BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs,including the colon.Accordingly,studies aimed at developing therapies targeting this pathway in var...BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs,including the colon.Accordingly,studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression.Although Numb,Itch,and seven in absentia homolog-1(Siah-1)have been shown to contribute to the regulation of Notch signaling,their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date.AIM To evaluate Numb,Itch,and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior.METHODS Expression of Notch-1,Numb,Itch,and Siah-1 was investigated in 50 colorectal carcinomas,30 adenomas,and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction(PCR)analyses.RESULTS In contrast to Notch-1,which is expressed at higher levels in tumor tissues and adenomas,expression of Numb,Itch,and Siah-1 was stronger and more frequent in normal mucosa(P<0.01).There was a positive correlation between Notch-1 expression and high histological grade,the presence of lymph node metastasis,and advanced-stage tumors,whereas expression of Numb,Itch,and Siah-1 was absent or reduced in tumors with these clinicopathological parameters(P<0.05).In survival analysis,expression of Notch was related to poor prognosis but that of Numb,Itch,and Siah-1 correlated with improved survival(P<0.05).Multivariate analysis revealed Notch-1 expression and loss of Numb expression to be independent prognostic parameters together with lymph node metastasis(P<0.05).CONCLUSION Our findings support the role of Notch-1 in colorectal carcinoma and indicate that loss of Numb,Itch,and Siah-1 expression is associated with carcinogenesis.Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma(CRC)progression and might play an essential role in approaches targeting Notch as novel molecular therapies for CRC.展开更多
The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differenti...The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differential gene expression patterns were analyzed in the lower thoracic spinal cord involved in cholestatic pruritus after BDL operation using high-throughput RNA sequencing. At 21st day after BDL, the expression levels of ENSRNOG00000060523, ENSRNOG00000058405 and ENSRNOG00000055193 mRNA were significantly up-regulated, and those of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289, Gemin8, Serpina3n and Trim63 mRNA were significantly down-regulated in BDL group. The RNAseq data of selected mRNAs were validated by RT-qPCR. The expression levels of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289 and Serpina3n mRNA were significantly down-regulated in BDL group. This study suggested that cholestatic pruritus in experimental obstructive jaundice mouse model is related with in the changes of gene expression profiles in spinal cord.展开更多
Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Metho...Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Methods · Flinching, as well as licking and forelimb wiping of the site of injection were counted as pain responses, whereas biting and hind paw scratching of the cheek were counted as itchy responses. To discriminate formalin-induced sensations in rats, the irritant(saline as control) was injected, and then pain and itchy responses were recorded.Results · Intraplantar injection of formalin elicited biphasic behavior responses characterized as flinching, as well as biting or licking of the hind paw without significant gender differences. Following intradermal administration of formalin to the cheek, rats exhibited episodic forelimb wiping of the cheek, representative of pain. No gender difference was noticed for this type of behavior. In addition, episodes of hind paw scratches of the cheek, representative of pruritoceptive responses, also occurred. Interestingly, hind paw scratches appeared to be more pronounced in male than in female rats. Conclusion · Intradermal administration of formalin elicits pruritoceptive as well as nociceptive responses in rats.展开更多
The averaging in optimal switching control problems is considered under the following two cases: the switching cost does not depend on ε and the switching cost vanishes as ε tends to zero. The value ...The averaging in optimal switching control problems is considered under the following two cases: the switching cost does not depend on ε and the switching cost vanishes as ε tends to zero. The value function of the original fast problem converges locally uniformly to the value function of the averaged problem under both cases. The ways of averaging turn out to be different between both cases.展开更多
Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular se...Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.展开更多
基金Akdeniz University Scientific Research Foundation,Turkey,No.2017040103020.
