Explore the vast range of titles available.

This study aimed to elucidate distinct cellular and immunological characteristics associated with chronic inflammatory conditions of the urinary bladder, including Hunner-type interstitial cystitis (HIC), bacillus Calmette–Guérin (BCG)-related cystitis, follicular cystitis (FC), and chronic bacterial cystitis (CBC). Transcriptomic analyses using next-generation RNA sequencing, along with quantitative polymerase chain reaction, were performed on mucosal bladder biopsies to assess the whole transcriptional and immune-response profiles. Furthermore, digital immunohistochemical quantification evaluated urothelial denudation and the densities of infiltrating immune cells, including T-lymphocytes, B-lymphocytes, mast cells, and plasma cells. HIC specimens exhibited a markedly distinct transcriptional profile, with 3,566 differentially expressed genes and enrichment of 116 biological processes particularly associated with microbial response and heightened autoimmunity with Th1/Th17 axis polarization. Histologically, HIC bladders demonstrated significant epithelial denudation, elevated IL-17-positive cell density, and increased plasma cell ratios compared to other cystitis types. No significant differences were observed in overall lymphoplasmacytic or mast cell densities, nor in B cell ratios among the groups. These findings underscore a unique immunopathological signature in HIC, characterized by plasma cell predominance within a Th1/17-polarized immune environment and epithelial denudation, offering new insights into its pathogenesis and therapeutic targeting.

Interstitial cystitis (IC) is an aseptic chronic bladder inflammation of unknown etiology and poorly understood pathophysiology with symptoms resembling bacterial cystitis (BC). There is limited data about the contribution of regulatory microRNAs (miRNAs) in IC. The study aimed to identify differences in miRNA expression between mouse models of IC and BC to find potential miRNAs that would distinguish between the two types of cystitis and to evaluate the use of the mouse model of IC as a tool to study the pathogenic mechanisms of IC in humans. Two mouse models were utilized: cyclophosphamide was used for induction of chronic aseptic cystitis, and uropathogenic E.coli for induction of acute bacterial cystitis. Potential regulatory miRNAs were selected based on publicly available human IC datasets and validated in mice. Quantitative PCR and RNA isolated from formalin-fixed, paraffin-embedded mouse bladder tissue were used. An enrichment analysis of the target mRNAs of the validated miRNAs was performed to suggest the differences in the possible mechanisms of inflammation between the IC and BC. We observed differential expression of 20 of the 33 selected miRNAs in IC and BC compared to the control group, with 11 miRNAs showing the same trend of expression between mouse and human IC. There are 8 common reporter-assay (RA) validated targets (performed by others) of these miRNAs in mouse and human. Histopathological analysis of mouse IC and BC urinary bladders, miRNA expression analysis, and expression of their validated targets revealed significant differences between the urinary bladders of BC and IC mouse models. We identified as a possible marker of discrimination between two types of cystitis and its target gene, nuclear factor-κB (NF-κB) suppressing factor ( ). Our results show that miRNA expression and its RA-validated targets, and enriched signaling pathways, differ between the two types of cystitis and might depend on the type of bladder inflammation. The mouse model of IC has some similarities with human IC, confirming that it is a useful tool to identify novel potentially discriminatory biomarkers between BC and IC, such as , and also potential therapeutic targets for IC (e.g., and NF-κB).

Andrey Rzhetsky and colleagues analyze electronic medical records from over one-third of the US population to estimate disease heritability and to determine the genetic and environmental contributions to disease variance. They obtain 84 new heritability estimates and find that the genetic correlation values for disease pairs differ from their environmental correlation values. In this study, we used insurance claims for over one-third of the entire US population to create a subset of 128,989 families (481,657 unique individuals). We then used these data to (i) estimate the heritability and familial environmental patterns of 149 diseases and (ii) infer the genetic and environmental correlations for disease pairs from a set of 29 complex diseases. The majority (52 of 65) of our study's heritability estimates matched earlier reports, and 84 of our estimates appear to have been obtained for the first time. We used correlation matrices to compute environmental and genetic disease classifications and corresponding reliability measures. Among unexpected observations, we found that migraine, typically classified as a disease of the central nervous system, appeared to be most genetically similar to irritable bowel syndrome and most environmentally similar to cystitis and urethritis, all of which are inflammatory diseases.

