Prognostic value of fatty acid metabolism-related genes in colorectal cancer and their potential implications for immunotherapy.

Introduction: Colorectal cancer is one of the most common gastrointestinal cancers and the second leading cause of cancer-related death. Although colonoscopy screening has greatly improved the early diagnosis of colorectal cancer, its recurrence and metastasis are still significant problems. Tumour cells usually have the hallmark of metabolic reprogramming, while fatty acids play important roles in energy storage, cell membrane synthesis, and signal transduction. Many pathways of fatty acid metabolism (FAM) are involved in the occurrence and development of colon cancer, and the complex molecular interaction network contains a variety of genes encoding key enzymes and related products. Methods: Clinical information and RNA sequencing data were collected from TCGA and GEO databases. The prognosis model of colon cancer was constructed by LASSO-Cox regression analysis among the selected fatty acid metabolism genes with differential expression. Nomogram for the prognosis model was also constructed in order to analyze its value in evaluating the survival and clinical stage of the colon cancer patients. The differential expression of the selected genes was verified by qPCR and immunohistochemistry. GSEA and GSVA were used to analyze the enrichment pathways for high- and low-risk groups. CIBERSORT was used to analyze the immune microenvironment of colon cancer and to compare the infiltration of immune cells in the high- and low-risk groups. The "circlize" package was used to explore the correlation between the risk score signature and immunotherapy for colon cancer. Results: We analysed the differential expression of 704 FAM-related genes between colon tumour and normal tissue and screened 10 genes with prognostic value. Subsequently, we constructed a prognostic model for colon cancer based on eight optimal FAM genes through LASSO Cox regression analysis in the TCGA-COAD dataset, and its practicality was validated in the GSE39582 dataset. Moreover, the risk score calculated based on the prognostic model was validated as an independent prognostic factor for colon cancer patients. We further constructed a nomogram composed of the risk score signature, age and American Joint Committee on Cancer (AJCC) stage for clinical application. The colon cancer cohort was divided into high- and low-risk groups according to the optimal cut-off value, and different enrichment pathways and immune microenvironments were depicted in the groups. Discussion: Since the risk score signature was significantly correlated with the expression of immune checkpoint molecules, the prognostic model might be able to predict the immunotherapy response of colon cancer patients. In summary, our findings expand the prognostic value of FAM-related genes in colon cancer and provide evidence for their application in guiding immunotherapy.

Estrogen alleviates acute and chronic itch in mice.

Itching is associated with various skin diseases, including atopic dermatitis and allergic dermatitis, and leads to repeated scratching behavior and unpleasant sensation. Although clinical and laboratory research data have shown that estrogen is involved in regulating itch, the molecular and cellular basis of estrogen in itch sensation remains elusive. In the present study, it was found that estrogen-treated mice exhibited reduced scratching bouts when challenged with histamine, chloroquine, the proteinase-activated receptor-2 activating peptide SLIGRL-NH2 (SLIGRL), compound 48/80, and 5-hydroxytryptamine when compared with mice in the placebo group. Moreover, estrogen also suppressed scratching bouts in the mouse model of chronic itch induced by acetone-ether-water treatment. Notably, consistent with the behavioral tests, the present RNA-seq analysis showed that estrogen treatment caused significantly reduced expression levels of itch-related molecules such as Mas-related G-protein coupled receptor member A3, neuromedin B and natriuretic polypeptide b. In addition, estradiol attenuated histamine-induced and chloroquine-induced calcium influx in dorsal root ganglion neurons. Collectively, the data of the present study suggested that estrogen modulates the expression of itch-related molecules and suppresses both acute and chronic itch in mice.

Fecal Signatures of Streptococcus anginosus and Streptococcus constellatus for Noninvasive Screening and Early Warning of Gastric Cancer.

