Delving into the Latest Updates on PAG (University of Chicago) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

cystathionine gamma-lyase inhibitor (University of Chicago), L-PAG, L-propargylglycine

+ [1]

Target

CGL

Action

inhibitors

Mechanism

CGL inhibitors(cystathionine gamma-lyase inhibitors)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication

Sleep Wake Disorders

Inactive Indication-

Originator Organization

The University of Chicago

Active Organization

The University of Chicago

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

The aim of this study was to determine if remote ischemic per-conditioning (RIPerC) can provide protection to the kidneys from ischemia-reperfusion injury (IRI) by increasing the expression of the Gclc and Gclm genes involved in innate defenses. Rats undergoing sham surgery were used as controls. Induction of renal IRI involved blocking the renal pedicles for 60 min, then allowing 24 h of reperfusion. RIPerC involved 4 cycles (5 min) of limb I/R. Animals were divided into seven groups in a random manner: sham, I/R, I/R + RIPerC, I/R + NaHS (NaHS, 100 μmol /kg, i.p), I/R + RIPerC+NaHS, I/R + PAG (propargyl glycine, 50 mg/kg, i.p.) and I/R + RIPerC+PAG. Following reperfusion, samples of urine, blood, and renal tissue were gathered for functional, molecular, and histological analysis. Renal IRI impaired kidney function (reduced C_Cr, increased FE_Na, decreased water reabsorption, and reduced urine osmolality), increased oxidative stress (an increase in total oxidative status and a decrease in total antioxidant capacity), and reduced expression of CBS, CSE, Gclc and Gclm genes, causing tissue damage. RIPerC attenuated the IRI-induced kidney dysfunction, oxidative stress, and gene expression changes. Inhibiting hydrogen sulfide signaling with propargylglycine reduced the benefits of RIPerC, while the hydrogen sulfide donor NaHS enhanced them. These findings suggest RIPerC's renal protective effects involve upregulation of antioxidant defense pathways.

01 Aug 2025·Acta Physiologica

Hypotaurine Reduces Glucose‐Mediated Vascular Calcification

Article

Author: Gräber, Steffen ; Goettsch, Claudia ; Heuschkel, Marina A. ; Schurgers, Leon ; Jaminon, Armand ; Marx, Nikolaus ; Jankowski, Joachim ; Artati, Anna ; Jahnen‐Dechent, Willi ; Adamski, Jerzy

ABSTRACT:

Aim:

Vascular calcification (VC), a characteristic feature of peripheral artery disease in patients with diabetes and chronic kidney disease, has been associated with poor prognosis. We hypothesize that hyperglycemia drives VC through alterations in metabolomic and transcriptomic profiles.

Methods:

Human coronary artery smooth muscle cells (SMCs) were cultured with 0, 5.5, and 25 mM glucose under calcifying conditions. Untargeted metabolomic and transcriptomic analyses were performed at different time points. Mitochondrial respiration was examined using Seahorse analysis.

Results:

Glucose‐treated SMCs promoted extracellular matrix (ECM) calcification in a concentration‐ and time‐dependent manner. The absence of glucose entirely abolished SMC calcification but reduced SMC proliferation in control and calcifying conditions compared to 25 mM glucose. Multi‐omics data integration revealed key players from the hypotaurine/taurine metabolic pathway as the center hub of the reconstructed network. Glucose promoted the hypotaurine secretion, while its intracellular abundance was not altered. Blocking hypotaurine production by propargylglycine increased ECM calcification, while hypotaurine treatment prevented it. Furthermore, omics data suggest energy remodeling in calcifying SMCs under hyperglycemia. Calcifying SMCs exhibited decreased oxygen consumption that was partially restored by hypotaurine. Validation of our in vitro models using the murine warfarin model demonstrated reduced hypotaurine/taurine transporter (TAUT) expression in SMCs.

Conclusions:

Our multi‐omics analysis revealed a role of the hypotaurine/taurine metabolic pathway in glucose‐induced SMC calcification. Moreover, our data suggest a glucose‐dependent energy remodeling in calcifying SMCs and that increasing glucose concentrations fuel ECM calcification. Our work highlights potential novel therapeutic targets that warrant further investigation in hyperglycemia‐dependent in vitro SMC calcification.

01 Aug 2025·ANTICANCER RESEARCH

Methionine Deprivation-induced Cancer Cell Death and Methylation Changes in Key Genes and Gene Promoters of Prostate Cancer Cell Lines

Article

Author: Babu, Yatin Srinivash Ramesh ; Venkatachalam, Kallidaikurichi V

BACKGROUND/AIM:

While normal cells are highly regulated, cancer cells take a dysregulated path which bolsters their survival. Currently, a limited number of uniform treatments are available for cancer cure. Our goal was to deprive cancer cells of the key nutrient methionine and determine what effect it would have on cell death and alterations in DNA methylation of prostate cancer cells.

MATERIALS AND METHODS:

PC3 and other cell lines were transfected with plasmid gene constructs for methionine gamma lyase deaminase (MEGL), a methionine-degrading enzyme, targeted for expression in the cytoplasm (cMEGL) or the nucleus (nMEGL). For assessing cell death due to MEGL-mediated methionine deprivation, a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used. PC3, and DU145 prostate cancer cells were selected for whole-methylome sequencing to determine the effects of MEGL expression. Key gene products comprising the Prolaris Molecular Score, specifically 31 cell-cycle progression genes, were chosen for assessing putative differences in methylome.

RESULTS:

Treatment with MEGL gene targeted for expression in either the cytoplasm or nucleus caused significant cell death, similar to that due to the anticancer drug methotrexate. Azacytidine showed no effect on PC3 cell death. Propargylglycine, an inhibitor of MEGL, prevented cell death. Methylome analysis showed increased methylation of two genes: Spindle and kinetochore-associated complex subunit 1 (SKA1), origin recognition complex subunit 6 (ORC6L), and reduced methylation of six promoters: BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B), PDZ binding kinase (PBK), baculoviral IAP repeat-containing 5 (BIRC5), centromere protein M (CENPM), DNA topoisomerase II alpha (TOP2A), minichromosome maintenance 10 replication initiation factor (MCM10), upon forced expression of MEGL.

CONCLUSION:

Methionine deprivation through MEGL-targeted gene therapy may be a viable option for inducing cancer cell death compared to unrestricted levels of methionine.

100 Deals associated with PAG (University of Chicago)

Login to view more data