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The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10 µM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100 µM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10 µM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100 µM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.
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Objective To investigate the effects of pterostilbene on human colon cancer LoVo cells and study the regulatory mechanism of nuclear factor E2-related factor 2 (Nrf2) in the process of pterostilbene acting on LoVo cells. Methods LoVo cells were treated with different concentrations (5,10,20,40,60,80,100 µmol/L) of pterostilbene.Cell viability,migration,invasion,and apoptosis were examined by CCK-8,scratch,Transwell,and TUNEL assays,respectively.The mitochondrial membrane potential was measured by the mitochondrial membrane potential assay kit with JC-1.The reactive oxygen species level was measured by 2',7'-dichlorofluorescein diacetate.The protein levels of Nrf2,phosphorylated Nrf2,heme oxygenase 1,and apoptotic proteins (Bcl2 and Bax) were determined by Western blotting.In addition,cell viability,Nrf2 expression,and apoptosis rate were determined after co-application of the Nrf2-specific agonist sulforaphane. Results Compared with the control group,40,60,80,100 µmol/L pterostilbene reduced the viability of LoVo cells (P=0.014,P<0.001,P<0.001,P<0.001).Pterostilbene at 5,10,20 µmol/L did not show effects on cell viability but inhibited cell migration (P=0.008,P<0.001,P<0.001) and invasion (all P<0.001).Pterostilbene at 40,60,80 µmol/L increased apoptosis (P=0.014,P<0.001,P<0.001),promoted mitochondrial membrane potential depolarization (P=0.026,P<0.001,P<0.001) and reactive oxygen species accumulation (all P<0.001),and down-regulated the expression of phosphorylated Nrf2 (P=0.030,P<0.001,P<0.001),heme oxygenase 1 (P=0.015,P<0.001,P<0.001),and Bcl2 (P=0.039,P<0.001,P<0.001) in LoVo cells.Pterostilbene at 60,80 µmol/L down-regulated Nrf2 expression (P=0.001,P<0.001) and up-regulated Bax expression (both P<0.001).The application of sulforaphane reversed the effects of pterostilbene on cell viability (P<0.001),apoptosis (P<0.001),and Nrf2 expression (P=0.022). Conclusion Pterostilbene is a compound that can effectively inhibit colon cancer cells by inhibiting the Nrf2 pathway.
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Apoptosis , Neoplasias del Colon , Factor 2 Relacionado con NF-E2 , Estilbenos , Humanos , Estilbenos/farmacología , Apoptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Neoplasias del Colon/tratamiento farmacológico , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Aim: 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].
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Nanocápsulas , Neoplasias de la Próstata , Resveratrol , Estilbenos , Masculino , Resveratrol/administración & dosificación , Resveratrol/farmacocinética , Resveratrol/farmacología , Resveratrol/química , Estilbenos/administración & dosificación , Estilbenos/farmacocinética , Estilbenos/química , Estilbenos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Humanos , Nanocápsulas/química , Animales , Células PC-3 , Distribución Tisular , Línea Celular Tumoral , Tamaño de la Partícula , Liberación de Fármacos , Supervivencia Celular/efectos de los fármacosRESUMEN
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.
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Calgranulina A , Sulfato de Dextran , Mucosa Intestinal , Ratones Endogámicos C57BL , FN-kappa B , Transducción de Señal , Estilbenos , Receptor Toll-Like 4 , Sulfato de Dextran/efectos adversos , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Humanos , Ratones , Calgranulina A/genética , Calgranulina A/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Estilbenos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Masculino , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/genéticaRESUMEN
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-3ß 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-3ß pathway, reducing GSK-3ß activity, and mitigating Tau hyperphosphorylation and Aß 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.
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Disfunción Cognitiva , Glucógeno Sintasa Quinasa 3 beta , Proteínas Sustrato del Receptor de Insulina , Resistencia a la Insulina , Metformina , Fosfatidilinositol 3-Quinasas , Síndrome del Ovario Poliquístico , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Estilbenos , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Femenino , Metformina/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Ratas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Modelos Animales de Enfermedad , Hipoglucemiantes/farmacología , Ratas WistarRESUMEN
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.
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The aberrant activation of NLRP3 inflammasomes is intricately linked to various inflammatory diseases. In this study, we present the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the pterostilbene skeleton. All compounds underwent screening to evaluate their inhibitory effects on LPS/Nigericin-induced IL-1ß secretion and anti-cellular pyroptosis. Most compounds exhibit good biological activity and cellular safety, with compound D20 showing the most prominent activity. Preliminary mechanism studies suggest that compound D20 may affect the assembly of NLRP3 inflammasomes by targeting the NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasomes. The in vivo anti-inflammatory activity demonstrated significant therapeutic effect of compound D20 on DSS-induced acute colitis model in mice. This work has important reference significance for the development of drugs targeting NLRP3 inflammasomes.
