RÉSUMÉ
PURPOSE: To evaluate the neuroprotective effect of resveratrol, urapidil, and a combined administration of these drugs against middle cerebral artery occlusion (MCAO) induced ischemia/reperfusion (IR) injury model in rats. METHODS: Thirty-five rats were divided into five groups of seven animals each. Animals in IR, IR resveratrol (IRr), IR urapidil (IRu), and IR + combination of resveratrol and urapidil (IRc) were exposed to MCAO induced cerebral ischemia reperfusion injury model. Rats in IRr and IRu groups received 30-mg/kg resveratrol and 5-mg/kg urapidil respectively. Animals in IRc received a combined treatment of both drugs. At the end of the study, brain tissues were used for oxidative stress (malondialdehyde, glutathione, and superoxide dismutase), pro-apoptotic caspase-3, anti-apoptotic Bcl-2, and pro-inflammatory tumor necrosis factor-α cytokine level measurements. RESULTS: The MCAO model successfully replicated IR injury with significant histopathological changes, elevated tissue oxidative stress, and upregulated apoptotic and inflammatory protein expression in IR group compared to control group (p < 0.001). All parameters were significantly alleviated in IRr group compared to IR group (all p < 0.05). In IRu group, all parameters except for caspase-3 and Bcl-2 were also significantly different than IR group (all p < 0.05). The IRc group showed the biggest difference compared to IR group in all parameters (all p < 0.001). The IRc had higher superoxide dismutase and Bcl-2 levels, and lower caspase-3 levels compared to both IRr and IRu groups (all p < 0.05). Also, the IRc group had lower MDA and TNF-α levels compared to IRu group (all p < 0.05). CONCLUSIONS: The results indicate that combined treatment of resveratrol and urapidil may be a novel strategy to downregulate neurodegeneration in cerebral IR injury.
Sujet(s)
Modèles animaux de maladie humaine , Neuroprotecteurs , Stress oxydatif , Lésion d'ischémie-reperfusion , Resvératrol , Stilbènes , Animaux , Resvératrol/pharmacologie , Resvératrol/usage thérapeutique , Lésion d'ischémie-reperfusion/traitement médicamenteux , Lésion d'ischémie-reperfusion/prévention et contrôle , Neuroprotecteurs/usage thérapeutique , Neuroprotecteurs/pharmacologie , Mâle , Stress oxydatif/effets des médicaments et des substances chimiques , Stilbènes/usage thérapeutique , Stilbènes/pharmacologie , Association de médicaments , Rat Wistar , Infarctus du territoire de l'artère cérébrale moyenne/traitement médicamenteux , Résultat thérapeutique , Rats , Facteur de nécrose tumorale alpha/analyse , Superoxide dismutase/analyse , Superoxide dismutase/métabolisme , Malonaldéhyde/analyse , Malonaldéhyde/métabolisme , Reproductibilité des résultats , Apoptose/effets des médicaments et des substances chimiques , Répartition aléatoire , Encéphalopathie ischémique/traitement médicamenteux , Antioxydants/usage thérapeutique , Antioxydants/pharmacologie , Caspase-3/métabolisme , Caspase-3/analyseRÉSUMÉ
Tendinopathy is one of the most frequent musculoskeletal disorders characterized by sustained tissue inflammation and oxidative stress, accompanied by extracellular matrix remodeling. Patients suffering from this pathology frequently experience pain, swelling, stiffness, and muscle weakness. Current pharmacological interventions are based on nonsteroidal anti-inflammatory drugs; however, the effectiveness of these strategies remains ambiguous. Accumulating evidence supports that oral supplementation of natural compounds can provide preventive, and possibly curative, effects. Vitamin C (Vit C), collagen peptides (Coll), resveratrol (Res), and astaxanthin (Asx) were reported to be endowed with potential beneficial effects based on their anti-inflammatory and antioxidant activities. Here, we analyzed the efficacy of a novel combination of these compounds (Mix) in counteracting proinflammatory (IL-1ß) and prooxidant (H2O2) stimuli in human tenocytes. We demonstrated that Mix significantly impairs IL-6-induced IL-1ß secretion, NF-κB nuclear translocation, and MMP-2 production; notably, a synergistic effect of Mix over the single compounds could be observed. Moreover, Mix was able to significantly counteract H2O2-triggered ROS production. Together, these results point out that Mix, a novel combination of Vit C, Coll, Resv, and Asx, significantly impairs proinflammatory and prooxidant stimuli in tenocytes, mechanisms that contribute to the onset of tendinopathies.
