrobial, anticancer, and CAXII gene expression as per the standard methods. Results: In silico molecular docking results revealed that ResD1 is capable of attaching to the ERα (estrogen receptor alpha) protein via hydrogen and hydrophobic bonds and has -7.12 kcal/mol as docking score. The novel derivative (IC50 = 42.8 µg/ml) exhibited better radical scavenging ability than ascorbic acid (control). The antimicrobial activities exemplify that it can induce microbial cell death for all the strains at higher concentrations. MTT assay results portrayed the potent antiproliferative activity against MCF-7 cell lines (IC50 = 155.2 µg/ml) and non-cytotoxicity for MDA-MB-231 cell lines. Moreover, the synthesized resveratrol derivative induced ROS (reactive oxygen species) levels in MCF-7 cells, indicating cytotoxicity. CAXII gene expression study showed that it downregulated the CAXII genes. Conclusion: This study serves as an example of how a newly proposed resveratrol analogue might be utilized as a viable pharmacophore for specifically targeting the ER alpha protein which will be beneficial in investigating a fresh batch of effective resveratrol mimics as prospective anticancer agents.

Exploring the therapeutic potential of naturally occurring piceatannol in non-communicable diseases.

Piceatannol is a naturally occurring hydroxylated resveratrol analogue that can be found in a variety of fruits and vegetables. It has been documented to have a wide range of beneficial effects, including anti-inflammatory, antioxidant, anti-aging, anti-allergic, antidiabetic, neuroprotective, cardioprotective, and chemopreventive properties. Piceatannol has significantly higher antioxidant activity than resveratrol. Piceatannol has been shown in preclinical studies to have the ability to inhibit or reduce the growth of cancers in various organs such as the brain, breast, lung, colon, cervical, liver, prostate, and skin. However, the bioavailability of Piceatannol is comparatively lower than resveratrol and other stilbenes. Several approaches have been reported in recent years to enhance its bioavailability and biological activity, and clinical trials are required to validate these findings. This review focuses on several aspects of natural stilbene Piceatannol, its chemistry, and its mechanism of action, and its promising therapeutic potential for the prevention and treatment of a wide variety of complex human diseases.

Improvement of the Physicochemical Limitations of Rhapontigenin, a Cytotoxic Analogue of Resveratrol against Colon Cancer.

It has been argued that methoxylated stilbenes are better candidates for oral administration than hydroxylated stilbenes, including resveratrol, as they share many biological activities but have better bioavailability. By contrast, they have a disadvantage to consider, i.e., their lower hydrophilic character that leads to precipitation issues in the final product. In this work, we analysed and compared the growth inhibition of colorectal cancer cells of the methoxylated stilbene rhapontigenin and some analogues and overcame potential problems in the development of fortified products by designing inclusion complexes. Among several cyclodextrins, we found the one that best fit the molecule by physicochemical and bioinformatics assays. The stoichiometry and the encapsulation constants with natural and modified cyclodextrins were determined by fluorescence spectroscopy. The most promising complexes were analysed at different temperature and pH conditions, determining the thermodynamic parameters, to discover the optimal conditions for the preparation and storage of the products. The results showed that rhapontigenin solubility and stability were significantly improved, achieving a sevenfold increase in water solubility and maintaining more than 73% of the stilbene after three months. These findings could be of great interest for industries that aim to deliver novel bioactive compounds with higher solubility and lower degradation.

Steroidogenic activity of liposomal methylated resveratrol analog 3,4,5,4′-tetramethoxystilbene (DMU-212) in human luteinized granulosa cells in a primary three-dimensional in vitro model

PurposeSteroid hormone secretion is one of the key functions of granulosa cells (GCs). Resveratrol is a natural polyphenol, known for its beneficial health effects, such as improving reproductive health. However, its application is limited due to poor bioavailability. The methoxy derivative of resveratrol (DMU-212) was demonstrated to be more lipophilic, and therefore of greater bioavailability. However, since the addition of methoxy groups to the stilbene scaffold was found to make the molecule insoluble in water, DMU-212 was loaded into liposomes. This study aimed to evaluate how the liposomal formulation of DMU-212 (lipDMU-212) alters estradiol and progesterone secretion of human ovarian GCs in a primary three-dimensional cell culture model.MethodsDMU-212-loaded liposomes were prepared by thin film hydration followed by extrusion. Cell viability was measured after exposure of GCs spheroids to the liposomal formulation of DMU-212 using CellTiter-Glo® 3D Cell Viability Assay. The secretion of estradiol and progesterone was determined using commercial ELISA kits. RT-qPCR was conducted to analyze the expression of steroidogenesis-related genes. Finally, the western blot technique was used to analyze the effect of lipDMU-212 and FSH treatments on CYP11A1 and HSD3B1 protein levels.ResultslipDMU-212 was found to significantly increase estradiol and progesterone secretion in a dose-dependent manner by enhancing the expression of CYP11A1, HSD3B1, StAR, CYP17A1, CYP19A1, and HSD17B1 genes. We have also shown that lipDMU-212, used alone and in combination with FSH, significantly increased the expression of the HSD3B1 and CYP11A1 proteins in GCs. Furthermore, our study suggests that lipDMU-212 increases FSH activity.ConclusionsThis is the first study to describe the steroidogenic activity of liposomal formulation of DMU-212, possibly through increasing the StAR and CYP19A1 expression. These findings suggest that lipDMU-212 might have a beneficial effect in the treatment of disorders related to estrogen deficiency and hyperandrogenism, such as PCOS.

