The role of intracellular calcium and Rho kinase pathways in G protein-coupled receptor-mediated contractions of urinary bladder urothelium and lamina propria

AJP Cell Physiology, Journal Year: 2023, Volume and Issue: 324(3), P. C787 - C797

Published: Jan. 23, 2023

The influence of extracellular and intracellular calcium on smooth muscle contractile activity varies between organs. In response to G protein-coupled receptor (GPCR) stimulation, the urinary bladder detrusor has shown a 70% dependence calcium, whereas urothelium lamina propria (U&LP) 20%-50% dependence. However, as this only accounts for partial activity, contribution sensitization pathways remains unclear. This study assessed role signaling GPCR-mediated U&LP contraction. Porcine responses activation Gq/11-coupled muscarinic, histamine, 5-hydroxytryptamine (serotonin), neurokinin, prostaglandin, angiotensin II receptors were with three selective inhibitors store-released 2-aminoethyl diphenylborinate (2-APB), cyclopiazonic acid (CPA), ruthenium red, Rho kinase inhibitors, fasudil, Y-27632, GSK269962. There was no discernible impact agonist-induced contractions after blocking pathways, suggesting that tissue is more sensitive alterations in availability calcium. an alternative mechanism action contraction identified be kinase, such when Y-27632 significantly reduced by approximately 50% (P < 0.05, n = 8). suggests do not involve significant release from stores, but causes via kinase. highlights key bladder, which may provide novel target future pharmaceutical management disorders.

Language: Английский

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Insulin receptor signaling engages bladder urothelial defenses that limit urinary tract infection

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114007 - 114007

Published: March 21, 2024

Urinary tract infections (UTIs) commonly afflict people with diabetes. To better understand the mechanisms that predispose diabetics to UTIs, we employ diabetic mouse models and altered insulin signaling show receptor (IR) shapes UTI defenses. Our findings are validated in human biosamples. We report mice have suppressed IR expression more susceptible UTIs caused by uropathogenic Escherichia coli (UPEC). Systemic inhibition increases UPEC susceptibility, while activation reduces UTIs. Localized deletion bladder urothelium promotes increasing barrier permeability suppressing antimicrobial peptides. Mechanistically, nuclear factor κB (NF-κB)-dependent programming co-regulates urothelial tight junction integrity Exfoliated cells or urine samples from youths of IR, genes, These observations demonstrate has a role prevention link maintenance peptide expression.

Language: Английский

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Somatic Mutation: What Shapes the Mutational Landscape of Normal Epithelia?

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(7), P. 1642 - 1655

Published: April 9, 2022

Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the cell niche persist to acquire further genome alterations. After a transient expansion, mutant must revert homeostatic behavior so normal tissue architecture is maintained. positively selected promote cancer development, whereas others inhibit carcinogenesis. Factors shape mutational landscape include wild-type dynamics, competition for niche, environmental exposures. Understanding processes give new insight into basis risk opportunities prevention. Recent advances in sequencing have found somatic all epithelial tissues studied date. Here we review how epithelia shaped by clonal within combined with genes are oncogenic, be inhibitory transformation. Discoveries this area leave many open questions, such as definition driver genes, mechanisms which constrain high proportion oncogenic cells, whether can modulated decrease risk.

Language: Английский

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Implantation of adipose-derived mesenchymal stem cell sheets promotes axonal regeneration and restores bladder function after spinal cord injury

Stem Cell Research & Therapy, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 12, 2022

Abstract Background Cell-based therapy using adipose-derived mesenchymal stem cells (ADSCs) is a promising treatment strategy for neurogenic bladder (NB) associated with spinal cord injury (SCI). However, therapeutic efficacy low because of inefficient cell delivery. Cell sheets improve the transplantation. Therefore, this study was conducted to investigate transplanting ADSC into an SCI rat model and focused on function pathological changes bladder. Methods were prepared from adipose tissue Sprague–Dawley (SD) rats temperature-responsive culture dishes. Adult female SD subjected by transection at T10 level administered or gelatin sponge (the control group). Four 8 weeks later, in vivo cystometrograms obtained voiding assessment. Rats sacrificed expression various markers analyzed tissues. Results The number β-tubulin III-positive axons sheet transplantation group higher than that group. Conversely, glial fibrillary acidic protein lower Cystometry showed impairment after SCI, which improved increased high-frequency oscillation activity. Furthermore, prevented disruption urothelium rats, thereby maintaining intact barrier. Compared fibrosis wall group, had normal morphology reduced as shown downregulation type 1 collagen. also resulted strong upregulation contractile smooth muscle (SMC) (α-smooth actin smoothelin) synthetic SMC (MYH10 RBP1). Conclusion significantly recovery SCI. delivery option NB related

