Transcriptomic analysis of the mechanisms of alleviating renal interstitial fibrosis using the traditional Chinese medicine Kangxianling in a rat model.

Renal interstitial fibrosis (RIF) is currently recognized as a crucial mechanism of the pathogenesis of chronic kidney disease (CKD). Kangxianling (KXL, anti-fibrin) is a traditional Chinese medicine that has been proven to significantly reduce the levels of ECM deposition and inhibit renal fibrosis. To characterize the mechanisms and drug targets of KXL, we established a RIF rat model and treated the rats with KXL and losartan. Histological analyses validated the establishment of the RIF model and the treatment effect of KXL. Multiple levels of transcriptomic datasets were generated using lncRNA, mRNA and microRNA sequencing of kidney tissues. Functional annotations and pathway analyses were performed to unravel the therapeutic mechanisms. A multi-level transcriptomic regulatory network was built to illustrate the core factors in fibrosis pathogenesis and therapeutic regulation. KXL and losartan significantly reduced the progression of RIF, and a better therapeutic effect was shown with higher concentrations of KXL. According to the cluster analysis results of the RNA-seq data, the normal control (NC) and high concentration of KXL (HK) treatment groups were the closest in terms of differentially expressed genes. The WNT, TGF-ß and MAPK pathways were enriched and dominated the pathogenesis and therapy of RIF. miR-15b, miR-21, and miR-6216 were upregulated and miR-107 was downregulated in the fibrosis model. These small RNAs were shown to play critical roles in the regulation of the above fibrosis-related genes and could be inhibited by KXL treatment. Finally, based on the lncRNA datasets, we constructed a mRNA-lncRNA-miRNA coexpression ceRNA network, which identified key regulatory factors in the pathogenesis of kidney fibrosis and therapeutic mechanisms of KXL. Our work revealed the potential mechanism of the Chinese medicine Kangxianling in inhibiting renal interstitial fibrosis and supported the clinical use of KXL in the treatment of kidney fibrosis.

Community-Acquired Urinary Tract Infection by Escherichia coli in the Era of Antibiotic Resistance.

Urinary tract infections (UTIs) caused by Escherichia coli (E. coli) are the most common types of infections in women. The antibiotic resistance of E. coli is increasing rapidly, causing physicians to hesitate when selecting oral antibiotics. In this review, our objective is to ensure that clinicians understand the current seriousness of antibiotic-resistant E. coli, the mechanisms by which resistance is selected for, and methods that can be used to prevent antibiotic resistance.

High Consumption of Green Tea Suppresses Urinary Tract Recurrence of Urothelial Cancer via Down-regulation of Human Antigen-R Expression in Never Smokers.

BACKGROUND/AIM: Smoking is a risk factor for carcinogenesis and progression of urothelial cancer (UC). Green tea polyphenol inhibits these malignant behaviors and suppresses human antigen R (HuR) expression, which is associated with malignant aggressiveness. This study aimed to clarify the anti-cancer effects of green tea based on the smoking status of UC patients. PATIENTS AND METHODS: Three hundred and sixty (260 with bladder cancer, BC and 100 with upper tract UC) patients were divided into three groups based on consumption of green tea: low (<1 cup/day, n=119), middle (1-4 cup/day, n=160), and high (>5 cup/day, n=81). HuR immunoreactivity was evaluated immunohistochemically in formalin-fixed specimens. RESULTS: In never smokers, multivariate analysis showed that the frequency of green tea consumption was a significant predictor (middle: hazard ratio, HR, 0.36, p=0.002; high: HR, 0.20, p=0.003) of urinary tract recurrence. A high consumption of green tea was associated with low rates of urinary tract recurrence and up-grading in UC patients. In BC, high consumption was associated with a lower risk of up-grading (p=0.011) and up-staging (p=0.041) in recurrent cancer. HuR expression in the high-consumption group was lower (p=0.019) than that in other groups. These significant findings were not detected in ever smokers. CONCLUSION: High consumption of green tea suppressed urinary tract recurrence and the risks of up-grading and up-staging by recurrence in never smokers. Our results suggested that HuR expression played important roles in such mechanisms.

