Search Results (143)

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, arises from chronic hyperglycemia-induced oxidative stress, inflammation, and vascular dysfunction. Current therapies such as laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and steroids target advanced stages but fail to prevent early neuronal and microvascular damage. Emerging evidence highlights oxidative stress as a key driver of DR pathogenesis, disrupting the blood-retinal barrier (BRB), promoting neurodegeneration and angiogenesis. Advances in imaging, particularly optical coherence tomography angiography (OCTA), enable earlier detection of neurodegeneration and microvascular changes, underscoring DR as a neurovascular disorder. Polyphenols, such as resveratrol, curcumin, and pterostilbene, exhibit multitarget antioxidant, anti-inflammatory, and anti-angiogenic effects, showing promise in preclinical and limited clinical studies. However, their low bioavailability limits therapeutic efficacy. Nanotechnology-based delivery systems enhance drug stability, tissue targeting, and sustained release, offering potential for early intervention. Future strategies should integrate antioxidant therapies and precision diagnostics to prevent early irreversible retinal damage in diabetic patients. Full article

Ethylmalonic encephalopathy (EE) is a serious metabolic disorder that usually appears in early childhood development and the effects are seen primarily in the brain, gastrointestinal tract, and peripheral vessels. EE is caused by pathogenic variants in the gene that encodes the ETHE1 protein, and its main features are high levels of acidic compounds in body fluids and decreased activity of the mitochondrial complex IV, which limits energy production in tissues that require a large supply of energy. ETHE1 is a mitochondrial sulfur dioxygenase that plays the role of hydrogen sulfide (H₂S) detoxification, and, when altered, it leads to the accumulation of this gaseous molecule due to its deficient elimination. In this article, we characterised the pathophysiology of ETHE1 deficiency in cellular models, fibroblasts, and induced neurons, derived from a patient with a homozygous pathogenic variant in ETHE1. Furthermore, we evaluated the effect of the activation of the mitochondrial unfolded protein response (mtUPR) on the mutant phenotype. Our results suggest that mutant fibroblasts have alterations in ETHE1 protein expression levels, associated with elevated levels of H₂S and protein persulfidation, mitochondrial dysfunction, iron/lipofuscin accumulation, and oxidative stress. We also identified a cocktail of compounds consisting of pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid, and L-carnitine that improved the cellular and metabolic alterations. The positive effect of the cocktail was dependent on sirtuin 3 activation (SIRT3) and was also confirmed in induced neurons obtained by direct reprogramming. In conclusion, personalised precision medicine in EE using patient-derived cellular models can be an interesting approach for the screening and evaluation of potential therapies. In addition, the activation of the SIRT3 axe of mtUPR is a promising therapeutic strategy for rescuing ETHE1 pathogenic variants. Full article

Interstitial cystitis/bladder pain syndrome (IC/BPS) causes significant discomfort in patients and impairs the quality of urination. Pterostilbene (PTE), a natural polyphenol antioxidant, has demonstrated beneficial effects in mitigating inflammation, enhancing antioxidant capacity, and ameliorating organ dysfunction in various chronic nonspecific inflammatory conditions. The aim of this study was to evaluate the efficacy of PTE in IC/BPS and elucidate its underlying mechanisms using a rat model of cyclophosphamide (CYP)-induced interstitial cystitis. In comparison, chronic pain progression, histopathological features, and cytokine levels demonstrated that PTE mitigated the severity of symptoms in CYP-induced rats by inhibiting the NLRP3 inflammasome in a dose-dependent manner. Further mechanistic investigations indicated that PTE intervention alleviated oxidative stress in CYP-induced IC in rats via activation of the Nrf2/HO-1 signaling pathway. Moreover, inhibitors of the Nrf2/HO-1 pathway effectively blocked PTE-mediated attenuation of oxidative stress. The suppression of NLRP3 inflammasome activation by PTE could also be reversed by inhibition of the Nrf2/HO-1 pathway. In vitro studies revealed that PTE enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and suppressed NLRP3 inflammasome activation in SV-HUC-1 cells exposed to lipopolysaccharide (LPS) and Adenosine Triphosphate (ATP). These findings collectively suggest that PTE treatment inhibits oxidative stress and suppresses NLRP3 inflammasome activation through modulation of the Nrf2/HO-1 pathway. Full article

