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1.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802033

RESUMO

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/imunologia , Antígeno B7-H1/imunologia , Sinergismo Farmacológico , Humanos , /uso terapêutico , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Receptor de Morte Celular Programada 1/imunologia , Fatores de Risco , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/imunologia
2.
Eur J Pharmacol ; 899: 173995, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33675781

RESUMO

Transient receptor potential melastatin 8 (TRPM8) channels may contribute to the pathophysiological bladder afferent hyperactivity, thus a TRPM8 antagonist would be a promising therapeutic target for the bladder hypersensitive disorders including urinary urgency in overactive bladder (OAB). We aimed to investigate a pharmacological effect of KPR-5714, a novel selective TRPM8 antagonist, on TRPM8 channels, M3 receptors and ß3-adrenoceptors using the transfected cells of each gene at first. Then, combination effects of KPR-5714 and mirabegron, a ß3-adrenoceptor agonist, or tolterodine tartrate, an anticholinergic agent, were studied on rhythmic bladder contractions (RBCs) in normal rats and bladder function in frequent-voiding rats. In vitro measurements showed that KPR-5714 acts on neither ß3-adrenoceptor nor M3 receptor. In normal rats, KPR-5714 and mirabegron significantly reduced the frequency of RBCs, and a combined administration showed an additive effect. In rats with cerebral infarction, KPR-5714 and mirabegron significantly reduced the voiding frequency, and a combined administration showed an additive effect. In rats exposed to cold temperature, KPR-5714 and tolterodine tartrate significantly reduced the voiding frequency accompanied by the increased mean voided volume, and a combined administration showed additive effects. The present study demonstrated that the combined administration of KPR-5714 and mirabegron or tolterodine tartrate showed the additive effects on bladder dysfunction in different animal models, suggesting that the combination therapy of TRPM8 antagonist and ß3-adrenoceptor agonist or anticholinergic agent can be the potential treatment option for obtaining additive effects in comparison with monotherapy for OAB.


Assuntos
Acetanilidas/farmacologia , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Antagonistas Muscarínicos/farmacologia , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Tiazóis/farmacologia , Tartarato de Tolterodina/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Urodinâmica/efeitos dos fármacos , Animais , Sinalização do Cálcio , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Células HEK293 , Humanos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 3/metabolismo , Canais de Cátion TRPM/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia
3.
Eur J Pharmacol ; 899: 174040, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737012

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel activated by various physical stimuli such as cell swelling and shear stress. TRPV4 is expressed in bladder sensory nerves and epithelium, and its activation produces urinary dysfunction in rodents. However, there have been few reports regarding its involvement in bladder pain. Therefore, we investigated whether TRPV4 is involved in bladder pain in mouse cystitis model. Intraperitoneal injection of cyclophosphamide (CYP; 300 mg/kg) produced mechanical hypersensitivity in the lower abdomen associated with a severe inflammatory bladder in mice. The mechanical threshold was reversed significantly in Trpv4-knockout (KO) mice. Repeated injections of CYP (150 mg/kg) daily for 4 days provoked mild bladder inflammation and persistent mechanical hypersensitivity in mice. Trpv4-KO mice prevented a reduction of the mechanical threshold without an alteration in bladder inflammation. A selective TRPV4 antagonist also reversed the mechanical threshold in chronic cystitis mice. Although expression of Trpv4 was unchanged in the bladders of chronic cystitis mice, the level of phosphorylated TRPV4 was increased significantly. These results suggest involvement of TRPV4 in bladder pain of cystitis mice. A TRPV4 antagonist might be useful for patients with irritable bladder pain such as those with interstitial cystitis/painful bladder syndrome.


Assuntos
Analgésicos/farmacologia , Cistite Intersticial/prevenção & controle , Gânglios Espinais/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Canais de Cátion TRPV/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Ciclofosfamida , Cistite Intersticial/induzido quimicamente , Cistite Intersticial/metabolismo , Cistite Intersticial/fisiopatologia , Modelos Animais de Doenças , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dor Nociceptiva/induzido quimicamente , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Fosforilação , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia
4.
Aquat Toxicol ; 234: 105796, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713916