Comparación entre ciprofloxacina y antibióticos de otros grupos farmacológicos para el tratamiento de infecciones del tracto urinario / Comparison between ciprofloxacine and antibiotics of other pharmacological groups for urinary tract infection treatment / Comparação entre a ciprofloxacina e outros antibióticos grupos farmacológicos para o tratamento de infecções do tracto urinário

ResumenIntroducción. Las infecciones de tracto urinario son un tema común en los servicios de consulta externa y emergencias de los centros de salud. El uso inadecuado e irracional de antibióticos puede favorecer la aparición de cepas resistentes y limitar la capacidad de respuesta de estos fármacos. Este artículo busca revisar el uso de quinolonas (específicamente ciprofloxacina) con antibióticos de otros grupos farmacológicos y comparar efectividad y resistencia bacteriana.Método. A partir de la metodología que señala la práctica clínica basada en la evidencia para las revisiones rápidas, se estableció una pregunta clínica a la que se le procuró responder mediante la búsqueda de investigaciones primarias en bases de datos electrónicas como MEDLINE, PubMed, Cochrane Library Plus y el Journal of Infection.Resultado. Según el tipo de bacteria y cepa analizada, hay presencia de resistencia a diversos antibióticos. Las infecciones de origen comunitario han sido tratadas con betalactámicos, nitrofurantoína, trimetoprimsulfametoxasol y fluoroquinolonas (especialmente ciprofloxacina).Conclusión. No se determinó si las quinolonas son más efectivas que los antibióticos que pertenecen a otros grupos farmacológicos

AbstractIntroduction. Urinary tract infections are a common reason of consultation in medical practical in ambulatory and emergency rooms in centers of health. The inadequate and irrational use of antibiotics can favor the appearance of resistant bacterial strain and limit the capacity of response of these medicines. This article seeks to review the use of quinolones (specifically ciprofloxacine) with antibiotics of other pharmacological groups and to compare efficiency and bacterial resistance.Method.From the methodology that indicates the clinical practice based on the evidence for the rapid reviews, there was established a clinical question to which response was tried to give by means of the search of primary investigations in electronic databases like MEDLINE, PubMed, Cochrane Library Plus and the Journal of Infection.Result. According to the type of bacterium and analyzed bacterial strain there is presence of resistance to diverse antibiotics. The infections of community origin have been treated by beta-lactamics, nitrofurantoine, trimetoprimsulfametoxasol and fluoroquinolones (specially ciprofloxacine).Conclusion. It was not possible to determine if the quinolonas are more effective than the antibiotics that belong to other pharmacological groups.

ResumoIntrodução. As infecções do trato urinário são um tema comum nos serviços de consulta externa e emergências dos centros de saúde. O uso inadequado e irracional de antibióticos pode favorecer o aparecimento de cepas resistentes e limitar a capacidade de resposta destes medicamentos. Este artigo busca revisar o uso de quinolonas (especificamente ciprofloxacina) com antibióticos de outros grupos farmacológicos e comparar efetividade e resistência bacteriana.Método. A partir da metodologia que aponta a prática clínica baseada na evidência para as revisões rápidas, se estabeleceu uma pergunta clínica que se procurou responder mediante pesquisas primárias em bases de dados eletrônicas como MEDLINE, PubMed, Cochrane Library Plus e o Journal of Infection.Resultado. Segundo o tipo de bactéria e cepa analisada, há presença de resistência a diversos antibióticos. As infecções de origem comunitária tem sido tratadas com betalactâmicos, nitrofurantoína, trimetoprimsulfametoxasol e fluoroquinolonas (especialmente ciprofloxacina).Conclusão. Não se determinou se as quinolonas são mais eficazes que os antibióticos que pertencem a outros grupos farmacológicos

The effects of resveratrol against trifluralin toxicity in the urinary tract of rats.