Language: Английский

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Pathophysiological Mechanisms Involved in Overactive Bladder/Detrusor Overactivity

Current Bladder Dysfunction Reports, Journal Year: 2023, Volume and Issue: 18(2), P. 79 - 88

Published: Feb. 28, 2023

Abstract Purpose of Review To examine the latest published findings on pathophysiological mechanisms involved in development overactive bladder (OAB) and detrusor overactivity (DO), to identify common pathways linked risk factors associated with these conditions. Recent Findings Evidence is accumulating, both clinical experimental, that many OAB/DO, including ageing, outlet obstruction, psychological stress, obesity are reduced blood flow. This induces local tissue inflammation cytokine release enhanced oxidative ultimately resulting altered sensitivity, hypertrophy fibrosis, together afferent hypersensitivity. These would explain symptoms urgency frequency observed OAB patients. Although not a characteristic OAB, undetected low level bacterial infections have been proposed patients resistant standard treatments. In this condition, inflammatory responses without reductions perfusion activate pathways. Summary mounting poor central OAB/DO. As our understanding advances, new avenues for drug will be identified treatment may become more individualized depending particular pathway drugs available.

Language: Английский

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D-Mannose reduces cellular senescence and NLRP3/GasderminD/IL-1β-driven pyroptotic uroepithelial cell shedding in the murine bladder

Developmental Cell, Journal Year: 2023, Volume and Issue: 59(1), P. 33 - 47.e5

Published: Dec. 14, 2023

Language: Английский

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Disruption of circadian rhythm as a potential pathogenesis of nocturia

Nature Reviews Urology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 14, 2024

Language: Английский

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Innovative applications of natural polysaccharide polymers in intravesical therapy of bladder diseases

Carbohydrate Polymers, Journal Year: 2025, Volume and Issue: 354, P. 123307 - 123307

Published: Jan. 22, 2025

Language: Английский

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Application of microfluidic chips in the simulation of the urinary system microenvironment

Materials Today Bio, Journal Year: 2023, Volume and Issue: 19, P. 100553 - 100553

Published: Jan. 20, 2023

The urinary system, comprising the kidneys, ureters, bladder, and urethra, has a unique mechanical fluid microenvironment, which is essential to system growth development. Microfluidic models, based on micromachining tissue engineering technology, can integrate pathophysiological characteristics, maintain cell-cell cell-extracellular matrix interactions, accurately simulate vital characteristics of human microenvironments. Additionally, these models facilitate improved visualization integration meet requirements laminar flow environment system. However, several challenges continue impede development microenvironment with controllable conditions closely resemble physiological conditions. In this review, we describe biochemical physical explore feasibility microfluidic technology in simulating

Language: Английский

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Patient-derived bladder cancer organoid model to predict sensitivity and feasibility of tailored precision therapy

Current Urology, Journal Year: 2023, Volume and Issue: 17(4), P. 221 - 228

Published: July 20, 2023

Abstract Background Bladder cancer is a common and highly heterogeneous malignant tumor with relatively poor prognosis. Thus, personalized treatment strategies for bladder are essential improving patient outcomes. Materials methods We developed an efficient 3-dimensional in vitro organoid culture system organoids (BCOs), which maintains the homology original tumors heterogeneity between different individuals. In addition, we constructed chimeric antigen receptor (CAR)-T cells targeting B7H3 evaluated antitumor function of CAR-T by coculturing them BCOs. Results The BCOs closely resembled characteristics human were used to test individual sensitivity platinum-based drugs olaparib therapy. Coculture demonstrated specific recognition immune activation, indicating their potential immunotherapy. Conclusions Our study highlights facilitate development medicine improve efficiency drug discovery

Language: Английский

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