scholarly journals New Amino Acid Schiff Bases as Anticancer Agents via Potential Mitochondrial Complex I-Associated Hexokinase Inhibition and Targeting AMP-Protein Kinases/mTOR Signaling Pathway

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5332
Author(s):  
Ahmed A. Noser ◽  
Aboubakr H. Abdelmonsef ◽  
Mohamed El-Naggar ◽  
Maha M. Salem
Keyword(s):  
Amino Acid ◽  
Signaling Pathway ◽  
Complex I ◽  
Cytotoxic Effect ◽  
Alternative Pathway ◽  
Mtor Signaling ◽  
Mitochondrial Complex I ◽  
Spectroscopic Techniques ◽  
Mtor Signaling Pathway ◽  
Mitochondrial Complex

Two series of novel amino acid Schiff base ligands containing heterocyclic moieties, such as quinazolinone 3–11 and indole 12–20 were successfully synthesized and confirmed by spectroscopic techniques and elemental analysis. Furthermore, all compounds were investigated in silico for their ability to inhibit mitochondrial NADH: ubiquinone oxidoreductase (complex I) by targeting the AMPK/mTOR signaling pathway and inhibiting hexokinase, a key glycolytic enzyme to prevent the Warburg effect in cancer cells. This inhibitory pathway may be an effective strategy to cause cancer cell death due to an insufficient amount of ATP. Our results revealed that, out of 18 compounds, two (11 and 20) were top-ranked as they exhibited the highest binding energies of −8.8, −13.0, −7.9, and −10.0 kcal/mol in the docking analysis, so they were then selected for in vitro assessment. Compound 11 promoted the best cytotoxic effect on MCF-7 with IC50 = 64.05 ± 0.14 μg/mL (0.135 mM) while compound 20 exhibited the best cytotoxic effect on MDA-231 with IC50 = 46.29 ± 0.09 μg/mL (0.166 mM) Compounds 11 and 20 showed significant activation of AMPK protein and oxidative stress, which led to elevated expression of p53 and Bax, reduced Bcl-2 expression, and caused cell cycle arrest at the sub-G0/G1 phase. Moreover, compounds 11 and 20 showed significant inhibition of the mTOR protein, which led to the activation of aerobic glycolysis for survival. This alternative pathway was also blocked as compounds 11 and 20 showed significant inhibitory effects on the hexokinase enzyme. These findings demonstrate that compounds 11 and 20 obeyed Lipinski’s rule of five and could be used as privileged scaffolds for cancer therapy via their potential inhibition of mitochondrial complex I-associated hexokinase.

scholarly journals Thiol Oxidation and Loss of Mitochondrial Complex I Precede Excitatory Amino Acid-Mediated Neurodegeneration

1998 ◽  
Vol 18 (24) ◽  
pp. 10287-10296 ◽  
Author(s):  
Krishnan Sriram ◽  
Susarla K. Shankar ◽  
Michael R. Boyd ◽  
Vijayalakshmi Ravindranath
Keyword(s):  
Amino Acid ◽  
Complex I ◽  
Excitatory Amino Acid ◽  
Mitochondrial Complex I ◽  
Thiol Oxidation ◽  
Mitochondrial Complex

scholarly journals N-Carbamylglutamate and l-Arginine Promote Intestinal Absorption of Amino Acids by Regulating the mTOR Signaling Pathway and Amino Acid and Peptide Transporters in Suckling Lambs with Intrauterine Growth Restriction

2019 ◽  
Vol 149 (6) ◽  
pp. 923-932 ◽  
Author(s):  
Hao Zhang ◽  
Along Peng ◽  
Yin Yu ◽  
Shuang Guo ◽  
Mengzhi Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
Signaling Pathway ◽  
Intrauterine Growth Restriction ◽  
Nutrient Absorption ◽  
Mtor Signaling ◽  
Growth Restriction ◽  
Peptide Transporter ◽  
Mtor Signaling Pathway ◽  
Intrauterine Growth ◽  
Peptide Transporters

ABSTRACT Background Previous studies have revealed that dietary N-carbamylglutamate (NCG) and l-arginine (Arg) improve intestinal integrity, oxidative state, and immune function in Hu suckling lambs with intrauterine growth restriction (IUGR). Whether these treatments alter intestinal nutrient absorption is unknown. Objective The aim of this study was to determine the influence of dietary NCG and Arg treatment during the suckling period on intestinal amino acid (AA) absorption, alterations in the mechanistic target of rapamycin (mTOR) signaling pathway, and the abundance of AA and peptide transporters in IUGR lambs. Methods On day 7 after birth, 48 newborn Hu lambs were selected from a cohort of 424 twin lambs. Normal-birth-weight and IUGR Hu lambs were allocated randomly (n = 12/group) to a control (4.09 ± 0.12 kg), IUGR (3.52 ± 0.09 kg), IUGR + 0.1% NCG (3.49 ± 0.11 kg), or IUGR + 1% Arg (3.53 ± 0.10 kg). Results At day 28, compared with the IUGR group, the IUGR groups receiving NCG and Arg had 7.4% and 7.2% greater (P < 0.05) body weight, respectively. Compared with the IUGR group, the serum concentration of insulin was greater (P < 0.05) and the cortisol was lower (P < 0.05) in the IUGR groups receiving NCG and Arg. Compared with the IUGR group, the IUGR groups receiving NCG and Arg had 13.2%–62.6% greater (P < 0.05) serum concentrations of arginine, cysteine, isoleucine, and proline. Dietary NCG or Arg to IUGR lambs resulted in greater protein abundance (P < 0.05) of peptide transporter 1 (41.9% or 38.2%) in the ileum compared with the unsupplemented IUGR lambs, respectively. Furthermore, dietary NCG or Arg treatment normalized the IUGR-induced variation (P < 0.05) in the ileal ratio of phosphorylated mTOR to total mTOR protein. Conclusion Both NCG and Arg can help mitigate the negative effect of IUGR on nutrient absorption in neonatal lambs.

