Multi-omics analyses uncover metabolic signatures and gene expression profiles of interstitial cystitis/bladder pain syndrome.

BACKGROUND AND OBJECTIVE: We explore molecular and metabolic pathways involved in interstitial cystitis (IC) with integrating multi-omics analysis for identifying potential diagnostic and therapeutic targets. METHODS: Mouse models of IC/bladder pain syndrome (BPS) were established by intraperitoneal injection of cyclophosphamide and bladder tissue samples were collected for metabolomics and transcriptome analysis. RESULTS: We found a total of 82 and 145 differential metabolites in positive ion modes and negative ion modes, respectively. Glycerophospholipid metabolism, choline metabolism in cancer, and nucleotide metabolism pathways were significantly enriched in the IC/BPS group. Transcriptome analysis demonstrated that 1069 upregulated genes and 1087 downregulated genes were detected. Importantly, the stronger enrichment for cell cycle pathway was observed in IC/BPS than that in normal bladder tissue, which may be involved in the process of bladder remodeling. Moreover, the inflammatory response and inflammatory factors related pathways were enriched in the IC/BPS group. CONCLUSIONS: Our findings provide critical directions for further exploration of the molecular pathology underlying IC/BPS.

Advances in tumor nanotechnology: theragnostic implications in tumors via targeting regulated cell death.

Cell death constitutes an indispensable part of the organismal balance in the human body. Generally, cell death includes regulated cell death (RCD) and accidental cell death (ACD), reflecting the intricately molecule-dependent process and the uncontrolled response, respectively. Furthermore, diverse RCD pathways correlate with multiple diseases, such as tumors and neurodegenerative diseases. Meanwhile, with the development of precision medicine, novel nano-based materials have gradually been applied in the clinical diagnosis and treatment of tumor patients. As the carrier, organic, inorganic, and biomimetic nanomaterials could facilitate the distribution, improve solubility and bioavailability, enhance biocompatibility and decrease the toxicity of drugs in the body, therefore, benefiting tumor patients with better survival outcomes and quality of life. In terms of the most studied cell death pathways, such as apoptosis, necroptosis, and pyroptosis, plenty of studies have explored specific types of nanomaterials targeting the molecules and signals in these pathways. However, no attempt was made to display diverse nanomaterials targeting different RCD pathways comprehensively. In this review, we elaborate on the potential mechanisms of RCD, including intrinsic and extrinsic apoptosis, necroptosis, ferroptosis, pyroptosis, autophagy-dependent cell death, and other cell death pathways together with corresponding nanomaterials. The thorough presentation of RCD pathways and diverse nano-based materials may provide a wider cellular and molecular landscape of tumor diagnosis and treatments.

Carrot and carotene and multiple health outcomes: an umbrella review of the evidence.

In recent years, the benefits of carrots and carotene in different areas of health have been examined. The purpose of this umbrella review was to identify the associations between carrots and carotene and multiple health outcomes. The review considered evidence from meta-analyses of interventional and observational studies of carrots and carotene and any health outcome. We comprehensively searched Web of Science, PubMed, and Embase. For each association, we estimated the summary effect size using random and fixed effects models and the 95% confidence interval. A total of 1329 studies were searched, and 30 meta-analyses with 26 health outcomes were identified that met the eligibility criteria. Carrot intake was associated with a lower risk of multiple cancer outcomes including breast cancer, lung cancer, pancreatic cancer, gastric cancer, urothelial cancer, and prostate cancer. Carotene intake was associated with a lower risk of fracture, age-related cataract, sunburn, Alzheimer's disease, breast cancer, lung cancer, pancreatic cancer, gastric cancer, esophageal cancer, prostate cancer, and head and neck cancer (HNC). Serum carotene was inversely associated with all-cause mortality, breast cancer, and lung cancer. Our study revealed that carrot or carotene intake could reduce the risk of various negative health outcomes. © 2023 Society of Chemical Industry.

rAAV-based and intraprostatically delivered miR-34a therapeutics for efficient inhibition of prostate cancer progression.

