The Potential of Asiatic Acid in the Reversion of Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats

The purpose of this study was to determine if asiatic acid may act efficiently in the model of cyclophosphamide (CYP)-induced cystitis in rats. We performed experiments after administration of CYP (single dose 200 mg/kg, intraperitoneally), asiatic acid (30 mg/kg/day for 14 consecutive days, by oral gavage), or CYP plus asiatic acid, during which conscious cystometry, measurements of urothelium thickness and bladder edema, as well as selected biomarkers analyses were conducted. In rats that received asiatic acid together with CYP, a drop in bladder basal pressure, detrusor overactivity index, non-voiding contraction amplitude, non-voiding contraction frequency, and the area under the pressure curve were observed, when compared to the CYP group. Furthermore, a significant increase in threshold pressure, voided volume, intercontraction interval, bladder compliance, and volume threshold to elicit NVC were found in that group accordingly. Administration of the asiatic acid successfully restored concentrations of biomarkers both in bladder urothelium (BDNF, CGRP, OCT-3, IL-1β, IL-6, NGF, nitrotyrosine, malondialdehyde, TNF-α, SV2A, SNAP23, SNAP25, PAC-1, ORM1, occludin, IGFBP-3, HB-EGF, T–H protein, Z01, and HPX) and detrusor muscle (Rho kinase and VAChT) in CYP-treated rats. Finally, asiatic acid significantly decreased urothelium thickness and bladder oedema. Asiatic acid proved to be a potent and effective drug in the rat model of CYP-induced cystitis.

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NK2 receptor-mediated detrusor muscle contraction involves Gq/11-dependent activation of voltage-dependent Ca2+ channels and the RhoA-Rho kinase pathway

AJP Renal Physiology ◽

10.1152/ajprenal.00106.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. F1154-F1163 ◽

Cited By ~ 1

Author(s):

Bálint Dér ◽

Péter József Molnár ◽

Éva Ruisanchez ◽

Petra Őrsy ◽

Margit Kerék ◽

...

Keyword(s):

Urinary Bladder ◽

Rho Kinase ◽

Detrusor Muscle ◽

Dependent Manner ◽

Contraction Force ◽

Rhoa Activity ◽

Voltage Dependent ◽

Intracellular Ca ◽

Nk2 Receptor ◽

Kinase Pathway

Tachykinins (TKs) are involved in both the physiological regulation of urinary bladder functions and development of overactive bladder syndrome. The aim of the present study was to investigate the signal transduction pathways of TKs in the detrusor muscle to provide potential pharmacological targets for the treatment of bladder dysfunctions related to enhanced TK production. Contraction force, intracellular Ca2+ concentration, and RhoA activity were measured in the mouse urinary bladder smooth muscle (UBSM). TKs and the NK2 receptor (NK2R)-specific agonist [β-Ala8]-NKA(4–10) evoked contraction, which was inhibited by the NKR2 antagonist MEN10376. In Gαq/11-deficient mice, [β-Ala8]-NKA(4–10)-induced contraction and the intracellular Ca2+ concentration increase were abolished. Although Gq/11 proteins are linked principally to phospholipase Cβ and inositol trisphosphate-mediated Ca2+ release from intracellular stores, we found that phospholipase Cβ inhibition and sarcoplasmic reticulum Ca2+ depletion failed to have any effect on contraction induced by [β-Ala8]-NKA(4–10). In contrast, lack of extracellular Ca2+ or blockade of voltage-dependent Ca2+ channels (VDCCs) suppressed contraction. Furthermore, [β-Ala8]-NKA(4–10) increased RhoA activity in the UBSM in a Gq/11-dependent manner and inhibition of Rho kinase with Y-27632 decreased contraction force, whereas the combination of Y-27632 with either VDCC blockade or depletion of extracellular Ca2+ resulted in complete inhibition of [β-Ala8]-NKA(4–10)-induced contractions. In summary, our results indicate that NK2Rs are linked exclusively to Gq/11 proteins in the UBSM and that the intracellular signaling involves the simultaneous activation of VDCC and the RhoA-Rho kinase pathway. These findings may help to identify potential therapeutic targets of bladder dysfunctions related to upregulation of TKs.

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1960 COMPARISON OF NOCTURIA SEVERITY IN MEN, INTERQUARTILE RANGES OF VOIDED VOLUME AND BLADDER COMPLIANCE

The Journal of Urology ◽

10.1016/j.juro.2012.02.2119 ◽

2012 ◽

Vol 187 (4S) ◽

Author(s):

Stephen Marshall ◽

Johnson Tsui ◽

Jeffrey Weiss ◽

Jerry Blaivas ◽

J.L.H. Ruud Bosch

Keyword(s):

Bladder Compliance ◽

Voided Volume

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Mechanisms of BDNF regulation in asthmatic airway smooth muscle

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00414.2015 ◽

2016 ◽

Vol 311 (2) ◽

pp. L270-L279 ◽

Cited By ~ 13

Author(s):

Bharathi Aravamudan ◽

Michael A. Thompson ◽

Christina M. Pabelick ◽

Y. S. Prakash

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Transient Receptor Potential ◽

Rho Kinase ◽

Receptor Potential ◽

Camp Response Element Binding ◽

Transient Receptor Potential Channels ◽

Bdnf Expression ◽

Activated T Cells ◽

Tnf Α

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous, as well as inflammation (TNF-α)-induced BDNF secretion in ASM of nonasthmatic vs. asthmatic humans. We focused on specific Ca2+ regulation- and inflammation-related signaling cascades and quantified BDNF secretion. We find that TNF-α enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC, and PKC cascades, Rho kinase, and transcription factors cAMP response element binding protein and nuclear factor of activated T cells. Basal BDNF expression and secretion are elevated in asthmatic ASM and increase further with TNF-α exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling.

