Progesterone resistance is mediated through epigenetic modification through SirT1 activation and is thought to contribute to infertility and progression of endometriosis. Endometriosis is a leading cause of unexplained IVF failure secondary to inflammatory changes that induce SirT1. The current study is designed to investigate a small molecule inhibitor of SirT1, in the clinical setting of In Vitro Fertilization and Embryo Transfer. The SAFER trial will compare EX-527 to placebo in a randomized, double-blind trial. Primary endpoints include Live Birth Rate (LBR) and secondary outcomes include pregnancy rate (PR), miscarriage rate (MR) and implantation failure rate.

开始日期2022-01-01

申办/合作机构

Wake Forest School of Medicine

NCT01485965 / Completed临床1期

A Phase 1b, Open-label, Parallel-group Study in Subjects With Huntington Disease to Assess the Safety, Tolerability, and Fed/Fasted Pharmacokinetics of Repeated Oral Doses of SEN0014196

The primary purpose of this study is to assess the effect of food upon the pharmacokinetics (PK) of SEN0014196 in subjects with Huntington disease (HD).

开始日期2011-11-01

申办/合作机构

Siena Biotech SpA

NCT01521585 / Completed临床2期

A Double-blind, Placebo-controlled Study in Huntington's Disease Patients to Determine the Safety and Tolerability of SEN0014196

The principal aim of this study is to obtain safety and tolerability data when SEN0014196 is administered orally over 12 weeks to male and female patients with Huntington's Disease.

开始日期2011-11-01

申办/合作机构

Siena Biotech SpA

100 项与 Selisistat 相关的临床结果

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100 项与 Selisistat 相关的转化医学

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100 项与 Selisistat 相关的专利（医药）

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项与 Selisistat 相关的文献（医药）

2025-01-01·Journal of Ethnopharmacology

Gypenosides alleviate oxidative stress in the hippocampus, promote mitophagy, and mitigate depressive-like behaviors induced by CUMS via SIRT1

Article

作者: Li, Yingfeng ; Rao, Hui ; Li, Jingqi ; Liu, Yuhang ; Sun, Jianfei ; Wu, Ning ; Xiu, Jiangfan

ETHNOPHARMACOLOGICAL RELEVANCEThe use and efficacy of Gynostemma [Gynostemma pentaphyllum (Thunb.) Makino], a versatile traditional Chinese herb, was first documented in the renowned pharmacopoeia, "Compendium of Materia Medica". Gypenosides (Gps), saponin components are the primary constituents responsible for its biological activities and clinical effects, which include antioxidant, immunoregulatory, antitumor, and neuroprotective properties. Pharmacological studies have shown that Gps has the potential to combat depression. However, the exact molecular mechanisms underlying its antidepressant effects remain unclear.AIM OF THE STUDYThis study aims to elucidate the mechanisms underlying the antidepressant effects of Gps through antioxidative stress, utilizing an integrated approach that includes network pharmacology, molecular simulations, and experimental validation.MATERIALS AND METHODSSprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) and were orally administered doses of Gps (50 and 100 mg/kg) and fluoxetine (10 mg/kg). The regulatory effects of Gps on depression-like behaviors in CUMS rats and their impact on oxidative stress levels in the hippocampus region were evaluated. Network pharmacology was used to investigate the mechanisms by which Gps affects oxidative stress in depression, and was accompanied by molecular docking and dynamics simulations. CUMS rats were treated orally with Gps (100 mg/kg) and injected with EX527 for rescue experiments to validate the role of SIRT1 in antioxidative stress and evaluate the impact of Gps on mitophagy.RESULTSGps ameliorated depression-like behaviors induced by CUMS in rats. The improvements observed included an increased sucrose preference, reduced immobility time in the tail suspension and forced swim tests, and an increased movement distance in the open-field test. Additionally, Gps effectively reduced reactive oxygen species, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine levels in the hippocampus, while increasing the contents of ATP, catalase, superoxide dismutase, and glutathione, indicating an increased capacity for antioxidative stress in the hippocampus. Furthermore, Gps increased the number of neuronal cells in the hippocampal CA1 region and the level of mitochondrial autophagy, with SIRT1 as a potential key target. Inhibition of SIRT1 expression by exposure to EX527 reversed the beneficial effects of Gps, further validating the critical role of SIRT1 in the regulation of oxidative stress and improving depression-like behavior.CONCLUSIONGps improved the antioxidative stress capacity of the hippocampus and promoted mitophagy in CUMS rats through SIRT1, thus protecting hippocampal neurons and improving depression-like behavior.

2024-12-31·Cancer Biology & Therapy

EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein

Article

作者: Guo, Rongqi ; Zhang, Tingting ; Zhao, Lijun ; Du, Yating ; Liu, Luyue ; Xiong, Xiwen ; Ren, Ruiying ; Wang, Hongfei ; Zhang, Haoqi ; Zhu, Xiaofei ; Guo, Xiaofang ; Wei, Yihui ; Sun, Ruili

Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies.

2024-12-31·Pharmaceutical Biology

Nicotinamide mononucleotide alleviates endotoxin-induced acute lung injury by modulating macrophage polarization via the SIRT1/NF-κB pathway

Article

作者: Yang, Jing ; Dong, Shuan ; Zhang, Yuan ; Du, Shihan ; Gong, Lirong ; Jiang, Xianhong ; He, Simeng ; Wu, Xiaoyang ; Shi, Jia ; Yu, Jianbo ; Wu, Ya

CONTEXTSepsis-induced acute lung injury (ALI) is a severe condition with limited effective therapeutics; nicotinamide mononucleotide (NMN) has been reported to exert anti-inflammatory activities.OBJECTIVEThis study explores the potential mechanisms by which NMN ameliorates sepsis-induced ALI in vivo and in vitro.MATERIALS AND METHODSCultured MH-S cells and a murine model were used to evaluate the effect of NMN on sepsis-induced ALI. MH-S cells were stimulated with LPS (1 μg/mL) and NMN (500 μM) for 12 h grouping as control, LPS, and LPS + NMN. Cell viability, apoptotic status, and M1/2 macrophage-related markers were detected. The mice were pretreated intraperitoneally with NMN (500 mg/kg) and/or EX-527 (5 mg/kg) 1 h before LPS injection and randomized into 7 groups (n = 8): control, LPS, LPS + NMN, NMN, LPS + NMN + EX-527 (a SIRT1 inhibitor), LPS + EX-527, and EX-527. After 12 h, lung histopathology, W/D ratio, MPO activity, NAD⁺ and ATP levels, M1/2 macrophage-related markers, and expression of the SIRT1/NF-κB pathway were detected.RESULTSIn MH-S cells, NMN significantly decreased the apoptotic rate from 12.25% to 5.74%. In septic mice, NMN improved the typical pathologic findings in lungs and reduced W/D ratio and MPO activity, but increased NAD⁺ and ATP levels. Additionally, NMN suppressed M1 but promoted M2 polarization, and upregulated the expression of SIRT1, with inhibition of NF-κB-p65 acetylation and phosphorylation. Furthermore, inhibition of SIRT1 reversed the effects of NMN-induced M2 macrophage polarization.CONCLUSIONSNMN protects against sepsis-induced ALI by promoting M2 macrophage polarization via the SIRT1/NF-κB pathway, it might be an effective strategy for preventing or treating sepsis-induced ALI.

100 项与 Selisistat 相关的药物交易

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