Sujet(s)
Anti-inflammatoires , Antioxydants , Acide ascorbique , Collagène , Resvératrol , Tendinopathie , Ténocytes , Xanthophylles , Humains , Acide ascorbique/pharmacologie , Acide ascorbique/usage thérapeutique , Resvératrol/pharmacologie , Antioxydants/pharmacologie , Xanthophylles/pharmacologie , Xanthophylles/usage thérapeutique , Tendinopathie/traitement médicamenteux , Tendinopathie/métabolisme , Collagène/métabolisme , Anti-inflammatoires/pharmacologie , Ténocytes/métabolisme , Ténocytes/effets des médicaments et des substances chimiques , Interleukine-1 bêta/métabolisme , Peptides/composition chimique , Peptides/pharmacologie , Peroxyde d'hydrogène/métabolisme , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Espèces réactives de l'oxygène/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Cellules cultivées , Stress oxydatif/effets des médicaments et des substances chimiquesRÉSUMÉ
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.
Sujet(s)
Carcinome épidermoïde , Tumeurs du poumon , Stilbènes , Stilbènes/pharmacologie , Stilbènes/composition chimique , Stilbènes/usage thérapeutique , Humains , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/métabolisme , Tumeurs du poumon/anatomopathologie , Animaux , Carcinome épidermoïde/traitement médicamenteux , Carcinome épidermoïde/métabolisme , Carcinome épidermoïde/anatomopathologie , Souris , Lignée cellulaire tumorale , Apoptose/effets des médicaments et des substances chimiques , Mouvement cellulaire/effets des médicaments et des substances chimiques , Souris nude , Protéines adaptatrices de la transduction du signal/métabolisme , Protéines adaptatrices de la transduction du signal/antagonistes et inhibiteurs , Protéines adaptatrices de la transduction du signal/génétique , Mâle , Femelle , Souris de lignée BALB C , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Survie cellulaire/effets des médicaments et des substances chimiques , Protéines du cytosquelette/métabolisme , Protéines du cytosquelette/génétique , Protéines du cytosquelette/antagonistes et inhibiteurs , Régulation négative/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiquesRÉSUMÉ
Solid tumors create a hypoxic microenvironment and this character can be utilized for cancer therapy, but the hypoxia levels are insufficient to achieve satisfactory therapeutic benefits. Some tactics have been used to improve hypoxia, which however will cause side effects due to the uncontrolled drug release. We herein report near-infrared (NIR) photoactivatable three-in-one nanoagents (PCT) to aggravate tumor hypoxia and enable amplified photo-combinational chemotherapy. PCT are formed based on a thermal-responsive liposome nanoparticle containing three therapeutic agents: a hypoxia responsive prodrug tirapazamine (TPZ) for chemotherapy, a vascular targeting agent combretastatin A-4 (CA4) for vascular disturbance and a semiconducting polymer for both photodynamic therapy (PDT) and photothermal therapy (PTT). With NIR laser irradiation, PCT generate heat for PTT and destructing thermal-responsive liposomes to achieve activatable releases of TPZ and CA4. Moreover, PCT produce singlet oxygen (1O2) for PDT via consuming tumor oxygen. CA4 can disturb the blood vessels in tumor microenvironment to aggravate the hypoxic microenvironment, which results in the activation of TPZ for amplified chemotherapy. PCT thus enable PTT, PDT and hypoxia-amplified chemotherapy to afford a high therapeutic efficacy to almost absolutely eradicate subcutaneous 4 T1 tumors and effectively inhibit tumor metastases in lung and liver. This work presents an activatable three-in-one therapeutic nanoplatform with remotely controllable and efficient therapeutic actions to treat cancer.
