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X Dong, Z Zhou, L Wang, B Saremi, A Helmbrecht, Z Wang, J J Loor
Amino acids not only serve as precursors for protein synthesis but also function as signaling molecules that can regulate the mammalian target of rapamycin (mTOR) pathway. Methionine and Lys are the most-limiting AA for milk production and a ratio of ∼3:1 Lys:Met in the metabolizable protein has been determined to be ideal. Besides Met and Lys, recent studies have evaluated Ile, Leu, Val, and Thr as potentially limiting for milk protein synthesis. The objective of this experiment was to determine if varying the ratio of Lys:Thr, Lys:Ile, Lys:Val, and Lys:Leu while maintaining an ideal ratio of Lys:Met and fixed ratio of other essential AA (IPAA) elicits changes in intracellular metabolites, gene transcription related to protein synthesis, and phosphorylation status of mTOR pathway proteins...
March 14, 2018: Journal of Dairy Science
P Zanos, T D Gould
Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions. Although this finding has been met with enthusiasm, ketamine's widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine's antidepressant actions but lack its undesirable effects...
March 13, 2018: Molecular Psychiatry
Panos Zanos, Scott M Thompson, Ronald S Duman, Carlos A Zarate, Todd D Gould
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites...
March 7, 2018: CNS Drugs
Denis Susorov, Nikita Zakharov, Ekaterina Shuvalova, Alexander Ivanov, Tatiana Egorova, Alexey Shuvalov, Ivan N Shatsky, Elena Alkalaeva
During protein synthesis, a ribosome moves along the mRNA template and, using aminoacyl-tRNAs, decodes the template nucleotide triplets to assemble a protein amino acid sequence. This movement is accompanied by shifting of mRNA-tRNA complexes within the ribosome in a process called translocation. In living cells, this process proceeds in a unidirectional manner, bringing the ribosome to the 3'-end of mRNA, and is catalyzed by the GTPase translation elongation factor 2 (EF-G in prokaryotes, eEF2 in eukaryotes)...
February 16, 2018: Journal of Biological Chemistry
Mingjin Zou, Jing Wang, Jidong Gao, Hui Han, Yi Fang
The incidence of breast cancer has been increasing in China and the age of breast cancer onset is earlier compared with Western countries. Compounds commonly used in Traditional Chinese Medicine (TCM) are an important source of anticancer drugs. Ginseng is one of the most common medicines used in TCM. Ginsenosides, which are saponins found in the ginseng plant, are the major active components responsible for the chemopreventive effects of ginseng in cancer. However, the mechanisms by which ginsenosides exert their anticancer effects remain elusive...
March 2018: Oncology Letters
Craig T Werner, Michael T Stefanik, Mike Milovanovic, Aaron Caccamise, Marina E Wolf
Exposure to drug-associated cues can induce drug craving and relapse in abstinent addicts. Cue-induced craving that progressively intensifies ("incubates") during withdrawal from cocaine has been observed in both rats and humans. Building on recent evidence that aberrant protein translation underlies incubation-related adaptations in the nucleus accumbens (NAc), we used male rats to test the hypothesis that translation is dysregulated during cocaine withdrawal and/or when rats express incubated cocaine craving...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Soumya Maity, Amit Bera, Nandini Ghosh-Choudhury, Falguni Das, Balakuntalam S Kasinath, Goutam Ghosh Choudhury
TGFβ contributes to mesangial cell hypertrophy and matrix protein increase in various kidney diseases including diabetic nephropathy. Deptor is an mTOR-interacting protein and suppresses mTORC1 and mTORC2 activities. We have recently shown that TGFβ-induced inhibition of deptor increases the mTOR activity. The mechanism by which TGFβ regulates deptor expression is not known. Here we identify deptor as a target of the microRNA-181a. We show that in mesangial cells, TGFβ increases the expression of miR-181a to downregulate deptor...
January 31, 2018: Experimental Cell Research
Chinnakkaruppan Adaikkan, Elham Taha, Iliana Barrera, Orit David, Kobi Rosenblum
BACKGROUND: Ketamine is an N-methyl-D-aspartate receptor antagonist, which on administration produces fast-acting antidepressant responses in patients with major depressive disorder. Yet, the mechanism underlying the antidepressant action of ketamine remains unclear. METHODS: To unravel the mechanism of action of ketamine, we treated wild-type C57BL/6 mice with calcium/calmodulin-dependent protein kinase II (CaMKII) specific inhibitor tatCN21 peptide. We also used eukaryotic elongation factor 2 kinase (eEF2K) (also known as CaMKIII) knockout mice...