The herbicide itself and the degradation products are highly toxic on biological systems. The aim of this study is to investigate the potential toxic effects of trifluralin (TRF) on the urinary system of male rats and to investigate the protective effects of resveratrol (RSV) in TRF-induced urinary system damage. A total of 35 male Wistar rats were randomly divided into: (1) control group, (2) sham group, (3) low dose TRF group (0.8 g/kg/day), (4) high dose TRF group (2 g/kg/day) and (5) high dose TRF + RSV group 10 mg/kg/day. RSV was administered for 21 days by intragastric gavage at a dose of 10 mg/kg/day after induction of TRF. Kidney, ureter and urinary bladder tissue was examined using light microscopy and ultrastructurally. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling was performed to detect apoptosis. Superoxide dismutase (SOD), glutathion peroxidase (GPx) and malondialdehyde (MDA) levels were also evaluated biochemically for oxidative stress parameters. Histological evaluation showed that TRF increases apoptosis and oxidative stress, causes histological tissue damages and biochemical changes in the kidneys but does not cause any damage to the ureter and bladder. Treatment with RSV significantly attenuated tissue damage in the urinary system of rats. Apopitotic cells were significantly decreased in the treatment group. Additionally, treatment with RSV decreased SOD and GPx levels and increased MDA levels in the kidney tissue of animals subjected to TRF. These results show that RSV can significantly minimize histological damage and biochemical differences in treating TRF-induced kidney injury in rats.

Two Simple Rules for Improving the Accuracy of Empiric Treatment of Multidrug-Resistant Urinary Tract Infections.

The emergence of multidrug-resistant (MDR) uropathogens is making the treatment of urinary tract infections (UTIs) more challenging. We sought to evaluate the accuracy of empiric therapy for MDR UTIs and the utility of prior culture data in improving the accuracy of the therapy chosen. The electronic health records from three U.S. Department of Veterans Affairs facilities were retrospectively reviewed for the treatments used for MDR UTIs over 4 years. An MDR UTI was defined as an infection caused by a uropathogen resistant to three or more classes of drugs and identified by a clinician to require therapy. Previous data on culture results, antimicrobial use, and outcomes were captured from records from inpatient and outpatient settings. Among 126 patient episodes of MDR UTIs, the choices of empiric therapy against the index pathogen were accurate in 66 (52%) episodes. For the 95 patient episodes for which prior microbiologic data were available, when empiric therapy was concordant with the prior microbiologic data, the rate of accuracy of the treatment against the uropathogen improved from 32% to 76% (odds ratio, 6.9; 95% confidence interval, 2.7 to 17.1; P < 0.001). Genitourinary tract (GU)-directed agents (nitrofurantoin or sulfa agents) were equally as likely as broad-spectrum agents to be accurate (P = 0.3). Choosing an agent concordant with previous microbiologic data significantly increased the chance of accuracy of therapy for MDR UTIs, even if the previous uropathogen was a different species. Also, GU-directed or broad-spectrum therapy choices were equally likely to be accurate. The accuracy of empiric therapy could be improved by the use of these simple rules.

Fangjihuangqi tang improved lower urinary tract dysfunction in benign prostatic hyperplasia rats model.

OBJECTIVE: To investigated the effect and mechanism of Fangjihuangqi Tang (FHT) on lower urinary tract dysfunction induced by benign prostatic hyperplasia (BPH) in rats. METHODS: Male rats were randomly divided into seven groups: normal, model, finasteride (0.5 mg/ kg), terazosin (0.5 mg/kg), and FHT (10, 5, 2.5 g/kg). Rats were administered testosterone (0.5 mg sc) for 6 weeks after orchiectomy, excluding the normal group. All rats were intragastrically administered assigned drugs for 4 weeks from the third week. Urodynamics were assessed in rats under anesthesia. Serum dihydrotestosterone (DHT) and prostatic acid phosphatase (PAP) were measured. The prostate index (PI), bladder index (BI), and pathological detection were evaluated. RESULTS: In the model group, the PI, BI, serum DHT, serum PAP, threshold pressure (TP), micturition pressure (MP), and residual urine volume (RV) were significantly higher. Moreover, inter-micturition duration (IMD) was significantly lower and the prostatic and bladder showed obvious pathological changes. The IMD was significantly higher, while BI, TP, MP, and RV were significantly lower and bladder pathological changes were alleviated in the FHT (10, 5 g/kg), finasteride, and terazosin groups. The PI, DHT, and PAP were significantly lower in the finasteride group, but they did not change significantly in the FHT (10, 5, 2.5 g/kg) and terazosin groups. CONCLUSION: FHT could relieve symptoms of lower urinary tract dysfunction in BPH rats but with no apparent effect on reducing the volume of the enlarged prostate itself.