Sujet(s)
Rayons infrarouges , Liposomes , Nanoparticules , Photothérapie dynamique , Tirapazamine , Animaux , Humains , Photothérapie dynamique/méthodes , Tirapazamine/pharmacologie , Tirapazamine/composition chimique , Tirapazamine/usage thérapeutique , Nanoparticules/composition chimique , Nanoparticules/usage thérapeutique , Souris , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Thérapie photothermique/méthodes , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Stilbènes/composition chimique , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Promédicaments/pharmacologie , Promédicaments/composition chimique , Promédicaments/usage thérapeutique , Photosensibilisants/usage thérapeutique , Photosensibilisants/pharmacologie , Photosensibilisants/composition chimique , Hypoxie tumorale/effets des médicaments et des substances chimiquesRÉSUMÉ
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.
Sujet(s)
Souris de lignée C57BL , Maladies neuro-inflammatoires , Neuroprotecteurs , Stress oxydatif , Stilbènes , Animaux , Stress oxydatif/effets des médicaments et des substances chimiques , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Mâle , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Maladies neuro-inflammatoires/traitement médicamenteux , Maladies neuro-inflammatoires/métabolisme , Maladies neuro-inflammatoires/anatomopathologie , Souris , 1-Méthyl-4-phényl-1,2,3,6-tétrahydropyridine , Neurones dopaminergiques/effets des médicaments et des substances chimiques , Neurones dopaminergiques/métabolisme , Neurones dopaminergiques/anatomopathologie , Espèces réactives de l'oxygène/métabolisme , Intoxication au MPTP/traitement médicamenteux , Intoxication au MPTP/métabolisme , Intoxication au MPTP/anatomopathologie , alpha-Synucléine/métabolismeSujet(s)
Carcinome hépatocellulaire , Régulation négative , Tumeurs du foie , Resvératrol , Facteur de transcription Sp1 , Resvératrol/pharmacologie , Resvératrol/usage thérapeutique , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/anatomopathologie , Carcinome hépatocellulaire/métabolisme , Carcinome hépatocellulaire/génétique , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/anatomopathologie , Tumeurs du foie/génétique , Tumeurs du foie/métabolisme , Humains , Facteur de transcription Sp1/métabolisme , Facteur de transcription Sp1/génétique , Régulation négative/effets des médicaments et des substances chimiques , Métastase tumorale , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Lignée cellulaire tumoraleRÉSUMÉ
Background: Cisplatin (CIS) is a broad-spectrum anticancer drug, with cytotoxic effects on either malignant or normal cells. We aimed to evaluate the hepatotoxicity in rats caused by CIS and its amelioration by the co-administration of either curcumin or resveratrol. Materials and Methods: Forty adult male rats divided into four equal groups: (control group): rats were given a saline solution (0.9%) once intraperitoneally, daily for the next 28 days; (cisplatin group): rats were given a daily oral dose of saline solution (0.9%) for 28 days after receiving a single dose of cisplatin (3.3 mg/kg) intraperitoneally for three successive days; (CIS plus curcumin/resveratrol groups): rats received the same previous dose of cisplatin (3.3 mg/kg) daily for three successive days followed by oral administration of either curcumin/resveratrol solution at a dose of (20 mg/kg) or (10 mg/kg) consequently daily for 28 days. Different laboratory tests (ALT, AST, ALP, bilirubin, oxidative stress markers) and light microscopic investigations were done. Results: Administration of CIS resulted in hepatotoxicity in the form of increased liver enzymes, oxidative stress markers; degenerative and apoptotic changes, the co-administration of CIS with either curcumin or resveratrol improved hepatotoxicity through improved microscopic structural changes, reduction in liver enzymes activity, decreased oxidative stress markers, improved degenerative, and apoptotic changes in liver tissues. Conclusion: Co-administration of either curcumin or resveratrol with cisplatin treatment could ameliorate hepatotoxicity caused by cisplatin in rats via anti-inflammatory and oxidative stress-apoptotic pathways.