BACKGROUND & AIMS: Most patients with gastric cancer (GCa) are diagnosed at an advanced stage. We aimed to investigate novel fecal signatures for clinical application in early diagnosis of GCa. METHODS: This was an observational study that included 1043 patients from 10 hospitals in China. In the discovery cohort, 16S ribosomal RNA gene analysis was performed in paired samples (tissues and feces) from patients with GCa and chronic gastritis (ChG) to determine differential abundant microbes. Their relative abundances were detected using quantitative real-time polymerase chain reaction to test them as bacterial candidates in the training cohort. Their diagnostic efficacy was validated in the validation cohort. RESULTS: Significant enrichments of Streptococcus anginosus (Sa) and Streptococcus constellatus (Sc) in GCa tumor tissues (P < .05) and feces (P < .0001) were observed in patients with intraepithelial neoplasia, early and advanced GCa. Either the signature parallel test Sa∪Sc or single signature Sa/Sc demonstrated superior sensitivity (Sa: 75.6% vs 72.1%, P < .05; Sc: 84.4% vs 64.0%, P < .001; and Sa∪Sc: 91.1% vs 81.4%, P < .01) in detecting early GCa compared with advanced GCa (specificity: Sa: 84.0% vs 83.9%, Sc: 70.4% vs 82.3%, and Sa∪Sc: 64.0% vs 73.4%). Fecal signature Sa∪Sc outperformed Sa∪CEA/Sc∪CEA in the discrimination of advanced GCa (sensitivity: 81.4% vs 74.2% and 81.4% vs 72.3%, P < .01; specificity: 73.4% vs 81.0 % and 73.4% vs 81.0%). The performance of Sa∪Sc in the diagnosis of both early and advanced GCa was verified in the validation cohort. CONCLUSION: Fecal Sa and Sc are noninvasive, accurate, and sensitive signatures for early warning in GCa. (ClinicalTrials.gov, Number: NCT04638959).

TRPV4 Overexpression Promotes Metastasis Through Epithelial-Mesenchymal Transition in Gastric Cancer and Correlates with Poor Prognosis.

PURPOSE: Transient receptor potential vanilloid 4 (TRPV4) has been reported to be involved in the progression of several human tumors. Nevertheless, clinical significance and molecular mechanism of TRPV4 in gastric cancer (GC) remain poorly defined. PATIENTS AND METHODS: Immunohistochemistry assays were used to investigate the correlation between the expression of TRPV4 and epithelial-mesenchymal transition (EMT) markers in human GC tissues. The correlations between TRPV4 expression and clinicopathological features and between TRPV4 expression and survival rates were also examined. TRPV4 knockdown was performed by using small interfering RNAs. In vitro, Cell Counting Kit-8 (CCK-8) assay, colony formation assay, and transwell assay were employed to further explore the biological functions of TRPV4, and Western blotting was used to evaluate the changes in the expression of TRPV4 protein and EMT-related proteins in HGC-27 and MGC-803 human GC cell lines. RESULTS: TRPV4 expression was upregulated in GC tissues and cell lines. TRPV4 overexpression was associated with greater depth of tumor invasion, lymph node metastasis, higher TNM stage, poor overall survival, and worse disease-free survival. TRPV4 expression was inversely correlated with E-cadherin expression and positively correlated with vimentin expression. In vitro, knockdown of TRPV4 inhibited GC cell proliferation, colony formation, and invasion. Furthermore, the knockdown of TRPV4 modulated EMT by upregulating E-cadherin expression and downregulating the expression of N-cadherin and vimentin. In addition, the EMT-related transcription factor Snail was downregulated, whereas the expression levels of other transcription factors such as Slug and Twist did not change. CONCLUSION: TRPV4 was upregulated in human GC and the overexpression of TRPV4 could promote GC progression, partially through Snail-mediated EMT.

A nicotine-induced positive feedback loop between HIF1A and YAP1 contributes to epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma.

BACKGROUND: Nicotine, an active ingredient in tobacco, can promote epithelial-to-mesenchymal transition (EMT) processes that enhance the aggressiveness of a number of human cancers. In the present study, we investigated whether cigarette smoke/nicotine drives EMT in pancreatic ductal adenocarcinoma (PDAC). METHODS: Quantitative real-time PCR, western blot, immunohistochemistry, and immunofluorescence assays were used to evaluate Yes-associated protein 1 (YAP1) expression associated with cigarette smoking in human PDAC tissue samples and with nicotine exposure in PDAC cell lines. Bioinformatics, loss- and gain- of- function experiments, luciferase reporter assays, chromatin immunoprecipitation (ChIP), and murine tumor xenograft models were performed to examine the function of YAP1 in PDAC and to identify potential mechanisms of action. RESULTS: Exposure to smoking or nicotine promoted EMT and tumor growth in PDAC cells and in xenograft tumors. Functional studies revealed that YAP1 might drive nicotine-stimulated EMT and oncogenic activity in vitro and in vivo. In human PDAC tissues, upregulation of YAP1 was associated with "ever smoking" status and poor overall survival. In term of mechanism, hypoxia inducible factor (HIF)1A promoted YAP1 nuclear localization and YAP1 transactivation by directly binding to the hypoxia responsive elements of the YAP1 promoter upon nicotine treatment. Nicotine stimulated HIF1A and YAP1 expression by activating cholinergic receptor nicotinic alpha7 (CHRNA7). In addition, YAP1 increased and sustained the protein stability of HIF1A. CONCLUSIONS: These data demonstrate that YAP1 enhances nicotine-stimulated EMT and tumor progression of PDAC through a HIF1A/YAP1 positive feedback loop. Developing inhibitors that specifically target YAP1 may provide a novel therapeutic approach to suppress PDAC growth, especially in PDAC patients who have a history of smoking.