RESUMO

This study leveraged the Japanese medaka fish embryo model for the assessment of effects of select contaminants on early development in fish. Fish embryos were exposed to various pharmaceutical contaminants including synthetic hormones and non-steroidal anti-inflammatory drugs and their effects on development were observed. Initial screening determined that swim bladder inflation failure was the most common endpoint detected. Swim bladder inflation failure was first explored in a study demonstrating that medaka require access to the air-water interphase to inflate their swim bladders in a time-dependent manner, and swim bladder inflation failure was correlated with mortality. Fish embryos were exposed 24-hours post fertilization until hatch to concentration ranges of various pharmaceutical contaminants including: 17ß-estradiol, 17α-ethinylestradiol, and levonorgestrel (1 to 1000 µg/L), or diclofenac (0.32 to 100 mg/L). The main effect observed across all four compounds was a significant increase in failure of swim bladder inflation with increasing exposure concentration (24 to 72-hours post-hatch). Following single compound experiments combinatorial exposures using no-observed-effect concentrations were conducted. The main effect observed was a significant decrease in inflation success 24-hours post-hatch following a binary mixture of levonorgestrel and 17α-ethinylestradiol, as well as a significant decrease in swim bladder inflation success at all times following exposure to a quaternary mixture of all four compounds. This study demonstrated that embryonic exposure to pharmaceutical compounds, both alone and in combination, resulted in failure of swim bladder inflation in larval Japanese medaka.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Oryzias/crescimento & desenvolvimento , Bexiga Urinária/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Diclofenaco/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Estradiol/toxicidade , Oryzias/fisiologia , Bexiga Urinária/fisiologia
5.
Am J Physiol Renal Physiol ; 320(5): F838-F858, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33645317

RESUMO

Alteration of bladder morphology and function was the most important consequence of bladder outlet obstruction (BOO). Using a rat model of partial BOO (pBOO), we found that rats treated with metformin showed lower baseline pressures with a reduced inflammatory reaction in the early phase (2 wk) after pBOO. The NLR family pyrin domain containing 3 inflammasome pathway was inhibited in pBOO rat bladders with treatment of metformin in the early phase. Metformin reduced the activity of NLR family pyrin domain containing 3 in primary urothelial cells. In the chronic phase (9 wk after pBOO), metformin treatment ameliorated bladder fibrosis and improved the reduced compliance. Treatment with metformin suppressed the activation of Smad3 and compensated the diminished autophagy in 9-wk pBOO rat bladders. Autophagy was inhibited with upregulation of profibrotic proteins in primary fibroblasts from chronic pBOO bladders, which could be restored by administration of metformin. The antifibrotic effects of metformin on fibroblasts were diminished after silencing of AMP-activated protein kinase or light chain 3B. In summary, this study elucidates that oral administration of metformin relieves inflammation in the bladder during the early phase of pBOO. Long-term oral administration of metformin can prevent functional and histological changes in the pBOO rat bladder. The current study suggests that metformin might be used to prevent the development of bladder dysfunction secondary to BOO.NEW & NOTEWORTHY The present study in a rat model showed that oral administration of metformin alleviated inflammation following partial bladder outlet obstruction in the early phase and ameliorated bladder fibrosis as well as bladder dysfunction by long-term treatment. Our study indicated that metformin is a potential drug to inhibit bladder remodeling and alleviate bladder dysfunction. Clinical trials are needed to validate the effect of metformin on the bladder dysfunction and bladder fibrosis in the future.


Assuntos
Anti-Inflamatórios/farmacologia , Metformina/farmacologia , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Mediadores da Inflamação/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Fatores de Tempo , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/metabolismo , Obstrução do Colo da Bexiga Urinária/patologia , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Urodinâmica/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Urotélio/metabolismo , Urotélio/patologia
6.
Neurourol Urodyn ; 40(1): 137-146, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606304

RESUMO

AIMS: To investigate the effect of losartan on preventing bladder fibrosis and protecting renal function in rats with neurogenic paralysis bladder (NPB). MATERIALS AND METHODS: Rats were assigned to the transecting spinal nerves group (TSNG), transecting spinal nerves + losartan group (LSTG), and control group (CG). On Day 32 postsurgery, bladder capacity (BC), bladder compliance (ΔC), bladder leakage pressure (Pves.leak ) of TSNG and LSTG while BC, ΔC, and bladder threshold pressure (Pves.thre ) of CG were measured by cystometry in each cohort. Renal function and the expression quantity of Angiotensin Ⅱ (Ang II) in blood were detected, in addition Ang II, Ang II Type 1 receptor (AT1), transformation growth factor ß1 (TGFß1), Collagen Ⅲ, and collagen fibrin in the bladder tissue were detected too. RESULTS: ΔC in TSNG and LSTG decreased significantly compared to the CG. Pves.leak in TSNG and LSTG were significantly higher than Pves.thre in CG. Renal function of both TSNG and LSTG decreased significantly compared with the CG, but renal function in LSTG was better than in TSNG. Ang Ⅱ in blood and bladder tissue in TSNG and LSTG increased significantly compared with CG. AT1 was expressed in the bladder tissue of all rats. The TGFß1, Collagen Ⅲ, and collagen fibrin expression level increased significantly in TSNG compared with LSTG and CG, while these levels were not significantly different between CG and LSTG. CONCLUSION: Losartan might prevent NPB fibrosis by stopping the upregulated signaling of Ang II/AT1/TGFß1 and consequently may reduce kidney damage from occurring.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Fibrose/tratamento farmacológico , Losartan/uso terapêutico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Losartan/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
7.
Yakugaku Zasshi ; 141(2): 245-254, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33518645