Crosstalk among dietary polyunsaturated fatty acids, urolithiasis, chronic inflammation, and urinary tract tumor risk.

Based on a consistent bulk of experimental and epidemiologic works, we proposed that abnormal metabolism and/or dietary deprivation of essential polyunsaturated fatty acids by inducing a chronic and subclinical essential fatty acid deficiency (EFAD) in urothelial cell membranes may enhance the risk for urinary tract tumor (UTT) development. This threat may be enhanced by the unusual fact that the fatty-acid profile of the normal urothelium is similar to that reported in EFAD. The risk for UTT may be worsened when coexisting with a low-grade chronic inflammation (LGCI) state induced by urolithiasis or disbalance management of peroxides, free radical molecules, and their quenchers. There is cumulative evidence linking the LGCI of the urinary tract mucosa, calculi, and UTT, due to the long-standing release of promitotic, promutagen, and pro-inflammatory antiapoptotic cytokines in these conditions. The dual role played by pro- and anti-inflammatory eicosanoids and bioactive lipids, cytokines, and the disbalance of lipid peroxidation is discussed, concluding that the moderate, long-standing consumption or dietary supplementation of ω-3 PUFAs may improve the chances of avoiding UTT development.

[Cystostop helps the obstetrician].

Urinary infections are one of the most common infectious diseases. It affects mostly women. The disease become really important during pregnancy because of possible complications for pregnant woman and newborn. Cystostop is a drug that relieves symptoms of urinary infections in acute and chronic phase.

A flow cytometry-based assay for screening FimH antagonists.

Urinary tract infections (UTIs), including cystitis and pyelonephritis, affect a large proportion of the population and account for significant medical costs. In more than 80% of UTIs, uropathogenic Escherichia coli (UPEC) is the causative pathogen. The initial step in the pathogenesis of the infection is the adherence of UPEC to the human bladder epithelium, enabling the invasion into the host cells and the development of UTIs. This process is mediated by the lectin FimH located on type I pili and enables UPECs to attach to oligomannosides of the glycoprotein uroplakin Ia presented on uroepithelial cells. FimH antagonists such as α-d-mannopyranosides have been shown to interfere with the attachment of UPEC to their host cells, thus providing a novel therapeutic opportunity for the treatment and prevention of UTIs. In this article, we report a flow cytometry-based assay to evaluate the potential of FimH antagonists for the prevention of the infection of the human urinary bladder cell line 5637 by UPEC strain UTI89. The assay was optimized and validated, and the inhibitory potency of different α-d-mannopyranosides was determined. Finally, the IC(50) values measured by the flow cytometry-based assay were compared with those reported for other assay formats.

Ion channel modulators and urinary tract function.