Pterostilbene (PTS) has multiple benefits, but poor water solubility and bioavailability limit its application. PTS/β-CD inclusion complexes were synthesized through the phase solubility method to enhance their water solubility. The inclusion complexes were characterized through Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, nuclear magnetic resonance, and molecular docking techniques. The results demonstrated that PTS and β-CD successfully created inclusion complexes with a host–guest ratio of 1:1 and a stability constant of 166.7 M⁻¹. To further investigate its prebiotic function, simulated digestion experiments revealed that β-CD exhibited resistance to digestion, allowing it to reach the colon intact. During gastrointestinal digestion, PTS in the PTS/β-CD inclusion complexes was gradually released. Following digestion, the in vitro fermentation of healthy human feces further confirmed the probiotic properties. Compared to the β-CD and fructooligosaccharide (FOS) groups, the PTS/β-CD group significantly increased the production of acetic acid, butyric acid, and lactic acid, respectively. Additionally, beneficial bacteria, such as Bifidobacterium and Lactobacillus, proliferated in the PTS/β-CD group, while the relative abundance of potential pathogenic bacteria, such as Lactococcus, Streptococcus, and Klebsiella, was significantly reduced. Compared to the blank group, propionic acid and butyric acid concentrations in the β-CD group were significantly higher. The abundance of Lactobacillus and other key bacterial species in the β-CD group increased, while the relative abundance of Klebsiella and other pathogens decreased significantly. In conclusion, PTS/β-CD inclusion complexes altered the composition of intestinal flora, promoting the proliferation of beneficial bacteria and inhibiting the growth of harmful bacteria, thereby demonstrating dual probiotic functionality. Full article

Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant with a promising role in anti-cancer treatment. In endometrial cancer (EC), in vitro studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) with megestrol acetate (MA), a common treatment for EC. This is a randomized phase II clinical trial (NCT03671811) of PT+MA vs. MA for three weeks prior to scheduled hysterectomy. The primary objective is to determine the antiproliferative effect of PT+MA vs. MA using Ki-67 index. The secondary objectives are toxicity, histological response, transcriptional changes, and lipid metabolism. A total of 44 patients were enrolled between January 2019 and November 2022 with 23 randomized to Arm 1 (PT+MA) and 21 to Arm 2 (MA). Toxicities included one G3 thromboembolic event (PT+MA) and one G3 hypertension event (MA). Histological responses were high in both arms (>90%). There was no difference in Ki-67 changes, although, when restricted to endometroid subtype, the relative decrease in Ki67 was 33.8% in PT+MA vs. 20.1% in MA alone (p = 0.14). Whole transcriptomic gene profiling of samples before and after PT+MA exposure demonstrated the activation of interferon alpha response pathway and suppression of mTORC1 signaling, hypoxia, oxidative phosphorylation, and IL2-STAT5 signaling. Lipid metabolism analyses did not reveal any significant changes between arms. PT is well-tolerated in the preoperative treatment of EC and demonstrated in vivo anti-cancer effects on the transcriptomic level. Full article

