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Amino Acid Therapy

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https://www.readbyqxmd.com/read/28644842/investigation-of-discriminant-metabolites-in-tamoxifen-resistant-and-choline-kinase-alpha-downregulated-breast-cancer-cells-using-1h-nuclear-magnetic-resonance-spectroscopy
#1
Hoe Suk Kim, Lianji Tian, Hyeonjin Kim, Woo Kyung Moon
Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown...
2017: PloS One
https://www.readbyqxmd.com/read/28642127/exploiting-sequence-and-stability-information-for-directing-nanobody-stability-engineering
#2
Patrick Kunz, Tilman Flock, Nicolas Soler, Moritz Zaiss, Cécile Vincke, Yann Sterckx, Damjana Kastelic, Serge Muyldermans, Jörg D Hoheisel
BACKGROUND: Variable domains of camelid heavy-chain antibodies, commonly named nanobodies, have high biotechnological potential. In view of their broad range of applications in research, diagnostics and therapy, engineering their stability is of particular interest. One important aspect is the improvement of thermostability, because it can have immediate effects on conformational stability, protease resistance and aggregation propensity of the protein. METHODS: We analyzed the sequences and thermostabilities of 78 purified nanobody binders...
June 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28641051/beneficial-role-of-citrus-fruit-polyphenols-against-hepatic-dysfunctions-a-review
#3
Md Mohabbulla Mohib, Kazi Afnan, Tasfiq Zaman Paran, Salma Khan, Juthika Sarker, Nahid Hasan, Istiaque Hasan, Md Abu Taher Sagor
Alcoholic liver diseases and virus-induced hepatic dysfunctions are prevalent in western countries. Evidence also suggests that hyperglycemia and insulin resistance are key players in the development of hepatic diseases and their complications. Since the comorbid diseases like obesity, diabetes and vascular dysfunctions primarily affect liver, the modern therapies against other hepatic dysfunctions are becoming a major challenge to treat. In addition to these, polypharmacy and adverse drug reactions (ADRs) are further aggravating the phenomenon...
June 22, 2017: Journal of Dietary Supplements
https://www.readbyqxmd.com/read/28637339/emergence-of-ceftazidime-avibactam-non-susceptibility-in-an-mdr-klebsiella-pneumoniae-isolate
#4
Anna Both, Henning Büttner, Jiabin Huang, Markus Perbandt, Cristina Belmar Campos, Martin Christner, Florian P Maurer, Stefan Kluge, Christina König, Martin Aepfelbacher, Dominic Wichmann, Holger Rohde
Background: Avibactam is a novel broad-range β-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment. Methods and results: Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I)...
June 16, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28633377/emerging-mechanisms-of-aminoacyl-trna-synthetase-mutations-in-recessive-and-dominant-human-disease
#5
Rebecca Meyer-Schuman, Anthony Antonellis
Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28631420/expression-of-pten-long-mediated-by-crispr-cas9-can-repress-u87-cell-proliferation
#6
Na Fang, Tingxuan Gu, Yahui Wang, Shuzhen Wang, Fengling Wang, Yang An, Wenqiang Wei, Weijuan Zhang, Xiangqian Guo, Adil J Nazarali, Shaoping Ji
PTEN is a tumour suppressor that is frequently mutated in a variety of cancers. Hence, PTEN has significant potential as a therapeutic molecule. PTEN-long is an alternative translation variant, with an additional 173 amino acids added to the N-terminal of the canonical PTEN when CUG of the mRNA is utilized as the start codon. PTEN-long is secreted into serum and can re-enter cells throughout the body. One of the major barriers for gene therapy is to efficiently and specifically deliver DNA or RNA material to target cells...
June 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28630259/triacylglycerol-mimetics-regulate-membrane-interactions-of-glycogen-branching-enzyme-implications-for-therapy
#7
Rafael Alvarez, Jesús Casas, David J López, Maitane Ibarguren, Ariadna Suari-Rivera, Silvia Terés, Francisca Guardiola-Serrano, Alexander Lossos, Xavier Busquets, Or Kakhlon, Pablo V Escribá
Adult Polyglucosan Body Disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE1-Y329S) yielding less branched, globular and soluble glycogen which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Since soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified wild-type and Y329S GBE1 proteins with different types of model membranes (liposomes)...