scholarly journals Early leucine programming  on  protein utilization and mTOR signaling by DNA methylation in zebrafish (Danio rerio)

2020 ◽  
Author(s):  
Qiang-Sheng Zhu ◽  
Jie Wang ◽  
shan he ◽  
Xu-Fang Liang ◽  
Shuang Xie ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Signaling Pathway ◽  
Danio Rerio ◽  
Mtor Signaling ◽  
Translation Initiation Factor ◽  
Mtor Signaling Pathway ◽  
Nutritional Programming ◽  
Expression Of Genes

Abstract Background Early nutritional programming affects a series of metabolism, growth and development in mammals. Fish also exhibit the developmental plasticity by early nutritional programming. However, little is known about the effect of early amino acid programming on growth and metabolism. Methods In the present study, zebrafish (Danio rerio) was used as the experimental animal to study whether early leucine stimulation can programmatically affect the mechanistic target of rapamycin (mTOR) signaling pathway, growth and metabolism in the later life, and to undercover the mechanism of epigenetic regulation. Zebrafish larvas at 3 days post hatching (dph) were raised with 1.0% leucine from 3 to 13 dph during the critical developmental stage, then back to normal water for 70 days (83 dph). Results The growth performance and crude protein content of zebrafish in the early leucine programming group were increased, and consistent with the activation of the mTOR signaling pathway and the high expression of genes involved in the metabolism of amino acid and glycolipid. Furthermore, we compared the DNA methylation profiles between the control and leucine-stimulated zebrafish, and found that the methylation levels of CG-differentially methylated regions (DMGs) and CHH-DMGs of genes involved in mTOR signaling pathway were different between the two groups. With quantitative PCR analysis, the decreased methylation levels of CG type of Growth factor receptor-bound protein 10 (Grb10), eukaryotic translation initiation factor 4E (eIF4E) and mTOR genes of mTOR signaling pathway in the leucine programming group, might contribute to the enhanced gene expression. Conclusions The early leucine programming could improve the protein synthesis and growth, which might be attributed to the methylation of genes in mTOR pathway and the expression of genes involved in protein synthesis and glycolipid metabolism in zebrafish. These results could be beneficial for better understanding of the epigenetic regulatory mechanism of early nutritional programming.

scholarly journals Early leucine programming on protein utilization and mTOR signaling by DNA methylation in zebrafish (Danio rerio)

2020 ◽  
Author(s):  
Qiang-Sheng Zhu ◽  
Jie Wang ◽  
shan he ◽  
Xu-Fang Liang ◽  
Shuang Xie ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Signaling Pathway ◽  
Danio Rerio ◽  
Mtor Signaling ◽  
Translation Initiation Factor ◽  
Mtor Signaling Pathway ◽  
Nutritional Programming ◽  
Expression Of Genes

Abstract Background: Early nutritional programming affects a series of metabolism, growth and development in mammals. Fish also exhibit the developmental plasticity by early nutritional programming. However, little is known about the effect of early amino acid programming on growth and metabolism. Methods: In the present study, zebrafish (Danio rerio) was used as the experimental animal to study whether early leucine stimulation can programmatically affect the mechanistic target of rapamycin (mTOR) signaling pathway, growth and metabolism in the later life, and to undercover the mechanism of epigenetic regulation. Zebrafish larvas at 3 days post hatching (dph) were raised with 1.0% leucine from 3 to 13 dph during the critical developmental stage, then back to normal water for 70 days (83 dph). Results: The growth performance and crude protein content of zebrafish in the early leucine programming group were increased, and consistent with the activation of the mTOR signaling pathway and the high expression of genes involved in the metabolism of amino acid and glycolipid. Furthermore, we compared the DNA methylation profiles between the control and leucine-stimulated zebrafish, and found that the methylation levels of CG-differentially methylated regions (DMGs) and CHH-DMGs of genes involved in mTOR signaling pathway were different between the two groups. With quantitative PCR analysis, the decreased methylation levels of CG type of Growth factor receptor-bound protein 10 (Grb10), eukaryotic translation initiation factor 4E (eIF4E) and mTOR genes of mTOR signaling pathway in the leucine programming group, might contribute to the enhanced gene expression. Conclusions: The early leucine programming could improve the protein synthesis and growth, which might be attributed to the methylation of genes in mTOR pathway and the expression of genes involved in protein synthesis and glycolipid metabolism in zebrafish. These results could be beneficial for better understanding of the epigenetic regulatory mechanism of early nutritional programming.

