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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812

项与亮氨酸/西地那非相关的文献（医药）

2024-12-01·Poultry Science

Different dietary branched-chain amino acid ratios, crude protein levels, and protein sources can affect the growth performance and meat yield in broilers

Article

作者: Lee, Jihwan ; Kim, Woo Kyun ; Sharma, Milan K ; Sharma, Milan K. ; Goo, Doyun ; Kong, Byungwhi ; Paneru, Deependra ; Zhuang, Hong ; Katha, Hemanth R ; Choi, Janghan ; Bowker, Brian ; Katha, Hemanth R. ; Singh, Amit K ; Singh, Amit K.

Balanced ratios of branched-chain amino acids (BCAAs) can enhance chicken growth, immunity, and muscle synthesis. However, these ratios can be affected by changes in crude protein (CP) levels or the substitution of protein sources, leading to BCAA antagonism. This, in turn, can have a negative impact on chicken growth. In Experiment 1, a total of 960 0-d-old male Cobb 500 broilers were divided into 6 treatments with 8 replicates. Three different BCAA ratios were used in High or Low CP diets as follows: 1) Low Leu group (Low level of leucine with increased valine and isoleucine levels), 2) Med Leu group, and 3) High Leu group (High level of leucine with reduced valine and isoleucine levels) for a total of 6 diets. In Experiment 2, a total of 640 0-d-old male Cobb 500 broilers were divided into 4 treatments with 8 replicates. The four diets had either High or Low CP and one of two protein sources with the same medium levels of BCAAs: 1) the soybean meal (SBM) group, which had SBM as the main protein source (protein bound AA), and 2) the wheat middlings with non-bound AAs (WM+AA) group (non-bound AA), which had additional non-bound AAs to replace SBM. The High Leu diet had a negative effect on overall growth performance, carcass weight, breast muscle weight, and body mineral composition compared to the Low Leu and Med Leu groups, particularly in the High CP diet (P < 0.05). The SBM group showed increased growth performance, breast muscle weight, expression levels of genes promoting muscle growth, and improved bone mineral composition compared to the WM+AA group, and the High CP group intensified the negative effect of the WM+AA diet (P < 0.05). In summary, balanced BCAA ratios and SBM-based diets have positive effects on chicken growth and muscle accretion, whereas excessive leucine and non-bound AA levels in the diets may negatively affect growth performance and meat yield in chickens.

2024-11-05·ACS Omega

Impact of MTHFD2 Expression in Bladder/Breast Cancer and Screening of Its Potential Inhibitor

Article

作者: Tariq, Aamira ; Elahi, Muhammad Affan ; Sattar, Sadia ; Aruge, Samreen ; Asif, Saaim ; Zafar, Muhammad ; Bostan, Nazish ; Javed, Aneela ; Asif, Maleeha ; Riaz, Lubna

Genes of folate-mediated 1 carbon metabolism are found to be highly upregulated in tumor cells and promote cancer cell proliferation. The current study aimed to determine the expression of the MTHFD2 gene in bladder and breast cancers. Furthermore, the determination of potential ligand-based inhibitors against MTHFD2 was performed in comparison with those of chemotherapeutic drugs and natural plant-based compounds. Semiquantitative expression analysis along with structure-based virtual ligand library screening was done to find plausible inhibitors. MTHFD2 expression was significantly increased with tumor stage progression both in low- and high-grade bladder cancer and especially in triple-negative breast cancer. Virtual ligand-based library screening against the three-dimensional MTHFD2 protein structure led to the identification of plausible inhibitors like MCULE-8109969891-0 and MCULE-9715677418-0-1 that displayed lower binding free energy as compared to that of already documented LY345899. Similar scaffold commercial drugs leucal (LEU), epirubicin (EPI), and lometrexol also displayed strong binding to the active site of MTHFD2. EPI and LEU in combinatorial therapy were also tested in vitro on MDA-MB-231 cells. The high doses of LEU in combination with EPI showed a significant reduction in cell viability at 2 and 3 μM concentrations. The interaction of breast cancer serum with high expression of MTHFD2 also showed an increase in binding of epirubicin in the presence of leucovorin. The decrease in the absorbance spectra of epirubicin at 37 and 53 °C displayed the stability induced by LEU on the interaction of EPI with the MTHFD2 binding pocket. Leucovorin tends to stabilize the interaction as the binding affinity is high even at 53 °C. Thus, MTHFD2 might be used as a cancer biomarker since its expression level changes drastically with tumor progression. Further experimental studies are required to establish the potential mode of inhibition of the novel small ligands. Future in vivo trials may validate the effectiveness of the combinatorial therapy.

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 ; Yang, Fang ; Yan, Jianhua ; 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.

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 Sciences, Inc.	2018-01-08
肥胖	临床2期	美国	NuSirt Biopharma, 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)	鬱鏇繭艱衊淵選鹽簾獵(襯鏇廠築網糧膚遞網糧) = 積蓋蓋壓衊餘積遞鏇鬱觸憲廠鑰夢窪餘壓製憲 (獵醖鹹選繭鬱衊鏇鹽鹹, 鏇製膚願壓網繭衊範餘 ~ 蓋壓鏇夢廠憲構夢壓製) 更多	-	2018-11-27
				Leu Sil 4.0mg (Leu Sil 1.0mg)	鬱鏇繭艱衊淵選鹽簾獵(襯鏇廠築網糧膚遞網糧) = 鹽艱淵顧製簾積餘夢鏇觸憲廠鑰夢窪餘壓製憲 (獵醖鹹選繭鬱衊鏇鹽鹹, 夢遞繭選夢襯獵鹽選蓋 ~ 夢鏇襯餘構鹹夢願襯構) 更多
AUA2016	临床2期	遗传性前列腺癌7型一线	75	TAK-385 80 mg	(築遞餘鑰構憲醖壓艱廠) = All-grade adverse events occurred in 91% vs 95% pts (TAK-385 vs LEU); the most common were hot flush and fatigue 顧餘齋遞繭顧鹹夢鑰蓋 (餘積繭製糧鏇鏇鏇鑰憲 ) 更多	-	2016-04-01
				TAK-385 120 mg