Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00544 - e00544

Published: Feb. 1, 2025

ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation activation survival signaling pathways, clinical trials have been initiated. More recently, has suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it a consequence direct binding the molecule α-synuclein. We studied mechanisms involved effects on aggregation using α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were real time quaking inducing conversion (RT-QuiC). Fasudil decreased number cells with inclusions size neurons glial cells, inhibited microglial endocytosis aggregates. These changes not due protein expression or phosphorylation related rather than interaction α-synuclein, confirmed second inhibitor (Y27632) gene silencing. observed that downregulates factors are known promote NADPH-oxidase-derived oxidative stress, intracellular calcium increase, endocytosis, promotes autophagy. The present results support useful drug Parkinson's disease progression. In addition reported neuroprotective properties, inhibits aggregates, which enhances inflammatory response. mostly inhibition, we shown two structurally different knockdown data, further supported by RT-QuiC.

Language: Английский

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Local urothelial cell-driven detrusor contractions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Abstract Signaling molecules released from the urothelium by mechanical stretch are known to play a sensory role in bladder contractions via neuronal signaling. It is also theorized that these could act locally induce urothelial cell-mediated local contractions. In this study, we specifically stimulated cells using optogenetics investigate how signaling can influence locally. Using an ex-vivo whole preparation, activating channelrhodopsin-2 (ChR2) with blue light and initiated The P2X receptor antagonist, PPADS, nearly abolished muscarinic atropine, significantly inhibited Nifedipine, which blocks extracellular Ca 2+ entry, G protein-coupled inhibitor YM-254890 Hemichannel carbenoxolone disodium exocytotic pathway of transmitter release brefeldin A showed significant inhibition conclusion, validated previous hypothesis factors without need for central nervous system. Further studies needed determine relevance normal physiology pathophysiologic conditions.

Language: Английский

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Comparisons of urinary bladder responses to common antimuscarinics reveals unique effects of darifenacin

Frontiers in Physiology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 20, 2025

Antimuscarinics are the first-line pharmaceutical treatment for overactive bladder (OAB). However, some literature suggests that responses to these antimuscarinics can influence a variety of non-muscarinic receptors. This study aimed identify any influences on contraction from commonly prescribed clinical using porcine detrusor or urothelium with lamina propria (U&LP) tissues. Porcine bladders were dissected into strips juvenile adult U&LP. Carbachol concentration-response curves performed paired tissues in absence presence antimuscarinics: darifenacin, fesoterodine, oxybutynin, solifenacin, trospium, and tolterodine. Estimated affinities each antimuscarinic calculated, maximum values control intervention compared. Experiments darifenacin (100 nM) completed serotonin µM), prostaglandin E2 (10 histamine αβ-methylene-ATP angiotensin II nM), neurokinin A (300 carbachol µM). Darifenacin significantly reduced preparations by 46%, 50%, 73%, 64%, 53%. U&LP 49% 35%. presents as an medication pathways urinary tissue, indicating its potential assist OAB patients pathophysiology.

Language: Английский

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The Role of microRNA in Overactive Bladder: Relationship and Clinical Correlation

Medicina, Journal Year: 2025, Volume and Issue: 61(3), P. 475 - 475

Published: March 8, 2025

Background and Objectives: This study aimed to determine the relationship between miRNAs overactive bladder (OAB). We also reveal diagnostic properties of their potential predict responses therapy. Materials Methods: The included 60 patients with OAB as treatment group healthy individuals control group. blood levels 15 in both groups were determined using PCR. Also, high values identified receiver operating characteristic (ROC) curves. Finally, Turkish-validated questionnaire form was filled out before after by participants In this way, score changes miRNA examined. Results: let-7a, let-7c, let-7e, let-7f, let-7g molecules higher, a level significance (p = 0.0001). Additionally, miR-135b, miR-300, miR-372, miR-373, miR-381, miR-520a, miR-520d, miR-520e found be statistically higher addition, let-7c (area under curve [AUC] 0.985) + miR-381 combination 1) highest ROC analysis. patient group, significant difference detected (let-7f miR-135b) clinical improvements 50% above score. Conclusions: may help elucidate pathophysiology OAB. They shed light on diagnosis evaluation effectiveness.

