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481.
Ilan Attali William Sam Tobelaim Avinash Persaud Khatereh Motamedchaboki Kobi J Simpson‐Lavy Bayan Mashahreh Olga Levin‐Kravets Tal Keren‐Kaplan Inbar Pilzer Martin Kupiec Reuven Wiener Dieter A Wolf Daniela Rotin Gali Prag 《The EMBO journal》2017,36(4):425-440
Ubiquitylation controls protein function and degradation. Therefore, ubiquitin ligases need to be tightly controlled. We discovered an evolutionarily conserved allosteric restraint mechanism for Nedd4 ligases and demonstrated its function with diverse substrates: the yeast soluble proteins Rpn10 and Rvs167, and the human receptor tyrosine kinase FGFR1 and cardiac IKS potassium channel. We found that a potential trimerization interface is structurally blocked by the HECT domain α1‐helix, which further undergoes ubiquitylation on a conserved lysine residue. Genetic, bioinformatics, biochemical and biophysical data show that attraction between this α1‐conjugated ubiquitin and the HECT ubiquitin‐binding patch pulls the α1‐helix out of the interface, thereby promoting trimerization. Strikingly, trimerization renders the ligase inactive. Arginine substitution of the ubiquitylated lysine impairs this inactivation mechanism and results in unrestrained FGFR1 ubiquitylation in cells. Similarly, electrophysiological data and TIRF microscopy show that NEDD4 unrestrained mutant constitutively downregulates the IKS channel, thus confirming the functional importance of E3‐ligase autoinhibition. 相似文献
482.
Keren Cohen Maayan Waldman Nader G. Abraham Michal Laniado-Schwartzman Danny Gurfield Dan Aravot Michael Arad Edith Hochhauser 《Experimental cell research》2017,350(1):147-153
Background
The db/db mouse is an animal model of diabetes in which leptin receptor activity is deficient resulting accelerated cardiomyopathy when exposed to angiotensin (AT). Toll-like receptors 4 and 2 (TLR4, TLR2) are pattern recognition receptors, that recognize pathogen-associated molecular patterns and exacerbate and release inflammatory cytokines. Fetuin A (Fet A) is a fatty acid carrier which affects inflammation and insulin resistance in obese humans and animals through TLRs.The aim of this study was to investigate the effect of caloric restriction (CR) on free fatty acids (FFA) level and the inflammatory response in diabetic cardiomyopathy.Methods and results
Left ventricular hypertrophy, increased fibrosis and leukocytes infiltration were observed in db/db AT treated hearts. Serum glucose, FFA, and cholesterol levels were elevated in db/db AT treated mice. Cardiac expression of PPARα increased while AKT phosphorylation was decreased.Conclusions
Cumulatively, CR elevated cardiac PPARα improved the utilization of fatty acids, and reduced myocardial inflammation as seen by reduced levels of Fet A. Thus CR negated cardiomyopathy associated with AT in an animal model of diabetes suggesting that CR is an effective therapeutic approach in the treatment of diabetes and associated cardiomyopathy. 相似文献483.
An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer
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484.
Ambrin Fatima Jan Hoeber Jens Schuster Eriko Koshimizu Carolina Maya-Gonzalez Boris Keren Cyril Mignot Talia Akram Zafar Ali Satoko Miyatake Junpei Tanigawa Takayoshi Koike Mitsuhiro Kato Yoshiko Murakami Uzma Abdullah Muhammad Akhtar Ali Rein Fadoul Loora Laan Casimiro Castillejo-Lpez Maarika Liik Zhe Jin Bryndis Birnir Naomichi Matsumoto Shahid M. Baig Joakim Klar Niklas Dahl 《American journal of human genetics》2022,109(3):542-546
485.
486.
Sigrid A. Lehnert Kate J. Wilson Keren Byrne Stephen S. Moore 《Marine biotechnology (New York, N.Y.)》1999,1(5):465-476
Expressed sequence tag data were generated from complementary DNA libraries created from cephalothorax, eyestalk, and pleopod
tissue of the black tiger shrimp (Penaeus monodon). Significant database matches were found for 48 of 83 nuclear genes sequenced from the cephalothorax library, 22 of 55 nuclear
genes from the eyestalk library, and 6 of 13 nuclear genes from the pleopod library. The putative identities of these genes
reflected the expected tissue specificity. For example, genes for digestive enzymes were identified from the cephalothorax
library and genes involved in the visual and neuroendocrine system from the eyestalk library. A few sequences matched anonymous
EST or genomic sequences, and others contained mini-satellite or microsatellite repeat sequences. The remainder, 31 from the
cephalothorax library, 25 from the eyestalk library, and 5 from the pleopod library, were sequences of high nucleotide complexity
with no matches in any database searched and thus may represent novel genes.
Received February 12, 1999; accepted April 13, 1999 相似文献
487.
488.
Gaofeng Zhu Ping Bai Keren Wang Jing Mi Jing Yang Jiaqi Hu Yujuan Ban Ran Xu Rui Chen Changning Wang Lei Tang Zhipei Sang 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):1375
Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC50 = 0.32, 0.56, 0.54, 0.73, and 0.86 μM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Aβ1-42 aggregation, and potent neuroprotective effect on Aβ1-42-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood–brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [11C]5f demonstrated that [11C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD. 相似文献
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490.
ObjectiveTo determine the prevalence of obesity and assess the cardiometabolic risk profile and treatments associated with obesity management in the type 1 diabetes mellitus adult population.MethodsWe reviewed the records of all patients with type 1 diabetes mellitus seen in our institution’s outpatient endocrinology clinic between 2015 and 2018. We stratified the patients into 4 weight categories on the basis of body mass index (BMI) (normal, overweight, obesity class I, and combined obesity class II and III) and evaluated their associated clinical characteristics and relevant medications.ResultsOf 451 patients, 64% had a BMI of >25 kg/m2, and 25% had a BMI of ≥30 kg/m2. Over 40% of patients with a BMI of >30 kg/m2 had a history of cardiovascular disease. The off-label use of the glucagon-like peptide 1 receptor agonist was 12% and the sodium glucose cotransporter 2 inhibitor use was 5% in those with obesity. Only 2 patients were prescribed phentermine and 3 had undergone bariatric surgery. Hemoglobin A1C and low-density lipoprotein did not significantly differ between the normal weight and obesity groups. The obesity groups had significantly higher levels of median triglycerides and lower high-density lipoprotein than the normal weight group.ConclusionObesity was prevalent in a population of patients with type 1 diabetes mellitus seen in a specialty clinic. Those with obesity had a higher prevalence of cardiovascular disease than their normal weight counterparts. The use of weight loss medications was scarce. Studies exploring the safety and efficacy of obesity-targeted therapy in the type 1 diabetes mellitus population are needed. 相似文献