Pterostilbene

Pterostilbene, a polyphenolic compound and an analog of resveratrol, exerts various biological activities and has higher bioavailability and metabolic stability than resveratrol. However, the effectiveness of pterostilbene intake in humans, particularly its effect on blood microRNA (miRNA) expression levels, has not been evaluated. Accordingly, this pilot study aimed to investigate the effects of pterostilbene on blood biochemistry and blood miRNA expression levels and the safety of continuous intake at doses of 10 or 100 mg/d over 12 wk. A double-blind, placebo-controlled parallel-arm comparison trial was conducted with 30 healthy men. In the analysis of blood miRNA expression levels, miR-34a and miR-193b showed very high increases at week 4 and after week 4 of intake, respectively, suggesting that the responders might be present among participants in the pterostilbene intake group. No adverse events were reported during the trial in any participant, and no abnormalities were observed upon examination by the responsible physician. Thus, pterostilbene intake would regulate blood miRNA expression levels, and the results can be utilized in human studies investigating miRNA expression levels with functional food ingredients.

Background: Pterostilbene is an active molecule from the bark of the Pterocarpus marsupium tree with antioxidant and anti-inflammatory properties. Objective: This study aimed to evaluate the clinical safety of a standardized P. marsupium extract (PME) containing 90% pterostilbene (200 mg per day) in healthy adults. Methods: In a randomized, double-blind, placebo-controlled study, 60 healthy adult participants (27 males and 33 females) were randomized to receive PME-100 mg or placebo capsule twice a day for two months. The primary objectives of the study were to assess any changes in laboratory parameters, vital signs, and the occurrence of adverse events from screening to the final visit. Serum antioxidant enzyme levels were evaluated as a secondary outcome. Results: The hematological, lipid, glycemic, thyroid profiles and liver and renal functions remained within the normal range in all participants, with no difference between PME and placebo. Vital signs, including blood pressure, pulse rate, body weight, body mass index and electrocardiogram, did not reveal any significant differences between the PME and placebo groups at the beginning and end of the study. No serious adverse events were observed in any participant throughout the study period. The serum antioxidant profile was not significantly different between the treatment groups, although the glutathione levels were relatively higher in the PME group. Conclusions: Scientific evaluation of clinical safety of standardized extract is mandatory for its use as a supplement for various health benefits. The results of this study convincingly establish the safety of PME (>90% Pterostilbene) at 200 mg/day (100 mg bid) for human use. The study was approved by the Institutional Ethics Committee of BGS Global Institute of Medical Sciences & Hospital, Bangalore with the registration number CTRI/2019/08/020736.

BACKGROUND AND AIMS: The prevalence of NAFLD is increasing globally and on a path to becoming the most frequent cause of chronic liver disease. Strategies for the prevention and treatment of NAFLD are urgently needed. APPROACH AND RESULTS: A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy of daily NRPT (commercially known as Basis, a combination of nicotinamide riboside and pterostilbene) supplementation in 111 adults with NAFLD. The study consisted of three arms: placebo, recommended daily dose of NRPT (NRPT 1×), and a double dose of NRPT (NRPT 2×). NRPT appeared safe and well tolerated. At the end of the study, no significant change was seen in the primary endpoint of hepatic fat fraction with respect to placebo. However, among prespecified secondary outcomes, a time-dependent decrease in the circulating levels of the liver enzymes alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) was observed in the NRPT 1× group, and this decrease was significant with respect to placebo. Furthermore, a significant decrease in the circulating levels of the toxic lipid ceramide 14:0 was also observed in the NRPT 1× group versus placebo, and this decrease was associated with a decrease in ALT in individuals of this group. A dose-dependent effect was not observed with respect to ALT, GGT, or ceramide 14:0 in the NRPT 2× group. CONCLUSIONS: This study demonstrates that NRPT at the recommended dose is safe and may hold promise in lowering markers of hepatic inflammation in patients with NAFLD.