Language: Английский

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Inhibition of contractility of isolated caprine detrusor by the rho kinase inhibitor fasudil and reversal by the guanylyl cyclase inhibitor ODQ

Current Therapeutic Research, Journal Year: 2025, Volume and Issue: unknown, P. 100795 - 100795

Published: April 1, 2025

Language: Английский

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Hypoparathyroidism is associated with bladder dysfunction, a preliminary study

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 29, 2025

Language: Английский

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Rational computational design and development of an immunogenic multiepitope vaccine incorporating transmembrane proteins of Fusobacterium necrophorum

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: May 4, 2025

Fusobacterium necrophorum is a Gram-negative, anaerobic pathogen responsible for Lemierre's syndrome, bovine foot rot, and other necrotizing infections. The rise in antimicrobial resistance the absence of effective vaccines underscore need alternative therapeutic strategies. This study employs computational biology to design multi-epitope vaccine targeting transmembrane proteins F. elicit strong immune responses. selected were evaluated toxicity, allergenicity, antigenicity, followed by epitope prediction screening. B T cell epitopes linked using immunogenic linkers, forming construct with VaxiJen score 0.7293 solubility 8.30 E. coli. Structural validation TrRosetta Ramachandran plots confirmed 97.4% residues favored regions, indicating high stability. Population coverage analysis indicated over 99% global applicability, further enhancing its potential impact. Docking studies revealed interactions receptors TLR7 TLR8. formed 12 hydrogen bonds, while TLR8(A) 9, TLR8(B) exhibited highest interaction, 13 bonds construct. Molecular dynamics simulations structural stability receptor engagement. RMSD stabilized around 4-5 Å, Vaccine-TLR8(B) complex. Radius Gyration remained 36 showing slight compaction time, RMSF peaked at 8-9 Å flexible lower fluctuations (1.5-2.5 Å) stable core regions. Principal component (PCA) identified elastic regions critical biological activity, energy levels (-5000 kJ/mol) reliability binding. Moreover, expression coli, as demonstrated SnapGene software pET-29a( +) vector. binding affinities predicted activation both humoral cellular responses, including increased IgM, IgG, cytokine levels. However, experimental necessary confirm safety efficacy, challenges manufacturing variable responses across populations must also be addressed.

Language: Английский

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Multi-omic analysis revealed the therapeutic mechanisms of Alpinia oxyphylla fructus water extract against bladder overactivity in spontaneously hypertensive rats

Phytomedicine, Journal Year: 2023, Volume and Issue: 123, P. 155154 - 155154

Published: Oct. 18, 2023

Language: Английский

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Recent insights into pharmaceutical treatments for underactive bladder: a scoping review of recent studies

Australian and New Zealand Continence Journal, Journal Year: 2024, Volume and Issue: 30(1)

Published: March 1, 2024

Underactive bladder is a relatively prevalent condition, yet there only limited research into its diagnosis, treatment, and management. This has increased interest in researching novel treatments for underactive enhancing understanding of the underlying mechanisms presentation. The Preferred Reporting Items Systematic Reviews Meta-Analyses extension Scoping was followed as guiding outline. An priori protocol developed prior to commencement any searching or database assessment published online on Open Science Framework, after which PubMed searched articles over five-year period from 1 April 2018 2023. Thirty records were identified, with eight included scoping review. Most studies funded by industry, presenting risk considerable bias study design reporting. Overall, last five years, have not been new upcoming that present consistent evidence-based ability, across multiple articles, alleviate bladder. However, ongoing, some receptor systems may hold potential assist prevention disorder.

Language: Английский

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Antimuscarinic actions on bladder urothelium and lamina propria contractions are similar to those observed in detrusor smooth muscle preparations

Neurourology and Urodynamics, Journal Year: 2023, Volume and Issue: 42(5), P. 1080 - 1087

Published: March 28, 2023

Abstract Objectives Antimuscarinic medications are the first‐line treatments for overactive bladder, most common form of bladder dysfunction. Their primary action is thought to block detrusor muscarinic receptors. It unclear, however, if these therapeutics have actions on other tissues within lower urinary tract. This study assessed whether clinical antimuscarinics a functional impact urothelium with lamina propria (U&LP) tissue. Methods Strips porcine and U&LP were mounted in carbogen‐gassed Krebs‐bicarbonate solution at 37°C. The paired carbachol‐response curves performed absence or presence each antimuscarinic. pEC50 values curve analyzed estimated affinities calculated. Results Both contracted receptor stimulation, which was inhibited by commonly used antimuscarinics. In samples ( p < 0.001 all), right parallel shifts from control observed response oxybutynin (1 µM), solifenacin tolterodine darifenacin (100 nM), trospium nM) fesoterodine nM). shift consistent samples, no significant differences between two layers. Conclusions data suggests that as effective inhibiting tonic contractions they detrusor, presenting an alternate target treatment tract symptoms.

Language: Английский

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