RESUMO

Distigmine bromide (distigmine) is a carbamate cholinesterase (ChE) inhibitor, which is mainly used for the treatment of myasthenia gravis. Distigmine is also used in Japan for the treatment for underactive bladder and glaucoma. The effectiveness of distigmine for underactive bladder treatment has been confirmed by many clinical reports, and this effect is thought to be caused by potentiating urinary bladder smooth muscle contraction due to inhibition of acetylcholine degradation during micturition. However, the pharmacological effects of distigmine on urinary bladder smooth muscle have not been well studied. The most distinctive pharmacological feature of distigmine is that it shows long-lasting effects than other ChE inhibitors; however, few studies have investigated the persistence of the enhancing effect of distigmine on the contractile function of urinary bladder smooth muscle. Moreover, this mechanism remains unclear. In this review, we present our findings on the mechanism of the potentiating effect of distigmine on isolated guinea pig urinary bladder smooth muscle contraction. We also discuss the long-lasting potentiating effect of distigmine on urinary bladder motility and the mechanism of these effects using guinea pig urinary bladder smooth muscle in vivo and in vitro. In addition, we present our investigations on the long-lasting mechanism of distigmine using recombinant human acetylcholinesterase.


Assuntos
Inibidores da Colinesterase/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Compostos de Piridínio/farmacologia , Bexiga Urinária/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Cobaias , Humanos , Técnicas In Vitro , Camundongos , Ratos , Estimulação Química , Micção/efeitos dos fármacos
8.
Methods Mol Biol ; 2240: 93-102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33423229

RESUMO

The urinary bladder is a target organ of several toxic agents. Exposure to those agents induces mild-to-severe changes, which can be evaluated by different methods. Among them, the scanning-electron microscopy (SEM) is the "gold standard" for characterizing urothelial damage since it provides high-definition images, making it possible to detect early lesions on the surface of the urinary bladder. In addition, molecular technologies allow detecting changes in genetic material and investigating the interaction between genes and environmental stress in disease causation. The urinary bladder epithelium is where the most common type of bladder cancer occurs in humans, that is, the transitional-cell carcinoma (TCC). In animal models, the TCC can be similar to the disease in humans. Techniques to evaluate urothelium in experimental models aid in the comprehension of risk factors for urothelial carcinogenesis.


Assuntos
Técnicas Genéticas , Microscopia Eletroquímica de Varredura , RNA/isolamento & purificação , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Animais , RNA/genética , Ratos , Bexiga Urinária/metabolismo , Bexiga Urinária/ultraestrutura , Urotélio/metabolismo , Urotélio/ultraestrutura
9.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478005

RESUMO

The objective was to investigate the anti-cancer effects and underlying molecular mechanisms of cytostasis which were activated by an anti-microtubule drug, ABT-751, in two urinary bladder urothelial carcinoma (UBUC)-derived cell lines, BFTC905 and J82, with distinct genetic backgrounds. A series of in vitro assays demonstrated that ABT-751 induced G2/M cell cycle arrest, decreased cell number in the S phase of the cell cycle and suppressed colony formation/independent cell growth, accompanied with alterations of the protein levels of several cell cycle regulators. In addition, ABT-751 treatment significantly hurdled cell migration and invasion along with the regulation of epithelial-mesenchymal transition-related proteins. ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Inhibition of autophagosome and autolysosome enhanced apoptosis was also observed. Through the inhibition of the NFκB signaling pathway, ABT-751 suppressed S-phase kinase associated protein 2 (SKP2) transcription and subsequent translation by downregulation of active/phospho-AKT serine/threonine kinase 1 (AKT1), component of inhibitor of nuclear factor kappa B kinase complex (CHUK), NFKB inhibitor alpha (NFKBIA), nuclear RELA proto-oncogene, NFκB subunit (RELA) and maintained a strong interaction between NFKBIA and RELA to prevent RELA nuclear translocation for SKP2 transcription. ABT-751 downregulated stable/phospho-SKP2 including pSKP2(S64) and pSKP2(S72), which targeted cyclin-dependent kinase inhibitors for degradation through the inactivation of AKT. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of SKP2 at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins.