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Alkannin Inhibited Hepatic Inflammation in Diabetic Db/Db Mice

Cellular Physiology and Biochemistry ◽

10.1159/000488264 ◽

2018 ◽

Vol 45 (6) ◽

pp. 2461-2470 ◽

Cited By ~ 3

Author(s):

Wenhua Xue ◽

Zhirui Fan ◽

Yuanzhe Li ◽

Lifeng Li ◽

Tengfei Zhang ◽

...

Keyword(s):

Western Blotting ◽

Tumour Necrosis ◽

Rho Kinase ◽

Hepatic Inflammation ◽

Tnf Α ◽

Hepatoprotective Effects ◽

Kinase Pathway ◽

Necrosis Factor ◽

Pro Inflammatory Cytokines

Background/Aims: The current study was designed to investigate the protective role of alkannin (ALK) on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms. Methods: An oral glucose tolerance test (OGTT) was performed. The levels of insulin, alanine aminotransferase (ALT), aspartate aminotransaminase (AST), total cholesterol (TC) and triglyceride (TG) were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were determined by ELISA. The levels of the ROCK/NF-κB pathway were determined by Western blotting. Results: The contents of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were inhibited by ALK, metformin or fasudil in diabetic db/db mice. Further, Western blotting analysis showed that the expression of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα was significantly reversed by ALK treatment. In human hepatic HepG2 cells, the hepatoprotective effects of ALK were further characterized. With response to palmitic acid-challenge, increased amounts of insulin, ALT, AST, TG, and TC were observed, whereas ALK pretreatment significantly inhibited their leakage in HepG2 cells without appreciable cytotoxic effects. The inflammation condition was recovered with ALK treatment as shown by changes of IL-1β, IL-6 and TNF-α. Further, Western blotting analysis also suggested that ALK improves hepatic inflammation in a Rho-kinase pathway. Conclusion: The present study successfully investigated the role of Rho-kinase signalling in diabetic liver injury. ALK exhibited hepatoprotective effects in diabetic db/db mice, and it might act through improving hepatic inflammation through the Rho-kinase pathway.

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Protective effect of simvastatin in the cyclophosphamide-induced hemohrragic cystitis in rats

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502010000100011 ◽

2010 ◽

Vol 25 (1) ◽

pp. 43-46 ◽

Cited By ~ 23

Author(s):

Anna Carolina Batista Dantas ◽

Francisco Fábio de Araújo Batista-Júnior ◽

Larissa Freitas Macedo ◽

Mariana Noronha Castro Mendes ◽

Ítalo Medeiros Azevedo ◽

...

Keyword(s):

Wistar Rats ◽

Inflammatory Diseases ◽

Hemorrhagic Cystitis ◽

Antineoplastic Agent ◽

Kidney Injury ◽

Immunomodulatory Effects ◽

Tnf Α ◽

Microscopic Evaluation ◽

Plasma Cytokines ◽

Male Wistar Rats

PURPOSE: Cyclophosphamide (CYP) is an antineoplastic agent used for the treatment of many neoplastic and inflammatory diseases. Hemorrhagic cystitis is a frequent side effect of CYP. Several studies show that simvastatin has important pleiotropic (anti-inflammatory and immunomodulatory) effects. The purpose of the study was to investigate the effect of simvastatin on bladder, ureter and kidney injury caused by CYP. METHODS: Adult male Wistar rats were randomly divided into three groups. The CYP/SIM group received simvastatin microemulsion by gavage during 7 days (10 mg/kg body wt) before the administration of CYP and the CYP/SAL group rats received saline 0.9%. The control rats were not treated. After that, all rats were treated with a single dose of CYP 200 mg/kg body wt intraperitoneally. The rats were killed 24 h after CYP administration. Plasma cytokines (TNF-α, IL-1β, IL-6) were measured by ELISA. Macro and light microscopic study was performed in the bladder, kidney and ureter. RESULTS: In the bladders of CYP/SIMV treated rats edema of lamina propria with epithelial and sub-epithelial hemorrhage were lower than in CYP/SAL treated rats. The scores for macroscopic and microscopic evaluation of bladder and ureter were significantly lower in CYP/SIMV rats than in CYP/SAL rats. The kidney was not affected. The expression of TNF-α, IL-1β and IL-6 was significatly lower in CF/SINV rats (164.8±22, 44.8±8 and 52.4±13) than in CF/SAL rats (378.5±66, 122.9±26 e 123.6±18), respectively. CONCLUSION: The results of the current study suggest that simvastatin pretreatment attenuated CYP-induced urotelium inflammation and decreased the activities of cytokines.

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