Recurrent urinary tract infection genetic risk: a systematic review and gene network analysis.

INTRODUCTION AND HYPOTHESIS: The development of recurrent urinary tract infections (rUTIs) is not completely understood. This review is aimed at investigating the connection between genetics and rUTIs and summarizing the results of studies that have documented variations in gene expression among individuals with rUTIs compared with healthy individuals. METHODS: A systematic search was conducted in Cochrane, Ovid, and PubMed, limiting the results to articles published between 1 January 2000, and 5 July 2022. Only studies comparing the difference in gene expression between individuals with rUTI and healthy individuals utilizing molecular techniques to measure gene expression in blood or urine samples were included in this systematic review. Gene network and pathways analyses were performed using Cytoscape software, with input data obtained from our systematic review of differentially expressed genes in rUTIs. RESULTS: Six studies met our criteria for inclusion. The selected studies used molecular biology methods to quantify gene expression data from blood specimens. The analysis revealed that gene expressions of CXCR1 and TLR4 decreased, whereas CXCR2, TRIF, and SIGIRR increased in patients with rUTI compared with healthy controls. The analysis demonstrated that the most significant pathways were associated with TLR receptor signaling and tolerance, I-kappa B kinase/NF-kappa B signaling, and MyD88-independent TLR signaling. CONCLUSIONS: This systematic review uncovered gene expression variations in several candidate genes and identified a number of underlying biological pathways associated with rUTIs. These findings could shift the treatment and prevention strategies for rUTIs.

A systematic review and in silico study of potential genetic markers implicated in cases of overactive bladder.

OBJECTIVE: The contribution of genetic factors to the presence of an overactive bladder is recognized. This study aimed to (1) assemble and synthesize available data from studies assessing differential gene expression in patients with overactive bladder vs controls without overactive bladder and (2) determine possible correlations and functional pathways between genes. DATA SOURCES: We searched PubMed, Ovid or Medline, and Wiley Cochrane Central Register of Controlled Trials databases between January 1, 2000, and December 15, 2021. STUDY ELIGIBILITY CRITERIA: Studies were included if gene expression was detected and quantified using molecular approaches performed on human bladder tissue specimens directly and excluded if the gene expression analysis was carried out from blood and urine specimens alone. METHODS: A systematic review was completed to identify publications that reported differently expressed gene candidates among patients with overactive bladder vs healthy individuals. Gene networking connections and pathway analysis were performed employing Metascape software, where inputs were identified from our systematic review of differentially expressed genes in overactive bladder. RESULTS: A total of 9 studies were included in the final analysis and 11 genes were identified as being up-regulated (purinergic receptor P2X 2 [P2RX2], smoothelin [SMTN], growth-associated protein 43 [GAP43], transient receptor potential cation channel subfamily M member 8 [TRPM8], cadherin 11 [CDH1], gap junction protein gamma 1 [GJC1], cholinergic receptor muscarinic 2 [CHRM2], cholinergic receptor muscarinic 3 [CHRM3], and transient receptor potential cation channel subfamily V member 4 [TRPV4]) or down-regulated (purinergic receptor P2X 2 [P2RX3] and purinergic receptor P2X 5 [P2RX5]) in patients with overactive bladder. Gene network analysis showed that genes are involved in chemical synaptic transmission, smooth muscle contraction, blood circulation, and response to temperature stimulus. Network analysis demonstrated a significant genetic interaction between TRPV4, TRPM8, P2RX3, and PR2X2 genes. CONCLUSION: Outcomes of this systematic review highlighted potential biomarkers for treatment efficacy and have laid the groundwork for developing future gene therapies for overactive bladder in clinical settings.

Genomic Risk Factors for Urethral Stricture: A Systematic Review and Gene Network Analysis.

OBJECTIVE: To identify genes that may play a role in urethral stricture and summarize the results of studies that have documented variations in gene expression among individuals with urethral stricture compared to healthy individuals. METHODS: A systematic search was conducted in Cochrane, Ovid, Web of Science, and PubMed, limiting the results to articles published between January 1, 2000 and January 30, 2023. Only studies comparing the difference in gene expression between individuals with urethral stricture and healthy individuals utilizing molecular techniques to measure gene expression in blood, urine, or tissue samples were included in this systematic review. Gene network and pathway analyses were performed using Cytoscape software, with input data obtained from our systematic review of differentially expressed genes in urethral stricture. RESULTS: Four studies met our criteria for inclusion. The studies used molecular biology methods to quantify gene expression data from specimens. The analysis revealed gene expressions of CXCR3 and NOS2 were downregulated in urethral tissue samples, while TGFB1, UPK3A, and CTGF were upregulated in plasma, urine and urethral tissue samples, respectively, in patients with urethral stricture compared to healthy controls. The analysis demonstrated that the most significant pathways were associated with phosphoinositide 3-kinase (PI3 kinase) and transforming growth factor beta 1/suppressor of mothers against decapentaplegic (TGF-ß1/SMAD) signaling pathways. CONCLUSION: This systematic review identified gene expression variations in several candidate genes and identified underlying biological pathways associated with urethral stricture. These findings could inform further research and potentially shift treatment and prevention strategies for urethral stricture.