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INTRODUCTION: Oxidative stress and neuroapoptosis are significant pathological processes that occur in response to intracerebral hemorrhage (ICH), however, the optimal therapeutic strategy to treat these responses remains unknown. Pterostilbene (PTE) influences neural cell survival in in the pathology of a number of neurological diseases, but the mechanisms underlying this influence at present are not clear. The objective of the present study was to examine the potential impact of PTE on mitigating oxidative stress and neuronal apoptosis following ICH, while also elucidating the potential underlying pathways. MATERIAL & METHOD: For in vivo experimentation, male C57BL/6 mice were used to establish ICH models. Wet-to-dry weight ratios were utilized to assess the degree of cerebral edema in the context of PTE intervention. Behavioral experiments were conducted to evaluate neurological dysfunction and cognitive impairment, and hematoxylin and eosin staining was employed to observe histopathological changes in the brain. Furthermore, oxidative stress levels in hippocampal tissues were measured, and cell apoptosis was examined using TUNEL staining and western blotting techniques. In vitro experiments were conducted to evaluate the extent of oxidative stress and neural apoptosis after sirtuin 1 (SIRT1) siRNA treatment. Immunofluorescence cytochemistry was used to analyze the immunofluorescence colocalization of SIRT1 and NeuN. RESULT: Mice that experienced ICH exhibited worsening neurological deterioration, increased oxidative stress and neuronal cell apoptosis. However, the addition of PTE was found to lessen these effects. Furthermore, PTE was found to activate the SIRT1-mediated Nrf2 pathway in mice with ICH. When SIRT1 was inhibited, levels of oxidative stress and neuronal apoptosis increased, even in the presence of PTE. CONCLUSION: The present study provided evidence to indicate that PTE can suppress oxidative damage and neuronal apoptosis following ICH by activating the SIRT1/Nrf2 pathway.
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Oxidative stress is recognized as a prominent factor contributing to follicular atresia and ovarian aging, which leads to decreased laying performance in hens. Reducing oxidative stress can improve ovarian function and prolong the laying period in poultry. This study investigates the impact of Pterostilbene (PTS), a natural antioxidant, on ovarian oxidative stress in low-laying chickens. Thirty-six Hy-Line White laying chickens were evenly divided into four groups and fed diets containing varying doses of PTS for 15 consecutive days. The results showed that dietary supplementation with PTS significantly increased the laying rate, with the most effective group exhibiting a remarkable 42.7% increase. Furthermore, PTS significantly enhanced the antioxidant capacity of aging laying hens, as evidenced by increased levels of glutathione, glutathione peroxidase, superoxide dismutase, catalase, and total antioxidant capacity in the ovaries, livers, and serum. Subsequent experiments revealed decreased expressions of Bax, Caspase-3, and γ-H2AX, along with an increased expression of BCL-2 in the ovaries and livers of laying hens. PTS supplementation also positively affects fat metabolism by reducing abdominal fat accumulation and promoting fat transfer from the liver to the ovary. To elucidate the mechanism underlying the effects of PTS on ovarian function, a series of in vitro experiments were conducted. These in vitro experiments revealed that PTS pretreatment restored the antioxidant capacity of D-galactose-induced small white follicles by upregulating SIRT1/Nrf2 expression. This protective effect was inhibited by EX-527, a specific inhibitor of SIRT1. These findings suggest that the natural antioxidant PTS has the potential to regulate cell apoptosis and fat metabolism in laying chickens by ameliorating oxidative stress, thereby enhancing laying performance.
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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 â« 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 â¼50 % 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.
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Queratinocitos , Oxidación-Reducción , Estilbenos , Humanos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Relación Estructura-Actividad , Estilbenos/farmacología , Estilbenos/química , Dermatitis Fototóxica , Resveratrol/farmacología , Resveratrol/análogos & derivados , Resveratrol/química , Rayos Ultravioleta , Piel/efectos de los fármacos , Piel/metabolismo , Piel/efectos de la radiación , Piel/patología , Antioxidantes/farmacología , Antioxidantes/química , Células HaCaTRESUMEN
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.
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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-1ß 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.
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Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Estrés Oxidativo , Estilbenos , Animales , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Estilbenos/uso terapéutico , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Especies Reactivas de Oxígeno/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , alfa-Sinucleína/metabolismoRESUMEN
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.