Protective potential of pterostilbene against cyclophosphamide-induced nephrotoxicity and cystitis in rats.

Cyclophosphamide (CYP) is an antitumor drug. However, in addition to its antitumor affect, CYP can also lead to nephrotoxicity and hemorrhagic cystitis. The purpose of this study was to investigate the potential protective effects of Pterostilbene (Pte), a natural antioxidant as a resveratrol analog against CYP-induced nephrotoxicity and cystitis in rats. Twenty-one male Sprague Dawley rats were divided into 3 equal groups. The control group and the CYP group (CYPG) received 1ml/kg sunflower oil per day, and the CYP + Pte group (CYP + PteG) 40mg/kg per day Pte dissolved in sunflower oil once a day via the oral route for 14days. In addition, on day 9 of the experiment, CYPG and CYP + PteG received a single dose of 200mg/kg CYP dissolved in saline solution, while the control group received a single dose of 10ml/kg saline solution, via the intraperitoneal route. Bladder and kidney tissues were collected for histological and biochemical evaluations. Pte was observed to reduce CYP-derived increases in malondialdehyde level, total oxidant status (TOS), the oxidative stress index (OSI), and apoptosis in kidney tissues and to cause an increase in superoxide dismutase levels. It also reduced CYP-derived increases in TOS, OSI, and apoptosis in bladder tissue. Moreover, Pte also ameliorated histopathological findings associated with CYP-induced tissue damage in both the kidney and bladder. Our study findings show that Pte may exhibit a protective effect against CYP-induced nephrotoxicity and cystitis.

Pterostilbene Enhances Thermogenesis and Mitochondrial Biogenesis by Activating the SIRT1/PGC-1α/SIRT3 Pathway to Prevent Western Diet-Induced Obesity.

Sirtuin 1/peroxisome proliferator-activated receptor gamma co-activator 1 alpha (SIRT1/PGC-1α) pathway activation is known to promote thermogenesis and mitochondrial biogenesis. Pterostilbene (PSB) and pinostilbene (PIN), the methylated analogs of resveratrol, are potential candidates to enhance thermogenesis and mitochondrial biogenesis. A model of Western diet-induced obesity in mice is designed. Either PSB or PIN is supplemented in the diet for 16 weeks. Both samples can significantly reduce body weight gain but only PSB can decrease inguinal adipose tissue weight. Besides, both samples can promote lipolysis but only PSB supplementation activates the SIRT1/PGC-1α/SIRT3 pathway to enhance mitochondrial biogenesis and thermogenesis in the inguinal adipose tissue. In addition, although both samples exert a modulatory effect on gut microbiota but significant increments in fecal isobutyric acid, valeric acid, and isovaleric acid are only observed in the PSB group, functioning as gut microbial metabolites. Overall, these findings suggest PSB and PIN as potential candidates for the improvement of obesity and gut microbiota dysbiosis. With its higher stability, PSB exerts a greater effect than PIN by promoting thermogenesis and mitochondrial biogenesis via SIRT1 activation.

Piceatannol improved cerebral blood flow and attenuated JNK3 and mitochondrial apoptotic pathway in a global ischemic model to produce neuroprotection.

Cerebral ischemia is one of the leading causes of death and disability worldwide. The only FDA-approved treatment is recanalization with systemic tissue plasminogen activators like alteplase, although reperfusion caused by recanalization can result in neuroinflammation, which can cause brain cell apoptosis. Therefore, after an ischemic/reperfusion injury, interventions are needed to minimize the neuroinflammatory cascade. In the present study, piceatannol (PCT) was studied for its neuroprotective efficacy in a rat model of global ischemic injury by attenuating c-Jun N-terminal kinase 3 (JNK3) downstream signaling. PCT is a resveratrol analog and a polyphenolic stilbenoid naturally occurring in passion fruit and grapes. The neuroprotective efficacy of PCT (1, 5, 10 mg/kg) in ischemic conditions was assessed through pre- and post-treatment. Cerebral blood flow (CBF) and tests for functional recovery were assessed. Protein and gene expression were done for JNK3 and other inflammatory markers. A docking study was performed to identify the amino acid interaction. The results showed that PCT improved motor and memory function as measured by a functional recovery test believed to be due to an increase in cerebral blood flow. Also, the caspase signaling which promotes apoptosis was found to be down-regulated; however, nitric oxide synthase expression was up-regulated, which could explain the enhanced cerebral blood flow (CBF). According to our findings, PCT impeded c-Jun N-terminal kinase 3 (JNK3) signaling by suppressing phosphorylation and disrupting the mitochondrial apoptotic pathway, which resulted in the neuroprotective effect. Molecular docking analysis was performed to investigate the atomic-level interaction of JNK3 and PCT, which reveals that Met149, Leu206, and Lys93 amino acid residues are critical for the interaction of PCT and JNK3. According to our current research, JNK3 downstream signaling and the mitochondrial apoptosis pathway are both inhibited by PCT, which results in neuroprotection under conditions of global brain ischemia. Piceatannol attenuated JNK3 phosphorylation during the ischemic condition and prevented neuronal apoptosis.