Assuntos
Carcinoma/tratamento farmacológico , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Proteínas Quinases Associadas a Fase S/genética , Transcrição Genética/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma/genética , Carcinoma/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinase/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases Associadas a Fase S/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Urotélio/efeitos dos fármacos , Urotélio/patologia
10.
Environ Mol Mutagen ; 62(2): 143-154, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33496997

RESUMO

Pioglitazone (PIO), an oral hypoglycemic agent, is used in the treatment of type 2 diabetes. Some studies have suggested that an increased risk of bladder cancer with PIO exposure, while the others reported there is no such relationship. Therefore, it is doubtful whether PIO can increase the risk of bladder cancer. The effects of PIO on DNA damage and/or transformation of human bladder cells are not fully known. We investigated the effects of PIO on cytotoxicity, DNA single and double strand breaks and repair and neoplastic transformation in human bladder cells (hTU1) treated with 10, 20, and 40 µM PIO for 24, 48 and 72 hr. PIO decreased cell viability in a concentration-dependent manner. Increased levels of comet parameters showed that PIO and its metabolites can significantly induce DNA double strand breaks at all concentrations tested. PIO also significantly induced the formation of phosphorylated H2AX and p53 binding protein 1 foci. DNA damage was not repaired in a 24 hr recovery period. PIO can also induce malignant transformation of human bladder cells exhibiting loss of contact inhibition and anchorage independent growth. This is the first study to indicate that PIO can induce DNA damage and malignant transformation, reduce or alter the DNA repair capacity in human bladder cells. From these results, we suggest that patients with diabetes treated with PIO may have an increased risk of bladder cancer.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , DNA/efeitos dos fármacos , Pioglitazona/efeitos adversos , Neoplasias da Bexiga Urinária/induzido quimicamente , Bexiga Urinária/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Células Epiteliais/efeitos dos fármacos , Humanos , Pioglitazona/farmacologia , Neoplasias da Bexiga Urinária/genética
11.
Nat Commun ; 11(1): 5485, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127883

RESUMO

Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. However, current machine-learning-based predictions of drug response often fail to identify robust translational biomarkers from preclinical models. Here, we present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data derived from three-dimensional organoid culture models. The biomarkers identified by our approach accurately predict the drug responses of 114 colorectal cancer patients treated with 5-fluorouracil and 77 bladder cancer patients treated with cisplatin. We further confirm our biomarkers using external transcriptomic datasets of drug-sensitive and -resistant isogenic cancer cell lines. Finally, concordance analysis between the transcriptomic biomarkers and independent somatic mutation-based biomarkers further validate our method. This work presents a method to predict cancer patient drug responses using pharmacogenomic data derived from organoid models by combining the application of gene modules and network-based approaches.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Aprendizado de Máquina , Organoides/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Desenvolvimento de Medicamentos/métodos , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Organoides/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Transcriptoma , Bexiga Urinária/efeitos dos fármacos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
12.
Life Sci ; 261: 118468, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32961232

RESUMO

AIMS: RacGTPase-mediated proliferation and smooth muscle contraction in the lower urinary tract has been recently suggested and may offer putative targets for treamtment of lower urinary tract symptoms. However, RacGTPase function for proliferation of detrusor smooth muscle cells is unknown and the specificity of Rac inhibitors has been questioned. Here, we examined effects of Rac1 knockdown and of the Rac inhibitors NSC23766 and EHT1864 in human bladder smooth muscle cells (hBSMCs). MAIN METHODS: Rac1 expression was silenced by shRNA expression. Effects of silencing and Rac inhibitors were assessed by CCK-8 assay, EdU staining, RT-PCR, colony formation assay, flow cytometry, and phalloidin staining. KEY FINDINGS: Silencing of Rac1 expression reduced the viability (up to 83% compared to scramble shRNA) and proliferation (virtually completely in proliferation assay), increased apoptosis (124%) and the number of dead cells (51%), and caused breakdown of actin organization (56% reduction of polymerized actin compared to scramble shRNA). Effects on proliferation, viability, and actin organization were mimicked by NSC23766 and EHT1864, while both compounds showed divergent effects on cell death (32-fold increase of dead cells by EHT1864, but not NSC23766). Effects of NSC23766 and EHT1864 on viability of hBSMCs were not altered by Rac1 knockdown. SIGNIFICANCE: Rac1 promotes proliferation, viability, and cytoskeletal organization, and suppresses apoptosis in bladder smooth muscle cells, which may be relevant in overactive bladder or diabetes-related bladder dysfunction. NSC23766 and EHT1864 mimick these effects, but may act Rac1-independently, by shared and divergent effects.