At present, there is no effective treatment for prostate cancer (PCa). Previous studies have reported that miR-34a is significantly downregulated in PCa cells; therefore, modulation of miR-34a expression might be a promising therapeutic approach for PCa treatment. To this end, we first verified the downregulation of miR-34a in prostate tumors from a transgenic adenocarcinoma mouse prostate (TRAMP) model. We found that miR-34a overexpression significantly inhibited the cell cycle, viability, and migration of PCa cells by targeting its downstream genes. Next, we tested the concept of intraprostatic injection of rAAV9·pri-miR-34a into 8-week-old TRAMP mice to inhibit PCa progression. We observed that the treatment lowered body weights significantly compared to the control treatment starting at 30 weeks after injection. rAAV9·pri-miR-34a treatment also obviously extended the lifespan of TRAMP mice. Moreover, we confirmed that the neoplasia in the treated prostates was significantly diminished compared to that in the control group. In addition, overexpressed miR-34a downregulated the expression of its target genes. Taken together, our results demonstrated, for the first time, the potential of rAAV-mediated efficient modulation of miR-34a expression in the prostate to inhibit PCa progression by regulating its downstream gene expression.

Preparation and characterization of a polyclonal antibody against PTEN-Long.

Phosphatase and tensin homolog-long (PTEN-L) is a translational isoform of PTEN, which exists in both intracellular and extracellular locations. Previous studies demonstrated that PTEN-L could inhibit oncogenesis due to its lipid phosphatase activity. However, recent studies found that PTEN-L could promote the proliferation of some types of cancer cells. Moreover, as a protein phosphatase, PTEN-L can suppress mitophagy by counteracting PTEN-induced putative kinase protein 1 (PINK1)-Parkin-mediated ubiquitin phosphorylation, namely, PTEN-L is critical for exploring the mitophagy progression and the treatment of mitochondrial diseases. Accounting for the critical functions of PTEN-L, its antibody can be used for the treatment or prognosis of tumors and mitochondrial diseases. Currently, the commercial antibody of PTEN-L is not available. In our study, the recombinant PTEN-L protein was expressed in Escherichia coli BL21 and used as an antigen to immunize Japan's big-eared white rabbit for the preparation of polyclonal antibody. The PTEN-L protein can be captured by PTEN-L antibody specifically and effectively. Taken together, a PTEN_L antibody is a valuable tool for further exploring the function of PTEN-L in oncogenesis and mitochondrial diseases, and it would be a new choice for the prognosis or treatment of cancer and mitochondrial diseases.

Broaden Horizons: The Advancement of Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating disease that induces mental stress, lower urinary symptoms, and pelvic pain, therefore resulting in a decline in quality of life. The present diagnoses and treatments still lead to unsatisfactory outcomes, and novel diagnostic and therapeutic modalities are needed. Although our understanding of the etiology and pathophysiology of IC/BPS is growing, the altered permeability of the impaired urothelium, the sensitized nerves on the bladder wall, and the chronic or intermittent sensory pain with inaccurate location, as well as pathologic angiogenesis, fibrosis, and Hunner lesions, all act as barriers to better diagnoses and treatments. This study aimed to summarize the comprehensive information on IC/BPS research, thereby promoting the progress of IC/BPS in the aspects of diagnosis, treatment, and prognosis. According to diverse international guidelines, the etiology of IC/BPS is associated with multiple factors, while the presence of Hunner lesions could largely distinguish the pathology, diagnosis, and treatment of non-Hunner lesions in IC/BPS patients. On the basis of the diagnosis of exclusion, the diverse present diagnostic and therapeutic procedures are undergoing a transition from a single approach to multimodal strategies targeting different potential phenotypes recommended by different guidelines. Investigations into the mechanisms involved in urinary symptoms, pain sensation, and bladder fibrosis indicate the pathophysiology of IC/BPS for further potential strategies, both in diagnosis and treatment. An overview of IC/BPS in terms of epidemiology, etiology, pathology, diagnosis, treatment, and fundamental research is provided with the latest evidence. On the basis of shared decision-making, a multimodal strategy of diagnosis and treatment targeting potential phenotypes for individual patients with IC/BPS would be of great benefit for the entire process of management. The complexity and emerging evidence on IC/BPS elicit more relevant studies and research and could optimize the management of IC/BPS patients.

