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Regulative effect of anandamide-mediated cannabinoid receptor in rats with visceral hypersensitivity
Yu-qin HE,Lei JI,Qiang CHEN,Bo ZHANG
Medical Journal of Chinese People's Liberation Army , 2012,
Abstract: Objective  To investigate the role of anandamide(ANA)-mediated cannabinoid receptor 1(CB1) on the acquisition of visceral hypersensitivity in rats, and explore its underlying mechanism. Methods  The visceral hypersensitivity non-noxious/noxious colorectal distension (NNCRD/NCRD) model of rat was reproduced by ovalbumin (OVA) sensitization combined with NNCRD/NCRD. Fifty-four rats were randomly divided into control group (n=7), saline+CRD group (n=7), OVA+CRD+dimethyl sulfoxide (DMSO) group (n=8), OVA+CRD+different concentrations of ANA (0.5, 5.0, 10.0mg/kg) groups (8 each), and OVA+CRD+ANA+AM251 group (n=8). The expression and quantitative assessment of CB1 were monitored by immunoflurorescence and laser scanning confocal analysis. The visceral sensitivity was evaluated by the area under curve (AUC) of myoelectrical activity of abdominal wall muscle. Results  By NCRD at 80mmHg, the density of CB1 immunofluorescence intensity was significantly higher in L4–L6 of the spinal cord of the rats in saline+CRD group compared with that in control group (P < 0.05). The expression of CB1 was higher in OVA+CRD+DMSO group than in saline+CRD group (P < 0.05). By NNCRD at 20 mmHg, no statistical difference was found in the AUC of visceromotor reflex (VMR) among various groups (P>0.05). By NCRD at 80mmHg, the VMR-AUC increased obviously in OVA+CRD+DMSO group as compared with that of saline+CRD group, but it decreased significantly in OVA+CRD+high concentration ANA group (P < 0.05). When AM251 was intravenously given, VMR-AUC increased significantly in OVA+CRD+ANA+AM251 group compared with that in OVA+CRD+different concentrations of ANA groups (P < 0.05). Conclusions Intravenous administration of ANA may mitigate the visceral nociception induced by basic OVAsensitization combined with NCRD stimulation in CB1-mediated manner. It indicated that anandamide-mediated CB1 cannabinoid receptor may regulate the development and maintenance of visceral hypersensitivity.
Peroxisome proliferator-activated receptor γ and colorectal cancer  [cached]
Yun Dai,Wei-Hong Wang
World Journal of Gastrointestinal Oncology , 2010,
Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and ligand-activated transcription factors. PPARγ plays an important role in adipocyte differentiation, lipid storage and energy dissipation in adipose tissue, and is involved in the control of inflammatory reactions as well as in glucose metabolism through the improvement of insulin sensitivity. Growing evidence has demonstrated that activation of PPARγ has an antineoplastic effect in tumors, including colorectal cancer. High expression of PPARγ is detected in human colon cancer cell lines and adenocarcinoma. This review describes the molecular mechanisms by which PPARγ regulates tumorigenesis in colorectal cancer, and examines current clinical trials evaluating PPARγ agonists as therapeutic agents for colorectal cancer.
NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs) during inflammation induced visceral hypersensitivity
Shelby K Suckow, Robert M Caudle
Molecular Pain , 2009, DOI: 10.1186/1744-8069-5-54
Abstract: CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs.Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned animals. Therefore, these data suggest that CANs contribute to visceral hypersensitivity during inflammation.Functional bowel disorders are commonly characterized by altered motility of the gut as well as abdominal pain. Patients with bowel disorders are known to have decreased thresholds to pain for both visceral and somatic stimuli [1]. Ritchie [2] reported that patients with irritable bowel syndrome (IBS) experience colonic pain at lower balloon distension pressures than controls following colorectal distension (CRD). Pain associated with low pressure balloon distension is thought to be indicative of visceral hypersensitivity caused by abnormal motility patterns in patients with bowel disorders. The molecular mechanism that is responsible for visceral hypersensitivity is still currently unknown; however, it is thought to be caused by changes in neuronal excitability of visceral afferents [1].To date, it is thought that visceral hypersensitivity is mediated by sensory nociceptors of the dorsal root gangl
The Role of Peroxisome Proliferator-Activated Receptors in Colorectal Cancer  [PDF]
Joo-In Park,Jong-Young Kwak
PPAR Research , 2012, DOI: 10.1155/2012/876418