BACKGROUNDDuring aging, there is a functional decline in the pool of muscle stem cells (MuSCs) that influences the functional and regenerative capacity of skeletal muscle. Preclinical evidence has suggested that nicotinamide riboside (NR) and pterostilbene (PT) can improve muscle regeneration, e.g., by increasing MuSC function. The objective of this study was to investigate if supplementation with NR and PT (NRPT) promotes skeletal muscle regeneration after muscle injury in elderly individuals by improved recruitment of MuSCs.METHODSThirty-two elderly individuals (55-80 years of age) were randomized to daily supplementation with either NRPT (1,000 mg NR and 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, skeletal muscle injury was induced by electrically induced eccentric muscle work. Skeletal muscle biopsies were obtained before, 2 hours after, and 2, 8, and 30 days after injury.RESULTSA substantial skeletal muscle injury was induced by the protocol and associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content, proliferation, and cell size revealed a large demand for recruitment after injury, but this was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, central nuclei, and embryonic myosin heavy chain showed no NRPT supplementation effect.CONCLUSIONDaily supplementation with 1,000 mg NR and 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly individuals.TRIAL REGISTRATIONClinicalTrials.gov NCT03754842.FUNDINGNovo Nordisk Foundation (NNF17OC0027242) and Novo Nordisk Foundation CBMR.

Colistin is a crucial antibiotic for treating infections caused by multidrug-resistant Enterobacterales. However, the emergence of plasmid-mediated mcr genes has significantly compromised their clinical efficacy. Natural adjuvants, such as pterostilbene, offer a promising strategy to restore antibiotic efficacy against resistant bacteria. This study aims to elucidate the molecular mechanisms underlying the synergistic action between pterostilbene and colistin (polymyxin E) against mcr-3-positive Escherichia coli. The in vitro synergistic activity between pterostilbene and colistin was confirmed by checkerboard assays. This effect was further supported by bacterial viability and membrane potential analysis. In the Galleria mellonella infection model, combination therapy also demonstrated therapeutic efficacy. Molecular docking revealed that pterostilbene directly targets key catalytic residues (H380 and E111) of the MCR-3 enzyme, inhibiting its phosphoethanolamine transferase activity, a finding validated by site-directed mutagenesis. Transcriptomic analysis further revealed that pterostilbene downregulated genes involved in fatty acid biosynthesis and central carbon metabolism while upregulating fatty acid degradation pathways. These metabolic disruptions were associated with compromised membrane integrity, as confirmed by electron microscopy and membrane permeability assays. Supplementation with exogenous phospholipids attenuated the synergistic effect, supporting a lipid-mediated mechanism. This study demonstrates that pterostilbene enhances colistin efficacy through dual mechanisms: direct inhibition of MCR-3 enzymatic function and disruption of bacterial membrane stability. These findings provide a strong theoretical foundation for developing pterostilbene-based adjuvants to combat mcr-mediated colistin resistance.IMPORTANCEColistin remains one of the last therapeutic options for infections caused by multidrug-resistant Enterobacteriaceae, but plasmid-borne mcr genes threaten their utility. We identified that the natural compound pterostilbene restores polymyxin activity against mcr-3-positive Escherichia coli through dual mechanisms: direct inhibition of MC

OBJECTIVE: The cosmetics industry increasingly prioritizes the development of formulations that are both safe and effective. This study aimed to investigate the synergistic anti-inflammatory effects of pterostilbene (Pt) and honokiol (Ho) in lipopolysaccharide (LPS)-stimulated THP-1 macrophages and to evaluate their systemic safety using the Threshold of Toxicological Concern (TTC) framework. METHODS: Human THP-1 monocytes were differentiated with PMA and stimulated with LPS to model inflammatory conditions. Pt and Ho were tested individually and in combination for their ability to suppress macrophage proliferation and proinflammatory cytokine production (TNF-α, IL-1β, IL-6). Synergistic effects were assessed through combination index and isobolographic analyses. NF-κB pathway modulation was evaluated via Western blot, and molecular docking was performed to explore compound-target interactions. Maximum systemically safe concentrations were calculated using TTC values integrated with default dermal absorption percentages and product-specific exposure parameters. RESULTS: Pt and Ho significantly inhibited LPS-induced macrophage proliferation and cytokine production, both individually and in combination. Combination index and isobologram analyses confirmed synergistic suppression of cytokines at low, non-cytotoxic concentrations. Both compounds attenuated NF-κB activation; however, no statistical synergy was observed at the signalling level, indicating coordinated but distinct mechanisms. Molecular docking revealed direct binding of Pt to NF-κB, while Ho exhibited no appreciable binding, further supporting mechanistic divergence. TTC-based calculations established systemically safe concentration limits for Pt and Ho across various cosmetic product categories. CONCLUSION: Pt and Ho exert synergistic anti-inflammatory effects in macrophages and can be safely used within systemically acceptable concentration limits in cosmetic formulations. These findings support their development as a multifunctional combination targeting inflammation-related skin conditions, while underscoring the need for further investigation into dermal safety, optimized dosing strategies and bro