Sujet(s)
Apoptose , Lésions hépatiques dues aux substances , Cisplatine , Curcumine , Stress oxydatif , Resvératrol , Animaux , Resvératrol/pharmacologie , Resvératrol/administration et posologie , Cisplatine/toxicité , Cisplatine/administration et posologie , Curcumine/pharmacologie , Curcumine/administration et posologie , Stress oxydatif/effets des médicaments et des substances chimiques , Mâle , Rats , Apoptose/effets des médicaments et des substances chimiques , Lésions hépatiques dues aux substances/anatomopathologie , Lésions hépatiques dues aux substances/traitement médicamenteux , Lésions hépatiques dues aux substances/métabolisme , Lésions hépatiques dues aux substances/prévention et contrôle , Lésions hépatiques dues aux substances/étiologie , Antinéoplasiques/administration et posologie , Antinéoplasiques/effets indésirables , Antinéoplasiques/toxicité , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Foie/anatomopathologie , Antioxydants/pharmacologie , Antioxydants/administration et posologie , Stilbènes/administration et posologie , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/administration et posologie , Rat WistarRÉSUMÉ
Diabetic nephropathy (DN) is a complication of diabetes and is mainly characterized by renal fibrosis, which could be attributed to chronic kidney inflammation. Stimulator of interferon genes (STING), a linker between immunity and metabolism, could ameliorate various metabolic and inflammatory diseases. However, the regulatory role of STING in DN remains largely unexplored. In this study, knockdown of STING decreased extracellular matrix (ECM), pro-inflammatory, and fibrotic factors in high glucose (HG)-induced glomerular mesangial cells (GMCs), whereas overexpression of STING triggered the inflammatory fibrosis process, suggesting that STING was a potential target for DN. Polydatin (PD) is a glucoside of resveratrol and has been reported to ameliorate DN by inhibiting inflammatory responses. Nevertheless, whether PD improved DN via STING remains unclear. Here, transcriptomic profiling implied that the STING/NF-κB pathway might be an important target for PD. We further found that PD decreased the protein expression of STING, and subsequently suppressed the activation of downstream targets including TBK1 phosphorylation and NF-κB nuclear translocation, and eventually inhibited the production of ECM, pro-inflammatory and fibrotic factors in HG-induced GMCs. Notably, results of molecular docking, molecular dynamic simulations, surface plasmon resonance, cellular thermal shift assay and Co-immunoprecipitation assay indicated that PD directly bound to STING and restored the declined proteasome-mediated degradation of STING induced by HG. In diabetic mice, PD also inhibited the STING pathway and improved the pathological changes of renal inflammatory fibrosis. Our study elucidated the regulatory role of STING in DN, and the novel mechanism of PD treating DN via inhibiting STING expression.
Sujet(s)
Diabète expérimental , Néphropathies diabétiques , Fibrose , Glucosides , Protéines membranaires , Souris de lignée C57BL , Stilbènes , Glucosides/pharmacologie , Glucosides/usage thérapeutique , Animaux , Néphropathies diabétiques/métabolisme , Néphropathies diabétiques/traitement médicamenteux , Néphropathies diabétiques/anatomopathologie , Souris , Protéines membranaires/métabolisme , Protéines membranaires/génétique , Fibrose/traitement médicamenteux , Mâle , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Diabète expérimental/traitement médicamenteux , Diabète expérimental/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Cellules mésangiales/effets des médicaments et des substances chimiques , Cellules mésangiales/métabolisme , Cellules mésangiales/anatomopathologie , HumainsRÉSUMÉ
BACKGROUND: Bladder cancer (BC) is among the most prevalent malignant urothelial tumors globally, yet the prognosis for patients with muscle-invasive bladder cancer (MIBC) remains dismal, with a very poor 5-year survival rate. Consequently, identifying more effective and less toxic chemotherapeutic alternatives is critical for enhancing clinical outcomes for BC patients. Isorhapontigenin (ISO), a novel stilbene isolated from a Gnetum found in certain provinces of China, has shown potential as an anticancer agent due to its diverse anticancer activities. Despite its promising profile, the specific anticancer effects of ISO on BC and the underlying mechanisms are still largely unexplored. METHODS: The anchorage-independent growth, migration and invasion of BC cells were assessed by soft agar and transwell invasion assays, respectively. The RNA levels of SOX2, miR-129 and SNHG1 were quantified by qRT-PCR, while the protein expression levels were validated through Western blotting. Furthermore, methylation-specific PCR was employed to assess the methylation status of the miR-129 promoter. Functional assays utilized siRNA knockdown, plasmid-mediated overexpression, and chemical inhibition approaches. RESULTS: Our study demonstrated that ISO treatment significantly reduced SNHG1 expression in a dose- and time-dependent manner in BC cells, leading to the inhibition of anchorage-independent growth and invasion in human basal MIBC cells. This effect was accompanied by the downregulation of MMP-2 and MMP-9 and the upregulation of the tumor suppressor PTEN. Further mechanistic investigations revealed that SOX2, a key upstream regulator of SNHG1, played a crucial role in mediating the ISO-induced transcriptional suppression of SNHG1. Additionally, we found that ISO treatment led to a decrease in DNMT3b protein levels, which in turn mediated the hypomethylation of the miR-129 promoter and the subsequent suppression of SOX2 mRNA 3'-UTR activity, highlighting a novel pathway through which ISO exerts its anticancer effects. CONCLUSIONS: Collectively, our study highlights the critical role of SNHG1 downregulation as well as its upstream DNMT3b/miR-129/SOX2 axis in mediating ISO anticancer activity. These findings not only elucidate the mechanism of action of ISO but also suggest novel targets for BC therapy.
