Spinal cord-mediated cross-organ sensitization between the uterus and the lower urinary tract may underlie the high concurrence of obstetrical/gynecological inflammation and chronic pelvic pain syndrome characterized by urogenital pain. However, the neural pathway and the neurotransmitters involved are still unknown. We tested the hypothesis that the excitation of capsaicin-sensitive primary afferent fibers arising from the uterus through the stimulation of transient receptor potential vanilloid 1 (TRPV1) induces cross-organ sensitization on the pelvic-urethra reflex activity. Capsaicin (1-1,000 microM, 0.05 ml) was instilled into the uterus to induce cross-organ reflex sensitization. Activation of capsaicin-sensitive primary afferent fibers by capsaicin instillation into the uterine horn sensitized the pelvic-urethra reflex activity that was reversed by an intrauterine pretreatment with capsaizepine, a TRPV1-selective antagonist. Intrathecal injection of AP5, a glutamatergic N-methyl-D-aspartate (NMDA) antagonist, and Co-101244, an NMDA NR2B-selective antagonist, both abolished the cross-organ reflex sensitization caused by capsaicin instillation. These results demonstrated that TRPV1 plays a crucial role in contributing to the capsaicin-sensitive primary afferent fibers mediating the glutamatergic NMDA-dependent cross-organ sensitization between the uterus and the lower urinary tract when there is a tissue injury.

Endogenous ephrinB2 mediates colon-urethra cross-organ sensitization via Src kinase-dependent tyrosine phosphorylation of NR2B. Am J Physiol Renal Physiol 298: F109 -F117, 2010. First published October 28, 2009 doi:10.1152/ajprenal.00287.2009.-Recently, the role of EphB receptor (EphBR) tyrosine kinase and their ephrinB ligands in spinal pain-related neural plasticity has been identified. To test whether Src-family non-receptor tyrosine kinase-dependent glutamatergic Nmethyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation underlies lumbosacral spinal EphBR activation to mediate crossorgan sensitization between the colon and the urethra, external urethra sphincter electromyogram activity evoked by pelvic nerve stimulation and protein expression in the lumbosacral (L6 -S2) dorsal horn were studied before and after intracolonic mustard oil (MO) instillation. We found MO instillation produced colon-urethra reflex sensitization along with an upregulation of endogenous ephrinB2 expression as well as phosphorylation of EphB1/2, Src-family kinase, and NR2B tyrosine residues. Intrathecal immunoglobulin fusion protein of EphB1 and EphB2 as well as PP2 reversed the reflex sensitization and NR2B phosphorylation caused by MO. All these results suggest that EphBR-ephrinB interactions, which provoke Src-family kinase-dependent NMDAR NR2B phosphorylation at the lumbosacral spinal cord level, are involved in cross-organ sensitization, contributing to the development of viscero-visceral referred pain between the bowel and the urethra. pelvic pain syndrome; urethra; irritable bowel syndrome; colon; NMDA ALTHOUGH THE ETIOLOGY IS NOT fully understood, patients with irritable bowel syndrome (IBS) have a higher prevalence of lower urinary tract dysfunction with pelvic pain compared with control groups (15). In addition, pelvic visceral pain might not only arise from an inflamed/injured organ itself but might also be referred from other diseased viscera, and thus results in viscero-visceral referred pain (6). Despite the fact that bowelto-urethra cross-organ sensitization has been demonstrated previously (25), little information is available to explain the underlying mechanism because it could involve complicated interactions in afferent inputs arising from different viscera, known as central sensitization (33).It is established that spinal glutamatergic N-methyl-D-aspartate receptor (NMDAR)-dependent neurotransmission underlies pain-related central sensitization (10, 11). The NMDAR NR2B subunit, as a major unit controlling NMDAR activity via phosphorylation mechanisms, was found to play a pivot role in the NMDA-dependent form of neural plasticity at the spinal cord level (10,11,17,19,20). Chronic inflammatory pain caused by Freund's adjuvant injections was shown to be associated with increases in spinal NR2B subunit phosphorylation (10). Moreover, Slack and colleagues (28) revealed that intrathecal administration of Src-family kinase inhibitors prevented hyperalgesia-related NR2B subunit phosphorylation in the spinal dorsa...