AIMS: This study aimed to develop optimized doxorubicin (DOX) and pterostilbene (PTS) co-loaded solid lipid nanoparticles (SLNs) for synergistic triple-negative breast cancer (TNBC) therapy, enhancing drug stability, tumor targeting, and therapeutic efficacy. MATERIALS & METHODS: Calibration curves for DOX and PTS were validated. Synergy was assessed in MDA-MB-231 cells via Combination Index (CI) and Loewe-HSA models. SLNs were optimized using Box-Behnken Design (BBD), evaluating lipid content, surfactant concentration, and sonication time. Formulations were characterized by Zetasizer, high-resolution transmission electron microscopy (HR-TEM), Fourier-transform infrared (FTIR), X-ray powder diffraction (XRD), and differential scanning calorimetry (DSC). In in-vitro cytotoxicity, Reactive Oxygen Species (ROS) generation, apoptosis, and mitochondrial depolarization were assessed. Pharmacokinetics and tumor regression were studied in rats. RESULTS: The optimal 1:4 (DOX:PTS) ratio showed strong synergy (CI = 0.83). BBD-optimized SLNs had 97.92 nm size, high entrapment (DOX: 54.%; PTS: 77.5%), and pH-responsive release (78.78% DOX at pH 5.5). SLNs exhibited enhanced cytotoxicity (IC₅₀ = 0.833 µg/mL), elevated ROS (59.5%), and apoptosis induction. In in-vivo, SLNs prolonged circulation, increased tumor accumulation, and reduced tumor volume (701.50 ± 11.83 mm3 vs. 3506.58 ± 17.06 mm3 control). CONCLUSIONS: DOX-PTS SLNs demonstrated synergistic anticancer effects, improved stability, and targeted delivery, offering a promising strategy for TNBC treatment.

This efficacy trial evaluated the effects of two polyphenolic stilbenes, resveratrol and pterostilbene, mostly found in grapes, on the brush border membrane functionality, morphology and gut microbiome. This study applied the validated Gallus gallus intra-amniotic approach to investigate the effects of stilbene administration versus the controls. Three treatment groups (5% resveratrol; 5% pterostilbene; and synergistic: 4.75% resveratrol and 0.25% pterostilbene) and three controls (18 MΩ H2O; no injection; 5% inulin) were employed. We observed beneficial morphological changes, specifically an increase in the villus length, diameter, depth of crypts and goblet cell diameter in the pterostilbene and synergistic groups, with concomitant increases in the serum iron and zinc concentrations. Further, the alterations in gene expression of the mineral metabolism proteins and pro-inflammatory cytokines indicate a potential improvement in gut health and mineral bioavailability. The cecal microbiota was analyzed using 16S rRNA sequencing. A lower α-diversity was observed in the synergistic group compared with the other treatment groups. However, beneficial compositional and functional alterations in the gut microbiome were detected. Several key microbial metabolic pathways were differentially enriched in the pterostilbene treatment group. These observations demonstrate a significant bacterial-host interaction that contributed to enhancements in intestinal functionality, morphology and physiological status. Our data demonstrate a novel understanding of the nutritional benefits of dietary stilbenes and their effects on intestinal functionality, morphology and gut microbiota in vivo.

