다중혈관 관상동맥 환자에서 y-문합을 이용하여 양쪽 내흉동맥만을 사용한 우회술의 조기 성적

https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00621-X.pdf

The Emerging Hallmarks of Cancer Metabolism

MYC on the Path to Cancer

Degeneration and regeneration of the nervous system

Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

Fundamentals of cancer metabolism

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP+, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate (5i) showed more potent antiproliferative activity than 6AN. Metabolite analysis revealed that compound 5i produced a marked increase in metabolites upstream of 6PGD, indicating intracellular inhibition of 6PGD by 6-amino-NADP+ derived from compound 5i through 6-aminonicotinic acid (6ANA) via the Preiss-Handler pathway. Despite the more potent pharmacological effects shown by compound 5i in A38-5, compound 5i was found to be substantially less toxic to primary hippocampal rat neurons compared to 6AN, indicating its therapeutic potential in targeting distant metastatic cells.

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma.

Reduced haloperidol (1) was previously reported to act as a potent sigma-1 receptor (S1R) ligand with substantially lower affinity to the dopamine D2 receptor (D2R) compared to haloperidol. It was also found to facilitate brain-derived neurotrophic factor (BDNF) secretion from astrocytic glial cell lines in a sigma-1 receptor (S1R)-dependent manner. Although an increase in BDNF secretion may have beneficial effects in some neurological conditions, the therapeutic utility of reduced haloperidol (1) is limited because it can be oxidized back to haloperidol in the body, a potent dopamine D2 receptor antagonist associated with well-documented adverse effects. A difluorinated analogue of reduced haloperidol, (±)-4-(4-chlorophenyl)-1-(3,3-difluoro-4-(4-fluorophenyl)-4-hydroxybutyl)piperidin-4-ol (2), was synthesized in an attempt to minimize the oxidation. Compound (±)-2 was found to exhibit high affinity to S1R and facilitate BDNF release from mouse brain astrocytes. It was also confirmed that compound 2 cannot be oxidized back to the corresponding haloperidol analogue in liver microsomes. Furthermore, compound 2 was distributed to the brain following intraperitoneal administration in mice and reversed the learning deficits in active avoidance tasks. These findings suggest that compound 2 could serve as a promising S1R ligand with therapeutic potential for the treatment of cognitive impairments. 

Synthesis and Pharmacological Characterization of a Difluorinated Analogue of Reduced Haloperidol as a Sigma-1 Receptor Ligand

Reducing the Level of Ethnocultural Tensions in Thailand: Transformation Through National Unity with Otherness

Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates.

/pdf/d-dopa-is-a-potent-orally-bioavailable-allosteric-inhibitor-3gflh30l.pdf

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

Described herein are high-throughput methods of monitoring D-serine levels in plasma. The assay involves the use of strong cation solid phase extraction (SPE) to isolate D-serine from plasma, followed by quantitation of D-serine using the D-amino acid oxidase- (DAAO-) catalyzed reaction. Also described are methods of screening for compounds that act as DAAO inhibitors.

Takashi Tsukamoto

Papers

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma.

Synthesis and Pharmacological Characterization of a Difluorinated Analogue of Reduced Haloperidol as a Sigma-1 Receptor Ligand

Reducing the Level of Ethnocultural Tensions in Thailand: Transformation Through National Unity with Otherness

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

High-throughput methods for determining pharmacological levels of plasma D-serine