A Randomized, Double-blind, Placebo-controlled Study of Effects of Two Fixed-dose Leucine-sildenafil Combinations (NS-0300) or Two Fixed-dose Leucine-sildenafil-metformin Combinations (NS-0200) Versus Placebo on Body Weight in Obesity

This is a 24-week study to evaluate the effects of two fixed-dose combinations of leucine and sildenafil or two fixed-dose combinations of leucine, sildenafil and metformin compared to placebo. The primary objective of this study is to evaluate the percentage change in body weight in subjects from Baseline/Visit 2 (Day 1) to Study Termination/Visit 8 (Day 168/Week 24).

开始日期2018-01-08

申办/合作机构

NuSirt Biopharma, Inc.

100 项与亮氨酸/西地那非相关的临床结果

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100 项与亮氨酸/西地那非相关的转化医学

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100 项与亮氨酸/西地那非相关的专利（医药）

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807

项与亮氨酸/西地那非相关的文献（医药）

2024-11-01·Anti-Cancer Agents in Medicinal Chemistry

Silibinin Induces Both Apoptosis and Necroptosis with Potential Anti-tumor Efficacy in Lung Cancer

Article

作者: Lu, Chunhua ; Zhang, Guoqing ; Wang, Haiping ; Zhang, Song ; Zhao, Limei ; Wang, Li ; Yan, Jianhua ; Yang, Fang ; Li, Yixiang

Background:The incidence of lung cancer is steadily on the rise, posing a growing threat to human health. The search for therapeutic drugs from natural active substances and elucidating their mechanism have been the focus of anti-tumor research.Objective:Silibinin (SiL) has been shown to be a natural product with a wide range of pharmacological activities, including anti-tumour activity. In our work, SiL was chosen as a possible substance that could inhibit lung cancer. Moreover, its effects on inducing tumor cell death were also studied.Methods:CCK-8 analysis and morphological observation were used to assess the cytotoxic impacts of SiL on lung cancer cells in vitro. The alterations in mitochondrial membrane potential (MMP) and apoptosis rate of cells were detected by flow cytometry. The level of lactate dehydrogenase (LDH) release out of cells was measured. The expression changes of apoptosis or necroptosis-related proteins were detected using western blotting. Protein interactions among RIPK1, RIPK3, and MLKL were analyzed using the co-immunoprecipitation (co-IP) technique. Necrosulfonamide (Nec, an MLKL inhibitor) was used to carry out experiments to assess the changes in apoptosis following the blockade of cell necroptosis. In vivo, SiL was evaluated for its antitumor effects using LLC tumor-bearing mice with mouse lung cancer.Results:With an increased dose of SiL, the proliferation ability of A549 cells was considerably inhibited, and the accompanying cell morphology changed. The results of flow cytometry showed that after SiL treatment, MMP levels decreased, and the proportion of cells undergoing apoptosis increased. There was an increase in cleaved caspase-9, caspase-3, and PARP, with a down-regulation of Bcl-2 and an up-regulation of Bax. In addition, the amount of LDH released from the cells increased following SiL treatment, accompanied by augmented expression and phosphorylation levels of necroptosis-related proteins (MLKL, RIPK1, and RIPK3), and the co-IP assay further confirmed the interactions among these three proteins, indicating the necrosome formation induced by SiL. Furthermore, Nec increased the apoptotic rate of SiL-treated cells and aggravated the cytotoxic effect of SiL, indicating that necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL on A549 cells. In LLC-bearing mice, gastric administration of SiL significantly inhibited tumor growth, and H&E staining showed significant damage to the tumour tissue. The results of the IHC showed that the expression of RIPK1, RIPK3, and MLKL was more pronounced in the tumor tissue.Conclusion:This study confirmed the dual effect of SiL, as it can induce both biological processes, apoptosis and necroptosis, in lung cancer. SiL-induced apoptosis involved the mitochondrial pathway, as indicated by changes in caspase-9, Bcl-2, and Bax. Necroptosis may be activated due to the changes in the expression of associated proteins in tumour cells and tissues. It has been observed that blocking necroptosis by SiL increased cell death efficiency. This study helps clarify the anti-tumor mechanism of SiL against lung cancer, elucidating its role in the dual induction of apoptosis and necroptosis. Our work provides an experimental basis for the research on cell death induced by SiL and reveals its possible applications for improving the management of lung cancer.

2024-09-01·Journal of Pharmaceutical Sciences

Leucine as a Moisture-Protective Excipient in Spray-Dried Protein/Trehalose Formulation

Article

作者: Rantanen, Jukka ; Zhang, Chengqian ; Bjerregaard, Simon ; van de Weert, Marco ; Yang, Mingshi

