Restoring the barrier of chronically damaged urothelium using chondroitin sulfate glycosaminoglycan-replenishment therapy

Current Opinion in Urology, Journal Year: 2023, Volume and Issue: 34(2), P. 44 - 51

Published: Nov. 14, 2023

Purpose of review This study aims to further understand the physiological mechanism chondroitin sulfate treatment on urinary bladder in cases inflammation, by investigating effect therapy recovery urothelial barrier an in-vitro chronic injury model. Recent findings With inflammatory conditions, seems decreased. Glycosaminoglycan (GAG) replacement is supposed help restore this barrier. Clinical studies conditions are complicated because heterogeneous patient population, hence need for preclinical models. Summary In a model using porcine cells, functional (TEER) and markers were assessed. Chronic damage was simulated through protamine instillations with without subsequent during 3 days. Chondroitin significantly improved TEER compared only (TEER difference 310 Ω.cm 2 , P < 0.001). consistent over days resulted significant higher mean value treated group (difference 1855 Enhanced other observed. shows promise facilitating damage. lends support use clinical GAG replenishment patients chronically impaired urothelium.

Language: Английский

---

Enhancing Therapeutic Efficacy and Safety of Immune Checkpoint Inhibition for Bladder Cancer: A Comparative Analysis of Injectable vs. Intravesical Administration

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(9), P. 4945 - 4945

Published: May 1, 2024

Bladder cancer (BC) presents a significant global health burden, characterized by high recurrence rates post-initial treatment. Gender differences in BC prevalence and response to therapy emphasize the importance of personalized treatment strategies. While Bacillus Calmette–Guérin (BCG) remains cornerstone therapy, resistance poses challenge, necessitating alternative Immune checkpoint inhibitors (ICIs) have shown promise, yet systemic toxicity raises concern. Intravesical administration ICIs offers potential solution, with recent studies demonstrating feasibility efficacy intravesical pembrolizumab. Although concern, its localized may mitigate adverse events. Additionally, liposomal delivery exhibits promises enhancing drug penetration reducing toxicity. Novel imaging modalities compatible Vesical Imaging-Reporting Data System (VI-RADS) capable predicting high-grade bladder can aid pre-operative shared decision making patient surgeon. Future research should focus on refining approaches, optimizing dosing regimens, leveraging advanced techniques improve outcomes. In conclusion, immunotherapy promising avenue for treatment, offering enhanced therapeutic effectiveness while minimizing Continued efforts are essential validate these findings optimize immunotherapy’s role management, ultimately improving

Language: Английский

---

The effect of antibiotic selection on collateral effects and evolvability of uropathogenic Escherichia coli

npj Antimicrobials and Resistance, Journal Year: 2024, Volume and Issue: 2(1)

Published: July 17, 2024

Abstract Trimethoprim is recommended as a first-line treatment of urinary tract infections (UTIs) in the UK. In 2018, 31.4% Escherichia coli isolated from UTIs England were trimethoprim-resistant, leading to overreliance on other first and second-line antibiotics. Here, we assessed whether, principle, prior selection with trimethoprim results collateral effects antibiotics for UTIs. As effects, considered changes susceptibility, mutation-selection window population establishment probability. We selected 10 trimethoprim-resistant derivatives three clinical isolates uropathogenic . found that mutations conferring resistance did not have any fosfomycin. contrast, resulted decreased susceptibility (collateral resistance) nitrofurantoin, below breakpoint narrowed window, thereby reducing maximum concentration nitrofurantoin mutations. Our analyses demonstrate multiple responses should be accounted when predicting optimising antibiotic use, limiting future antimicrobial emergence.