BackgroundMany studies have examined the association between air pollutants (including sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], nitric oxide [NO], ozone [O3], and particulate matter < 10 μm [PM10]) and lung cancer. However, data from previous studies on pathological cell types were limited, especially for SO2 exposure. We aimed to explore the association between SO2 exposure from outdoor air pollutants and female lung cancer incidence by cell type specificity.MethodsWe conducted an ecological study and calculated annual average concentration of 6 air pollutants (SO2, CO, NO2, NO, O3, and PM10) using data from Taiwan Environmental Protection Administration air quality monitoring stations. The Poisson regression models were used to evaluate the association between SO2 and age-standardized incidence rate of female lung cancer by two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]). In order to understand whether there is a dose-response relationship between SO2 and two major pathological types, we analyzed 4 levels of exposure based on quartiles of concentration of SO2.ResultsThe Poisson regression results showed that with the first quartile of SO2 concentration as the baseline, the relative risks for AC/SCC type cancer among females were 1.20 (95% confidence interval [CI], 1.04-1.37)/1.39 (95% CI, 0.96-2.01) for the second, 1.22 (95% CI, 1.04-1.43)/1.58 (95% CI, 1.06-2.37) for the third, and 1.27 (95% CI, 1.06-1.52)/1.80 (95% CI, 1.15-2.84) for the fourth quartile of SO2 concentration. The tests for trend were statistically significant for both AC and SCC at P = 0.0272 and 0.0145, respectively.ConclusionThe current study suggests that SO2 exposure as an air pollutant may increase female lung cancer incidence and the associations with female lung cancer is much stronger for SCC than for AC. The findings of this study warrant further investigation on the role of SO2 in the etiology of SCC.

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Abstract. Epigallocatechin-3-gallate (EGCG), a polyphenol constituent present in green tea, has been shown to inhibit the growth of cancer cells in vitro and in vivo. However, studies regarding human bladder carcinoma cells are limited and not well investigated. Hence, our study focused on the evaluation of EGCG-triggered apoptosis in TSGH-8301 human urinary bladder carcinoma cells in vivo and in vitro as well as its related molecular mechanisms. In an in vivo study, EGCG inhibited xenograft tumor size of TSGH-8301 cells in a nude mouse model. Based on an in vitro study, EGCG resulted in morphological changes and increased growth inhibition in a dose-and time-dependent manner in TSGH-8301 cells. Furthermore, sub-G1 populations were shown and caspase-9 and -3 activities were stimulated in EGCG-treated TSGH-8301 cells. Moreover, a caspase-9 inhibitor (Z-LEHD-FMK) and a caspase-3 inhibitor (Z-DEVD-FMK) were able to reduce EGCG-stimulated caspase-9 and -3 activities, respectively. Loss of mitochondrial membrane potential (∆Ψm) resulted in an increase of protein levels of cytochrome c, Apaf-1, caspase-9 and -3 in TSGH-8301 cells following exposure to EGCG. Proteomic analysis revealed that EGCG affected the expression levels of various proteins, including HSP27, porin, tropomyosin 3 isoform 2, prohibitin and keratin 5, 14, 17 in TSGH-8301 cells. EGCG also suppressed AKT kinase activity and protein levels and also altered the expression levels of Bcl-2 family-related proteins such as Bcl-2, Bax, BAD and p-BAD. Based on the above findings, this study suggests that EGCGprovoked apoptotic death in TSGH-8301 cells is mediated through targeting AKT and HSP27 and modulating p-BAD, leading to activation of the intrinsic apoptotic pathway.