Abstract: Colorectal cancer is one of the most common cancers in the world. Dietary fat intake is a major risk factor for colorectal cancer. Some nuclear hormone receptors play an important role in regulating nutrient metabolism and energy homeostasis. Among these receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in colorectal cancer, because PPARs are involved in regulation of lipid and carbohydrate metabolism. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARβ/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPARs. Even though many investigators have studied the expression and clinical implications of PPARs in colorectal cancer, there are still many controversies about the role of PPARs in colorectal cancer. In this paper, the recent progresses in understanding the role of PPARs in colorectal cancer are summarized. 1. Introduction Colorectal cancer is one of the most common cancers in the world. Its incidence appears to be increasing, particularly in developed countries [1–3]. Colorectal carcinogenesis results from the loss of the normal regulatory pathways involved in cell proliferation and cell death. Especially, molecular alterations of multiple pathways including Wnt (Wingless type)/adenomatous polyposis coli (APC), cyclooxygenase-2 (COX-2), and Ras are known to play important roles in progression of colorectal cancer. Recent progresses in the development of new chemotherapeutic agents have improved the prognosis of colorectal cancer patients [4]. However, for most patients with advanced colorectal cancer, it is still difficult to achieve a complete remission, especially with surgery or chemotherapy. Therefore, significant effort has been exerted to identify novel drug targets for both the prevention and treatment of colorectal cancer. The peroxisome proliferator-activated receptors (PPARs) belong to members of the nuclear hormone receptor superfamily including receptors for steroid, retinoid, vitamin D, and thyroid hormones [5]. PPARs have received the attention of investigators interested in studying about the intracellular pathways that control signal transduction and gene transcription since their discovery in 1990. The name of PPARs was derived from its property to proliferate peroxisomes in rodent liver, where PPARα plays the major role. However, none of the PPARs could be contributed to peroxisome proliferation in humans [6]. PPARs are metabolic regulators involved in the
Peripheral corticotropin releasing hormone mediates post-inflammatory visceral hypersensitivity in rats  [cached]
Jun-Ho La, Tae-Sik Sung, Hyun-Ju Kim, Tae-Wan Kim, Tong Mook Kang, Il-Suk Yang
World Journal of Gastroenterology , 2008,
Abstract: AIM: To investigate whether peripheral corticotropin releasing hormone (CRH), which is up-regulated in intestinal inflammation, mediates the post-inflammatory visceral hypersensitivity in a rat model of colitis.METHODS: We measured mucosal myeloperoxidase (MPO) activity as a marker of inflammation, plasma CRH level, and abdominal withdrawal reflex (AWR) to colorectal distension as a visceral nociceptive response at 2, 7 and 14 d after the induction of colitis with 4% acetic acid.RESULTS: Colonic inflammation, quantified by MPO activity, significantly increased on d 2 and subsided thereafter, which indicated a resolution of inflammation within 7 d. On the contrary, plasma CRH level and AWR score were increased on d 2, remained high on d 7, and returned to control level on d 14. Intraperitoneal injection of a CRH antagonist, astressin (30 μg/kg), significantly attenuated the post-inflammatory visceral hypersensitivity on d 7. Furthermore, intraperitoneal administration of CRH (3 and 10 μg/kg) mimicked the post-inflammatory visceral hypersensitivity in naive rats.CONCLUSION: These results suggest that increased peripheral CRH mediates the enhanced visceral nociception in rats recovered from experimental colitis.
Peroxisome proliferator activated receptor-γ and the ubiquitin-proteasome system in colorectal cancer  [cached]
Ioannis A Voutsadakis
World Journal of Gastrointestinal Oncology , 2010,
Abstract: Peroxisome proliferator activated receptor-γ (PPARγ), a transcription factor of the nuclear receptor superfamily plays a significant role in colorectal cancer pathogenesis. In most experimental systems PPARγ activation has tumor suppressing effects in the colon. PPARγ is regulated at multiple levels by the ubiquitin-proteasome system (UPS). At a first level, UPS regulates PPARγ transcription. This regulation involves both PPARγ transcription specific factors and the general transcription machinery. At a second level UPS regulates PPARγ and its co-factors themselves, as PPARγ and many co-factors are proteasome substrates. At a third level of regulation, transduction pathways working in parallel but also having interrelations with PPARγ are regulated by the UPS, creating a network of regulation in the colorectal carcinogenesis-related pathways that are under UPS control. Activation of PPARγ transcription by direct pharmacologic activators and by stabilization of its molecule by proteasome inhibitors could be strategies to be exploited in colorectal cancer treatment.