The membrane potential fulfils an important role in initiating smooth muscle contraction, through its depolarization and the subsequent influx of Ca(2+) through voltage-gated Ca(2+) channels. Changes in membrane potential can also coordinate contraction across great distances, utilizing the speed of electrical current flow through gap junctions. Hence, regulating membrane potential can greatly influence smooth muscle function. In this chapter, we will consider the influence of ion channels, as dynamic gatekeepers of membrane permeability, on urogenital function. Through their ability to act as key regulators of both the resting membrane potential and its dynamic changes, they provide important pharmacological targets for influencing urogenital function.Urogenital smooth muscle and urothelia contain a diverse range of molecularly and functionally distinct K(+) channels, which are key to regulating the resting membrane and for re-establishing the normal membrane potential following both active and passive changes. The voltage-gated Ca(2+) channels are key to initiating contraction and causing rapid depolarization, supplemented in some smooth muscles by rapid Na(+) conductances. The Cl(-) channels, often assumed to be passive, can actively change the membrane potential, and hence, cellular function, because Cl(-) is not usually at its equilibrium potential. The useful ways in which these ion channels can be targeted therapeutically in the ureter, bladder and urethra are discussed, focussing particularly on treatments for ureteric obstruction and detrusor overactivity. Current treatments for many urinary tract disorders, particularly the overactive bladder, are complicated by side effects. While ion channels have traditionally been considered as poor therapeutic targets by the pharmaceutical industry, our increasing knowledge of the molecular diversity of K(+) and Cl(-) channels gives new hope for more narrowly focused drug targeting, while the exciting discoveries of active currents in interstitial cells give us a new set of cellular targets for drugs.

Long-term efficacy of Serenoa repens treatment in patients with mild and moderate symptomatic benign prostatic hyperplasia.

INTRODUCTION: The study aimed to evaluate the long-term efficacy of treatment with extract of Serenoa repens (Prostamol Uno) in patients with lower urinary tract symptoms (LUTS) induced by benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: We studied 120 patients with mild or moderate LUTS induced by BPH, maximal urinary flow (Q(max)) <15 ml with a voided volume ≥150 ml, prostate-specific antigen <4 ng/ml, and residual urinary volume <150 ml, treated daily for 24 months with one capsule of 320 mg ethanolic extract of Serenoa repens. RESULTS: Statistically significant improvements in the International Prostate Symptom Score (5.5 points), quality of life (QoL; 1.8 points), Q(max) (5.6 ml/s), International Index of Erectile Function (IIEF; 6.4 points) and reduction in residual urinary volume were observed during the study period. The mean prostate volume at 24 months was 36 ml, compared to 39.8 ml at baseline. CONCLUSIONS: Long-term treatment with 320 mg ethanolic extract of Serenoa repens proved to be efficient in reducing urinary obstruction, improving symptomatology and QoL of BPH patients. It also had a positive effect on sexual function, demonstrated by the statistically significant increase in the IIEF.

Dietary, but not supplemental, intakes of carotenoids and vitamin C are associated with decreased odds of lower urinary tract symptoms in men.

Lower urinary tract symptoms (LUTS) in men may be related to micronutrients involved in prevention of oxidative damage or cell growth and differentiation. We tested the hypothesis that carotenoid, vitamin A, and vitamin C intake were inversely associated with total LUTS, voiding, and storage symptoms. We conducted a cross-sectional multivariate analysis of 1466 men aged 30-79 y in the Boston Area Community Health survey (2002-2005), a population-based random sample survey. Data were collected by in-person interview and validated FFQ. Moderate-to-severe LUTS were defined using the American Urological Symptom Index and analyzed using multivariate logistic regression. Overall, men consuming greater dietary lycopene, ß-carotene, total carotenoid, or vitamin A had ~40-50% decreased odds of LUTS compared with the lowest intake quartiles (e.g. ß-carotene and storage symptoms, OR = 0.56, 95% CI = 0.39, 0.82; P-trend = 0.02). Interactions were observed between dietary iron and vitamin C or ß-cryptoxanthin, whereby inverse associations with LUTS, particularly voiding symptoms, occurred only among men with moderate-to-high iron intake (P-interaction = 0.001). High-dose supplemental and total vitamin C were positively associated with LUTS (e.g. supplemental vitamin C ≥ 250 mg/d, OR = 1.83, 95% CI = 1.21, 2.77; P-trend = 0.02). An interaction between ß-carotene and smoking status (P-interaction = 0.004) indicated greater odds of LUTS with higher ß-carotene intake among current smokers. Results suggest that modifying consumption of carotenoids and vitamin C may influence LUTS in men.

