ABSTARCTAim: Development and evaluation of aqueous core nanocapsules (ACNs) of BCS-II-class drug like resveratrol (RSV) and pterostilbene (PTE) for prostate cancer. Materials & methods: Identify synergistic effects of molar ratios of RSV and PTE against PC-3 cell. Selected ratio of drugs was added to ACNs by double-emulsification-method using Box-Behnken design. Further, assessed for physicochemical characterization, release kinetics, compatibility, in vitro cytotoxicity, in vivo pharmacokinetic and biodistribution studies. Results: Selected 1:1 ratio of RSV and PTE had greatest synergy potential have smaller particle-size (128.1 ± 3.21 nm), zeta-potential (-22.12 ± 0.2 mV), 0.53 PDI, improved encapsulation (87% for RSV, 72% for PTE), stable, no systemic toxicity, high biodistributed/accumulated in prostate cells. Conclusion: ACNs exhibited high t1/2 (12.42 ± 1.92 hs) and 8.20 ± 8.21 hs Mean Residence Time and lower clearance, proving the high effectiveness for prostate cancer.
[Box: see text].

Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer\'s disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3β insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3β pathway, reducing GSK-3β activity, and mitigating Tau hyperphosphorylation and Aβ accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.

Intestinal barrier hemostasis is the key to health. As a resveratrol analogue, pterostilbene (PT) has been reported to prevent dextran sodium sulfate (DSS)-induced intestinal barrier dysfunction mainly associated with the intestinal NF-κB signaling pathway. However, the exact underlying mechanisms are not yet well-defined yet. In this study, we performed RNA-sequencing analysis and unexpectedly found that alarmin S100A8 sensitively responded to DSS-induced intestinal injury. Accordingly, histologic assessments suggested that the high expression of S100A8 was accompanied by increased intestinal infiltration of macrophages, upregulated intestinal epithelial Toll-like receptor 4 (TLR-4), and activated NF-κB signaling pathway. Interestingly, the above phenomena were effectively counteracted upon the addition of PT. Furthermore, by using a coculture system of macrophage THP-1 cells and HT-29 colon cells, we identified macrophage-secreted S100A8 activated intestinal epithelial NF-κB signaling pathway through TLR-4. Taken together, these findings suggested that PT ameliorated DSS-induced intestinal barrier injury through suppression of the macrophage S100A8-intestinal epithelial TLR-4-NF-κB signaling cascade.

A recent pilot study in amyotrophic lateral sclerosis (ALS) patients analyzed the effect of a Mediterranean diet (MeDi) supplemented with nicotinamide riboside (NR, a NAD+ promoter), pterostilbene (PTER, a natural antioxidant) and/or coconut oil on anthropometric variables in ALS patients. The results suggested that the MeDi supplemented with NR, PTER and coconut oil is the nutritional intervention showing the greatest benefits at anthropometric levels. Over the last 30 years, glucose intolerance has been reported in ALS patients. Thus, suggesting that an alternative source of energy may be preferential for motor neurons to survive. Ketone bodies (KBs), provided through a MeDi with a lower carbohydrate content but enriched with medium chain triglycerides, could be a therapeutic alternative to improve the neuromotor alterations associated with the disease. Nevertheless, the use of a coconut oil-supplemented diet, as potentially ketogenic, is a matter of controversy. In the present report we show that a MeDi supplemented with coconut oil increases the levels of circulating KBs in ALS patients.

