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Mechanisms of Fibril Formation and Cellular Response
Published in Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin, XIth International Symposium on Amyloidosis, 2007
Martha Skinner, John L. Berk, Lawreen H. Connors, David C. Seldin
An N-terminal peptide containing residues 1-18 was found in the tryptic digest but with a 1-Da mass decrease compared with the theoretical mass calculated from the cDNA sequence. The MS/MS spectrum of this peptide showed that the modification occurs within the first three amino acid residues (Figure 2). By deducing the elemental composition corresponding to the m/z of the b3 ion, we proposed a possible chemical structure for this modification in which the N-terminal Glu was oxidatively deaminated to alpha-ketoglutaric acid. ESI-MS and MS/MS analyses also showed that Trp 94 was heavily oxidized. The unmodified Trp and its singly and doubly oxidized variants (hydroxytryptophan and N-formylkynurenine) were all found in the digest, with the singly oxidized form being the most abundant. In addition, both Asp and Asn were observed at position 49, suggesting that the asparagine residue has been partially deamidated. ECD experiments on a tryptic peptide containing Asp 49 confirmed this modification by detecting both aspartyl and isoaspartyl residues at this position. S-sulfonation at Cys 194 was observed in a tryptic peptide. We have observed S-sulfonation modification in other kappa light chains and transthyretin, and this PTM may play a role in making these proteins amyloidogenic. A peptide in the Lys-C digest was found containing two segments 191-207 and 208-214, but with a 30-Da mass increase, which agrees with the mass difference observed between the two major protein components at 23,170 and 23,200 Da in the reduced sample. This modification may come from the formation of a thiosulfonate linkage between an oxidized C-terminal Cys and a nearby Cys. Besides the b and y series, some fragment ions resulting from the linkage breakdown between two peptides (e*7+SO2, e*7+O2-H, e*7-SH2) were also observed, which support the thiosulfonate linkage between the two cysteine
Theories Related to Physical Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
In contrast to the profusion of data and, even more so, of theories about the biochemical-physiological basis of tolerance to and physical dependence on opioids, corresponding information for barbiturates, nonbarbiturate sedatives, and “minor tranquilizers” is remarkable for its paucity. Data on changes in pentylenetetrazol-seizure thresholds during chronic pentobarbital intoxication have been reviewed in connection with the “disuse supersensitivity” theory (second section of this chapter). Other data have recently been reviewed by Wikler and Essig.61 Among these are the results of a number of investigations by Essig, which may be summarized as follows. Ablation of the cerebellum does not alter the pattern or frequency of generalized seizures in dogs abruptly withdrawn from sodium barbital after a period of chronic intoxication.62 In contrast, after prior bilateral decortication, the daily dose level of barbital required for the occurrence of withdrawal seizures is elevated, and such seizures are altered in pattern, consisting of tonic extension of the extremities and generalized trembling, preceded by “sham rage.”63 Focal cortical lesions produced by injection of aluminum hydroxide into the cerebral cortex of dogs chronically intoxicated with barbital resulted in the occurrence of both generalized and focal, contralateral seizures (usually at different times) after abrupt withdrawal of the drug, suggesting that the focal and most of the generalized seizures developed in two separate functional systems.64 Neither d i ρ he η y 1 hy d a nt oin65 nor chlorpromazine 66 proved to be effective in reducing the frequency of barbital-withdrawal seizures in intact dogs. Nor did reserpine, iproniozid, hydrazine, scopolamine, alpha-methyl-DOPA, or a number of aminoacids exert any protective effects. However, amino-oxyacetic acid (AOAA), which inhibits GABA alpha-ketoglutaric acid transaminase and elevates GABA levels in the brain,67,68 significantly reduced the predictable number of barbital-withdrawal seizures as long as the substitution of AOAA was maintained. However, several of the animals died while receiving AOAA and the remaining dogs had seizures when administration of AOAA was discontinued.69 It appears to be doubtful, therefore, that barbiturate-withdrawal seizures are due to a “GABA deficiency” state; rather, the “protection” afforded by AOAA could have been related to its anticonvulsant properties67 in a nonspecific sense. The older literature on the effects of barbiturates upon cerebral oxidative metabolism, including “uncoupling” of oxidation from phosphorylation, was reviewed in extenso by Wikler,70 but at the present time, there seems to be little basis for relating such metabolic changes to physical dependence.