Pharmacological effects of saw palmetto extract in the lower urinary tract.

Saw palmetto extract (SPE), an extract from the ripe berries of the American dwarf palm, has been widely used as a therapeutic remedy for urinary dysfunction due to benign prostatic hyperplasia (BPH) in Europe. Numerous mechanisms of action have been proposed for SPE, including the inhibition of 5alpha-reductase. Today, alpha(1)-adrenoceptor antagonists and muscarinic cholinoceptor antagonists are commonly used in the treatment of men with voiding symptoms secondary to BPH. The improvement of voiding symptoms in patients taking SPE may arise from its binding to pharmacologically relevant receptors in the lower urinary tract, such as alpha(1)-adrenoceptors, muscarinic cholinoceptors, 1,4-dihyropyridine receptors and vanilloid receptors. Furthermore, oral administration of SPE has been shown to attenuate the up-regulation of alpha(1)-adrenoceptors in the rat prostate induced by testosterone. Thus, SPE at clinically relevant doses may exert a direct effect on the pharmacological receptors in the lower urinary tract, thereby improving urinary dysfunction in patients with BPH and an overactive bladder. SPE does not have interactions with co-administered drugs or serious adverse events in blood biochemical parameters, suggestive of its relative safety, even with long-term intake. Clinical trials (placebo-controlled and active-controlled trials) of SPE conducted in men with BPH were also reviewed. This review should contribute to the understanding of the pharmacological effects of SPE in the treatment of patients with BPH and associated lower urinary tract symptoms (LUTS).

Isoflavone regulates vascular endothelial growth factor expression in urinary tract of castrated rats.

OBJECTIVE: The purpose of this study was to investigate Vascular Endothelial Growth Factor Expression (VEGF) gene regulation by isoflavone in urinary tract tissues of castrated adult rats. DESIGN: Forty-five adult rats, 90 days old, weighting 200 g were used, receiving a soy-free ration. The animals were castrated for drug administration for 30 days (125 microg genisteine/g body weight/day) and sacrificed, divided into three groups: Group I-control; Group II-started isoflavone administration on the 5th day after castration; Group III-started isoflavone administration on the 28th day after castration. RNA was isolated from each bladder and urethra. Determination of VEGF gene regulated by isoflavone was obtained using a semiquantitative RT-PCR and immunohistochemistry of total RNA isolated from bladder and urethra. RESULTS: Our results demonstrate that isoflavone was able to upregulate mRNA level of the VEGF gene in the lower urinary tract of rats in Group II, where isoflavone administration was started at an early phase of estrogen deprivation, while in Group III, where isoflavone administration was started in the late phase of hypoestrogenism, did not show alteration of bladder and urethra VEGF gene expression, compared to placebo, maintaining the same level of the castrated rats without treatment. CONCLUSIONS: The data indicate that VEGF expression in rats is also regulated by isoflavone in early phase of hypoestrogenism.

Metabolic urinary profiling of alcohol hepatotoxicity and intervention effects of Yin Chen Hao Tang in rats using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry.

This paper was designed to study metabonomic characters of the hepatotoxicity induced by alcohol and the intervention effects of Yin Chen Hao Tang (YCHT), a classic traditional Chinese medicine formula for treatment of jaundice and liver disorders in China. Urinary samples from control, alcohol- and YCHT-treated rats were analyzed by ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC/ESI-QTOF-MS) in positive ionization mode. The total ion chromatograms obtained from the control, alcohol- and YCHT-treated rats were easily distinguishable using a multivariate statistical analysis method such as the principal components analysis (PCA). The greatest difference in metabolic profiling was observed from alcohol-treated rats compared with the control and YCHT-treated rats. The positive ions m/z 664.3126 (9.00 min) was elevated in urine of alcohol-treated rats, whereas, ions m/z 155.3547 (10.96 min) and 708.2932 (9.01 min) were at a lower concentration compared with that in urine of control rats, however, these ions did not indicate a statistical difference between control rats and YCHT-treated rats. The ion m/z 664.3126 was found to correspond to ceramide (d18:1/25:0), providing further support for an involvement of the sphingomyelin signaling pathway in alcohol hepatotoxicity and the intervention effects of YCHT.