Relationship between Helicobacter pylori and expression of programmed death-1 and its ligand in gastric intraepithelial neoplasia and early-stage gastric cancer.

Background: Many studies have shown that programmed cell death protein 1 (PD-1) and its ligand, PD-L1, are expressed in advanced gastric cancer. Furthermore, detection of these proteins is associated with infiltrating CD8+ T-cells, indicating that an adaptive immune resistance mechanism occurs in advanced gastric cancer. However, PD-L1 and PD-1 expression in gastric intraepithelial neoplasia and early-stage gastric cancer (EGC) has yet to be elucidated. Patients and methods: Fifty-four resections of low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and EGC were stained by immunohistochemistry for PD-1, PD-L1, and CD8. CD8+ T-cell densities both within tumors and in the tumor-stromal interface were analyzed. Flow cytometry (FACS) was used to analyze the PD-1 expression in tumor tissues and peripheral blood mononuclear cells. Furthermore, the relationship between Helicobacter pylori (Hp) infection and PD-1 and PD-L1 was also evaluated. Results: We demonstrated that PD-L1 expression was significantly increased in HGIN and EGC compared with LGIN, and both PD-1 and PD-L1 showed similar expression patterns, being mainly detected in infiltrating immune cells. FACS also showed that PD-1 was expressed on both CD4+ and CD8+ T-cells. However, no difference was found in CD8+ T-cell infiltration between LGIN and HGIN+EGC, and this was not not found to be associated with PD-L1 or PD-1 expression. However, Hp infection was significantly associated with expression of PD-L1 and PD-1. Conclusions: The PD-1/PD-L1 checkpoint is involved in intraepithelial neoplasia and EGC, but an adaptive immune resistance mechanism does not occur. Expression of PD-1/PD-L1 is also associated with Hp infection, and so Hp infection may be an important initiating factor. Clinical Trial Registration information: This study was approved by the Institutional Review Board of Ruijin Hospital and written informed consent was obtained from all patients.

TRPV4 Channel Signaling in Macrophages Promotes Gastrointestinal Motility via Direct Effects on Smooth Muscle Cells.

Intestinal macrophages are critical for gastrointestinal (GI) homeostasis, but our understanding of their role in regulating intestinal motility is incomplete. Here, we report that CX3C chemokine receptor 1-expressing muscularis macrophages (MMs) were required to maintain normal GI motility. MMs expressed the transient receptor potential vanilloid 4 (TRPV4) channel, which senses thermal, mechanical, and chemical cues. Selective pharmacologic inhibition of TRPV4 or conditional deletion of TRPV4 from macrophages decreased intestinal motility and was sufficient to reverse the GI hypermotility that is associated with chemotherapy treatment. Mechanistically, stimulation of MMs via TRPV4 promoted the release of prostaglandin E2 and elicited colon contraction in a paracrine manner via prostaglandin E receptor signaling in intestinal smooth muscle cells without input from the enteric nervous system. Collectively, our data identify TRPV4-expressing MMs as an essential component required for maintaining normal GI motility and provide potential drug targets for GI motility disorders.

Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch.