Aldehyde dehydrogenase 2 (ALDH2) serves an important role in regulating the development of organ injury. The present study aimed to investigate the effects of ALDH2 gene expression on the oxidative stress-mediated NF-κB/mTOR pathway in ketamine (Ket)-induced cystitis (KIC). Primarily, human bladder epithelial cells of the SV-HUC-1 cell line were divided into groups for incubation with different concentrations of Ket: 0, 0.5, 1, 1.5 and 2 mM. ALDH2 protein expression was then detected after 48 h of incubation with Ket. Subsequently, SV-HUC-1 cells were separated into a number of treatment groups, including: i) Control groups, comprising negative control (NC), NC + mTOR activator MHY1485 (Act), NC + Ket and NC + Ket + Act groups; ii) ALDH2 knockdown groups that were transfected with siRNA sequences targeting ALDH2 (si-ALDH2), including si-ALDH2, si-ALDH2 + Act, si-ALDH2 + Ket and si-ALDH2 + Ket + Act groups; and iii) ALDH2 overexpression (OE-ALDH2) transfection groups, comprising OE-ALDH2, OE-ALDH2 + Act, OE-ALDH2 + Ket and OE-ALDH2 + Ket + Act groups. The levels of apoptosis, oxidative stress and inflammatory protein expression were assessed in each group. The results of the present study demonstrated that ALDH2 protein expression was significantly higher after treatment with Ket compared with the control group. Further analysis revealed that the si-ALDH2 + Ket group demonstrated the highest levels of apoptosis, oxidative stress and inflammatory protein expression amongst all treatment groups. The levels of these indicators notably improved in the OE-ALDH2 + Ket group compared with the NC + Ket group. Therefore, the results of the present study revealed that ALDH2 overexpression reduced Ket-induced apoptosis, oxidative stress and inflammatory protein expression. Furthermore, co-treatment with Act was shown to mitigate these factors. Additionally, ALDH2 may have modulated the inflammatory response by promoting mTOR activation and inhibiting NF-κB phosphorylation. The present study concluded that ALDH2 may represent a novel target for KIC treatment.

Sensitization of primary afferents is essential for the development of pain, but the molecular events involved in this process and its reversal are poorly defined. Recent studies revealed that acid-sensing ion channels (ASICs) control the excitability of nociceptors in the urinary bladder. Using genetic and pharmacological tools we show that ASICs are functionally coupled with voltage-gated Ca2+ channels to mediate Ca2+ transients evoked by acidification in sensory neurons. Genetic deletion of Asic3 of these sensory neurons does not alter the mechanical response of bladder afferents to distension in naïve mice. Both control and sensory neuron conditional Asic3 knockout (Asic3-KO) mice with chemical cystitis induced by cyclophosphamide (CYP) administration exhibit frequent low volume voiding events. However, these changes are transient and revert over time. Of major significance, in Asic3-KO mice, CYP treatment results in the sensitization of a subset of bladder afferents and pelvic allodynia that persist beyond the resolution of the inflammatory process. Thus, ASICs function is necessary to prevent long-term sensitization of visceral nociceptors.

Background Hemorrhagic cystitis (HC), a frequent complication of hematopoietic stem cell transplantation (HSCT), significantly affects quality of life and may worsen prognosis. Mesenchymal stem cells (MSCs) are known for their anti-inflammatory and tissue-regenerative properties. IL-1 receptor antagonist (IL-1Ra) blocks IL-1α and IL-1β by binding IL-1 receptors, offering potential therapeutic benefits. The aim of this study was to explore the therapeutic effect of MSCs overexpressing IL-1Ra on HC and investigate the underlying mechanisms. Methods MSCs were isolated from human umbilical cord tissues, and IL-1Ra-overexpressing MSCs (oeIL-1Ra-MSCs) were generated using lentiviral transfections. HC was induced in rats by cyclophosphamide administration. Rats received tail vein injections of either oeIL-1Ra-MSCs or control MSCs (Mock-MSCs). Hematuria and bladder tissue changes were assessed using test strips and hematoxylin & eosin (HE) staining. Immunohistochemistry detected molecular changes in bladder tissues. Gene expression differences between the two MSC groups were analyzed by mRNA sequencing and ChIP techniques. Results Treatment with oeIL-1Ra-MSCs significantly alleviated hematuria and reduced bladder edema and hemorrhage, and reduced mRNA expression levels of IL-1β, IL-6, and TNF-α in bladder tissues, compared with those in the Mock-MSC treatment group. Immunohistochemical staining showed a higher presence of CD105-positive cells (a marker for human MSCs) and CD31-positive vessels in bladder tissues treated with oeIL-1Ra-MSCs, indicating enhanced MSC migration and vascular stability. In vitro migration assay demonstrated a higher migration capacity of IL-1Ra overexpressing MSCs compared with that of control MSCs. Moreover, angiopoietin-1 (Ang-1) expression increased, while Angiopoietin-2 (Ang-2) expression decreased in bladder tissues treated with oeIL-1Ra-MSCs, suggesting enhanced blood vessel stabilization. Conditioned medium from oeIL-1Ra-MSC cultures stimulated human umbilical vein endothelial cell (hUVEC) migration, proliferation, and angiogenesis more effectively compared with that in control MSCs. mRNA sequencing revealed elevated HtrA3 expression in oeIL-1Ra-MSCs compared with that in control MSCs. Molecular analysis suggested that IL-1Ra overexpression in MSCs upregulated HtrA3 expression through inhibition of the JNK-c-Jun pathway and activation of the ERK–Egr-1 pathway. Conclusion Overexpression of IL-1Ra significantly enhances the therapeutic efficacy of MSCs in HC by promoting MSC migration to damaged bladder tissues, suppressing inflammation, stabilizing blood vessels, and upregulating angiogenesis via activation of HtrA3 signaling pathways.