Sujet(s)
DNA (cytosine-5-)-methyltransferase , , Régulation négative , Régulation de l'expression des gènes tumoraux , ARN long non codant , Stilbènes , Tumeurs de la vessie urinaire , Humains , Tumeurs de la vessie urinaire/traitement médicamenteux , Tumeurs de la vessie urinaire/génétique , Tumeurs de la vessie urinaire/anatomopathologie , Tumeurs de la vessie urinaire/métabolisme , ARN long non codant/génétique , Lignée cellulaire tumorale , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Régulation négative/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , DNA (cytosine-5-)-methyltransferase/génétique , DNA (cytosine-5-)-methyltransferase/métabolisme , Invasion tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Méthylation de l'ADN/effets des médicaments et des substances chimiques , microARN/génétiqueRÉSUMÉ
Nonsmall cell lung cancer (NSCLC) is one of the major causes of cancerrelated death worldwide. Cisplatin is a frontline chemotherapeutic agent in NSCLC. Nevertheless, subsequent harsh side effects and drug resistance limit its further clinical application. Polydatin (PD) induces apoptosis in various cancer cells by generating reactive oxygen species (ROS). However, underlying molecular mechanisms of PD and its effects on cisplatinmediated antitumor activity in NSCLC remains unknown. MTT, colony formation, wound healing analyses and flow cytometry was employed to investigate the cell phenotypic changes and ROS generation. Relative gene and protein expressions were evaluated by reverse transcriptionquantitative PCR and western blot analyses. The antitumor effects of PD, cisplatin and their combination were evaluated by mouse xenograft model. In the present study, it was found that PD in combination with cisplatin synergistically enhances the antitumor activity in NSCLC by stimulating ROSmediated endoplasmic reticulum stress, and the CJunaminoterminal kinase and p38 mitogenactivated protein kinase signaling pathways. PD treatment elevated ROS generation by promoting expression of NADPH oxidase 5 (NOX5), and NOX5 knockdown attenuated ROSmediated cytotoxicity of PD in NSCLC cells. Mice xenograft model further confirmed the synergistic antitumor efficacy of combined therapy with PD and cisplatin. The present study exhibited a superior therapeutic strategy for some patients with NSCLC by combining PD and cisplatin.
Sujet(s)
Carcinome pulmonaire non à petites cellules , Cisplatine , Synergie des médicaments , Glucosides , Tumeurs du poumon , NADPH Oxidase 5 , Stress oxydatif , Espèces réactives de l'oxygène , Stilbènes , Tests d'activité antitumorale sur modèle de xénogreffe , Cisplatine/pharmacologie , Cisplatine/usage thérapeutique , Glucosides/pharmacologie , Glucosides/usage thérapeutique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Carcinome pulmonaire non à petites cellules/anatomopathologie , Carcinome pulmonaire non à petites cellules/métabolisme , Animaux , Humains , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Souris , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Lignée cellulaire tumorale , Apoptose/effets des médicaments et des substances chimiques , Cellules A549 , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , MâleRÉSUMÉ
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder that is linked to metabolic syndrome, mitochondrial dysfunction and impaired autophagy. Polydatin (PD), a natural polyphenol from Polygonum cuspidatum, exhibits various pharmacological effects and protects against NAFLD. The aim of this study was to reveal the molecular mechanisms and therapeutic potential of PD for NAFLD, with a focus on the role of mitochondrial autophagy mediated by sirtuin 3 (SIRT3), fork-head box O3 (FOXO3) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), and by PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN). We combined network pharmacology analysis, animal models and cell culture experiments to show that PD could regulate the mitochondrial autophagy pathway by modulating several key genes related to mitochondrial function, and ameliorate the liver function, histopathology and mitochondrial biogenesis of NAFLD mice and hepatocytes by activating the SIRT3-FOXO3-BNIP3 axis and the PINK1-PRKN-dependent mechanism of mitochondrial autophagy. We also identified the core targets of PD, including SIRT3, FOXO3A, CASP3, PARKIN, EGFR, STAT3, MMP9 and PINK, and confirmed that silencing SIRT3 could significantly attenuate the beneficial effect of PD. This study provided novel theoretical and experimental support for PD as a promising candidate for NAFLD treatment, and also suggested new avenues and methods for investigating the role of mitochondrial autophagy in the pathogenesis and intervention of NAFLD.