Assuntos
Actinas/metabolismo , Aminoquinolinas/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Pirimidinas/farmacologia , Pironas/farmacologia , Quinolinas/farmacologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inativação Gênica , Células HEK293 , Humanos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Bexiga Urinária/citologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
13.
Life Sci ; 258: 118179, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758626

RESUMO

OBJECTIVE: To evaluate whether approved gastroprokinetic agent, acotiamide exerts a direct excitatory effect on bladder to help explain the reported meaningful reduction of post-void residual urine volume (PVR) in detrusor underactivity (DU) patients after thrice daily oral intake of acotiamide 100 mg for 2 weeks. METHODS: Effect of acotiamide [1-16 µM] was assessed on nerve-mediated contractions evoked by electrical field stimulation (EFS) for 5 s with 5 ms pulse trains of 10 V in longitudinal, mucosa intact rat and human bladder strips to construct frequency response curve (1-32 Hz) and repeat 10 Hz stimulation at 60s interval. Effect of acotiamide 2 µM on spontaneous and carbachol evoked contractions was also assessed. RESULTS: Acotiamide 2 µM significantly enhanced the Atropine and Tetrodotoxin (TTX)-sensitive EFS evoked contractions of rat and human bladder at 8-32 Hz (Two-way ANOVA followed Sidak's multiple comparison; *p < 0.01) and on repeat 10 Hz stimulation (Paired Student's t-test; *p < 0.05), while producing a modest effect on the spontaneous contractions and a negligible effect on the carbachol evoked contractions. CONCLUSIONS: Enhancement of TTX-sensitive evoked contractions of rat and human bladder by acotiamide is consistent with the enhancement of excitatory neuro-effector transmission mainly through prejunctional mechanisms. Findings highlight immense therapeutic potential of antimuscarinics with low M3 receptor affinity like acotiamide in Underactive bladder (UAB)/DU treatment.


Assuntos
Benzamidas/uso terapêutico , Tiazóis/uso terapêutico , Bexiga Inativa/tratamento farmacológico , Bexiga Urinária/patologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Carbacol/farmacologia , Estimulação Elétrica , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Tiazóis/química , Tiazóis/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/inervação
14.
Am J Physiol Renal Physiol ; 319(3): F506-F514, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32715761

RESUMO

To assess whether quantitative T1 relaxometry can measure permeability, chronic inflammation and mural thickening of mouse bladder wall. Adult female C57BL6 mice unexposed to radiation (controls) or 40 wk postirradiation of 10 Gy were scanned at 9.4 T before and after instillation (0.1 mL) of aqueous, novel contrast mixture (NCM) containing 4 mM gadobutrol and 5 mM ferumoxytol. Rapid acquisition with refocused echo (RARE) sequence was used with variable repetition times (TR). Pixel-wise maps of T1 relaxation times for the segmented bladder wall layers were generated from voxel-wise, nonlinear least square data fitting of TR-dependent signal intensity acquired with TR array of 0.4-10 s followed by the histology of harvested bladder. Significant differences between precontrast and postcontrast T1 (ΔT1) were noted in urothelium and lamina propria of both groups but only in detrusor of irradiated group (P < 0.001; 2-way ANOVA). Nearly twofold higher gadobutrol permeability (550 ± 73 vs. 294 ± 160 µM; P < 0.01) derived as per 1/ΔT1 = r1. [C] in urothelium of irradiated group. Inflammation and bladder wall thickening (0.75 ± 0. vs. 0.44 ± 0.08 mm; P < 0.001) predicted by MRI was subsequently confirmed by histology and altered expression of CD45 and zonula occludens-1 (ZO-1) relative to controls. NCM enhanced MRI relies on the retention of large molecular weight ferumoxytol in lumen for negative contrast, while permeation of the non-ionic, small molecular weight gadobutrol through ZO-1 generates positive contrast in bladder wall for virtual measurement of paracellular permeability and assessment of chronic inflammation in thin and distensible bladder wall, which is also defined by its variable shape and location within pelvis.