•There are a few reports on levofloxacin-induced TEN and the relationship between levofloxacin-induced TEN and genetic variants has not been investigated.•This is the first report of levofloxacin-induced TEN suspected to be caused by mutations in the HLA-B*1502 allele. To determine the relationship between HLA-B gene mutations and levofloxacin-induced toxic epidermal necrolysis (TEN). A 71-year-old Chinese woman developed TEN after oral administration of solifenacin (5 mg) and levofloxacin (0.5 g) for cystitis. HLA-B*5801 and HLA-B*1502 alleles were detected using real-time PCR. After supportive therapy (antiallergic treatments, plasma exchange, etc) and withdrawal of the culprit medication levofloxacin, the patient was discharged with re-epithelialization of the exfoliated skin. The patient was HLA-B*1502 allele positive and HLA-B*5801 allele negative. This is the first report of levofloxacin-induced TEN suspected to be caused by mutations in the HLA-B*1502 allele.

Small-conductance Ca 2+ -activated K + (SK) channels regulate neuronal excitability and act as a feedback mechanism to limit firing during sustained stimulation. In the present study, we demonstrated that SK2 plays an important role in the control of bladder function and visceral pain processing. SK2 channels are expressed in bladder-innervating afferent neurons, and ablation of this subunit results in elevated afferent firing rates in response to physiological levels of bladder distension, supporting a role for SK2 in modulating mechanosensory excitability. Mice overexpressing SK2 exhibit increased bladder capacity and reduced voiding frequency. Furthermore, overexpression of SK2 prevents the onset of pelvic mechanical allodynia and attenuates the exaggerated visceromotor response to bladder distension seen in wild-type mice with chemical cystitis. Thus, SK2 may be a promising target for treating overactive bladder and pain originating from the urinary bladder and other pelvic organs.

Although behavioral risk factors are strongly associated with urinary tract infection (UTI) risk, the role of genetics in acquiring this disease is poorly understood. To test the hypothesis that polymorphisms in Toll-like receptor (TLR) pathway genes are associated with susceptibility to UTIs, we conducted a population-based case-control study of women ages 18-49 years. We examined DNA variants in 9 TLR pathway genes in 431 recurrent cystitis (rUTI) cases, 400 pyelonephritis cases, and 430 controls with no history of UTIs. In the Caucasian subgroup of 987 women, polymorphism TLR4_A896G was associated with protection from rUTI, but not pyelonephritis, with an odds ratio (OR) of 0.54 and a 95% confidence interval (CI) of 0.31 to 0.96. Polymorphism TLR5_C1174T, which encodes a variant that abrogates flagellin-induced signaling, was associated with an increased risk of rUTI (OR(95%CI): 1.81 (1.00-3.08)), but not pyelonephritis. Polymorphism TLR1_G1805T was associated with protection from pyelonephritis (OR(95%CI): 0.53 (0.29-0.96)). These results provide the first evidence of associations of TLR5 and TLR1 variants with altered risks of acquiring rUTI and pyelonephritis, respectively. Although these data suggest that TLR polymorphisms are associated with adult susceptibility to UTIs, the statistical significance was modest and will require further study including validation with independent cohorts.

Tissue damage is usually regarded as a necessary price to pay for successful elimination of pathogens by the innate immune defense. Yet, it is possible to distinguish protective from destructive effects of innate immune activation and selectively attenuate molecular nodes that create pathology. Here, we identify acute cystitis as an Interleukin-1 beta (IL-1β)-driven, hyper-inflammatory condition of the infected urinary bladder and IL-1 receptor blockade as a novel therapeutic strategy. Disease severity was controlled by the mechanism of IL-1β processing and mice with intact inflammasome function developed a moderate, self-limiting form of cystitis. The most severe form of acute cystitis was detected in mice lacking the inflammasome constituents ASC or NLRP-3. IL-1β processing was hyperactive in these mice, due to a new, non-canonical mechanism involving the matrix metalloproteinase 7- (MMP-7). ASC and NLRP-3 served as transcriptional repressors of MMP7 and as a result, Mmp7 was markedly overexpressed in the bladder epithelium of Asc-/- and Nlrp3-/- mice. The resulting IL-1β hyper-activation loop included a large number of IL-1β-dependent pro-inflammatory genes and the IL-1 receptor antagonist Anakinra inhibited their expression and rescued susceptible Asc-/- mice from bladder pathology. An MMP inhibitor had a similar therapeutic effect. Finally, elevated levels of IL-1β and MMP-7 were detected in patients with acute cystitis, suggesting a potential role as biomarkers and immunotherapeutic targets. The results reproduce important aspects of human acute cystitis in the murine model and provide a comprehensive molecular framework for the pathogenesis and immunotherapy of acute cystitis, one of the most common infections in man. The clinical studies were approved by the Human Ethics Committee at Lund University (approval numbers LU106-02, LU236-99 and Clinical Trial Registration RTP-A2003, International Committee of Medical Journal Editors, www.clinicaltrials.gov).