Crosstalk between Tumor-Associated Macrophages and MicroRNAs: A Key Role in Tumor Microenvironment.

As an in-depth understanding of immunotherapy continues to grow, current anticancer therapy research is increasingly focused on the tumor microenvironment (TME). MicroRNAs (miRNAs) play crucial roles in the regulation of genetic information and expression and mediate interactions between tumor cells and components in the TME, such as tumor-associated macrophages (macrophages). Macrophages are abundant in the TME, and their different polarization directions can promote or inhibit tumor growth and progression. By regulating biological behaviors, such as macrophage recruitment, infiltration, and polarization, miRNAs can affect various molecular pathways to regulate tumor progression and treatment response. In this review, we discuss in detail the effects of macrophages on tumors and the multifaceted effects of miRNAs on macrophages. We also discuss the potential clinical applications and prospects of targeted therapy based on miRNAs, novel clinical biomarkers, and drug delivery systems.

Tumor antigens and immune subtypes guided mRNA vaccine development for kidney renal clear cell carcinoma.

Current treatment strategy for kidney renal clear cell carcinoma (KIRC) is limited. Tumor-associated antigens, especially neoantigen-based personalized mRNA vaccines represent new strategies and manifest clinical benefits in solid tumors, but only a small proportion of patients could benefit from them, which prompts us to identify effective antigens and suitable populations to facilitate mRNA vaccines application in cancer therapy. Through performing expression, mutation, survival and correlation analyses in TCGA-KIRC dataset, we identified four genes including DNA topoisomerase II alpha (TOP2A), neutrophil cytosol factor 4 (NCF4), formin-like protein 1 (FMNL1) and docking protein 3 (DOK3) as potential KIRC-specific neoantigen candidates. These four genes were upregulated, mutated and positively associated with survival and antigen-presenting cells in TCGA-KIRC. Furthermore, we identified two immune subtypes, named renal cell carcinoma immune subtype 1 (RIS1) and RIS2, of KIRC. Distinct clinical, molecular and immune-related signatures were observed between RIS1 and RIS2. Patients of RIS2 had better survival outcomes than those of RIS1. Further comprehensive immune-related analyses indicated that RIS1 is immunologically "hot" and represent an immunosuppressive phenotype, whereas RIS2 represents an immunologically "cold" phenotype. RIS1 and RIS2 also showed differential features with regard to tumor infiltrating immune cells and immune checkpoint-related genes. Moreover, the immune landscape construction identified the immune cell components of each KIRC patient, predicted their survival outcomes, and assisted the development of personalized mRNA vaccines. In summary, our study identified TOP2A, NCF4, FMNL1 and DOK3 as potential effective neoantigens for KIRC mRNA vaccine development, and patients with RIS2 tumor might benefit more from mRNA vaccination.

Tumor-antigens and immune landscapes identification for prostate adenocarcinoma mRNA vaccine.

Prostate adenocarcinoma (PRAD) is a leading cause of death among men. Messenger ribonucleic acid (mRNA) vaccine presents an attractive approach to achieve satisfactory outcomes; however, tumor antigen screening and vaccination candidates show a bottleneck in this field. We aimed to investigate the tumor antigens for mRNA vaccine development and immune subtypes for choosing appropriate patients for vaccination. We identified eight overexpressed and mutated tumor antigens with poor prognostic value of PRAD, including KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3. The correlation of those genes with antigen-presenting immune cells were assessed. We further identified three immune subtypes of PRAD (PRAD immune subtype [PIS] 1-3) with distinct clinical, molecular, and cellular characteristics. PIS1 showed better survival and immune cell infiltration, nevertheless, PIS2 and PIS3 showed cold tumor features with poorer prognosis and higher tumor genomic instability. Moreover, these immune subtypes presented distinguished association with immune checkpoints, immunogenic cell death modulators, and prognostic factors of PRAD. Furthermore, immune landscape characterization unraveled the immune heterogeneity among patients with PRAD. To summarize, our study suggests KLHL17, CPT1B, IQGAP3, LIME1, YJEFN3, KIAA1529, MSH5 and CELSR3 are potential antigens for PRAD mRNA vaccine development, and patients in the PIS2 and PIS3 groups are more suitable for vaccination.