Tapinarof (3,5-dihydroxy-4-isopropylstilbene) is a therapeutic agent used in the treatment of psoriasis (VTAMA®). In this study, we examined the redox behaviour, (photo)stability, (photo)toxicity and (bio)transformation of tapinarof in the context of a structure-activity relationship study. Selected derivatives of the structurally related tapinarof were investigated, namely resveratrol, pterostilbene, pinosylvin and its methyl ether. Tapinarof undergoes electrochemical oxidation in a neutral aqueous medium at a potential of around +0.5 V (vs. Ag|AgCl|3M KCl). The anodic reaction of this substance is a proton-dependent irreversible and adsorption-driven process. The pKa value of tapinarof corresponds to 9.19 or 9.93, based on empirical and QM calculation approach, respectively. The oxidation potentials of tapinarof and its analogues correlate well with their HOMO (highest occupied molecular orbital) energy level. The ability to scavenge the DPPH radical decreased in the order trolox ≥ resveratrol > pterostilbene > tapinarof > pinosylvin ≫ pinosylvin methyl ether. It was also confirmed that tapinarof, being a moderate electron donor, is able to scavenge the ABTS radical and inhibit lipid peroxidation. The 4\'-OH group plays a pivotal role in antioxidant action of stilbenols. During the stability studies, it was shown that tapinarof is subject to spontaneous degradation under aqueous conditions, and its degradation is accelerated at elevated temperatures and after exposure to UVA (315-399 nm) radiation. In aqueous media at pH 7.4, we observed an ∼50 % degradation of tapinarof after 48 h at laboratory temperature. The main UVA photodegradation processes include dihydroxylation and hydration. In conclusion, the phototoxic effect of tapinarof on a human keratinocytes cell line (HaCaT) was evaluated. Tapinarof exhibited a clear phototoxic effect, similar to phototoxic standard chlorpromazine. The IC50 values of the cytotoxicity and phototoxic effects of tapinarof correspond to 27.6 and 3.7 μM, respectively. The main HaCaT biotransformation products of tapinarof are sulfates and glucuronides.

Early detection of lung squamous cell carcinoma (LUSC) has a significant impact on clinical outcomes, and pterostilbene (PT) is a natural compound with promising anti-oncogenic activities. This study aimed to identify potential LUSC biomarkers through a series of bioinformatic analyses and clinical verification and explored the interaction between PT and selected biomarkers during the treatment of LUSC. The analysis of the expression profile of the clinical samples of LUSC was performed to identify dysexpressed genes (DEGs) and validated by IHC. The role of KANK3 in the anti-LUSC effects of PT was assessed with a series of in vitro and in vivo assays. 4335 DEGs were identified, including 1851 upregulated genes and 2484 downregulated genes. Survival analysis showed that KANK3 was significantly higher in patients with LUSC with an advanced tumor stage. In in vitro assays, PT suppressed cell viability, induced apoptosis, and inhibited migration and invasion in LUSC cell lines, which was associated with downregulation of KANK3. After the reinduction of the KANK3 level in LUSC cells, the anti-LUSC function of PT was impaired. In mice model, reinduction of KANK3 increased tumor growth and metastasis even under the treatment of PT. The findings outlined in the current study indicated that PT exerted anti-LUSC function in a KANK3 inhibition-dependent manner.

The epigenetic regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal redox transcription factor, plays a crucial role in maintaining cellular homeostasis. Recent research has underscored the significance of epigenetic modifications of Nrf2 in the pathogenesis of diabetic foot ulcers (DFUs). This study investigates the epigenetic reversal of Nrf2 by pterostilbene (PTS) in human endothelial cells in a hyperglycemic microenvironment (HGM). The activation potential of PTS on Nrf2 was evaluated through ARE-Luciferase reporter assays and nuclear translocation studies. Following 72 h of exposure to an HGM, mRNA expression and protein levels of Nrf2 and its downstream targets NAD(P)H quinone oxidoreductase 1 (NQO1), heme-oxygenase 1(HO-1), superoxide dismutase (SOD), and catalase (CAT) exhibited a decrease, which was mitigated in PTS-pretreated endothelial cells. Epigenetic markers, including histone deacetylases (HDACs class I-IV) and DNA methyltransferases (DNMTs 1/3A and 3B), were found to be downregulated under diabetic conditions. Specifically, Nrf2-associated HDACs, including HDAC1, HDAC2, HDAC3, and HDAC4, were upregulated in HGM-induced endothelial cells. This upregulation was reversed in PTS-pretreated cells, except for HDAC2, which exhibited elevated expression in endothelial cells treated with PTS in a hyperglycemic microenvironment. Additionally, PTS was observed to reverse the activity of the methyltransferase enzyme DNMT. Furthermore, CpG islands in the Nrf2 promoter were hypermethylated in cells exposed to an HGM, a phenomenon potentially counteracted by PTS pretreatment, as shown by methyl-sensitive restriction enzyme PCR (MSRE-qPCR) analysis. Collectively, our findings highlight the ability of PTS to epigenetically regulate Nrf2 expression under hyperglycemic conditions, suggesting its therapeutic potential in managing diabetic complications.