Plant-based stilbenes are low-molecular-weight polyphenolic compounds that exhibit anti-oxidant, anti-microbial, anti-fungal, anti-inflammatory, anti-diabetic, cardioprotective, neuroprotective, and anti-cancer activities. They are phytoalexins produced in diverse plant species in response to stress, such as fungal and bacterial infections or excessive UV irradiation. Plant-derived dietary products containing stilbenes are common components of the human diet. Stilbenes appear to be promising chemopreventive and chemotherapeutic agents. Accumulating evidence indicates that stilbenes are able to trigger both apoptotic and autophagic molecular pathways in many human cancer cell lines. Of note, the molecular crosstalk between autophagy and apoptosis under cellular stress conditions determines the cell fate. The autophagy and apoptosis relationship is complex and depends on the cellular context, e.g., cell type and cellular stress level. Apoptosis is a type of regulated cell death, whereas autophagy may act as a pro-survival or pro-death mechanism depending on the context. The interplay between autophagy and apoptosis may have an important impact on chemotherapy efficiency. This review focuses on the in vitro effects of stilbenes in different human cancer cell lines concerning the interplay between autophagy and apoptosis. Full article

Stilbenes are a class of natural polyphenols with multiple positive pharmacologic assets such as antioxidant, anti-inflammatory and anticancer effects. While monomeric stilbenes, represented mostly by resveratrol and pterostilbene, have been studied intensely in the last two decades, oligomeric compounds, which may have better prospects of becoming potent nutraceuticals, are much less studied. The goal of this review is to compile all available literature to date on the beneficial pharmacologic effects of Gnetin C, a resveratrol dimer, in cancer and other diseases. While studies have shown the beneficial effects of Gnetin C, as a single compound or a component of melinjo seed extract, through cellular models, in vivo preclinical studies are still lacking. This is except for prostate cancer, where various animal models, including xenografts and transgenic mice, have been used to evaluate Gnetin C’s more potent anti-inflammatory and anticancer effects compared to resveratrol and its monomeric analogs. Since Gnetin C’s safety has already been demonstrated in healthy volunteers, it is now logical to evaluate its efficacy for prostate cancer chemoprevention, interception and therapy in clinical trials. Full article

Chronic hyperglycemia is a major driver of neurovascular damage in diabetic retinopathy (DR), a leading cause of preventable blindness in adults. DR progression is often undetected until its advanced stages, with oxidative stress recognized as a primary contributor. In diabetes, oxidative stress disrupts retinal cellular balance, damaging proteins, DNA, and lipids, and triggering photoreceptor degeneration. Pterostilbene (Pter), a polyphenol with antioxidant properties, has demonstrated protective effects in DR animal models and was assessed in a pilot clinical study. DR patients treated with 250 mg/day of oral Pter showed a reduction in the development of retinal vascular alterations characteristic of the disease. Urinary analyses confirmed Pter’s role in reducing the lipid peroxidation of polyunsaturated fatty acids (PUFAs), including arachidonic and adrenic acids, indicators of oxidative damage in DR. Pter also improved the GSH/GSSG ratio, reflecting a restored redox balance. However, after six months without treatment, retinal damage indicators reappeared, highlighting the importance of sustained intervention. These findings suggest that Pter may help slow the progression of DR by protecting against oxidative stress and highlight the importance of implementing antioxidant therapies from the diagnosis of diabetes, although its long-term impact and the development of consistent biomarkers deserve more research to optimize DR management. Full article

Stilbenoids are a class of naturally occurring phenolic compounds found in various plant species, characterized by a stilbene backbone with diverse substituents that confer a range of biological activities. These compounds exhibit antioxidant, anti-inflammatory, and antimicrobial properties, making them promising candidates for improving intestinal health. The intestinal tract plays a critical role in nutrient digestion, absorption, and immune defense, and maintaining its integrity is vital for animal growth. Stilbenoids contribute to gut health by enhancing intestinal morphology, supporting mucosal immune responses, regulating gut microbiota composition, modulating metabolic pathways, and maintaining mitochondrial health. This review provides a comprehensive analysis of key stilbenoids, including resveratrol, pterostilbene, piceatannol, and oxyresveratrol, focusing on their biological effects and regulatory mechanisms. By highlighting their roles in mitigating intestinal inflammation and promoting gut function, this review provides a basis for the practical application of stilbenoids in animal health and husbandry. Full article