Assuntos
Inflamação/diagnóstico por imagem , Doenças da Bexiga Urinária/diagnóstico por imagem , Animais , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Feminino , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/farmacocinética , Compostos Organometálicos/farmacologia , Permeabilidade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
15.
J Urol ; 204(6): 1150-1159, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32516030

RESUMO

PURPOSE: We reviewed the literature surrounding the role of opioids and their receptors in urological malignancy. Recent studies have suggested clinically significant effects of agonism or antagonism of opioid receptors on cancer related outcomes and tumorigenesis. The focus of these efforts has centered on nonurological malignancies. However, a compelling body of evidence is growing in the fields of prostate, bladder and kidney cancer. MATERIALS AND METHODS: A systematic review of English language articles published through 2020 was conducted with key phrases related to kidney, bladder or prostate cancer, and opioids or narcotics. A total of 837 unique records were identified, of which 49 were selected for full text review and 33 were included in the qualitative analysis. Eight records were identified via citation review and 1 study was recently presented at a national meeting. RESULTS: Retrospective reviews suggest poorer disease specific and recurrence-free survival with increased perioperative opioid administration in patients undergoing prostate or bladder cancer surgery. However, the data are controversial. Kappa opioid receptors are implicated in both proliferation and inhibition of prostate cancer cell growth across in vitro studies, with a proposed interaction with the androgen cascade. Similarly opioid growth factor receptor is highly expressed in prostate cancer cells and repressed by androgens. Prostate cancer tissue stains more intensely for the mu opioid receptor, and patients with higher expression have poorer oncologic outcomes. Opioid agonism in vitro induces urothelial cell carcinoma proliferation, migration and invasion, with possible additional influence from interactions with the bradykinin b2 receptor. Agonism of the mu, kappa and delta opioid receptors induces renal cell carcinoma tumorigenesis, possibly via upregulation of survivin. Meanwhile, opioid growth factor receptor agonism has the opposite effect in renal cell carcinoma. CONCLUSIONS: Evidence surrounding the role of opioids and their receptors in urological malignancy is provocative and should serve as an impetus for further investigation.


Assuntos
Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Carcinogênese/efeitos dos fármacos , Receptores Opioides/metabolismo , Neoplasias Urológicas/patologia , Analgésicos Opioides/administração & dosagem , Dor do Câncer/etiologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Invasividade Neoplásica/patologia , Manejo da Dor/efeitos adversos , Manejo da Dor/métodos , Período Perioperatório , Próstata/efeitos dos fármacos , Próstata/patologia , Receptores Opioides/agonistas , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Neoplasias Urológicas/complicações , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/terapia
16.
Int. j. morphol ; 38(3): 627-633, June 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1098298

RESUMO

Diabetes Mellitus (DM) is a condition marked by hyperglycaemia that causes systemic complications, including urinary vesicle dysfunction due to oxidative stress. Further, antioxidants, as well as alpha lipoic acid (ALA), may be a response to this pathological condition. The present study verified the action of ALA as a supplement in ration on glycemia and urinary vesicle structures of rats induced by streptozotocin. The rats were divided into 4 groups: Control (CG), Alpha Lipoic (ALAG), Diabetic control (DCG), and the Diabetic alpha lipoic (DALAG) group. For induction, the diabetic groups were initially induced with streptozotocin (dose 60 mg/kg). Subsequently, group glycemia was evaluated weekly. After 8 weeks, the rats were euthanized and the bladder was collected. The bladders were histologically processed and the slides were stained with Masson's Trichrome for the histomorphometry of epithelial height, connective and muscular tissue and coloration of PicroSirius Red for further analysis of collagen fibers of the bladder. The data of the glycemia demonstrated an inferior median in DALAG compared to DGC (p<0.01). The epithelial height and percentage of the muscle tissue were greater in DALAG compared to the DGC, but not significant. However, GDAL showed improvement in the organization of collagen fibers. In conclusion, bladder the morphology alterations caused by DM were not alleviated by the administration of ALA in 8 weeks of the experiments.