Adrenergic β2-Receptors Mediates Visceral Hypersensitivity Induced by Heterotypic Intermittent Stress in Rats  [PDF]
Chunhua Zhang, Yun-Yun Rui, Yuan-Yuan Zhou, Zhong Ju, Hong-Hong Zhang, Chuang-Ying Hu, Ying Xiao, Guang-Yin Xu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094726
Abstract: Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β–adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (IK) without any alteration of fast-inactivating potassium current density (IA). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the colon. The present study might provide a potential molecular target for therapy of visceral hypersensitivity in patents with IBS.
Peroxisome Proliferator-Activated Receptors and Progression of Colorectal Cancer  [PDF]
Dingzhi Wang,Raymond N. DuBois
PPAR Research , 2008, DOI: 10.1155/2008/931074
Abstract: The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. These receptors are also ligand-dependent transcription factors responsible for the regulation of cellular events that range from glucose and lipid homeostases to cell differentiation and apoptosis. The importance of these receptors in lipid homeostasis and energy balance is well established. In addition to these metabolic and anti-inflammatory properties, emerging evidence indicates that PPARs can function as either tumor suppressors or accelerators, suggesting that these receptors are potential candidates as drug targets for cancer prevention and treatment. However, conflicting results have emerged regarding the role of PPARs on colon carcinogenesis. Therefore, further investigation is warranted prior to considering modulation of PPARs as an efficacious therapy for colorectal cancer chemoprevention and treatment.
Leptin and peroxisome proliferator-activated receptor γ expression in colorectal adenoma  [cached]
Hyung Hun Kim,You Sun Kim,Yun Kyung Kang,Jeong Seop Moon
World Journal of Gastroenterology , 2012, DOI: 10.3748/wjg.v18.i6.557
Abstract: AIM: To investigate the expressions of leptin and peroxisome proliferator-activated receptor γ (PPARG) in relation to body mass index (BMI). METHODS: We evaluated leptin and PPARG expression in 30 adenomas over 1 cm in size by immunohistochemical staining. In addition, clinicopathologic features including BMI were assessed. RESULTS: PPARG and leptin expression showed a strong positive correlation (P = 0.035). The average BMI of the leptin-positive group was higher than that of the leptin-negative group (25.4 ± 3.4 kg/m2 vs 22.6 ± 2.4 kg/m2, P = 0.018), and leptin expression was significantly correlated with high BMI (P = 0.024). Leptin expression was more frequently observed in intermediate/high grade dysplasia than in low grade dysplasia (P = 0.030). However, PPARG expression was not correlated with BMI and grade of dysplasia. CONCLUSION: BMI has influenced on the leptin expression of colorectal adenoma. The exact mechanism underlies the strong correlation between leptin and PPARG expression needs further study.
Hydrogen sulphide induces μ opioid receptor-dependent analgesia in a rodent model of visceral pain
Eleonora Distrutti, Sabrina Cipriani, Barbara Renga, Andrea Mencarelli, Marco Migliorati, Stefano Cianetti, Stefano Fiorucci
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-36
Abstract: The perception of painful sensation induced by colorectal distension (CRD) in conscious rats was measured by assessing the abdominal withdrawal reflex. The contribution of opioid receptors to H2S-induced analgesia was investigated by administering rats with selective μ, κ and δ opioid receptor antagonists and antisenses. To investigate whether H2S causes μ opioid receptor (MOR) transactivation, the neuronal like cells SKNMCs were challenged with H2S in the presence of MOR agonist (DAMGO) or antagonist (CTAP). MOR activation and phosphorylation, its association to β arrestin and internalization were measured.H2S exerted a potent analgesic effects on CRD-induced pain. H2S-induced analgesia required the activation of the opioid system. By pharmacological and molecular analyses, a robust inhibition of H2S-induced analgesia was observed in response to central administration of CTAP and MOR antisense, while κ and δ receptors were less involved. H2S caused MOR transactivation and internalization in SKNMCs by a mechanism that required AKT phosphorylation. MOR transactivation was inhibited by LY294002, a PI3K inhibitor, and glibenclamide, a KATP channels blocker.This study provides pharmacological and molecular evidence that antinociception exerted by H2S in a rodent model of visceral pain is modulated by the transactivation of MOR. This observation provides support for development of new pharmacological approaches to visceral pain.Visceral pain is the most common sign of acute and chronic gastrointestinal, pelvic and genitourinary diseases. As one of the most common causes of persistent disability, visceral pain represents a frequent reason for patients to seek medical treatment. Despite multiple therapeutic approaches, the treatment of visceral pain remains a significant challenge.A complex network of signaling molecules mediates perception of visceral pain [1]. Hydrogen sulphide (H2S) is a gaseous neuromodulator generated from L-cysteine by the activity of two pyrodoxal-5
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