Pterostilbene is gaining increasing attention as an effective ingredient in cosmetics. This study was performed to investigate the antiaging efficacy of pterostilbene using a human-originated P2 generation fibroblast assay and an in vitro skin experiment. A fibroblast cytotoxicity assay was performed to evaluate the safety of pterostilbene: a 30 J/cm² UVA irradiated fibroblast cell assay and a 30 J/cm² UVA and 50 mJ/cm² UVB-irradiated in vitro skin experiment were carried out to evaluate the antiaging efficacy of pterostilbene. The cytotoxicity assay found that 3.90 µg/mL or lower concentrations of pterostilbene exerted no significant toxicity to fibroblasts. The fibroblast cell assay showed that 2.6 µg/mL pterostilbene alleviated the UVA damage to fibroblasts by down-regulating the gene expression of matrix metalloproteinase 1 (MMP-1) by 18.62% and decreasing the content of MMP-1 by 10.08%, MMP-3 by 15.10%, and collagen I by 33.92%. The in vitro skin experiment revealed that pterostilbene relieved the adverse UVA and UVB irradiation effects on skin tissue by increasing the thickness of the epidermis to maintain skin morphology, preventing the degradation of collagen fibers by 88.57%, and increasing the amount of collagen IV by 30.95%, collagen VII by 25.64%, and fibroblast growth factor-β (FGF-β) by 15.67%. This fibroblast assay and in vitro skin study consistently demonstrated the strong antiaging efficacy of pterostilbene. Full article

Resveratrol, a naturally occurring polyphenolic compound found in various plants, has been extensively studied for its broad spectrum of beneficial biological effects. These encompass its potent antioxidant properties, anti-inflammatory activities, anti-aging capabilities, cardioprotective functions, and neuroprotective potential. The diverse biological actions of resveratrol extend beyond these well-established properties. It also exerts a significant impact on metabolic processes and bioavailability, and critically, it demonstrates the ability to effectively traverse the blood–brain barrier. This capacity to penetrate the central nervous system renders resveratrol a promising therapeutic agent for the management of central nervous system malignancies, as it has been shown to inhibit tumor cell proliferation, induce apoptosis, and modulate key signaling cascades, such as PI3K/Akt, JAK/STAT, and NF-kB. The multifaceted nature of resveratrol’s biological effects, including its influence on diverse physiological processes, underscores its potential as a valuable therapeutic option for the treatment of central nervous system tumors. Full article

Background. The “Cell Cycle Hypothesis” suggests that the abnormal re-entry of neurons into the cell division cycle leads to neurodegeneration, a mechanism supported by in vitro studies on neuronal-like cells treated with the hyperphosphorylating agent forskolin. Pterostilbene, a bioavailable compound found in foods such as blueberries and grapes, may exert neuroprotective effects and could serve as a potential adjunct therapy for neurodegenerative diseases. Methods. In this study, we investigated the effects of pterostilbene on neuronal-like cells derived from the human neuroblastoma SK-N-BE cell line, where cell cycle reactivation was induced by forskolin treatment. We analyzed molecular endpoints associated with differentiated versus replicative cell states, specifically the following: (a) the expression of cyclin CCND1, (b) the Ki67 cell proliferation marker, (c) the AT8 nuclear tau epitope, and (d) genome-wide DNA methylation changes. Results. Our findings indicate that pterostilbene exerts distinct effects on the cell division cycle depending on the cellular state, with neuroprotective benefits observed in differentiated neuronal-like cells, but not in cells undergoing induced division. Additionally, pterostilbene alters DNA methylation patterns. Conclusion. These results suggest that pterostilbene may offer neuroprotective advantages for differentiated neuronal-like cells. However, further studies are required to confirm these effects in vivo by examining specific biomarkers in human populations consuming pterostilbene-containing foods. Full article

