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).

Start Date08 Jan 2018

Sponsor / Collaborator

NuSirt Biopharma, Inc.

100 Clinical Results associated with Leucine/Sildenafil

100 Translational Medicine associated with Leucine/Sildenafil

100 Patents (Medical) associated with Leucine/Sildenafil

810

Literatures (Medical) associated with Leucine/Sildenafil

01 Dec 2024·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

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

01 Nov 2024·Anti-Cancer Agents in Medicinal Chemistry

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

Article

Author: 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.

10 Sep 2024·Journal of animal science and biotechnology

Dietary supplementation of valine, isoleucine, and tryptophan may overcome the negative effects of excess leucine in diets for weanling pigs containing corn fermented protein.

Article

Author: Mallea, Andrea P ; Lee, Su A ; Cristobal, Minoy A ; Torrez-Mendoza, Leidy J ; Stein, Hans H ; Espinosa, Charmaine D

BACKGROUNDDiets with high inclusion of corn co-products such as corn fermented protein (CFP) may contain excess Leu, which has a negative impact on feed intake and growth performance of pigs due to increased catabolism of Val and Ile and reduced availability of Trp in the brain for serotonin synthesis. However, we hypothesized that the negative effect of using CFP in diets for weanling pigs may be overcome if diets are fortified with crystalline sources of Val, Trp, and (or) Ile.METHODSThree hundred and twenty weanling pigs were randomly allotted to one of 10 dietary treatments in a completely randomized design, with 4 pigs per pen and 8 replicate pens per treatment. A corn-soybean meal diet and 2 basal diets based on corn and 10% CFP or corn and 20% CFP were formulated. Seven additional diets were formulated by fortifying the basal diet with 20% CFP with Ile, Trp, Val, Ile and Val, Ile and Trp, Trp and Val, or Ile, Trp and Val. A two-phase feeding program was used, with d 1 to 14 being phase 1 and d 15 to 28 being phase 2. Fecal scores were recorded every other day. Blood samples were collected on d 14 and 28 from one pig per pen. On d 14, fecal samples were collected from one pig per pen in 3 of the 10 treatments to determine volatile fatty acids, ammonium concentration, and microbial protein. These pigs were also euthanized and ileal tissue was collected.RESULTSThere were no effects of dietary treatments on any of the parameters evaluated in phase 1. Inclusion of 10% or 20% CFP in diets reduced (P < 0.05) final body weight on d 28, and average daily gain (ADG) and average daily feed intake (ADFI) in phase 2 and for the entire experimental period. However, pigs fed the CFP diet supplemented with Val, Ile, and Trp had final body weight, ADFI, ADG and gain to feed ratio in phase 2 and for the entire experiment that was not different from pigs fed the control diet. Fecal scores in phase 2 were reduced (P < 0.05) if CFP was used.CONCLUSIONSCorn fermented protein may be included by up to 20% in diets for weanling pigs without affecting growth performance, gut health, or hindgut fermentation, if diets are fortified with extra Val, Trp, and Ile. Inclusion of CFP also improved fecal consistency of pigs.

100 Deals associated with Leucine/Sildenafil

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Indication	Highest Phase	Country/Location	Organization	Date
Obesity	Phase 2	US	NuSirt Biopharma, Inc.	08 Jan 2018
Obesity	Phase 2	US	Nusirt Sciences, Inc.	08 Jan 2018

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03364335 (CTgov)	Phase 2	Obesity	267	Placebo (Placebo)	eqqfisduwb(csoouhiaup) = amzbvcaudv roprxgmcbx (ttoavypnld, vihdkltjyq - rdamytlbrt) View more	-	27 Nov 2018
				Leu Sil 4.0mg (Leu Sil 1.0mg)	eqqfisduwb(csoouhiaup) = wzrtabdvqh roprxgmcbx (ttoavypnld, hrljmaksds - lqsqqyexjo) View more
AUA2016	Phase 2	Prostate Cancer, Hereditary, 7 First line	75	TAK-385 80 mg	(vazvovauqs) = All-grade adverse events occurred in 91% vs 95% pts (TAK-385 vs LEU); the most common were hot flush and fatigue cvpuizcxev (xlzcqnodwg ) View more	-	01 Apr 2016
				TAK-385 120 mg

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