Vinculin orchestrates prostate cancer progression by regulating tumor cell invasion, migration, and proliferation.

BACKGROUND: Prostate cancer (PCa) is a leading cause of death in men, and effective treatment of PCa requires further development. Our study aimed to investigate the potential role of vinculin (VCL) in PCa progression in vitro and in vivo. METHODS: We investigated the methylation level of the VCL promoter based on the TCGA database. The knockdown efficacy of VCL gene expression was confirmed by quantitative polymerase chain reaction, Western blot analysis, and immunofluorescence. Furthermore, morphological changes in PCa cells were detected using phalloidin staining. The mobility of PCa cells was measured using transwell assays and high-content analysis. Moreover, cell growth and viability were determined using the colony formation and cell counting kit-8 assays. The role of VCL in tumor growth in vivo was investigated using a subcutaneous xenograft model generated by injecting tumor cells into the right flank of BALB/c nude mice. RESULTS: The methylation level of the VCL promoter in PCa was significantly downregulated concomitant with age and the progression of nodal metastasis. VCL expression was markedly decreased by shRNA. Importantly, VCL knockdown significantly changed the cell morphology; inhibited the migration, invasion, and movement; and repressed colony formation and viability of PCa cells in vitro. Furthermore, downregulation of VCL suppressed tumor growth in vivo. CONCLUSIONS: Our study comprehensively evaluated the role of VCL in PCa progression in vivo and in vitro. The findings of the present study suggest that VCL can be a potential target for PCa prognosis and treatment.

The role of interleukin-6/interleukin-6 receptor signaling in the mechanical stress-induced extracellular matrix remodeling of bladder smooth muscle.

Extracellular matrix (ECM) remodeling is strongly associated with pathological changes induced by bladder outlet obstruction (BOO). In this study, we investigated the role of interleukin-6 (IL-6) in mechanical stretch-induced ECM remodeling of bladder smooth muscle. To construct a BOO animal model, the urethras of female Sprague-Dawley rats were partially ligated. In addition, increased hydrostatic pressure and mechanical stretching were applied to human bladder smooth muscle cells (HBSMCs) as an in vitro model. The expression of rat inflammatory genes was analyzed using DNA microarrays. We used quantitative RT-PCR (qRT-PCR) and immunohistochemical staining to detect IL-6 in the bladder smooth muscle of rats. To determine the specificity of IL-6, small interfering ribonucleic acid (siRNA) transfection and IL-6 receptor inhibitor (SC144) were applied to HBSMCs. qRT-PCR with siRNA transfection was also used to determine the specificity of downstream signaling. Moreover, western blotting was conducted to verify the expression results. In the animal model, the expression of ECM components and inflammatory genes was significantly upregulated. The expression of IL-6 was increased at both the mRNA level and the protein level in BOO rats. In vitro, hydrostatic pressure, and mechanical stretching both promoted MMP7 and MMP11 expression. Additionally, downregulation of collagen III occurred in both the hydrostatic pressure group and the mechanical stretch group. However, the expression of fibronectin exhibited opposing patterns between the hydrostatic pressure and mechanical stretch groups. The application of targeted siRNA transfection and an inhibitor (SC144) that targeted IL-6 significantly reversed the changes in MMP7 and MMP11 under mechanical stress and partially increased the expression of collagen III and fibronectin. In summary, IL-6 participated in the ECM remodeling of HBSMCs under mechanical stress, indicating that IL-6 may play an essential role in BOO..

The relationship between gut microbiota and short chain fatty acids in the renal calcium oxalate stones disease.

