Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 291 - 339
Published: Nov. 8, 2024
Language: Английский
Biomedicines, Journal Year: 2022, Volume and Issue: 10(2), P. 343 - 343
Published: Feb. 1, 2022
Despite recent leaps in modern medicine, progress the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents entry therapeutics into brain, and complexity processes, limits specificity potential therapeutics. Moreover, a lack etiological understanding irreversible nature conditions have resulted low tolerability high failure rates towards existing small molecule-based treatments. Neuropeptides, which are proteinaceous molecules produced by body, either nervous system or peripheral organs, modulate function. Although peptide-based originated from metabolic 1920s, adoption development peptide drugs for relatively recent. In this review, we examine natural roles neuropeptides modulation function disorders. Furthermore, highlight these filling gaps current
Language: Английский
Citations
33
Peptides, Journal Year: 2023, Volume and Issue: 167, P. 171048 - 171048
Published: June 28, 2023
Language: Английский
Citations
11
Journal of Tissue Engineering, Journal Year: 2022, Volume and Issue: 13
Published: Jan. 1, 2022
The blood-brain barrier (BBB) is the most specialized biological in body. This configuration of cells protects brain from invasion molecules and particles through formation tight junctions. To learn more about transport to brain, vitro modeling BBB continuously advanced. types models selected vary with goal each individual study, but same validation methods, quantification junctions, permeability assays are often used. With Transwells microfluidic devices, information regarding has been observed. Disease have developed examine effects on integrity. not only understand normal physiology, also create treatments for diseases. review will highlight several recent studies show diversity model selection many applications research.
Language: Английский
Citations
17
Physiological Reports, Journal Year: 2021, Volume and Issue: 9(5)
Published: March 1, 2021
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to be a world-wide pandemic with overwhelming socioeconomic impact. Since inflammation is one of the major causes COVID-19 complications, associated molecular mechanisms have been focus many studies better understand this and develop improved treatments for patients contracting SARS-CoV-2. Among these, strong emphasis has placed on pro-inflammatory cytokines, associating severity so-called "cytokine storm." More recently, peptide bradykinin, its dysregulated signaling or "bradykinin storm," emerged as primary mechanism explain COVID-19-related complications. Unfortunately, important development may not fully capture main players that underlie severity. To end, in focused review, several lines evidence are provided suggest addition two closely related vasoactive peptides, substance P neurotensin, also likely drive microvascular permeability inflammation, responsible pathology. Furthermore, based published experimental observations, it postulated ACE neprilysin, peptidase neurolysin (Nln) contribute accumulation progression disease. In conclusion, proposed "vasoactive storm" simultaneous inhibition all three peptidergic systems could therapeutically more advantageous rather than modulation any single alone.
Language: Английский
Citations
23
Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2022, Volume and Issue: 395(3), P. 275 - 283
Published: Jan. 28, 2022
Language: Английский
Citations
12
Chemical Science, Journal Year: 2023, Volume and Issue: 14(17), P. 4495 - 4499
Published: Jan. 1, 2023
We revealed higher neurolysin activity in the blood samples of patients with colorectal tumors, indicating that single-molecule is a promising candidate for biomarker cancer diagnosis.
Language: Английский
Citations
7
Current Neuropharmacology, Journal Year: 2024, Volume and Issue: 22(14), P. 2368 - 2383
Published: July 15, 2024
Stroke is a neurological disorder with high disability and mortality rates. Almost 80% of stroke cases are ischemic stroke, the remaining hemorrhagic stroke. The only approved treatment for thrombolysis and/or thrombectomy. However, these treatments cannot sufficiently relieve disease outcome, many patients remain disabled even after effective thrombolysis. Therefore, rehabilitative therapies necessary to induce remodeling in brain. Currently, stem cell transplantation, especially via use induced pluripotent cells (iPSCs), considered promising alternative therapy stimulating neurogenesis brain remodeling. iPSCs generated from somatic by specific transcription factors. biological functions similar those embryonic (ESCs), including immunomodulation, reduced cerebral blood flow, edema, autophagy. Although iPSC plays role both its application associated certain limitations. Tumor formation, immune rejection, survival, migration some concerns therapy. cell-free as an method can overcome This study reviews therapeutic models underlying mechanisms constraints cells. Moreover, using exosomes, apoptotic bodies, microvesicles discussed.
Language: Английский
Citations
2
Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(17), P. 12705 - 12722
Published: Aug. 26, 2021
Peptidase neurolysin (Nln) is an enzyme that functions to cleave various neuropeptides. Upregulation of Nln after stroke has identified the as a critical endogenous cerebroprotective mechanism and validated target for treatment ischemic stroke. Overexpression in mouse model results dramatic improvement outcomes, while pharmacological inhibition aggravates them. Activation therefore emerged intriguing drug discovery efforts Herein, we report hit-to-lead optimization first-in-class activators based on histidine-containing dipeptide hits from virtual screen. Adopting peptidomimetic approach provided lead compounds retain pharmacophoric histidine moiety possess single-digit micromolar potency over 40-fold greater than hit scaffolds. These exhibit 5-fold increased brain penetration, significant selectivity highly homologous peptidases, 65-fold increase stability, 'drug-like' fraction unbound brain.
Language: Английский
Citations
13
Pharmaceutical Research, Journal Year: 2022, Volume and Issue: 39(7), P. 1587 - 1598
Published: March 3, 2022
Language: Английский
Citations
9
Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2021, Volume and Issue: 379(2), P. 191 - 202
Published: Aug. 13, 2021
Neurolysin (Nln) is a recently recognized endogenous mechanism functioning to preserve the brain from ischemic injury. To further understand pathophysiological function of this peptidase in stroke and other neurologic disorders, present study was designed identify small molecule activators Nln. Using computational approach, structure Nln explored, which followed by docking silico screening ∼140,000 molecules National Cancer Institute Developmental Therapeutics Program database. Top ranking compounds were evaluated an enzymatic assay, two hit histidine-dipeptides studied detail. The identified dipeptides enhanced rate synthetic substrate hydrolysis recombinant (human rat) mouse brain–purified concentration-dependent manner (micromolar A50 Amax ≥ 300%) but had negligible effect on activity closely related peptidases. Both also substrates neurotensin, angiotensin I, bradykinin increased efficiency (Vmax/Km ratio) manner. competitive inhibitor dynorphin A (1-13) did not affect each other's affinity for Nln, suggesting differing nature their respective binding sites. Lastly, drug responsive target stability (DARTS) differential scanning fluorimetry (DSF) assays confirmed interaction with activator molecule. This first demonstrating that can be molecules, although peptidic low potency limit application. provide chemical scaffold develop high-potency, drug-like as research tools potential leads.
Language: Английский
Citations
11