Language: Английский

---

3D-UHU-TU: A Three-Dimensional Bladder Cancer Model in a Healthy Urothelial Environment

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 24, 2024

Abstract Bladder cancer cases and fatalities continue to rise worldwide with treatment outcomes not improving in the last four decades. Poor translation of potential new therapies from pre- clinical studies clinic could be one reason behind this. The patient-derived xenograft (PDX) mouse is gold-standard for testing bladder therapies, but there are key physiological molecular differences between human bladders. Thus, more cell-based models may improve treatments. Here, we introduce a microtissue model called 3D U rine-tolerant Hu man rothelium-Tumour (3D-UHU-TU), which incorporates spheroids derived cell lines RT112 (low grade) T24 (high into previously published 3D-UHU healthy urothelial 100% urine environment. Both low- high-grade 3D- UHU-TU were characterised using immunofluorescence immunohistochemistry staining diagnostic markers (CK7, CK20 GATA3), cadherin (E- N-Cadherin), invasion migration (MMP-2 MMP-9) proliferation marker (Ki-67). expressed correct spatial areas. We also investigated utility both 3D-UHU-TU as platform test treatments, conventional chemotherapeutic Mitomycin C proof principle. After 2 hours 24 recovery, lysis nuclear damage observed high- grade spheroids, minimal surrounding urothelium. At higher doses, either disintegrated or reduced size, urothelium still intact. Taken together, novel, vitro safety efficacy Furthermore, our work lays foundation treatments on tumour personalised medicine approach.

Language: Английский

---

Oral ciprofloxacin biofilm activity in a catheter-associated urinary tract infection model

Journal of Antimicrobial Chemotherapy, Journal Year: 2024, Volume and Issue: 80(2), P. 413 - 426

Published: Nov. 29, 2024

Catheter-associated urinary tract infections (CA-UTIs) are a common hospital-acquired infection. We examined ciprofloxacin activity in novel CA-UTI vitro model. Three ATCC strains [Escherichia coli (ECO)-25922, Klebsiella pneumoniae (KPN)-700721, Pseudomonas aeruginosa (PAE)-27853] and 45 clinical isolates were assessed. Biofilm mass planktonic bacterial density quantified during drug-free incubation (72 h) following exposure (equivalent 750 mg orally q12h, 3 days). ECO produced smaller biofilms (6.3 ± 1.1 log10 cfu/cm2) compared with KPN (7.1 0.7 PAE (7.0 1.2 cfu/cm2), which extended along the entire catheter length. Following ciprofloxacin, all MIC > 4 mg/L had minimal biofilm disruption or kill. Ciprofloxacin resistance was most (10/16 isolates), (3/16 isolates) (6/16 isolates). Greater (AUC0-24/MIC) required for kill (5858; R2 = 0.7774) (2117; 0.7907) (2485; 0.8260). Due to persistent growth bladder, greater (5920; 0.8440) (2825; 0.9121) (1760; 0.8781). Monte Carlo simulation supported 95% PTA both ≤ 0.5 1 mg/L. In model, simulated therapy, comparatively more difficult disrupt, frequently persisted propensity emergence of resistance.

Language: Английский

---

In Vitro Bladder Cancer Models

Published: Jan. 1, 2024

---

Bacterial multispecies invasion of human epithelial bladder cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 17, 2023

Abstract Urinary tract infections (UTI) are one of the most common bacterial worldwide. While overall infection course is known on a macroscale, behavior not fully understood at cellular level and pathophysiology during multispecies well characterized. Here we establish co-infection models combined with high resolution imaging to compare single- multi-species bladder cell invasion events in three uropathogens: uropathogenic Escherichia coli (UPEC), Klebsiella pneumoniae Enterococcus faecalis . all species invaded cells, under flow conditions Gram-positive E. was significantly less invasive compared Gram-negative UPEC K. When introduced simultaneously an experiment, sometimes same cell, differing frequencies suggesting complex interactions between cells. Inside host observed encasement colonies specifically by UPEC. During subsequent dispersal from only bacteria underwent infection-related filamentation (IRF). Taken together, our data suggest that invasions single cells frequent support earlier studies showing intraspecies cooperation biochemical UTI.

Language: Английский

---