This study was focused to determine an individual and combined effect of mycotoxin citrinin (CIT) and two compounds of the stilbene family- resveratrol (RES) and his dimethyl ether analogue pterostilbene (PTE) which have many health benefits. As a model the human adenocarcinoma cell line HT-29 was used which may exhibits the properties of small intestine cells. Viability, plasma membrane integrity, lysosomal functionality, intracellular production of superoxide anions and superoxide dismutase activity were examined. The results indicate that concentrations of 50 and 100 μg/mL of the tested compounds were cytotoxic in mostly monitored parameters and probably caused apoptosis. HT-29 cells were more sensitive to PTE than to RES with a higher antioxidant effect of PTE than RES, which may be caused by its chemical structure. Both stilbenes at medium doses act as effective superoxide anions scavengers leading to reduction of oxidative stress and consequent cell damage. The nontoxic concentration of RES (25 µg/mL) protects the HT-29 cell line faced to the toxicity of CIT at 25 µg/mL by increasing viability of cells and by reducing the superoxide production induced by CIT concentrations of 12.5 µg/mL and 25 µg/mL.

Sorafenib has been approved for the treatment of certain cancers in clinic. However, the effects of sorafenib on gastric adenocarcinoma (GAC) were still limited. This study aimed to evaluate both in vitro and in vivo efficacy of sorafenib in combination with pterostilbene (PTE) on the treatment of GAC. Here, the morphological changes and cell viability were recorded in both N87 and MKN45 cells. The cell cycle profile and apoptosis were assessed by flow cytometry. Subcutaneous tumour xenografts were constructed in nude mice, and IHC staining of the dissected tumour tissues was conducted. Our results showed that PTE enhanced sorafenib's inhibitory effects on cell viability. The obvious down-regulation of cyclin D1, Cdk-2, Cdk-4, Cdk-6 and p62 and the up-regulation of LC3II, caspase-9, caspase-3 and PARP cleavages were observed for the combination treatment with PTE and sorafenib than monotherapy. The combination treatment resulted in a higher level of cell cycle arrest at G1 phase and apoptosis than either drug. Besides, drug combination significantly enhanced the inhibition of tumour growth than sorafenib or PET alone in nude mice. The percentage of Ki-67- and PCNA-positive cells was distinctly reduced, and the apoptotic cells was obviously increased when compared with single drug therapy. Altogether, PET obviously enhanced sorafenib's antitumour effects against GAC through inhibiting cell proliferation, inducing autophagy and promoting apoptosis. The combination therapy with PET and sorafenib may serve as a novel therapeutic strategy for treating GAC and deserve further clinical trials. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Pterostilbene (PT) is a natural stilbene common in small berries and food supplements, possessing numerous pharmacological activities. However, whether PT can affect the activities of UDP-glucuronosyltransferases (UGT) enzymes remains unclear. The aim of the present study was to investigate the effect of PT on UGT activities and to quantitatively evaluate the food-drug interaction potential due to UGT inhibition. Our data indicated that PT exhibited potent inhibition against HLM, UGT1A6, UGT1A9, UGT2B7, and UGT2B15, moderate inhibition against UGT1A1, UGT1A3, UGT1A8, and UGT2B4, negligible inhibition against UGT1A4, UGT1A7, UGT1A10, and UGT2B17. Further kinetic investigation demonstrated that PT exerted potent noncompetitive inhibition 4-MU glucuronidation by UGT1A9, with IC50 and Ki values of 0.92 μM and 0.52 ± 0.04 μM, respectively. Quantitative prediction study suggested that coadministration of PT supplements at 100 mg/day or higher doses may result in at least a 50% increase in the AUC of drugs predominantly cleared by UGT1A9. Thus, the coadministration of PT supplements and drugs primarily cleared by UGT1A9 may result in potential drug interaction, and precautions should be taken when coadministration of PT supplements and drugs metabolized by UGT1A9.

Monotherapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) still leads to incomplete responses in most EGFR-mutation positive non-small cell lung cancer (NSCLC) patients, often due to acquired resistance through activation of parallel compensatory pathways. We have previously shown that co-targeting EGFR, signal transducer and activator of transcription 3 (STAT3), and Src-yes-associated protein 1 (YAP1) was highly synergistic in vitro and in vivo. In the present study, we treated EGFR-mutation positive cell lines with the combination of osimertinib plus a natural compound, pterostilbene, which has been reported to abrogate Src and STAT3 activation. Methods: Cell viability assays and immunoblotting were performed to reveal the mechanisms of action of pterostilbene, osimertinib and pterostilbene plus osimertinib in five EGFR-mutation positive NSCLC and one triple negative breast cancer (TNBC) cell lines. Results: Osimertinib plus pterostilbene yielded synergistic effects in all EGFR-mutation positive NSCLC cell lines investigated. Surprisingly, pterostilbene alone did not inhibit, nor downregulate Src phosphorylation in the EGFR-mutation positive NSCLC cell lines or the TNBC cell line, MDA-MB-231. However, the double combination of osimertinib plus pterostilbene reversed the osimertinib-induced STAT3, YAP1, and CUB domain-containing protein-1 (CDCP1) phosphorylation and slightly suppressed Src phosphorylation in PC9 and H1975 cells. Conclusion: The results of this study indicate that pterostilbene may be used to abrogate the activated resistance pathways of single osimertinib treatment in EGFR-mutation positive NSCLC. Future studies should focus on in vivo translation and confirmation of these results. © The author(s).

Resveratrol (RSV) is a stilbene phytochemical common in food and red wine. RSV inhibits cytochrome P450 CYP3A4 activity and interacts with the pregnane X receptor (PXR), the central regulator of drug/xenobiotic metabolizing enzyme expression. In this work, we comprehensively examined the effects of 13 stilbenes (trans- and cis-resveratrol, trans- and cis-piceatannol, oxyresveratrol, pterostilbene, pinostilbene, a,b-dihydroresveratrol, trans- and cis-trismethoxyresveratrol, trans-3,4,5,4'-tetramethoxystilbene, trans-2,4,3',5'-tetramethoxystilbene, trans-4-methoxystilbene), on CYP3A4 and CYP2B6 mRNA induction, and on CYP3A4/5, CYP2C8/9/19, CYP2D6, CYP2A6, CYP2E1, CYP1A2 and CYP2B6 cytochrome P450 enzyme activities. Expression experiments in five different primary human hepatocyte preparations, reporter gene assays, and ligand binding assays with pregnane X (PXR) and constitutive androstane (CAR) receptors were performed. Inhibition of cytochrome P450 enzymes was examined in human microsomes. We found that only polymethoxylated stilbenes are prone to significantly induce CYP2B6 or CYP3A4 in primary human hepatocytes via pregnane X receptor (PXR) interaction. Natural resveratrol derivatives such as trans- and cis-RSV, oxyresveratrol, pinostilbene and pterostilbene significantly inhibit CYP3A4/5 enzymatic activities; however, only trans-RSV significantly inhibits CYP3A4/5 activity (both testosterone 6β-hydroxylation and midazolam 1´-hydroxylation) in micromolar concentrations by a non-competitive mechanism, suggesting a potential risk of food-drug interactions with CYP3A4/5 substrates.

Phenylephrine (PE) has low and variable oral bioavailability in humans, due in part to presystemic metabolism by sulfation. LS180 cells were used as a model of the human intestinal epithelium to examine phenylephrine metabolism and its inhibition by generally recognized as safe (GRAS) and dietary compounds. Curcumin, zingerone, resveratrol, guaiacol, pterostilbene and isoeugenol significantly inhibited phenylephrine disappearance, while vanillin, propylparaben and eugenol did not. However, when propylparaben was combined with either vanillin or eugenol, the phenylephrine disappearance was significantly inhibited. These data suggest that these compounds or combinations thereof may have potential to improve phenylephrine oral bioavailability. © 2018 John Wiley & Sons, Ltd.