The relationship of gut microbiota and calcium oxalate stone has been limited investigated, especially with no study of gut microbiota and short chain fatty acids (SCFAs) in nephrolithiasis. We provided Sprague Dawley rats of renal calcium oxalate stones with antibiotics and examined the renal crystals deposition. We also performed a case-control study by analyzing 16S rRNA microbial profiling, shotgun metagenomics and SCFAs in 153 fecal samples from non-kidney stone (NS) controls, patients with occasional renal calcium oxalate stones (OS) and patients with recurrent stones (RS). Antibiotics reduced bacterial load in feces and could promote the formation of renal calcium crystals in model rats. In addition, both OS and RS patients exhibited higher fecal microbial diversity than NS controls. Several SCFAs-producing gut bacteria, as well as metabolic pathways associated with SCFAs production, were considerably lower in the gut microbiota among the kidney stone patients compared with the NS controls. Representation of genes involved in oxalate degradation showed no significance difference among groups. However, fecal acetic acid concentration was the highest in RS patients with high level of urinary oxalate, which was positively correlated with genes involvement in oxalate synthesis. Administration of SCFAs reduced renal crystals. These results shed new light on bacteria and SCFAs, which may promote the development of treatment strategy in nephrolithiasis.

Association of the inflammatory potential of diet and lower urinary tract symptoms among men in the United States.

BACKGROUND: Inflammation is crucial in the pathogenesis of lower urinary tract symptoms (LUTS) in men. Diet modulates inflammation. Therefore, diet could be a modifiable factor in male LUTS prevention and treatment. We aimed to investigate the association between dietary inflammatory potential and male LUTS. METHODS: We used two cycles of National Health and Nutrition Examination Survey (NHANES) with self-report LUTS data. We calculated the dietary inflammatory index (DII) based on a 24 h diet recall and evaluated male LUTS. Clinical LUTS was defined as two or more coexisting symptoms. We used univariate and multivariate logistic regression models, the smooth curve fitting to analyze the relationship between clinical LUTS and the DII score. Subgroup analyses were conducted. RESULTS: We observed a positive non-linear relationship between clinical LUTS and DII. We found that when DII was higher than the inflection point 2.39, a 1-unit increase in DII was associated with 26.1% higher adjusted odds of clinical LUTS. Subgroup analyses showed that the DII score was only positively correlated with clinical LUTS risk in non-drinkers, smokers, and non-obese people (DII >2.39). CONCLUSIONS: Inflammation might be the key mechanism bridging dietary consumption to male LUTS. Excessive pro-inflammatory food intake (DII >2.39) warrants special vigilance, especially for non-drinkers, smokers, and non-obese men.

Use of Tregs as a cell-based therapy via CD39 for benign prostate hyperplasia with inflammation.

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg-associated cytokine production. Sorted CD39+/- Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL-10, IL-35 and TGF-ß. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down-regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39- Tregs in mice, however, CD39+ Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL-1ß and PSA secretion, and increasing IL-10 and TGF-ß secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.

M3 receptor modulates extracellular matrix synthesis via ERK1/2 signaling pathway in human bladder smooth muscle cells.

Extracellular matrix (ECM) accumulation plays a key role in the progression of bladder outlet obstruction (BOO). Muscarinic receptors have been widely reported to serve as pivotal regulators in lung tissue remodeling. However, the influence of them on human bladder smooth muscle cells (HBSMCs) and the underlying molecular mechanisms have not yet been evaluated. The purposes of the present study are to investigate the effect of muscarinic receptors on the synthesis of ECM in HBSMCs and the involvement of intracellular signal transducers. The results indicated that M1 -M5 muscarinic receptors were all encoded in HBSMCs. The expression rank order was M2 > M1 > M5 > M3 > M4 . The gene and protein expression of collagen I (COL1), TIMP-1, and TIMP-2 was carbachol (CCH) concentration-dependently enhanced. The synthesis of COL1 in the supernatant of cell culture medium was significantly elevated by exposure to CCH. The CCH-induced protein expression of COL1, TIMP-1, and TIMP-2, however, was obviously reduced by the pretreatment of muscarinic receptor antagonists, atropine, and M3 -preferring antagonist (1,1-dimethyl-4-diphenyl-acetoxypiperidinium iodide [4-DAMP]). Furthermore, ERK1/2 was activated by 100 µM CCH when compared with the control group and the pretreatment of ERK1/2 inhibitor significantly suppressed the synthesis of COL1 induced by 100 µM CCH. Besides, CCH-induced phosphorylation of ERK1/2 was remarkably restrained by the pretreatment of 4-DAMP. All in all, these findings demonstrated that M3 receptor can modulate extracellular matrix synthesis via the ERK1/2 signaling pathway, which may provide potential novel therapeutic targets for BOO.