scholarly journals Effect of Heat Stress on Bovine Mammary Cellular Metabolites and Gene Transcription Related to Amino Acid Metabolism, Amino Acid Transportation and Mammalian Target of Rapamycin (mTOR) Signaling

Animals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 3153
Author(s):  
Lin Fu ◽  
Li Zhang ◽  
Li Liu ◽  
Heng Yang ◽  
Peng Zhou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Mammary Epithelial ◽  
Mtor Signaling ◽  
Control Group ◽  
Mtor Signaling Pathway ◽  
Lactation Performance

Heat stress (HS) is one of the most serious factors to negatively affect the lactation performance of dairy cows. Bovine mammary epithelial cells are important for lactation. It was demonstrated that HS decreases the lactation performance of dairy cows, partly through altering gene expression within bovine mammary epithelial tissue. However, the cellular metabolism mechanisms under HS remains largely unknown. The objective of this study was to determine whether HS induced changes in intracellular metabolites and gene transcription related to amino acid metabolism, amino acid transportation and the mTOR signaling pathway. Immortalized bovine mammary epithelial cell lines (MAC-T cells, n = 5 replicates/treatment) were incubated for 12 h at 37 °C (Control group) and 42 °C (HS group). Relative to the control group, HS led to a greater mRNA expression of heat shock protein genes HSF1, HSPB8, HSPA5, HSP90AB1 and HSPA1A. Compared with the control group, metabolomics using liquid chromatography tandem–mass spectrometry identified 417 differential metabolites with p < 0.05 and a variable importance in projection (VIP) score >1.0 in the HS group. HS resulted in significant changes to the intracellular amino acid metabolism of glutathione, phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, arginine, proline, cysteine, methionine, alanine, aspartate and glutamate. HS led to a greater mRNA expression of the amino acid transporter genes SLC43A1, SLC38A9, SLC36A1, and SLC3A2 but a lower mRNA expression of SLC7A5 and SLC38A2. Additionally, HS influenced the expression of genes associated with the mTOR signaling pathway and significantly upregulated the mRNA expression of mTOR, AKT, RHEB, eIF4E and eEF2K but decreased the mRNA expression of TSC1, TSC2 and eEF2 relative to the control group. Compared with the control group, HS also led to greater mRNA expression of the CSN1S2 gene. Overall, our study indicates that bovine mammary epithelial cells may have the ability to resist HS damage and continue milk protein synthesis partly through enhanced intracellular amino acid absorption and metabolism and by activating the mTOR signaling pathway during HS.

scholarly journals Early Leucine Programming on Protein Utilization and mTOR Signaling by DNA Methylation in Zebrafish (Danio Rerio)

2020 ◽  
Author(s):  
Qiang-Sheng Zhu ◽  
Jie Wang ◽  
shan he ◽  
Xu-Fang Liang ◽  
Shuang Xie ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Signaling Pathway ◽  
Danio Rerio ◽  
Mtor Signaling ◽  
Translation Initiation Factor ◽  
Mtor Signaling Pathway ◽  
Nutritional Programming ◽  
Expression Of Genes

Abstract Background: Early nutritional programming affects a series of metabolism, growth and development in mammals. Fish also exhibit the developmental plasticity by early nutritional programming. However, little is known about the effect of early amino acid programming on growth and metabolism. Methods: In the present study, zebrafish (Danio rerio) was used as the experimental animal to study whether early leucine stimulation can programmatically affect the mechanistic target of rapamycin (mTOR) signaling pathway, growth and metabolism in the later life, and to undercover the mechanism of epigenetic regulation. Zebrafish larvas at 3 days post hatching (dph) were raised with 1.0% leucine from 3 to 13 dph during the critical developmental stage, then back to normal water for 70 days (83 dph). Results: The growth performance and crude protein content of zebrafish in the early leucine programming group were increased, and consistent with the activation of the mTOR signaling pathway and the high expression of genes involved in the metabolism of amino acid and glycolipid. Furthermore, we compared the DNA methylation profiles between the control and leucine-stimulated zebrafish, and found that the methylation levels of CG-differentially methylated regions (DMGs) and CHH-DMGs of genes involved in mTOR signaling pathway were different between the two groups. With quantitative PCR analysis, the decreased methylation levels of CG type of Growth factor receptor-bound protein 10 (Grb10), eukaryotic translation initiation factor 4E (eIF4E) and mTOR genes of mTOR signaling pathway in the leucine programming group, might contribute to the enhanced gene expression. Conclusions: The early leucine programming could improve the protein synthesis and growth, which might be attributed to the methylation of genes in mTOR pathway and the expression of genes involved in protein synthesis and glycolipid metabolism in zebrafish. These results could be beneficial for better understanding of the epigenetic regulatory mechanism of early nutritional programming.

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