December 5, 2017: Biological Psychiatry
X Luo, J Y Wang, F L Zhang, Y Xia
Objective: To explore the regulation and mechanism of Prestin protein by identifying the proteins interacted with Prestin in cochlear outer hair cell(OHC) and analyzing their biological function. Methods: Co-immunoprecipitation combined mass spectrometry technology was used to isolate and identify the proteins interacted with Prestin protein of OHC, bioinformatics was used to construct Prestin protein interaction network. The proteins interacted with Prestin in OHC of guinea pig were determined by matching primary interaction mass spectrometry with protein interaction network, and annotated their functions...
January 7, 2018: Zhonghua Er Bi Yan Hou Tou Jing Wai Ke za Zhi, Chinese Journal of Otorhinolaryngology Head and Neck Surgery
Junya Nakajima, Shingo Oana, Tomohiro Sakaguchi, Mitsuko Nakashima, Hironao Numabe, Hisashi Kawashima, Naomichi Matsumoto, Noriko Miyake
The diphthamide biosynthesis 1 (DPH1) gene encodes one of the essential components of the enzyme catalyzing the first step of diphthamide formation on eukaryotic elongation factor 2 (EEF2). Diphthamide is the posttranslationally modified histidine residue on EEF2 that promotes protein chain elongation in the ribosome. DPH1 defects result in a failure of protein synthesis involving EEF2, leading to growth defects, embryonic lethality, and cell death. In humans, DPH1 mutations cause developmental delay with a short stature, dysmorphic features, and sparse hair, and are inherited in an autosomal recessive manner (MIM#616901)...
January 23, 2018: Journal of Human Genetics
Md Khurshidul Hassan, Dinesh Kumar, Monali Naik, Manjusha Dixit
Eukaryotic translation factors, especially initiation factors have garnered much attention with regards to their role in the onset and progression of different cancers. However, the expression levels and prognostic significance of translation elongation factors remain poorly explored in different cancers. In this study, we have investigated the mRNA transcript levels of seven translation elongation factors in different cancer types using Oncomine and TCGA databases. Furthermore, we have identified the prognostic significance of these factors using Kaplan-Meier Plotter and SurvExpress databases...
2018: PloS One
Helena R Zimmermann, Wenzhong Yang, Brenna C Beckelman, Nicole P Kasica, Xueyan Zhou, Lucas Galli, Alexey G Ryazanov, Tao Ma
Characterization of the molecular signaling pathways underlying protein synthesis-dependent forms of synaptic plasticity, such as late long-term potentiation (L-LTP), can provide insights not only into memory expression/maintenance under physiological conditions but also potential mechanisms associated with the pathogenesis of memory disorders. Here, we report in mice that L-LTP failure induced by the mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) inhibitor rapamycin is reversed by brain-specific genetic deletion of PKR-like ER kinase, PERK (PERK KO), a kinase for eukaryotic initiation factor 2α (eIF2α)...
January 16, 2018: Journal of Neurochemistry
Maria K Mateyak, Justyna K Pupek, Alexandra E Garino, McCllelan C Knapp, Sarah F Colmer, Terri Goss Kinzy, Stephen Dunaway
In most eukaryotic organisms, translation elongation requires two highly conserved elongation factors eEF1A and eEF2. Fungal systems are unique in requiring a third factor, the eukaryotic Elongation Factor 3 (eEF3). For decades, eEF3, a ribosome-dependent ATPase, was considered "fungal-specific", however, recent bioinformatics analysis indicates it may be more widely distributed among other unicellular eukaryotes. In order to determine whether divergent eEF3-like proteins from other eukaryotic organisms can provide the essential functions of eEF3 in budding yeast, the eEF3-like proteins from Schizosaccharomyes pombe and an oomycete, Phytophthora infestans, were cloned and expressed in Saccharomyces cerevisiae...