ß-Adrenoceptor regulates contraction and inflammatory cytokine expression of human bladder smooth muscle cells via autophagy under pathological hydrostatic pressure.

AIMS: Abnormal intravesical pressure created by partial bladder outlet obstruction (PBOO) triggered the progression from chronic inflammation to fibrosis, initiating structural and functional alterations of bladder. To elucidate the underlying mechanisms of contraction and inflammatory response, we investigated the isolated human bladder smooth muscle cells (hBSMC) under pathological hydrostatic pressure (HP) mimicking the in vivo PBOO condition. METHODS: hBSMCs were subjected to HP of 200 cm H2 O to explore the contraction and inflammatory cytokine expression of hBSMC treated with ß-adrenoceptors (ADRBs) and/or autophagy signaling pathway agonists and/or antagonists. RESULTS: We showed that pathological HP induced the release of the proinflammatory cytokines, including monocyte chemotactic protein-1, regulated upon activation normal T cell expressed and secreted factor, and interleukin-6. HP downregulated ADRB2 and ADRB3 expression, which was consistent with the results of the PBOO rat model. ADRB2 or autophagy activation repressed pathological HP-induced proinflammatory cytokine production. ADRB2, ADRB3 or autophagy activation ameliorated the HP-enhanced contraction. The increased contraction and autophagy activity by ADRB2 agonist under HP conditions were reversed by pretreatment with antagonists of adenosine monophosphate-activated protein kinase (AMPK). CONCLUSION: The present study provides evidence that the ADRB3 agonist suppresses hBSMC contraction under pathological HP conditions. Moreover, the ADRB2 agonist negatively regulates the contraction and inflammatory response of hBSMCs through AMPK/mTOR-mediated autophagy under pathological HP. These findings provide a theoretical basis for potential therapeutic strategies for patients with PBOO.

ß-Adrenoceptors regulate matrix metalloproteinase expression in human urothelial cells under hydrostatic pressure.

The bladder wall is constantly subjected to intravesical pressure during the filling and voiding cycles. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) under elevated intravesical pressure contributes to pathological changes in the bladder. To investigate the changes in human urothelial cells (HUCs) under elevated intravesical pressure, this study analyzed the effect of ß-adrenoceptor signaling on the expression of MMPs and TIMPs in HUCs exposed to pathological hydrostatic pressure (HP) (70 cm H2 O) for 6 hours. Quantitative polymerase chain reaction, Western blot analysis, and cell fluorescence staining were used to explore the effect of ß-adrenoceptor signaling on the expression of MMPs and TIMPs in HUCs after agonist and/or antagonist treatment. The expression levels of ß2 - and ß3 -adrenoceptor, MMP1, and MMP2 were greatly downregulated, while the expression of TIMP1 was greatly upregulated. Formoterol and BRL 37344, which are agonists of ß2 - and ß3 -adrenoceptor, respectively, significantly increased MMP1 and MMP2 expression under 70 cm H2 O. As a classic downstream pathway of ß2 - and ß3 -adrenoceptor, protein kinase A (PKA) signaling inhibited MMP1 and MMP2 expression by regulating cAMP response element binding protein (CREB) activity. MMP1 and MMP2 expression in HUCs under 70 cm H2 O was modified by ß2 - and ß3 -adrenoceptor via the PKA/CREB pathway. This outcome suggests that MMPs likely participate in the pathological effects of elevated intravesical pressure. The underlying mechanism of ß2 - and ß3 -adrenoceptor in elevated intravesical pressure was also revealed; this mechanism constitutes a new potential therapeutic target for partial bladder outlet obstruction.

The relationships between bariatric surgery and sexual function: current evidence based medicine.