June 19, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28628737/analysis-of-structure-activity-relationships-based-on-the-hcv-sliib-ires-rna-targeting-gghyrfk-cu-complex
#8
Martin J Ross, Insiya Fidai, James Allan Cowan
New therapeutics for the targeting of the hepatitis C virus have been released in recent years. Although these therapies are less prone to resistance, they are still administered in cocktails as a combination of drugs targeting various aspects of the viral life cycle. Herein, we aim to contribute to an arsenal of new HCV therapeutics by targeting HCV internal ribosomal entry sequence (IRES) RNA via development of catalytic metallodrugs that function to degrade rather than inhibit the target molecule. Based on a previously characterized HCV IRES stem-loop IIb RNA-targeting metallopeptide Cu-GGHYrFK (1-Cu), an all L-analogue (3-Cu) and a series of additional complexes with single alanine substitutions in the targeting domain were prepared and screened to determine the influence each amino acid side-chain on RNA localization and recognition, and catalytic reactivity toward the RNA...
June 19, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28627685/metabolomic-analysis-based-on-1h-nuclear-magnetic-resonance-spectroscopy-metabolic-profiles-in-tuberculous-malignant-and-transudative-pleural-effusion
#9
Cheng Wang, Jingjin Peng, Yanling Kuang, Jiaqiang Zhang, Luming Dai
Pleural effusion is a common clinical manifestation with various causes. Current diagnostic and therapeutic methods have exhibited numerous limitations. By involving the analysis of dynamic changes in low molecular weight catabolites, metabolomics has been widely applied in various types of disease and have provided platforms to distinguish many novel biomarkers. However, to the best of our knowledge, there are few studies regarding the metabolic profiling for pleural effusion. In the current study, 58 pleural effusion samples were collected, among which 20 were malignant pleural effusions, 20 were tuberculous pleural effusions and 18 were transudative pleural effusions...
June 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28627455/gemcitabine-vitamin-e-conjugates-synthesis-characterization-entrapment-into-nanoemulsions-and-in-vitro-deamination-and-antitumor-activity
#10
Ahmed Abu-Fayyad, Sami Nazzal
Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the γ-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienol isomers of vitamin E can potentiate the anticancer activity of gemcitabine...
June 13, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28626523/antiobesity-effect-of-a-short-length-peptide-yy-analogue-after-continuous-administration-in-mice
#11
Naoki Nishizawa, Ayumu Niida, Yasushi Masuda, Satoshi Kumano, Kotaro Yokoyama, Hideki Hirabayashi, Nobuyuki Amano, Tetsuya Ohtaki, Taiji Asami
Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY3-36 and a 12-amino acid PYY analogue, benzoyl-[Cha(27,28,36),Aib(31)]PYY25-36 (1), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of 1 with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of 1, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp(24),Cha(27,28,36),Aib(31)]PYY23-36 (18), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY3-36...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28626166/efficacy-of-denosumab-for-osteoporosis-in-three-female-patients-with-osteogenesis-imperfecta
#12
Masashi Uehara, Yukio Nakamura, Jun Takahashi, Mikio Kamimura, Shota Ikegami, Takako Suzuki, Shigeharu Uchiyama, Tomomi Yamaguchi, Tomoki Kosho, Hiroyuki Kato
Osteogenesis imperfecta (OI) is an inherited bone disorder that causes fractures due to impaired production of collagen type I. In recent years, denosumab, a human monoclonal antibody against receptor activator of nuclear factor κB ligand (RANKL), has become widely used as an anti-osteoclastic agent for osteoporosis. This study investigated osteoporotic cases of OI to examine effects of denosumab on bone fragility. This was a retrospective, consecutive case series that included 3 female patients aged 42, 40, and 14 years, respectively...
2017: Tohoku Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28625715/discovery-of-simplified-leucyladenylate-sulfamates-as-novel-leucyl-trna-synthetase-lrs-targeted-mammalian-target-of-rapamycin-complex-1-mtorc1-inhibitors
#13
Suyoung Yoon, Jong Hyun Kim, Yura Koh, Phuong-Thao Tran, Jihyae Ann, Ina Yoon, Jayun Jang, Won Kyung Kim, Sangkook Lee, Jiyoun Lee, Sunghoon Kim, Jeewoo Lee
Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4-dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers...
June 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28622288/optimization-of-design-and-production-strategies-for-novel-adeno-associated-viral-display-peptide-libraries
#14
J Körbelin, A Hunger, M Alawi, T Sieber, M Binder, M Trepel
Libraries displaying random peptides on the surface of adeno-associated virus (AAV) are powerful tools for the generation of target-specific gene therapy vectors. However, for unknown reasons the success rate of AAV library screenings is variable and the influence of the production procedure has not been thoroughly evaluated. During library screenings, the capsid variants with the most favorable tropism are enriched over several selection rounds on a target of choice and identified by subsequent sequencing of the encapsidated viral genomes encoding the library capsids with targeting peptide insertions...