Sujet(s)
Protéine O3 à motif en tête de fourche , Glucosides , Souris de lignée C57BL , Mitochondries , Stéatose hépatique non alcoolique , Protein kinases , Sirtuine-3 , Stilbènes , Ubiquitin-protein ligases , Animaux , Protéine O3 à motif en tête de fourche/métabolisme , Sirtuine-3/métabolisme , Sirtuine-3/génétique , Glucosides/pharmacologie , Glucosides/usage thérapeutique , Glucosides/composition chimique , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Souris , Stéatose hépatique non alcoolique/traitement médicamenteux , Stéatose hépatique non alcoolique/métabolisme , Stéatose hépatique non alcoolique/anatomopathologie , Ubiquitin-protein ligases/métabolisme , Ubiquitin-protein ligases/génétique , Protein kinases/métabolisme , Mâle , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Humains , Protéines mitochondriales/métabolisme , Protéines mitochondriales/génétique , Autophagie/effets des médicaments et des substances chimiques , Foie/effets des médicaments et des substances chimiques , Foie/métabolisme , Foie/anatomopathologie , Hépatocytes/effets des médicaments et des substances chimiques , Hépatocytes/métabolisme , Protéines membranairesRÉSUMÉ
New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain-blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents-sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer's and Parkinson's.
Sujet(s)
Acetylcholinesterase , Butyrylcholine esterase , Anticholinestérasiques , Simulation de docking moléculaire , Oximes , Triazoles , Oximes/composition chimique , Oximes/pharmacologie , Anticholinestérasiques/composition chimique , Anticholinestérasiques/pharmacologie , Anticholinestérasiques/synthèse chimique , Butyrylcholine esterase/métabolisme , Butyrylcholine esterase/composition chimique , Acetylcholinesterase/métabolisme , Acetylcholinesterase/composition chimique , Humains , Triazoles/composition chimique , Triazoles/pharmacologie , Triazoles/synthèse chimique , Stilbènes/composition chimique , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Stilbènes/synthèse chimique , Réactivateurs de la cholinestérase/composition chimique , Réactivateurs de la cholinestérase/pharmacologie , Réactivateurs de la cholinestérase/synthèse chimique , Réactivateurs de la cholinestérase/usage thérapeutique , Composés organiques du phosphore/composition chimique , Composés organiques du phosphore/pharmacologie , Système nerveux central/effets des médicaments et des substances chimiques , Système nerveux central/métabolismeRÉSUMÉ
Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.