Amitriptyline eliminates calculi through urinary tract smooth muscle relaxation.

BACKGROUND: We investigated the effects of amitriptyline in the urinary tract smooth muscle and urolithiasis. METHODS: Cats presenting with obstructive acute renal failure (ARF) received amitriptyline, and renal function and survival rates were analyzed. Isometric contractions and membrane potentials of rat, pig, or human isolated urinary tract smooth muscle were recorded in the presence or absence of amitriptyline. RESULTS: Twenty cats with obstructive ARF caused by urethral plugs received amitriptyline. In all cases, plugs were completely eliminated, and renal function returned to normal, with a 100% survival rate in the follow-up. Amitriptyline produced potent relaxations in rat urethral strips, accompanied by significant reductions in urethral ring membrane potential. This effect was prevented by pretreatment of urethral rings with 4-aminopyridine (4-AP), a voltage-dependent potassium channel blocker. Amitriptyline abolished in a reversible manner acetylcholine-, bradykinin-, and KCl-induced contractions in rat isolated bladder, and this effect was also prevented by 4-AP. Of interest, spontaneous and KCl-induced contractions of pig and human isolated ureter were also blocked by amitriptyline. CONCLUSION: Our results indicate that amitriptyline is an effective and potent relaxant of urinary tract smooth muscle and this effect is mediated by opening of voltage dependent-potassium channels. We suggest that amitriptyline administration may help to promote elimination of urinary calculi.

Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.

The coffee components kahweol and cafestol (K/C) have been reported to protect the colon and other organs of the rat against the formation of DNA adducts by 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and aflatoxin B1. PhIP is a cooked-food mutagen to which significant human exposure and a role in colon cancer etiology are attributed, and, interestingly, such cancers appear to develop at a lower rate in consumers of coffees with high amounts of K/C. Earlier studies in rodent liver have shown that a key role in the chemopreventive effect of K/C is likely to be due to the potential of these compounds to induce the detoxification of xenobiotics by glutathione transferase (GST) and to enhance the synthesis of the corresponding co-factor glutathione. However, mutagens like PhIP may also be detoxified by UDP-glucuronosyl transferase (UDPGT) for which data are lacking regarding a potential effect of K/C. Therefore, in the present study, we investigated the effect of K/C on UDPGT and, concomitantly, we studied overall GST and the pattern of individual GST classes, particularly GST-theta;, which was not included in earlier experiments. In addition, we analyzed the organ-dependence of these potentially chemopreventive effects. K/C was fed to male F344 rats at 0.122% in the chow for 10 days. Enzyme activities in liver, kidney, lung, colon, salivary gland, pancreas, testis, heart and spleen were quantified using five characteristic substrates and the hepatic protein pattern of GST classes alpha, mu, and pi was studied with affinity chromatography/HPLC. Our study showed that K/C is not only capable of increasing overall GST and GST classes alpha, mu, and pi but also of enhancing UDGPT and GST-theta. All investigated K/C effects were strongest in liver and kidney, and some response was seen in lung and colon but none in the other organs. In summary, our results show that K/C treatment leads to a wide spectrum of increases in phase II detoxification enzymes. Notably, these effects occurred preferentially in the well perfused organs liver and kidney, which may thus not only contribute to local protection but also to anti-carcinogenesis in distant, less stimulated organs such as the colon.

Chronic toxicity of thiabendazole (TBZ) in CD-1 mice.

Male and female CD-1 mice (50 mice per group) were administered thiabendazole (TBZ) in diet at levels of 0 (control), 0.031, 0.125 and 0.5% for 78 weeks. A life time study was terminated after 78 weeks due to enhanced strain specific mortality. There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 0.5% group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. It is concluded that TBZ is not carcinogenic to CD-1 mice of both sexes. However, caution should be exercised in the long-term application of high TBZ doses.