文摘BACKGROUND The role of the Notch pathway in carcinogenesis and tumor progression has been demonstrated in many organs,including the colon.Accordingly,studies aimed at developing therapies targeting this pathway in various cancers require the identification of several factors that may play a role in regulating Notch-1 expression.Although Numb,Itch,and seven in absentia homolog-1(Siah-1)have been shown to contribute to the regulation of Notch signaling,their role in colorectal carcinogenesis and tumor progression has not been fully elucidated to date.AIM To evaluate Numb,Itch,and Siah-1 expression in colorectal tumors to clarify their relationship with Notch-1 expression and their role in carcinogenesis and tumor behavior.METHODS Expression of Notch-1,Numb,Itch,and Siah-1 was investigated in 50 colorectal carcinomas,30 adenomas,and 20 healthy colonic tissues by immunohistochemistry and quantitative real-time polymerase chain reaction(PCR)analyses.RESULTS In contrast to Notch-1,which is expressed at higher levels in tumor tissues and adenomas,expression of Numb,Itch,and Siah-1 was stronger and more frequent in normal mucosa(P<0.01).There was a positive correlation between Notch-1 expression and high histological grade,the presence of lymph node metastasis,and advanced-stage tumors,whereas expression of Numb,Itch,and Siah-1 was absent or reduced in tumors with these clinicopathological parameters(P<0.05).In survival analysis,expression of Notch was related to poor prognosis but that of Numb,Itch,and Siah-1 correlated with improved survival(P<0.05).Multivariate analysis revealed Notch-1 expression and loss of Numb expression to be independent prognostic parameters together with lymph node metastasis(P<0.05).CONCLUSION Our findings support the role of Notch-1 in colorectal carcinoma and indicate that loss of Numb,Itch,and Siah-1 expression is associated with carcinogenesis.Our data also suggest that these three proteins might be involved in the Notch-1 pathway during colorectal carcinoma(CRC)progression and might play an essential role in approaches targeting Notch as novel molecular therapies for CRC.
文摘The spinal origin of cholestatic itch in experimental obstructive jaundice mouse model remains poorly understood. In this study, the jaundice model was established by bile duct ligation （BDL） in mice, and differential gene expression patterns were analyzed in the lower thoracic spinal cord involved in cholestatic pruritus after BDL operation using high-throughput RNA sequencing. At 21st day after BDL, the expression levels of ENSRNOG00000060523, ENSRNOG00000058405 and ENSRNOG00000055193 mRNA were significantly up-regulated, and those of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289, Gemin8, Serpina3n and Trim63 mRNA were significantly down-regulated in BDL group. The RNAseq data of selected mRNAs were validated by RT-qPCR. The expression levels of ENSRNOG00000042197, ENSRNOG00000008478, ENSRNOG00000019607, ENSRNOG00000020647, ENSRNOG00000046289 and Serpina3n mRNA were significantly down-regulated in BDL group. This study suggested that cholestatic pruritus in experimental obstructive jaundice mouse model is related with in the changes of gene expression profiles in spinal cord.
文摘Objective · Formalin is a classic and most widely used algogenic substance, but its itchy effect is not clear. The present study aims to explore the hypothesis that formalin may induce itch as well as pain. Methods · Flinching, as well as licking and forelimb wiping of the site of injection were counted as pain responses, whereas biting and hind paw scratching of the cheek were counted as itchy responses. To discriminate formalin-induced sensations in rats, the irritant(saline as control) was injected, and then pain and itchy responses were recorded.Results · Intraplantar injection of formalin elicited biphasic behavior responses characterized as flinching, as well as biting or licking of the hind paw without significant gender differences. Following intradermal administration of formalin to the cheek, rats exhibited episodic forelimb wiping of the cheek, representative of pain. No gender difference was noticed for this type of behavior. In addition, episodes of hind paw scratches of the cheek, representative of pruritoceptive responses, also occurred. Interestingly, hind paw scratches appeared to be more pronounced in male than in female rats. Conclusion · Intradermal administration of formalin elicits pruritoceptive as well as nociceptive responses in rats.
文摘The averaging in optimal switching control problems is considered under the following two cases: the switching cost does not depend on ε and the switching cost vanishes as ε tends to zero. The value function of the original fast problem converges locally uniformly to the value function of the averaged problem under both cases. The ways of averaging turn out to be different between both cases.
基金supported by the National Institutes of Health,USA(DE018549,UL1TR001117,P30AR066527,and AR48182 to WL,AR48182-S1 to WL as co-investigatorF33DE024668 and K12DE022793 to YC)+1 种基金the US Department of Defense(W81XWH-13-1-0299 to WL)the Harrington Discovery Institute,Cleveland OH(to WL)
文摘Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