Sujet(s)
Animaux nouveau-nés , Dysplasie bronchopulmonaire , Modèles animaux de maladie humaine , Stress oxydatif , Pneumopathie infectieuse , Resvératrol , Animaux , Resvératrol/pharmacologie , Stress oxydatif/effets des médicaments et des substances chimiques , Dysplasie bronchopulmonaire/prévention et contrôle , Dysplasie bronchopulmonaire/métabolisme , Pneumopathie infectieuse/prévention et contrôle , Pneumopathie infectieuse/métabolisme , Pneumopathie infectieuse/induit chimiquement , Rats , Hyperoxie/complications , Hyperoxie/métabolisme , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Antioxydants/pharmacologie , Hyperréactivité bronchique/prévention et contrôle , Hyperréactivité bronchique/métabolisme , Hyperréactivité bronchique/physiopathologie , Hyperréactivité bronchique/induit chimiquement , Rat Sprague-Dawley , MâleRÉSUMÉ
Cerebral Palsy (CP) is the main motor disorder in childhood resulting from damage to the developing brain. Treatment perspectives are required to reverse the primary damage caused by the early insult and consequently to recover motor skills. Resveratrol has been shown to act as neuroprotection with benefits to skeletal muscle. This study aimed to investigate the effects of neonatal resveratrol treatment on neurodevelopment, skeletal muscle morphology, and cerebellar damage in CP model. Wistar rat pups were allocated to four experimental groups (n = 15/group) according CP model and treatment: Control+Saline (CS), Control+Resveratrol (CR), CP + Saline (CPS), and CP + Resveratrol (CPR). CP model associated anoxia and sensorimotor restriction. CP group showed delay in the disappearance of the palmar grasp reflex (p < 0.0001) and delay in the appearance of reflexes of negative geotaxis (p = 0.01), and free-fall righting (p < 0.0001), reduced locomotor activity and motor coordination (p < 0.05) than CS group. These motor skills impairments were associated with a reduction in muscle weight (p < 0.001) and area and perimeter of soleus end extensor digitorum longus muscle fibers (p < 0.0001), changes in muscle fibers typing pattern (p < 0.05), and the cerebellum showed signs of neuroinflammation due to elevated density and percentage of activated microglia in the CPS group compared to CS group (p < 0.05). CP animals treated with resveratrol showed anticipation of the appearance of negative geotaxis and free-fall righting reflexes (p < 0.01), increased locomotor activity (p < 0.05), recovery muscle fiber types pattern (p < 0.05), and reversal of the increase in density and the percentage of activated microglia in the cerebellum (p < 0.01). Thus, we conclude that neonatal treatment with resveratrol can contribute to the recovery of the delay neurodevelopment resulting from experimental CP due to its action in restoring the skeletal muscle morphology and reducing neuroinflammation from cerebellum.
Sujet(s)
Animaux nouveau-nés , Cervelet , Paralysie cérébrale , Microglie , Muscles squelettiques , Rat Wistar , Resvératrol , Resvératrol/pharmacologie , Animaux , Cervelet/effets des médicaments et des substances chimiques , Cervelet/anatomopathologie , Rats , Microglie/effets des médicaments et des substances chimiques , Microglie/anatomopathologie , Paralysie cérébrale/traitement médicamenteux , Paralysie cérébrale/anatomopathologie , Muscles squelettiques/effets des médicaments et des substances chimiques , Muscles squelettiques/anatomopathologie , Modèles animaux de maladie humaine , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Mâle , Récupération fonctionnelle/effets des médicaments et des substances chimiques , FemelleRÉSUMÉ
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.
Sujet(s)
Biologie informatique , Simulation de docking moléculaire , Pharmacologie des réseaux , Stilbènes , Tumeurs du col de l'utérus , Humains , Stilbènes/pharmacologie , Stilbènes/composition chimique , Stilbènes/usage thérapeutique , Tumeurs du col de l'utérus/traitement médicamenteux , Tumeurs du col de l'utérus/métabolisme , Tumeurs du col de l'utérus/génétique , Femelle , Cartes d'interactions protéiques/effets des médicaments et des substances chimiques , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/usage thérapeutique , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-ß-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.