High alcohol-producing Klebsiella pneumoniae causes fatty liver disease through 2,3-butanediol fermentation pathway in vivo
Published in Gut Microbes, 2021
Nan-Nan Li, Wei Li, Jun-Xia Feng, Bing Du, Rui Zhang, Shu-Heng Du, Shi-Yu Liu, Guan-Hua Xue, Chao Yan, Jing-Hua Cui, Han-Qing Zhao, Yan-Ling Feng, Lin Gan, Qun Zhang, Wei-Wei Zhang, Di Liu, Chen Chen, Jing Yuan
To explore global metabolic alterations associated with alcohol induced during the development of hepatic steatosis, fecal metabolites in HiAlc Kpn-fed FLD mice and control mice at 4, 6, and 8 weeks were acquired as volatile organic compounds and analyzed by GC-MS (Figure S2, Table S3). Analysis of the metabolomic profiles in combination with principal component analysis revealed significant differences in metabolites among the HiAlc Kpn-fed, ethanol-fed, and pair-fed groups (Figure 4a, b). The ratio of metabolite peak intensity of the HiAlc Kpn-fed or ethanol-fed mice to the pair-fed mice was thus used as an indicator. A total of 18 main metabolites were significantly increased in HiAlc Kpn-fed or ethanol-fed mice, including urea, alcohols, sugars, amino acids, and acids (Figure 4a). Further analysis showed that these metabolites were all related to alcoholism, fatty metabolism, nitrogen metabolism, primary bile acid biosynthesis, butanoate metabolism, retrograde endocannabinoid signaling, and key pathways associated with alcohol production. Of special interest, we noticed that six main metabolites showed continuously elevated levels in HiAlc Kpn-fed mice, but not in ethanol-fed mice (Figure 4a). Three metabolites, including 2,3-butanediol (with the highest peak intensity), citric acid, and alpha-ketoglutaric acid, had higher concentrations in HiAlc Kpn-fed mice, but failed to be detected in ethanol-fed mice, suggesting that HiAlc Kpn could produce these metabolites as well as ethanol in vivo.
Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development
Published in Expert Review of Anticancer Therapy, 2020
Michael Ruff, Sani Kizilbash, Jan Buckner
Isocitrate dehydrogenase-1 (IDH-1) is a cytosolic NADP+-dependent enzyme involved in cellular metabolism, familiar to many from rote memorization of the (Kreb’s) citric-acid cycle. Somatic gain of function mutations in the IDH-1 (cytosolic) and IDH-2 (mitochondrial) genes initiate events in the majority of low-grade gliomas [30], whereas somatic IDH mutant mosaicism is seen in Ollier disease/Maffucci syndrome [31] and is associated with the formation of enchondromas, chondrosarcomas, glioma and spindle-cell hemangiomas. In its wild-type state, IDH normally functions to catalyze isocitric acid to alpha-ketoglutaric acid, while also producing NADPH, the reduced form of nicotinamide adenine dinucleotide phosphate. The canonical mutations are IDH-1 mutations, and the majority of these are R132 H mutations in which the highly conserved amino acid arginine (R7) in position 132 of the amino-acid sequence is substituted with histidine (H) in the binding site for isocitrate [30]. This substitution increases the function of the IDH mutation, which further catalyzes α-ketoglutarate to the pathogenic ‘onco-metabolite’ D-2-hydroxyglutarate (2-HG) while oxidizing NADPH to NADP+. The spectrum and significance of non-canonical IDH mutations comprise an ongoing field of study.
Glutaminase inhibitors: a patent review
Published in Expert Opinion on Therapeutic Patents, 2018
CanRong Wu, LiXia Chen, Sanshan Jin, Hua Li
Glutaminase has been considered as a ‘gate-keeper’ enzyme in glutamine metabolism. It is a mitochondrial amido-hydrolase enzyme that hydrolyzes glutamine to glutamate and ammonia [30,31]. Glutamate is deamidated by glutamate dehydrogenase (GDH) or transaminated by aspartate aminotransferase or alanine aminotransferase to produce alpha-ketoglutaric acid (α-KG), which is involved in the TCA cycle [17,32]. In actively proliferating cancer cells, the metabolism process of glutamine to lactate, also referred to ‘glutaminolysis’.