La diabetes mellitus (DM) es una afección marcada por hiperglucemia que causa complicaciones sistémicas, incluida la disfunción de la vejiga urinaria debido al estrés oxidativo. Además, los antioxidantes, así como el ácido alfa lipoico (ALA), pueden ser una respuesta a esta condición patológica. El presente estudio verificó la acción de ALA como suplemento en la ración sobre la glucemia y las estructuras de la vejiga urinaria de ratas inducidas por estreptozotocina. Las ratas se dividieron en 4 grupos: control (CG), alfa lipoico (ALAG), control diabético (DCG) y el grupo diabético alfa lipoico (DALAG). Para la inducción, los grupos diabéticos se aplicó estreptozotocina (dosis 60 mg/kg). Posteriormente, la glucemia grupal se evaluó semanalmente. Después de 8 semanas, las ratas se sacrificaron y se retiró la vejiga urinaria. Las vejigas se procesaron histológicamente y las muestras se tiñeron con tricromo de Masson para la histomorfometría y así evaluar la altura epitelial, el tejido conectivo y muscular. Además se tiñeron cond PicroSirius Red para un análisis posterior de las fibras colágenas de la vejiga urinaria. Los datos de la glucemia demostraron una mediana inferior en DALAG en comparación con DGC (p <0,01). La altura epitelial y el porcentaje de tejido muscular fueron mayores en DALAG en comparación con el DGC, pero no estadísticamente significativos. Sin embargo, GDAL mostró una mejora en la organización de las fibras de colágeno. En conclusión, la morfología de las alteraciones de la vejiga causada por DM no se alivió con la administración de ALA en 8 semanas de estudio.


Assuntos
Animais , Ratos , Bexiga Urinária/efeitos dos fármacos , Ácido Tióctico/administração & dosagem , Diabetes Mellitus Experimental/tratamento farmacológico , Antioxidantes/administração & dosagem , Glicemia/análise , Suplementos Nutricionais
17.
Sci Rep ; 10(1): 5824, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242027

RESUMO

Tissue engineering allows to combine biomaterials and seeded cells to experimentally replace urinary bladder wall. The normal bladder wall however, includes branched neuronal network propagating signals which regulate urine storage and voiding. In this study we introduced a novel biocomposite built from amniotic membrane (Am) and graphene which created interface between cells and external stimuli replacing neuronal network. Graphene layers were transferred without modifying Am surface. Applied method allowed to preserve the unique bioactive characteristic of Am. Tissue engineered constructs composed from biocomposite seeded with smooth muscle cells (SMC) derived from porcine detrusor and porcine urothelial cells (UC) were used to evaluate properties of developed biomaterial. The presence of graphene layer significantly increased electrical conductivity of biocomposite. UCs and SMCs showed an organized growth pattern on graphene covered surfaces. Electrical filed stimulation (EFS) applied in vitro led additionally to increased SMCs growth and linear arrangement. 3D printed chamber equipped with 3D printed graphene based electrodes was fabricated to deliver EFS and record pressure changes caused by contracting SMCs seeded biocomposite. Observed contractile response indicated on effective SMCs stimulation mediated by graphene layer which constituted efficient cell to biomaterial interface.


Assuntos
Âmnio/citologia , Materiais Biocompatíveis/administração & dosagem , Grafite/administração & dosagem , Reimplante/métodos , Engenharia Tecidual/métodos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Animais , Proliferação de Células/efeitos dos fármacos , Condutividade Elétrica/uso terapêutico , Masculino , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Suínos , Tecidos Suporte , Urotélio/efeitos dos fármacos
18.
J Pharmacol Exp Ther ; 374(1): 84-92, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32332112

RESUMO

Urinary incontinence is defined as an involuntary leakage of urine and is categorized into three types: stress urinary incontinence (SUI), urge urinary incontinence (UUI), and mixed urinary incontinence, which includes symptoms of SUI and UUI. As the underlying mechanisms of SUI and UUI are different, no drug is approved to treat all three types of urinary incontinence. TAS-303 is a selective norepinephrine reuptake inhibitor and has therapeutic potential for patients with SUI. In this report, we describe newly discovered pharmacological properties of TAS-303 and its effects on bladder function. Radioligand binding studies showed that TAS-303 inhibits M3 muscarinic receptor binding, with a Ki value of 547 nM. TAS-303 at 1, 3, and 10 mg/kg dose-dependently prolonged the intercontraction interval of carbachol-induced detrusor overactivity in rats, exhibiting a maximal effect that was comparable to tolterodine. These effects may result from coordinated regulation of bladder afferent activity via M3 muscarinic inhibition and ß3 adrenoreceptor activation by norepinephrine elevation due to norepinephrine transporter inhibition. Moreover, TAS-303 at the effective dose for bladder function did not induce dry mouth or constipation in rats, showing that this compound may have a lower risk of antimuscarinic side effects. Thus, TAS-303 is expected to be a new profile agent with therapeutic potential for all types of urinary incontinence. SIGNIFICANCE STATEMENT: Urinary incontinence is categorized into stress, urge, and mixed urinary incontinence, but because the underlying mechanisms of each differ, no drugs are available that treat all three. TAS-303 has therapeutic potential for stress urinary incontinence. This study describes newly discovered pharmacological properties of TAS-303, which ameliorated bladder afferent activity partly via M3 muscarinic inhibition, indicating improvement in urge urinary incontinence, and highlights the potential of TAS-303 as a new therapeutic agent for all types of urinary incontinence.