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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Estilbenos , Estilbenos/farmacología , Estilbenos/química , Estilbenos/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Ratones , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Masculino , Femenino , Ratones Endogámicos BALB C , Antineoplásicos/farmacología , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/antagonistas & inhibidores , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
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.
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Antioxidantes , Células Endoteliales , Epigénesis Genética , Hiperglucemia , Factor 2 Relacionado con NF-E2 , Estilbenos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Humanos , Epigénesis Genética/efectos de los fármacos , Estilbenos/farmacología , Hiperglucemia/metabolismo , Antioxidantes/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Microambiente Celular/efectos de los fármacos , Histona Desacetilasas/metabolismo , Histona Desacetilasas/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Silenciador del Gen , Estrés Oxidativo/efectos de los fármacos , Metilación de ADN/efectos de los fármacosRESUMEN
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 ß-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.
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Dieta Alta en Grasa , Síndrome Jet Lag , Metabolismo de los Lípidos , Hígado , Ratones Endogámicos C57BL , Estrés Oxidativo , Sirtuina 1 , Sirtuina 3 , Estilbenos , Animales , Sirtuina 1/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Masculino , Metabolismo de los Lípidos/efectos de los fármacos , Estilbenos/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Sirtuina 3/metabolismo , Síndrome Jet Lag/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Obesidad , Suplementos DietéticosRESUMEN
Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.
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Ecofriendly fabrics with antibacterial and anti-adhesion properties have been attracted an increasing attention in recent years. Herein, natural menthol modified polyacrylate (PMCA) antibacterial adhesion agent was synthesized by esterification and polymerisation while natural pterostilbene-grafted-chitosan (PGC) antibacterial agent was prepared through Mannich reaction. The antibacterial and anti-adhesion cotton fabric was fabricated through durable PMCA dip finishing and then layer-by-layer self-assembly of PGC. The results showed that the antibacterial adhesion rates and antibacterial rates of the dual-function cotton fabric against Staphylococcus aureus and Escherichia coli reached up to 99.9 %. Its antibacterial adhesion rates improved by 36.1 % and 40.1 % in comparison with those of cotton fabric treated by menthol alone. Meanwhile against S. aureus, the dual-function cotton fabrics improved the antibacterial rates by 56.7 % and 36.4 %, respectively, from those of chitosan- and pterostilbene-treated fabrics. Against E. coli, the improvements were 89.4 % and 24.8 %, respectively. After 20 household washings, the dual-function cotton fabric maintained >80 % of its original anti-adhesion and antibacterial rates against both species. The dual-function cotton fabric also possessed safe and excellent wearability.
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Antibacterianos , Quitosano , Fibra de Algodón , Escherichia coli , Staphylococcus aureus , Antibacterianos/farmacología , Antibacterianos/química , Escherichia coli/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Adhesión Bacteriana/efectos de los fármacos , Estilbenos/farmacología , Estilbenos/química , Textiles , Pruebas de Sensibilidad Microbiana , Resinas Acrílicas/químicaRESUMEN
Polystyrene nanoplastics (PS-NPs) have been reported to accumulate in the testes and constitute a new threat to reproductive health. However, the exact effects of PS-NPs exposure on testicular cells and the underlying mechanisms remain largely unknown. The C57BL/6 male mice were orally administered with PS-NPs (80â¯nm) at different dosages (0, 10, and 40â¯mg/kg/day) for 60 days, and GC-1 cells were treated with PS-NPs in this study. Enlarged seminiferous tubule lumens and a loose and vacuolated layer of spermatogenic cells were observed in PS-NPs-exposed mice. Spermatogenic cells which may be one of the target cells for this reproductive damage, were decreased in the mice from PS-NPs group. PS-NPs caused spermatogenic cells to undergo senescence, manifested as elevated SA-ß-galactosidase activity and activated senescence-related signaling p53-p21/Rb-p16 pathways, and induced cell cycle arrest. Mechanistically, Gene Ontology (GO) enrichment suggested the key role of reactive oxygen species (ROS) in PS-NPs-induced spermatogenic cell senescence, and this result was confirmed by measuring ROS levels. Moreover, ROS inhibition partially attenuated the senescence phenotype of spermatogenic cells and DNA damage. Using the male health atlas (MHA) database, Sirt1 was filtrated as the critical molecule in the regulation of testicular senescence. PS-NPs induced overexpression of the main ROS generator Nox2, downregulated Sirt1, increased p53 and acetylated p53 in vivo and in vitro, whereas these disturbances were partially restored by pterostilbene. In addition, pterostilbene intervention significantly alleviated the PS-NPs-induced spermatogenic cell senescence and attenuated ROS burst. Collectively, our study reveals that PS-NPs exposure can trigger spermatogenic cell senescence mediated by p53-p21/Rb-p16 signaling by regulating the Sirt1/ROS axis. Importantly, pterostilbene intervention may be a promising strategy to alleviate this damage.