Reactive Oxygen Species (ROS) play an important role in sperm physiology. They are required in processes such as capacitation and fertilization. However, the exposure of spermatozoa to ROS generated from internal or external sources may create a potentially detrimental redox imbalance. Antioxidant supplementation in semen is now a rather common approach to protect spermatozoa from oxidative stress (OS) during their handling and/or cryopreservation. Supplementation with pterostilbene, a potent antioxidant, protects spermatozoa from OS and ameliorates their post-thawing characteristics and viability. In the present study, we used freezing/thawing as a model of natural ROS overproduction and investigated the molecular mechanisms modulated by pterostilbene. Specifically, bovine frozen/thawed spermatozoa were incubated with 10 or 25 μM pterostilbene for 60 min. Results have shown that in a dose-independent manner, pterostilbene decreased lipid peroxidation and increased intracellular GSH levels. Moreover, pterostilbene ameliorated energy production, as ATP and AMP/ATP levels were restored, and increased autophagy levels through AMP-activated protein kinase (AMPK) activation, which finally resulted in the inhibition of apoptotic cell death in bovine spermatozoa when exposed to OS. This study sheds light on spermatozoa redox state, the crosstalk between apoptotic and autophagic pathways, and its role in determining the beneficial or detrimental effect of ROS in spermatozoa. Full article

The human skin, the body’s largest organ, undergoes continuous renewal but is significantly impacted by aging, which impairs its function and leads to visible changes. This study aimed to identify botanical compounds that mimic the anti-aging effects of baricitinib, a known JAK1/2 inhibitor. Through in silico screening of a botanical compound library, 14 potential candidates were identified, and 7 were further analyzed for their effects on cellular aging. The compounds were tested on both normal aged fibroblasts and premature aging fibroblasts derived from patients with Hutchinson–Gilford Progeria Syndrome (HGPS). Results showed that these botanical compounds effectively inhibited the JAK/STAT pathway, reduced the levels of phosphorylated STAT1 and STAT3, and ameliorated phenotypic changes associated with cellular aging. Treatments improved cell proliferation, reduced senescence markers, and enhanced autophagy without inducing cytotoxicity. Compounds, such as Resveratrol, Bisdemethoxycurcumin, Pinosylvin, Methyl P-Hydroxycinnamate, cis-Pterostilbene, and (+)-Gallocatechin, demonstrated significant improvements in both control and HGPS fibroblasts. These findings suggest that these botanical compounds have the potential to mitigate age-related cellular alterations, offering promising strategies for anti-aging therapies, particularly for skin health. Further in vivo studies are warranted to validate these results and explore their therapeutic applications. Full article

Background: Inflammation and immune cell dysfunction are critical facilitators of endometriosis pathophysiology. Macrophages are renowned for stimulating lesion growth, vascularization, innervation, and pain generation. By combining macrophages and endometriotic cells, we determined if resveratrol and its natural analogs can target the immune dysregulation and oxidative imbalance in endometriosis. Methods: After treatment with compounds (5, 10, 25 µM), we evaluated the expression of key inflammatory and oxidative stress markers, cytokines release, and ROS production by applying q-PCR, ELISA, Cytometric Beads Array, and multiplexed fluorogenic staining and flow cytometry analysis with bioimaging. Results: The results showed that endometriosis-related macrophages treated with stilbenes have impaired expression of pro-inflammatory markers (IL6, IL8, IL1B, TNF, CCL2, CXCL10, PTGS2). The effect of resveratrol, pterostilbene, and piceatannol was observed, especially in reducing IL1B, CCL2, and CXCL10 genes up to 3.5-, 5-, and 7.7-fold at 25 µM, respectively. Also, with piceatannol or polydatin exposure, the IL-6 decrease was noticeable. This study reported an antioxidant effect by reducing ROS-positive cells from 96% to 48% by pterostilbene. Results from flow cytometry correlated with the transcript activation of detoxification enzymes (SOD, GPX). Conclusions: Prospects for potential therapy based on regulating the immune microenvironment and reducing the accumulation of free radicals with stilbenes application were described in the article. Full article