The incorporation of leucine (Leu), a hydrophobic amino acid, into pharmaceutically relevant particles via spray-drying can improve the physicochemical and particulate properties, stability, and ultimately bioavailability of the final product. More specifically, Leu has been proposed to form a shell on the surface of spray-dried (SD) particles. The aim of this study was to explore the potential of Leu in the SD protein/trehalose (Tre) formulation to control the water uptake and moisture-induced recrystallization of amorphous Tre, using lysozyme (LZM) as a model protein. LZM/Tre (1:1, w/w) was dissolved in water with varied amounts of Leu (0 - 40%, w/w) and processed by spray-drying. The solid form, residual moisture content (RMC), hygroscopicity, and morphology of SD LZM/Tre/Leu powders were evaluated, before and after storage under 22°C/55% RH conditions for 90 and 180 days. The X-ray powder diffraction results showed that Leu was in crystalline form when the amount of Leu in the formulation was at least 20% (w/w). Thermo-gravimetric analysis and scanning electron microscopy results showed that 0%, 5%, and 10% (w/w) Leu formulations led to comparable RMC and raisin-like round particles. In contrast, higher Leu contents resulted in a lower RMC and increased surface corrugation of the SD particles. Dynamic vapor sorption analysis showed that partial recrystallization of amorphous Tre to crystalline Tre·dihydrate occurred in the 0% Leu formulation. However, adding as little as 5% (w/w) Leu inhibited this recrystallization during the water sorption/desorption cycle. In addition, after storage, the formulations with higher Leu contents showed reduced water uptake. Instead of observing recrystallization of amorphous Tre in 0%, 5%, and 10% (w/w) Leu formulations, recrystallization of amorphous Leu was noted in the 5% and 10% (w/w) Leu formulations after storage. In summary, our study demonstrated that the addition of Leu has the potential to reduce water uptake and inhibit moisture-induced recrystallization of amorphous Tre in the SD protein/Tre powder system.

2024-09-01·Comparative Biochemistry and Physiology Part D: Genomics and Proteomics

Leucine promotes energy metabolism and stimulates slow-twitch muscle fibers expression through AMPK/mTOR signaling in equine skeletal muscle satellite cells

Article

作者: Dugarjaviin, Manglai ; Bou, Gerelchimeg ; Li, Xinyu ; Xing, Jingya ; Zhao, Yiping ; Liu, Guiqin ; Akhtar, Muhammad Faheem ; Zhang, Xinzhuang ; Bai, Dongyi ; Shen, Yingchao

Previous research has shown that leucine (Leu) can stimulate and enhance the proliferation of equine skeletal muscle satellite cells (SCs). The gene expression profile associated with Leu-induced proliferation of equine SCs has also been documented. However, the specific role of Leu in regulating the expression of slow-twitch muscle fibers (slow-MyHC) and mitochondrial function in equine SCs, as well as the underlying mechanism, remains unclear. During this investigation, equine SCs underwent culturing in differentiation medium and were subjected to varying concentrations of Leu (0 mM, 0.5 mM, 1 mM, 2 mM, 5 mM, and 10 mM) over a span of 3 days. AMP-activated protein kinase (AMPK) inhibitor Compound C and mammalian target of rapamycin complex (mTOR) inhibitor Rapamycin were utilized to explore its underlying mechanism. Here we showed that the expression of slow-MyHC at 2 mM Leu level was significantly higher than the concentration levels of 0 mM,0.5 mM and 10 mM (P <0.01), and there was no significant difference compared to other groups (P > 0.05); the basal respiration, maximum respiration, standby respiration and the expression of slow-MyHC, PGC-1α, Cytc, ND1, TFAM, and COX1 were significantly increased with Leu supplementation (P < 0.01). We also found that Leu up-regulated the expression of key proteins on AMPK and mTOR signaling pathways, including LKB1, p-LKB1, AMPK, p-AMPK, S6, p-S6, 4EBP1, p-4EBP1, mTOR and p-mTOR (P < 0.05 or P < 0.01). Notably, when we treated the equine SCs with the AMPK inhibitor Compound C and the mTOR inhibitor Rapamycin, we observed a reduction in the beneficial effects of Leu on the expression of genes related to slow-MyHC and signaling pathway-related gene expressions. This study provides novel evidence that Leu promotes slow-MyHC expression and enhances mitochondrial function in equine SCs through the AMPK/mTOR signaling pathways, shedding light on the underlying mechanisms involved in these processes for the first time.

100 项与亮氨酸/西地那非相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
肥胖	临床2期	美国	NuSirt Biopharma, Inc.	2018-01-08
肥胖	临床2期	美国	Nusirt Sciences, Inc.	2018-01-08

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03364335 (CTgov)	临床2期	肥胖	267	Placebo (Placebo)	遞憲蓋夢築衊製繭鬱鹽(糧齋膚齋簾積壓遞網獵) = 艱鑰網鬱齋糧餘簾壓窪蓋鏇網繭膚壓齋齋蓋鬱 (鏇遞壓壓廠窪窪築糧繭, 蓋築鬱鹽顧觸繭淵憲襯 ~ 積醖鬱鏇糧艱壓顧選廠) 更多	-	2018-11-27
				Leu Sil 4.0mg (Leu Sil 1.0mg)	遞憲蓋夢築衊製繭鬱鹽(糧齋膚齋簾積壓遞網獵) = 壓廠鹹壓艱糧顧糧鹽壓蓋鏇網繭膚壓齋齋蓋鬱 (鏇遞壓壓廠窪窪築糧繭, 鑰網膚衊獵窪壓鑰淵糧 ~ 醖壓膚築遞選構艱餘觸) 更多
AUA2016	临床2期	遗传性前列腺癌7型一线	75	TAK-385 80 mg	(顧遞餘廠範鹽觸齋積願) = All-grade adverse events occurred in 91% vs 95% pts (TAK-385 vs LEU); the most common were hot flush and fatigue 艱構餘淵鏇範鑰膚獵簾 (襯衊繭廠齋淵廠廠餘憲 ) 更多	-	2016-04-01
				TAK-385 120 mg