A systematic review of underlying genetic factors associated with ureteropelvic junction obstruction in stenotic human tissue.

OBJECTIVE: Genetic factors are implicated in the development of ureteropelvic junction obstruction (UPJO). The aims of this study were: 1) condense and examine the existing data in studies containing information regarding differential gene expression in tissues from patients with UPJO and 2) investigate associations between genetic markers and their related pathways. MATERIALS AND METHODS: A systematic review of studies published between January 2000 and September 2021 was conducted using the following databases: Ovid/Medline, PubMed, Wiley Cochrane Central Register of Controlled Trials, Web of Science, and Scopus. Of 249 studies, 10 were included in the final analysis. The search was performed using the terms "ureteropelvic junction obstruction", "genetic", "gene", and "gene expression". Literature pertaining to differential gene expression in UPJO patients as compared to healthy controls was identified. Studies containing gene expression and quantification of molecular data carried out directly on stenotic tissue samples were selected for analysis. Gene network connections and functional analyses were then determined using MetaScape software. RESULTS: From the ten studies identified for analysis, fifteen genes were noted as differentially expressed. In UPJO patients, nine genes were upregulated (ET1, ACTA2, MCP-1, TGFB1, NFKB1, IL-6, HIF1A, S100A1, SYP) and six were downregulated (ADM, NOS2, EGF, PDGFRA, UCHL1, NGFR). These genes were principally involved in HIF-1 signaling pathway, blood vessel development, positive regulation of signaling receptor activity, and Ras signaling pathway. CONCLUSIONS: A potential link exists between genes related to hypoxia, excessive fibrous tissue formation, and inflammation in the development of UPJO, and these connections merit more detailed, tissue level investigations in UPJO patients. The outcomes of this systematic review may lay the groundwork for the development of future targeted therapies and novel biomarker detection for treatments, early detection, and possible prediction and prevention of development of UPJO.

In Vivo Delivery of M0, M1, and M2 Macrophage Subtypes via Genipin-Cross-Linked Collagen Biotextile.

Developing strategies to regulate the immune response poses significant challenges with respect to the clinical translation of tissue-engineered scaffolds. Prominent advancements have been made relating to macrophage-based therapies and biomaterials. Macrophages exhibit the potential to influence healing trajectory, and predominance of particular subtypes during early onset of healing influences repair outcomes. This study evaluated short- and long-term healing response and postoperative mechanical properties of genipin-cross-linked, electrochemically aligned collagen biotextiles with comparative administration of M0, M1, and M2 subtypes. Irrespective of macrophage subtype seeded, all the groups demonstrated existence of M2 macrophages at both time points as typified by arginase and Ym-1 expressions, and distinct absence of M1 macrophages, as indicated by lack of inducible nitric oxide synthase (iNOS) and interleukin-1ß expression in all the groups for both time points. M2 macrophage-seeded collagen biotextiles revealed promising host tissue responses, such as reduced fibrous capsule thickness and minimal granulation tissue formation. Furthermore, the M2-seeded group displayed more abundant interstitial collagen deposition following degradation of the collagen threads. M2 macrophage supplementation improved structural and mechanical properties at the tissue and cellular level as indicated by increased modulus and stiffness. This study demonstrates improved biomechanical and histological outcomes following incorporation of M2 macrophages into genipin-cross-linked collagen biotextiles for tissue repair and offers future strategies focused on connective tissue regeneration. Impact statement Macrophages exhibit significant plasticity with complex phenotypes ranging from proinflammatory (M1) to proregenerative (M2). They release cytokines and chemokines governing immunological stability, inflammation resolution, and tissue healing and regeneration. However, utilization of macrophages as therapeutic tools for tissue engineering remains limited. In this study, genipin-cross-linked collagen biotextiles were employed to deliver M0, M1, and M2 macrophages and evaluate tissue responses and postsurgical mechanical properties in vivo. M2-seeded collagen biotextiles showed reduced fibrous capsule and favorable healing response. These outcomes shed new light on designing tissue-engineered constructs that offer a novel cell-based therapeutic approach for applications requiring structural augmentation.