BACKGROUND: Controversy remains despite several studies have discussed the role of bariatric surgery in improving male's sexual function. This study aims to evaluate the efficacy of bariatric surgery in promoting male's erectile function. METHODS: PubMed, EMbase, The Cochrane Library, CNKI and Clinical Trails.gov were searched from database inception to May 2019. The language of publication was limited in English. The International Index of Erectile Function (IIEF) score and Brief Male Sexual Function Inventory (BSFI) score were set as the primary outcome. RESULTS: Eleven studies with a total of 370 patients were enrolled in this meta-analysis. The results showed significant improvement in the IIEF score (erectile function: MD = 5.33, 95% CI 4.12-6.54; intercourse satisfaction: MD = 2.57, 95% CI 1.19-3.94; orgasmic function: MD = 0.50, 95%CI 0.60-0.94; overall satisfaction: MD = 1.67, 95% CI 0.78-2.56; sexual desire: MD = 1.27, 95% CI 0.61-1.93; total erectile function: MD = 7.21, 95% CI 4.33-10.10) and the BSFI score (erection: MD =2.53, 95% CI 2.39-2.67; ejaculation: MD = 1.40, 95% CI 1.28-1.51; desire: MD =1.40, 95% CI 1.32-1.49; problem assessment: MD = 2.20, 95% CI 2.06-2.34; sexual satisfaction: MD = 0.70, 95% CI 0.60-0.76) in obese individuals after bariatric surgery. CONCLUSIONS: This systematic review and meta-analysis indicated that bariatric surgery could be effective in promoting males's sexual function for obese individuals.

ß-Adrenoceptor signaling regulates proliferation and contraction of human bladder smooth muscle cells under pathological hydrostatic pressure.

BACKGROUND: Partial bladder outlet obstruction (PBOO) promotes bladder detrusor hyperplasia, increases bladder pressure, and decreases bladder compliance. To extensively explore its underlying mechanism, our study aimed to investigate the effect of pathological hydrostatic pressure on human bladder smooth muscle cell (hBSMC) proliferation and contraction through ß-adrenoceptor (ADRB) signaling in vitro. METHODS: hBSMCs were subjected to pathological hydrostatic pressure (100 cm H2 O) to investigate the effect of ADRBs on the proliferation and contraction of hBSMCs treated with its agonists and/or antagonists. RESULTS: Firstly, exposure to 100 cm H2 O hydrostatic pressure significantly upregulated the expression of α-smooth muscle actin (α-SMA) in hBSMCs at 6 hours, and promoted cell proliferation at 24 hours. When subjected to hydrostatic pressure alone, hBSMCs treated with ADRB2 and ADRB3 agonists for 6 hours inhibited α-SMA expression compared with untreated cells. By contrast, hBSMCs treated with ADRB2 agonists for 24 hours suppressed cell proliferation compared with untreated cells. The two classical pathways of ADRB, protein kinase A (PKA), and exchange factor directly activated by cAMP (EPAC) inhibited the contraction of hBSMCs under hydrostatic pressure via regulating mothers against decapentaplegic homolog 2 (SMAD2) activity. The proliferation of hBSMCs was mainly regulated by the EPAC pathway through extracellular signal-regulated kinase 1/2 (ERK1/2) activity. CONCLUSION: The contraction of hBSMCs under hydrostatic pressure was regulated by ADRB2 and ADRB3 via the PKA/EPAC-SMAD2 pathway, and the proliferation of hBSMCs was regulated by ADRB2 via the EPAC-ERK1/2 pathway. Compared with ADRB3, ADRB2 played a predominant role under pathological hydrostatic pressure. These findings markedly uncovered the underlying mechanism of ADRBs in PBOO and provided new insights into the efficient treatment of patients with PBOO.

Tumor-associated macrophages promote bladder tumor growth through PI3K/AKT signal induced by collagen.

The tumor microenvironment is associated with various tumor progressions, including cancer metastasis, immunosuppression, and tumor sustained growth. Tumor-associated macrophages (TAMs) are considered an indispensable component of the tumor microenvironment, participating in the progression of tumor microenvironment remodeling and creating various compounds to regulate tumor activities. This study aims to observe enriched TAMs in tumor tissues during bladder cancer development, which markedly facilitated the proliferation of bladder cancer cells and promoted tumor growth in vivo. We determined that TAMs regulate tumor sustained growth by secreting type I collagen, which can activate the prosurvival integrin α2ß1/PI3K/AKT signaling pathway. Furthermore, traditional chemotherapeutic drugs combined with integrin α2ß1 inhibitor showed intensive anticancer effects, revealing an innovative approach in clinical bladder cancer treatment.