2018: PloS One
Brad A Seibel, Bryan E Luu, Shannon N Tessier, Trisha Towanda, Kenneth B Storey
The pelagic red crab, Pleuroncodes planipes, is abundant throughout the Eastern Tropical Pacific in both benthic and pelagic environments to depths of several hundred meters. The oxygen minimum zones in this region reaches oxygen levels as low as 0.1kPa at depths within the crabs vertical range. Crabs maintain aerobic metabolism to a critical PO2 of ~0.27±0.2kPa (10°C), in part by increasing ventilation as oxygen declines. At subcritical oxygen levels, they enhance anaerobic ATP production slightly as indicated by modest increases in lactate levels...
December 27, 2017: Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology
Milan Sedliak, Michal Zeman, Gabriel Buzgó, Jan Cvecka, Dusan Hamar, Eugen Laczo, Monika Okuliarova, Marian Vanderka, Tomas Kampmiller, Keijo Häkkinen, Juha P Ahtiainen, Juha J Hulmi, Tormod S Nilsen, Håvard Wiig, Truls Raastad
It has been clearly established that maximal force and power is lower in the morning compared to noon or afternoon hours. This morning neuromuscular deficit can be diminished by regularly training in the morning hours. However, there is limited and contradictory information upon hypertrophic adaptations to time-of-day-specific resistance training. Moreover, no cellular or molecular mechanisms related to muscle hypertrophy adaptation have been studied with this respect. Therefore, the present study examined effects of the time-of-day-specific resistance training on muscle hypertrophy, phosphorylation of selected proteins, hormonal concentrations and neuromuscular performance...
December 28, 2017: Chronobiology International
Madhu Nagappa, Parayil S Bindu, Sanjib Sinha, Rose D Bharath, Mangalore Sandhya, Jitender Saini, Pavagada S Mathuranath, Arun B Taly
This case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature...
December 18, 2017: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
Li-Chao Wang, Dan Liu, Yong Jiang, Peng-Fei Tu, Ke-Wu Zeng
This study aims to investigate the targets and targets-involved mechanism for the macrophage activation of low molecular weight saccharides from Cistanche deserticola (LMSC). The phagocytic activity and NO release of RAW264.7 cells were detected, and results showed that LMSC exerts immune activation effect by significantly increasing the phagocytic activity and NO release. LMSC-conjugated epoxy-activated sepharose beads were prepared as affinity reagent to capture the target proteins. Twenty-four proteins such as Eef2 were identified by LC-MS/MS analysis...
October 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Jianling Xie, Kaikai Shen, Roman V Lenchine, Lee A Gethings, Paul J Trim, Marten F Snel, Ying Zhou, Justin W Kenney, Makoto Kamei, Marina Kochetkova, Xuemin Wang, Christopher G Proud
Eukaryotic elongation factor 2 kinase (eEF2K) negatively regulates the elongation phase of mRNA translation and hence protein synthesis. Increasing evidence indicates that eEF2K plays an important role in the survival and migration of cancer cells and in tumor progression. As demonstrated by two-dimensional wound-healing and three-dimensional transwell invasion assays, knocking down or inhibiting eEF2K in cancer cells impairs migration and invasion of cancer cells. Conversely, exogenous expression of eEF2K or knocking down eEF2 (the substrate of eEF2K) accelerates wound healing and invasion...
May 1, 2018: International Journal of Cancer. Journal International du Cancer
Liang Ouyang, Lan Zhang, Jie Liu, Leilei Fu, Dahong Yao, Yuqian Zhao, Shouyue Zhang, Guan Wang, Gu He, Bo Liu
Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells...
December 28, 2017: Journal of Medicinal Chemistry
Hikari Hayashi, Riku Nagai, Taisho Abe, Miki Wada, Koichi Ito, Nono Takeuchi-Tomita
The stress-related protein Stm1 interacts with ribosomes, and is implicated in repressing translation. Stm1 was previously studied both in vivo and in vitro by cell-free translation systems using crude yeast lysates, but its precise functional mechanism remains obscure. Using an in vitro reconstituted translation system, we now show that Stm1 severely inhibits translation through its N-terminal region, aa 1 to 107, and this inhibition is antagonized by eEF3. We found that Stm1 stabilizes eEF2 on the 80S ribosome in the GTP-bound form, independently of eEF2's diphthamide modification, a conserved post-translational modification at the tip of domain IV...
October 23, 2017: Journal of Biochemistry
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