June 16, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28615649/andrographolide-ameliorates-inflammation-and-fibrogenesis-and-attenuates-inflammasome-activation-in-experimental-non-alcoholic-steatohepatitis
#15
Daniel Cabrera, Alexander Wree, Davide Povero, Nancy Solís, Alejandra Hernandez, Margarita Pizarro, Han Moshage, Javiera Torres, Ariel E Feldstein, Claudio Cabello-Verrugio, Enrique Brandan, Francisco Barrera, Juan Pablo Arab, Marco Arrese
Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-κB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid-defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week)...
June 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28611197/treatment-of-pancreatic-cancer-patient-derived-xenograft-panel-with-metabolic-inhibitors-reveals-efficacy-of-phenformin
#16
N V Rajeshkumar, Shinichi Yabuuchi, Shweta Pai, Elizabeth De Oliveira, Jurre J Kamphorst, Joshua D Rabinowitz, Héctor Tejero, Fatima Al-Shahrour, Manuel Hidalgo, Anirban Maitra, Chi V Dang
Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo anti-tumor efficacy of metabolic inhibitors in a panel of patient-derived PDAC xenograft models (PDXs), and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors. <p>Experimental Design: Mice with PDAC tumors from six to thirteen individual PDXs were randomized and treated, once daily for 4 weeks, with either PBS (vehicle) or the glutaminase inhibitor BPTES, transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), mitochondrial complex I inhibitor phenformin/metformin...
June 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28606519/folate-conjugated-thermosensitive-o-maleoyl-modified-chitosan-micellar-nanoparticles-for-targeted-delivery-of-erlotinib
#17
Marziyeh Fathi, Parham Sahandi Zangabad, Ayuob Aghanejad, Jaleh Barar, Hamid Erfan-Niya, Yadollah Omidi
In the present work, new self-assembled nanoparticles (NPs) were engineered using biocompatible and biodegradable natural polymer, chitosan (CS). The complexation of CS with sodium dodecyl sulfate (SDS) facilitated the regioselective chemical modification of CS hydroxyl groups with maleic anhydride, and produced polymerizable precursor of CS that was further grafted with N-isopropylacrylamide (NIPAAm) as temperature-sensitive moiety and oleic acid (OA) as hydrophobic monomer. After removal of SDS complex, the free amino groups were functionalized with folic acid (FA) to form folate-(PNIPAAm-co-OA)-g-CS micellar NPs...
September 15, 2017: Carbohydrate Polymers
https://www.readbyqxmd.com/read/28604565/droxidopa-for-symptomatic-neurogenic-hypotension
#18
Nadia Ferguson-Myrthil
Droxidopa is a first-in-class, orally available, synthetic amino acid precursor of norepinephrine that received accelerated Food and Drug Administration approval in February 2014 after Orphan Drug status for a debilitating condition known as symptomatic neurogenic orthostatic hypotension. Neurogenic disorders often lead to postural hypotension as a result of poor norepinephrine release from its storage sites. Clinical data suggest increases in standing systolic blood pressure and improvements in many other markers for subjective relief in patients with symptomatic neurogenic hypotension who received droxidopa therapy over 1-2 weeks...
May 4, 2017: Cardiology in Review
https://www.readbyqxmd.com/read/28598150/high-yield-site-specific-conjugation-of-fibroblast-growth-factor-1-with-monomethylauristatin-e-via-cysteine-flanked-by-basic-residues
#19
Michal Lobocki, Malgorzata Zakrzewska, Anna Szlachcic, Mateusz Adam Krzyscik, Aleksandra Sokolowska-Wedzina, Jacek Otlewski
Site-specific conjugation is a leading trend in the development of protein conjugates, including antibody-drug conjugates (ADCs), suitable for targeted cancer therapy. Here, we present a very efficient strategy for specific attachment of a cytotoxic drug to fibroblast growth factor 1 (FGF1), a natural ligand of FGF receptors (FGFRs), which are overexpressed in several types of lung, breast and gastric cancers and are therefore an attractive molecular target. Recently we showed that FGF1 fused to monomethylauristatin E (vcMMAE) was highly cytotoxic to cells presenting FGFRs on their surface and could be used as a targeting agent alternative to an antibody...
June 9, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28597811/mycobacterium-tuberculosis-in-the-face-of-host-imposed-nutrient-limitation
#20
Michael Berney, Linda Berney-Meyer
Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies...
June 2017: Microbiology Spectrum
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