Assuntos
Carbacol/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Atropina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Fluoxetina/análogos & derivados , Fluoxetina/farmacologia , Contração Muscular/efeitos dos fármacos , Ratos , Receptores Muscarínicos/metabolismo , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/induzido quimicamente , Bexiga Urinária Hiperativa/metabolismo
19.
PLoS One ; 15(3): e0230355, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226049

RESUMO

OBJECTIVE: To systematically review outcomes in patients with refractory overactive bladder (OAB) patients who underwent sacral neuromodulation therapy (SNM) therapy after unsuccessful onabotulinumtoxinA (BTX) therapy, and to compare outcomes with those who SNM as initial therapy. METHODS: A systematic search of Cochrane Library, Pubmed and Embase databases from July 2002 to November 2019, to analyze randomized controlled trials and retrospective studies of SNM therapy after failed initial BTX therapy. Two reviewers independently screened the studies and extracted data. A quality assessment of the included literature was conducted using Newcastle-Ottawa Scale (NOS), and Stata 12.0 software was used to conduct a meta-analysis of the collected data. RESULTS: A total of seven studies involving 319 patients were finally included. The success rate in refractory OAB patients who used SNM therapy after failed BTX therapy was 58.5%, 95% CI (0.47-0.70). There was no significant difference between refractory OAB patients who chose SNM as replacement therapy after failed BTX therapy and those who used SNM therapy as first choice [RR = 0.96, 95%CI (0.72-1.26), P = 0.735]. CONCLUSION: OAB patients for whom an initial choice of BTX therapy ends in failure or dissatisfaction may consider switching to SNM therapy. There is no difference in outcomes between these patients and those whose first choice was SNM therapy.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Terapia por Estimulação Elétrica/métodos , Plexo Lombossacral/fisiopatologia , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária/efeitos dos fármacos , Humanos , Plexo Lombossacral/efeitos dos fármacos , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Falha de Tratamento , Bexiga Urinária/inervação , Bexiga Urinária Hiperativa/fisiopatologia
20.
Sci Rep ; 10(1): 4182, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-32144403

RESUMO

We evaluated pathophysiological characteristics of the lower urinary tract dysfunction in a streptozotocin (STZ)-induced diabetic rat model. STZ (60 mg/kg) was injected intraperitoneally into male Wistar rats. In vitro bladder muscle strip experiments, in vivo cystometry, and simultaneous recordings of bladder pressure + urethral perfusion pressure (BP + UPP) with or without intravenous administration of L-arginine (300 mg/kg) or tadalafil (0.03 mg/kg) were performed at several time points. In vitro muscle strip experiments demonstrated that diabetic rats had significantly higher contractile responses to carbachol at 4-16 weeks, and a tendency for higher contractile responses to electrical field stimulation at 4-12 weeks, but this was reversed at 16 weeks. Diabetic rats had significant increases in voided volume, residual volume, bladder capacity, maximal voiding pressure, and amplitude and frequency of non-voiding contractions at 16 weeks. Tadalafil decreased the residual volume in diabetic rats. Diabetic rats had significantly higher UPP nadir and mean UPP during high-frequency oscillation at 16 weeks, which were reversed by tadalafil or L-arginine administration. The present results suggest that urethral relaxation failure, probably related to impairment of the NO/cGMP signalling pathway, rather than bladder contractile dysfunction may be a prominent cause for voiding dysfunction in STZ-induced chronic diabetic rats.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Estreptozocina/toxicidade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologia , Animais , Arginina/uso terapêutico , Diabetes Mellitus Experimental/fisiopatologia , Masculino , Ratos , Ratos Wistar , Volume Residual/efeitos dos fármacos , Tadalafila/uso terapêutico
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