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Senescencia Celular , Ratones Endogámicos C57BL , Poliestirenos , Especies Reactivas de Oxígeno , Sirtuina 1 , Animales , Masculino , Sirtuina 1/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Senescencia Celular/efectos de los fármacos , Ratones , Poliestirenos/toxicidad , Testículo/efectos de los fármacos , Testículo/patología , Espermatogénesis/efectos de los fármacos , Nanopartículas/toxicidad , Daño del ADN , Transducción de Señal/efectos de los fármacosRESUMEN
Aim The aim of this study is to examine the possible therapeutic effect of pterostilbene (PTS), a chemical present in grapes and blueberries, in the treatment of liver cancer by analysing its interactions with important proteins linked to the wingless/integrated (Wnt) signaling system. Objective Using computational techniques like molecular docking and absorption, distribution, metabolism, and excretion (ADME) studies, this research focuses on examining the pharmacokinetics and molecular interactions of PTS with proteins such as vimentin (Vim), glycogen synthase kinase 3 beta (GSK3-ß), epithelial cadherin (E-cadherin), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), c-Jun N-terminal kinase (JNK), and Wnt, all of which are connected to the Wnt signaling pathway in liver cancer. Methods The study includes the synthesis of proteins and ligands, ADME investigations for PTS, and AutoDock Vina molecular docking simulations to evaluate binding affinities and interactions. PTS is obtained from PubChem, while protein structures are obtained from the Protein Data Bank. Results Strong binding affinities between PTS and essential proteins in the Wnt signaling cascade are shown by molecular docking, which also highlights noteworthy hydrogen bonds, hydrophobic interactions, and electrostatic contacts. According to an ADME study, PTS has advantageous pharmacokinetic properties, such as moderate solubility, membrane permeability, and a minimal chance of drug interactions. Conclusion The extensive study highlights PTS's potential as a viable treatment option for liver cancer. The study promotes its investigation in cutting-edge liver cancer therapy approaches and urges more investigation into the molecular mechanisms, underpinning its anticancer properties. This paper sheds important light on the role of natural chemicals in cancer therapy and emphasizes the need for computational methods in drug discovery.
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Pterostilbene (PTE), a natural phenolic compound, has exhibited promising anticancer properties in the preclinical treatment of cervical cancer (CC). This study aims to comprehensively investigate the potential targets and mechanisms underlying PTE's anticancer effects in CC, thereby providing a theoretical foundation for its future clinical application and development. To accomplish this, we employed a range of methodologies, including network pharmacology, bioinformatics, and computer simulation, with specific techniques such as WGCNA, PPI network construction, ROC curve analysis, KM survival analysis, GO functional enrichment, KEGG pathway enrichment, molecular docking, MDS, and single-gene GSEA. Utilizing eight drug target prediction databases, we have identified a total of 532 potential targets for PTE. By combining CC-related genes from the GeneCards disease database with significant genes derived from WGCNA analysis of the GSE63514 dataset, we obtained 7915 unique CC-related genes. By analyzing the intersection of the 7915 CC-related genes and the 2810 genes that impact overall survival time in CC, we identified 690 genes as crucial for CC. Through the use of a Venn diagram, we discovered 36 overlapping targets shared by PTE and CC. We have constructed a PPI network and identified 9 core candidate targets. ROC and KM curve analyses subsequently revealed IL1B, EGFR, IL1A, JUN, MYC, MMP1, MMP3, and ANXA5 as the key targets modulated by PTE in CC. GO and KEGG pathway enrichment analyses indicated significant enrichment of these key targets, primarily in the MAPK and IL-17 signaling pathways. Molecular docking analysis verified the effective binding of PTE to all nine key targets. MDS results showed that the protein-ligand complex between MMP1 and PTE was the most stable among the nine targets. Additionally, GSEA enrichment analysis suggested a potential link between elevated MMP1 expression and the activation of the IL-17 signaling pathway. In conclusion, our study has identified key targets and uncovered the molecular mechanism behind PTE's anticancer activity in CC, establishing a firm theoretical basis for further exploration of PTE's pharmacological effects in CC therapy.