Pterostilbene ameliorates type-2 diabetes mellitus – Induced depressive-like behavior by mitigating insulin resistance, inflammation and ameliorating HPA axis dysfunction in rat brain

One of the most serious mental health comorbidities associated with diabetes mellitus is depression. The occurrence is almost double in type 2 diabetes mellitus (T2DM) compared with the general population. Pterostilbene (PTE), a dimethylated analog of resveratrol, has been reported for significant neuroprotective, anti-inflammatory, hypolipidemic, hypoglycaemic and antioxidant effects. However, its effect on diabetes-induced depression-like behavior (DID) has not been studied.The current study aimed at studying the effects of PTE on depressive-like behavior in male Wistar rats with T2DM. It was induced by single dose administration of nicotinamide (NA) and streptozotocin (STZ). On day 21, forced swim test (FST) was conducted for the confirmation of DID. Rats demonstrating depressive-like behavior were treated with PTE (10, 20 and 40 mg/kg), metformin (MET; 500 mg/kg) and fluoxetine (FLX; 10 mg/kg) for 28 days, orally. At the end of the treatment, behavioral assessment for depression, blood glucose (BG) and lipid profile, oxidative stress markers, gene expression of Sirtuin 1 (SIRT1) and histopathological parameters were investigated. PTE significantly reduced weight loss and mitigated depressive-like behavior paradigms such as sucrose preference test (SPT), resident intruder test (RIT) and open field test (OFT). It significantly restored BG, lipid and liver profile, creatinine and antioxidant level. It Improved glucose tolerance, insulin resistance (IR) and reduced cortisol level as well as inflammatory markers. It showed improved morphology of the pancreas, brain, liver and kidney. Gene expression studies revealed that, PTE significantly increased SIRT1 expression. PTE by its virtue to maintain BG, reduced IR, amelioration of the HPA axis, anti-inflammatory, antioxidant activity and improvement of SIRT1 gene expression proved to be effective in the treatment of DID-like behavior in rats.

Natural resveratrol analogs differentially target endometriotic cells into apoptosis pathways

The specific characteristics of endometriotic cells are their ability to evade the apoptotic machinery and abnormal response to apoptotic stimuli. Natural-originated compounds may constitute a beneficial strategy in apoptosis modulation in endometriosis. We investigated and compared the potency of natural resveratrol analogs, including piceatannol, polydatin, and pterostilbene, in targeting cell death pathways, including apoptosis-related morphologic and biochemical processes, alongside the modulation of the critical genes expression. Upon resveratrol and pterostilbene treatment, a significant reduction of endometriotic cell viability and an increased apoptotic proportion of cells were noted. The lower antiproliferative potential was found for piceatannol and polydatin. Endometrial stromal T HESC cells were significantly more resistant than endometriotic epithelial 12Z cells to the cytotoxic activity of all analyzed compounds. They differentially affected endometriotic cell viability, cell cycle, anti- and proapoptotic genes regulation, caspases expression and enzymatic activity, and DNA fragmentation. Pterostilbene-mediated endometriotic cell apoptosis modulation was confirmed to be most effective but without evident caspase 3 upregulation. Our study provides valuable insight into the apoptogenic activity of resveratrol and its natural analogs in endometriotic cells. Data obtained revealed the highest therapeutic potential of pterostilbene by effectively targeting cell death determinants in endometriosis, strengthening its optimization in further extensive research.

Pterostilbene, a Natural Methoxylated Analog of Resveratrol, Exhibits Antifungal Activity Induced by Reactive Oxygen Species Production and Plasma Membrane Injury

Pterostilbene has been shown to exhibit antifungal activities. However, the detailed action mechanism is unknown. Here, we analyzed the antifungal mechanism of pterostilbene against Saccharomyces cerevisiae. The minimum growth inhibitory and fungicidal concentrations of pterostilbene were 120 and 240 µM in a YPD medium, respectively. Although pterostilbene produced reactive oxygen species (ROS), resveratrol did not. This effect was maximized at 120 µM. Furthermore, α-tocopherol acetate inhibited ROS production and reversed pterostilbene-induced growth inhibition. At 240 µM, pterostilbene showed fungicidal effects accompanied by the leakage of intracellular potassium ions, suggesting the involvement of membrane injury in addition to oxidative stress in fungicidal action. Nevertheless, the antioxidants gradually reversed the decrease in cell viability caused by pterostilbene, suggesting that ROS production mainly contributed to the lethal effect. As Pterocarpus marsupium extract, mainly containing pterostilbene, is used as a traditional medicine, pterostilbene has great potential for development as a preservative with fewer adverse effects.