更新于：2024-11-01

MetP

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 MetP 相关的药物

SYNB-1353

靶点

MetDC x MetP

作用机制

MetDC刺激剂 [+3]

在研机构

Synlogic, Inc.

原研机构

Synlogic, Inc.

在研适应症

同型半胱氨酸尿症

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 MetP 相关的临床试验

NCT05462132 / Completed临床1期

A Phase 1, Dose-escalation, Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, and Pharmacodynamics of SYNB1353 in Healthy Volunteers

This is a Phase 1, double-blind (Sponsor-open), placebo-controlled, randomized, dose-escalation, inpatient study using a multiple-ascending dose (MAD) design to assess the safety, tolerability, and PD of SYNB1353 in HVs.

开始日期2022-07-07

申办/合作机构

Synlogic, Inc.

100 项与 MetP 相关的临床结果

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100 项与 MetP 相关的转化医学

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0 项与 MetP 相关的专利（医药）

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项与 MetP 相关的文献（医药）

2021-12-01·Arthritis Research & Therapy2区 · 医学

Lactate oxidative phosphorylation by annulus fibrosus cells: evidence for lactate-dependent metabolic symbiosis in intervertebral discs

2区 · 医学

ArticleOA

作者: Vo, Nam ; Han, Chao ; Wang, Dong ; Roginskaya, Vera ; Wendell, Stacy G ; Jurczak, Michael J ; Couch, Brandon ; Malkamaki, Matias ; Zhou, Chao-Ming ; Hartman, Robert ; Kang, James ; Sowa, Gwendolyn ; Van Houten, Bennett ; Mullett, Steven J ; Lee, Joon

AbstractBackgroundIntervertebral disc degeneration contributes to low back pain. The avascular intervertebral disc consists of a central hypoxic nucleus pulpous (NP) surrounded by the more oxygenated annulus fibrosus (AF). Lactic acid, an abundant end-product of NP glycolysis, has long been viewed as a harmful waste that acidifies disc tissue and decreases cell viability and function. As lactic acid is readily converted into lactate in disc tissue, the objective of this study was to determine whether lactate could be used by AF cells as a carbon source rather than being removed from disc tissue as a waste byproduct.MethodsImport and conversion of lactate to tricarboxylic acid (TCA) cycle intermediates and amino acids in rabbit AF cells were measured by heavy-isotope (13C-lactate) tracing experiments using mass spectrometry. Levels of protein expression of lactate converting enzymes, lactate importer and exporter in NP and AF tissues were quantified by Western blots. Effects of lactate on proteoglycan (35S-sulfate) and collagen (3H-proline) matrix protein synthesis and oxidative phosphorylation (Seahorse XFe96 Extracellular Flux Analyzer) in AF cells were assessed.ResultsHeavy-isotope tracing experiments revealed that AF cells imported and converted lactate into TCA cycle intermediates and amino acids using in vitro cell culture and in vivo models. Addition of exogenous lactate (4 mM) in culture media induced expression of the lactate importer MCT1 and increased oxygen consumption rate by 50%, mitochondrial ATP-linked respiration by 30%, and collagen synthesis by 50% in AF cell cultures grown under physiologic oxygen (2-5% O2) and glucose concentration (1-5 mM). AF tissue highly expresses MCT1, LDH-H, an enzyme that preferentially converts lactate to pyruvate, and PDH, an enzyme that converts pyruvate to acetyl-coA. In contrast, NP tissue highly expresses MCT4, a lactate exporter, and LDH-M, an enzyme that preferentially converts pyruvate to lactate.ConclusionsThese findings support disc lactate-dependent metabolic symbiosis in which lactate produced by the hypoxic, glycolytic NP cells is utilized by the more oxygenated AF cells via oxidative phosphorylation for energy and matrix production, thus shifting the current research paradigm of viewing disc lactate as a waste product to considering it as an important biofuel. These scientifically impactful results suggest novel therapeutic targets in disc metabolism and degeneration.

2020-09-18·Infection and Immunity2区 · 医学

Genome-Wide Assessment of Streptococcus agalactiae Genes Required for Survival in Human Whole Blood and Plasma

2区 · 医学

Article

作者: Waller, Andrew S. ; Zhu, Luchang ; Ojeda Saavedra, Matthew ; Musser, James M. ; Yerramilli, Prasanti ; Cantu, Concepcion C. ; Pruitt, Layne ; Beres, Stephen B. ; Olsen, Randall J.

2017-06-01·Seminars in Oncology3区 · 医学

Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma

3区 · 医学

Article

作者: Gooptu, Mahasweta ; Fratamico, Roberto ; Leiby, Benjamin ; Caro, Jaime ; Martinez-Outschoorn, Ubaldo ; Dulau-Florea, Alina ; Uppal, Guldeep ; Gong, Jerald ; Sprandio, John ; Whitaker-Menezes, Diana ; Domingo-Vidal, Marina ; Lin, Zhao

Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL.