Diroximel fumarate acts through Nrf2 to attenuate methylglyoxal-induced nociception in mice and decreases ISR activation in DRG neurons DOI Creative Commons
Muhammad Saad Yousuf,

Marisol Mancilla Moreno,

Jiahe Li

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 23, 2023

Abstract Diabetic neuropathic pain is associated with elevated plasma levels of methylglyoxal (MGO). MGO a metabolite glycolysis that causes mechanical hypersensitivity in mice by inducing the integrated stress response (ISR), which characterized phosphorylation eukaryotic initiation factor 2α (p-eIF2α). Nuclear erythroid 2-related 2 (Nrf2) transcription regulates expression antioxidant proteins neutralize MGO. We hypothesized activating Nrf2 using diroximel fumarate (DRF) would alleviate MGO-induced hypersensitivity. pretreated male and female C57BL/6 daily oral DRF prior to intraplantar injection (20 ng). (100 mg/kg) treated animals were protected from developing cold Using knockout we demonstrate necessary for anti-nociceptive effects DRF. In cultured mouse human dorsal root ganglion (DRG) sensory neurons, found induced p-eIF2α. Co-treatment (1 µM) monomethyl (MMF, 10, 20, 50 µM), active DRF, reduced p-eIF2α prevented aberrant neurite outgrowth DRG neurons. Our data show targeting system strategy potentially levels. Perspective This study demonstrates prevents development caused reduces ISR vitro models. propose activators like should be tested diabetic patients. Graphical Article Highlights induces pre-treatment does not protect Nrf2-knockout suggesting DRF’s antinociceptive effects. MMF, increase p-eIF2a neurons . MMF activators, FDA-approved an option patients diabetes.

Язык: Английский

ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans DOI Creative Commons
Eric T. David,

Muhammad Saad Yousuf,

Hao-Ruei Mei

и другие.

Pharmacological Research, Год журнала: 2024, Номер 206, С. 107284 - 107284

Опубликована: Июнь 25, 2024

Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in tissues synovium of rheumatoid osteoarthritis patients, indicating the clinical significance this signaling. The primary goal study was to understand how acts on mouse human neurons, which express receptors, nociceptor plasticity. We hypothesized that would plasticity hyperalgesic priming MNK-eIF4E signaling, a critical mechanism for nociceptive induced growth factors, cytokines nerve injury. Both male female mice developed dose-dependent mechanical hypersensitivity response ephrin-B2, both sexes showed when challenged with PGE

Язык: Английский

Процитировано

5
Structure-Affinity relationships of novel σ2R/TMEM97 ligands DOI
Grant D. Walby, Qi Gu, Hongfen Yang

и другие.

Bioorganic Chemistry, Год журнала: 2024, Номер 145, С. 107191 - 107191

Опубликована: Фев. 10, 2024

Язык: Английский

Процитировано

3
TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis DOI Creative Commons
Jing Li,

Yosuke Nagasaka,

Hongtao Shen

и другие.

Molecular Therapy — Nucleic Acids, Год журнала: 2025, Номер 36(1), С. 102460 - 102460

Опубликована: Янв. 21, 2025

Язык: Английский

Процитировано

0
Isolation and Bioassay of Linear Veraguamides from a Marine Cyanobacterium (Okeania sp.) DOI Creative Commons

Stacy‐Ann J. Parker,

Andrea Hough,

Thomas D. Wright

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation two new, veraguamide O ( 1 ) P 2 ), one known, C( 3 analogs isolated from cyanobacterial collection made Las Perlas Archipelago Panama. We hypothesized that these compounds would be cytotoxic cancer cell lines. The were screened against HEK-293, estrogen receptor positive (MCF-7), triple-negative breast (MDA-MB-231) cells well broad panel membrane bound receptors. planar structures determined based on NMR MS data along with comparison to previously analogs. Phylogenetic analysis suggests it an Okeania sp., similar species cyanobacterium reported produce other veraguamides. Veraguamide shows no cytotoxicity (greater than 100 M) ER (MCF-7) 13 M IC 50 MDA-MB-231 TNBC cells. Interestingly, show affinity for sigma2/TMEM-97 making them potential leads development non-toxic sigma targeting ligands.

Язык: Английский

Процитировано

0
Isolation and Bioassay of Linear Veraguamides from a Marine Cyanobacterium (Okeania sp.) DOI Creative Commons

Stacy‐Ann J. Parker,

Andrea Hough,

Thomas D. Wright

и другие.

Molecules, Год журнала: 2025, Номер 30(3), С. 680 - 680

Опубликована: Фев. 4, 2025

Marine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation two new (veraguamide O (1) veraguamide P (2)) one known C (3)) analogs isolated from cyanobacterial collection made Las Perlas Archipelago Panama. We hypothesized that these compounds would be cytotoxic cancer cell lines. The were screened against HEK-293, estrogen receptor positive (MCF-7), triple-negative breast (MDA-MB-231) cells well broad panel membrane-bound receptors. planar structures determined based on NMR MS data along with comparison to previously analogs. Phylogenetic analysis suggests it an Okeania sp., similar species cyanobacterium reported produce other veraguamides. Veraguamide shows no cytotoxicity (greater than 100 μM) ER-positive (MCF-7) 13 μM IC50 MDA-MB-231 TNBC cells. Interestingly, show affinity for sigma2/TMEM-97 receptor, making them potential leads development non-toxic sigma 2 targeting ligands.

Язык: Английский

Процитировано

0
Recent Advances in the Development of Sigma Receptor (Radio)Ligands and Their Application in Tumors DOI Creative Commons
Tao Wang, Na Sun, Yuefeng Ma

и другие.

ACS Pharmacology & Translational Science, Год журнала: 2025, Номер 8(4), С. 951 - 977

Опубликована: Март 7, 2025

Cancer ranks among the top triumvirate leading causes of human deaths worldwide. The pathological mechanisms are notably intricate, demonstrating proliferative and metastatic capabilities, which complicate therapeutic interventions. sigma-1 receptor (σ1R) plays a crucial role in tumor survival migration, while sigma-2 (σ2R) is intimately associated with proliferation. This review encapsulated investigation concerning σ1R σ2R neoplasms rigorously summarized ligands radio-ligands development their applications, such as antitumor cell proliferation PET/SPECT imaging tumors. A comprehensive classification discussion was undertaken regarding chemical structures emphasized possibility dual/multitargeted ligands. Ultimately, we discussed effects chiral pharmacological characteristics on affinity pharmacokinetic features vivo, particularly radiopharmaceuticals. functions beneficial resource, fostering ligand deployment stimulating generation innovative ideas for developing

Язык: Английский

Процитировано

0
Discovery of Iboga-Derived Ligands for the Sigma-2 Receptor DOI Creative Commons
Alexander J. Hughes,

Julie A. Talbert,

Steven D. Townsend

и другие.

ACS Bio & Med Chem Au, Год журнала: 2025, Номер unknown

Опубликована: Май 12, 2025

Язык: Английский

Процитировано

0
Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine expression DOI Creative Commons
Jing Li, Hongtao Shen, Lian‐Wang Guo

и другие.

Cellular Signalling, Год журнала: 2024, Номер 116, С. 111069 - 111069

Опубликована: Янв. 28, 2024

Язык: Английский

Процитировано

2
Loss of Sigma-2 Receptor/TMEM97 Is Associated with Neuropathic Injury-Induced Depression-Like Behaviors in Female Mice DOI Creative Commons
Veronica M. Hong,

Avaneesh Rade,

Shen M. Yan

и другие.

eNeuro, Год журнала: 2024, Номер 11(7), С. ENEURO.0488 - 23.2024

Опубликована: Июнь 12, 2024

Previous studies have shown that ligands bind to sigma-2 receptor/TMEM97 (s 2 R/TMEM97), a transmembrane protein, anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest s R/TMEM97, little affective pain behavioral characterization has been done using transgenic mice, which limits the development of R/TMEM97 as viable therapeutic target. Using wild-type (WT) global Tmem97 knock-out (KO) we sought identify contribution modulating behaviors battery assays, including open field, light/dark preference, elevated plus maze, forced swim test, tail suspension mechanical sensitivity tests. Our results demonstrate female KO mice show less anxiety-like depressive-like preference tests but not an at baseline. We next performed spared nerve injury WT assess role pain-induced anxiety depression. developed prolonged phenotype when tested 10 weeks after females. plays naive animals with significant change presence mice. Overall, these data could be target alleviate comorbidities disorders.

Язык: Английский

Процитировано

2
Recent Developments in Sigma-2 Receptor Compounds for Pain DOI Open Access

Robert B. Raffa,

Joseph V. Pergolizzi

Cureus, Год журнала: 2024, Номер unknown

Опубликована: Май 8, 2024

After years of enigmatic pharmacology, non-selective ligands, and uncertain clinical application, sigma receptors have emerged as interesting therapeutic drug discovery-development targets. Two subtypes now been cloned, sigma-1 receptor (S1R) sigma-2 (S2R), there has much complementary converging information from advances in molecular biology, computer modeling, virtual screening, vitro vivo testing. One several evolving areas potential is for the treatment pain. In particular, accumulating recent evidence preclinical models that demonstrated positive effects S2R compounds these suggest possible implications effectiveness against pains a neuropathic component. Such pain conditions imperfect options currently. The addition new drugs to available armamentarium would represent very significant advance large number patients who suffer types intractable Further research needed identify characterize not only good activity but also characteristics enter trials. Here, we summarize some reports analgesic compounds.

Язык: Английский

Процитировано

1