Sujet(s)
Maladie d'Alzheimer , Dysfonctionnement cognitif , Modèles animaux de maladie humaine , Histone Deacetylase 2 , Extraits de plantes , Stilbènes , Streptozocine , Animaux , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Rats , Dysfonctionnement cognitif/traitement médicamenteux , Dysfonctionnement cognitif/métabolisme , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Mâle , Histone Deacetylase 2/métabolisme , Cyclodextrines bêta/pharmacologie , Simulation de docking moléculaire , Hippocampe/métabolisme , Hippocampe/effets des médicaments et des substances chimiques , Malonaldéhyde/métabolisme , Donépézil/pharmacologie , Donépézil/usage thérapeutique , Simulation de dynamique moléculaire , Rat WistarSujet(s)
Association de médicaments , Glutathion , Mélanose , Resvératrol , Humains , Resvératrol/administration et posologie , Mélanose/traitement médicamenteux , Association de médicaments/méthodes , Femelle , Antioxydants/administration et posologie , Adulte , Stilbènes/administration et posologie , Stilbènes/usage thérapeutique , Résultat thérapeutiqueRÉSUMÉ
Pterostilbene, a stilbene compound, demonstrates neuroprotective effects through its antioxidant and anti-inflammatory properties. However, pterostilbene exhibits low bioavailability. We developed a pterostilbene nanoemulsion with better release stability and particle size. Behavioral tests, including the Y maze, new object recognition, and water maze, revealed that the pterostilbene nanoemulsion demonstrated a more significant effect on improving learning and memory function than pterostilbene. Immunofluorescence analysis revealed that pterostilbene nanoemulsion was more potent in safeguarding hippocampal neurons and inhibiting apoptosis and oxidative stress than pterostilbene. Further results from the Western blot and quantitative reverse transcription polymerase chain reaction indicated that the enhanced efficacy of pterostilbene nanoemulsion may be attributed to its stronger promotion of the nuclear factor erythroid 2-related factor 2 signaling pathway. Hence, enhanced drug delivery efficiency decreased dosage requirements and increased the bioavailability of pterostilbene, thereby potentially providing a safe, effective, and convenient treatment option for patients with Alzheimer's disease.
Sujet(s)
Maladie d'Alzheimer , Stilbènes , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Facteur-2 apparenté à NF-E2/métabolisme , Stress oxydatif , Transduction du signal , Stilbènes/pharmacologie , Stilbènes/usage thérapeutique , Animaux , SourisRÉSUMÉ
BACKGROUND: Increasing global overweight and obesity rates not only increase the prevalence of myocardial infarction (MI), but also exacerbate ischemic injury and result in worsened prognosis. Currently, there are no drugs that can reverse myocardial damage once MI has occurred, therefore discovering drugs that can potentially limit the extent of ischemic damage to the myocardium is critical. Resveratrol is a polyphenol known for its antioxidant properties, however whether prolonged daily intake of resveratrol during obesity can protect against MI-induced damage remains unexplored. METHODS: We established murine models of obesity via high-fat/high-fructose diet, along with daily administrations of resveratrol or vehicle, then performed surgical MI to examine the effects and mechanisms of resveratrol in protecting against myocardial ischemic injury. RESULTS: Daily administration of resveratrol in obese mice robustly protected against myocardial ischemic injury and improved post-MI cardiac function. Resveratrol strongly inhibited oxidative and DNA damage via activating SIRT3/FOXO3a-dependent antioxidant enzymes following MI, which were completely prevented upon administration of 3-TYP, a selective SIRT3 inhibitor. Hence, the cardioprotective effects of prolonged resveratrol intake in protecting obese mice against myocardial ischemic injury was due to reestablishment of intracellular redox homeostasis through activation of SIRT3/FOXO3a signaling pathway. CONCLUSION: Our findings provide important new evidence that supports the daily intake of resveratrol, especially in those overweight or obese, which can robustly decrease the extent of ischemic damage following MI. Our study therefore provides new mechanistic insight and suggests the therapeutic potential of resveratrol as an invaluable drug in the treatment of ischemic heart diseases.
Sujet(s)
Protéine O3 à motif en tête de fourche , Homéostasie , Souris de lignée C57BL , Souris obèse , Obésité , Oxydoréduction , Resvératrol , Transduction du signal , Sirtuine-3 , Animaux , Resvératrol/pharmacologie , Transduction du signal/effets des médicaments et des substances chimiques , Sirtuine-3/métabolisme , Mâle , Oxydoréduction/effets des médicaments et des substances chimiques , Obésité/traitement médicamenteux , Obésité/métabolisme , Obésité/complications , Protéine O3 à motif en tête de fourche/métabolisme , Homéostasie/effets des médicaments et des substances chimiques , Souris , Antioxydants/pharmacologie , Ischémie myocardique/métabolisme , Ischémie myocardique/traitement médicamenteux , Stress oxydatif/effets des médicaments et des substances chimiques , Alimentation riche en graisse/effets indésirables , Infarctus du myocarde/prévention et contrôle , Infarctus du myocarde/métabolisme , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/traitement médicamenteux , Cardiotoniques/pharmacologie , Stilbènes/pharmacologie , Stilbènes/usage thérapeutiqueRÉSUMÉ
Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.