This experiment was carried out to investigate the effect of pterostilbene (PTE) supplementation in feed on Arbor Acres broilers in terms of serum biochemical parameters, immune and inflammatory responses, antioxidant status, and intestinal morphological structure. For a duration of 42 days, a total of 480 1-day-old Arbor Acres broilers were randomly divided into four groups. Each group was assigned to receive either the basal diet or the basal diet supplemented with 200, 400, or 600 mg/kg of PTE. Each treatment consisted of eight replicates, with 15 chicks per replicate. In comparison with the control group, three PTE treatments significantly increased the lymphocyte transformation rate in the spleen of broilers. The automated biochemical analysis, enzyme-linked immunosorbent assay, and RT-qPCR analysis kits found that 400 mg/kg of PTE significantly increased the serum levels of complement C3, IL-4, and iNOS; reduced the serum levels of IL-6, TNF-α, and mRNA levels of the genes IL-6, IL-8, TNF-α, NLRP3, and IFN-γ; significantly improved the activities of antioxidant enzymes including CAT, GSH-Px, and T-SOD in the jejunum; and significantly reduced the MDA contents in the serum and jejunum of broilers. Nikon microscope observations and ImagePro Plus 6.0 measure results found that 400 mg/kg of PTE supplementation significantly reduced the relative length and weight of the jejunum and improved the jejunal villi structure, resulting in increased intestinal villi, deepened crypt, and an enhanced ratio of villi height to crypt depth (VH/CD). RT-qPCR and Western blot found that dietary PTE also resulted in increased mRNA levels of the genes Claudin-2, Occludin, ZO-1, and Sirt1, and decreased NF-κB protein levels in the jejunum. The results of this study demonstrated that dietary PTE improved the immune function and intestinal health of broilers by reducing inflammation and increasing the antioxidant capacity of the animals.

Pterostilbene (PTE), a naturally occurring phenolic compound primarily found in blueberries, demonstrates neuroprotective properties. However, the role of PTE in Parkinson\'s disease (PD) remains unclear. This study aimed to investigate the neuroprotective role of PTE in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. Our findings demonstrate that administering PTE effectively reversed the diminished levels of dopamine in the striatum, thereby ameliorating motor impairments in the MPTP model. Moreover, PTE administration mitigated the loss of dopaminergic (DA) neurons and reduced the upregulation of α-synuclein (α-syn) induced by MPTP. Mechanistic analysis revealed that PTE administration inhibited the activation of microglia and astrocytes, as well as pro-inflammatory factors such as TNF-α and IL-1β in the MPTP model. Additionally, PTE administration decreased MPTP-induced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing total antioxidant capacity (TAOC) and superoxide dismutase (SOD) activity, thereby attenuating oxidative stress. Collectively, these findings demonstrate that PTE exerts neuroprotective effects in the MPTP mouse model of PD by suppressing neuroinflammation and oxidative stress. Thus, PTE holds promise as a therapeutic agent for PD.

Hepatic lipid metabolism is modulated by the circadian rhythm; therefore, circadian disruption may promote obesity and hepatic lipid accumulation. This study aims to investigate dietary pterostilbene (PSB) \'s protective effect against high-fat-diet (HFD)-induced lipid accumulation exacerbated by chronic jet lag and the potential role of gut microbiota therein. Mice were treated with a HFD and chronic jet lag for 14 weeks. The experimental group was supplemented with 0.25% (w/w) PSB in its diet to evaluate whether PSB had a beneficial effect. Our study found that chronic jet lag exacerbates HFD-induced obesity and hepatic lipid accumulation, but these adverse effects were significantly mitigated by PSB supplementation. Specifically, PSB promoted hepatic lipolysis and β-oxidation by upregulating SIRT1 expression, which indirectly reduced oxidative stress caused by lipid accumulation. Additionally, the PSB-induced elevation of SIRT1 and SIRT3 expression helped prevent excessive autophagy and mitochondrial fission by activating Nrf2-mediated antioxidant enzymes. The result was evidenced by the use of SIRT1 and SIRT3 inhibitors in in vitro studies, which demonstrated that activation of SIRT1 and SIRT3 by PSB is crucial for the translocation of PGC-1α and Nrf2, respectively. Moreover, the analysis of gut microbiota suggested that PSB\'s beneficial effects were partly due to its positive modulation of gut microbial composition and functionality. The findings of this study suggest the potential of dietary PSB as a candidate to improve hepatic lipid metabolism via several mechanisms. It may be developed as a treatment adjuvant in the future.