BACKGROUND: Chronic itch is a highly debilitating symptom that underlies many medical disorders with no universally effective treatments. Although unique neuronal signaling cascades in the sensory ganglia and spinal cord have been shown to critically promote the pathogenesis of chronic itch, the role of skin-associated cells remains poorly understood. OBJECTIVE: We sought to examine the cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4)-mediated allergic and nonallergic chronic itch. METHODS: Expression of TRPV4 in chronic itch and healthy control skin preparations was examined by using real-time RT-PCR. Trpv4eGFP mice were used to study the expression and function of TRPV4 in the skin by means of immunofluorescence staining, flow cytometry, calcium imaging, and patch-clamp recordings. Genetic and pharmacologic approaches were used to examine the role and underlying mechanisms of TRPV4 in mouse models of dry skin-associated chronic itch and spontaneous scratching associated with squaric acid dibutylester-induced allergic contact dermatitis. RESULTS: TRPV4 is selectively expressed by dermal macrophages and epidermal keratinocytes in mice. Lineage-specific deletion of TRPV4 in macrophages and keratinocytes reduces allergic and nonallergic chronic itch in mice, respectively. Importantly, TRPV4 expression is significantly increased in skin biopsy specimens from patients with chronic idiopathic pruritus in comparison with skin from healthy control subjects. Moreover, TRPV4-dependent chronic itch requires 5-hydroxytryptamine (5-HT) signaling secondary to activation of distinct 5-HT receptors in mice with allergic and those with nonallergic chronic itch conditions. CONCLUSION: Our study reveals previously unrecognized mechanisms by which TRPV4-expressing epithelial and immune cells in the skin critically and dynamically mediate chronic itch and unravels novel targets for therapeutics in the setting of chronic itch.

Zinc Inhibits TRPV1 to Alleviate Chemotherapy-Induced Neuropathic Pain.

Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1.SIGNIFICANCE STATEMENT The chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.

Comparison of esophageal motility in gastroesophageal reflux disease with and without globus sensation

Backgrounds and aims: This study aimed to compare the esophageal motility between gastroesophageal reflux disease (GERD) patients with typical symptoms but without globus sensation and GERD patients only with globus symptoms. Methods: A total of 57 consecutive GERD patients diagnosed by endoscopy or by 24-hour pH monitoring between May 2013 and September 2015 were included retrospectively into the study. The patients were grouped based on the presence or absence of globus. Thirty patients presented with typical reflux symptoms but without globus were assigned to the typical GERD group and 27 patients only with globus symptom were assigned to the globus GERD group. All patients underwent esophageal high resolution manometry (HRM) and the differences in esophageal motility between the two groups were analyzed. Results: The globus GERD group showed a significantly greater lower esophageal sphincter (LES) length, LES basal pressure and upper esophageal sphincter (UES) residual pressure than that of the typical GERD group (3.47 ± 0.76 vs 2.65 ± 0.62 cm, 21.71 ± 9.68 vs 16.04 ± 8.49 mmHg, 7.30 ± 4.42 vs 4.12 ± 2.92 mmHg, all p < 0.05). There was no significant difference between the two groups in terms of the distal wave amplitude, mean wave duration, distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL), integrated relaxation pressure (IRP) and UES basal pressure. The incidence of esophageal dysmotility in the globus GERD group (33.3%) was higher than in the typical GERD group (23.3%). There was no significant difference in esophageal acid exposure of the non-erosive gastroesophageal reflux disease (NERD) patients between the two groups. Conclusions: Globus GERD patients have a higher UES residual pressure, longer LES length, higher LES basal pressure and greater esophageal dysmotility than typical GERD patients. HRM is useful in evaluating esophageal motility of GERD patients (AU)

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Comparison of esophageal motility in gastroesophageal reflux disease with and without globus sensation.

BACKGROUNDS AND AIMS: This study aimed to compare the esophageal motility between gastroesophageal reflux disease (GERD) patients with typical symptoms but without globus sensation and GERD patients only with globus symptoms. METHODS: A total of 57 consecutive GERD patients diagnosed by endoscopy or by 24-hour pH monitoring between May 2013 and September 2015 were included retrospectively into the study. The patients were grouped based on the presence or absence of globus. Thirty patients presented with typical reflux symptoms but without globus were assigned to the typical GERD group and 27 patients only with globus symptom were assigned to the globus GERD group. All patients underwent esophageal high resolution manometry (HRM) and the differences in esophageal motility between the two groups were analyzed. RESULTS: The globus GERD group showed a significantly greater lower esophageal sphincter (LES) length, LES basal pressure and upper esophageal sphincter (UES) residual pressure than that of the typical GERD group (3.47 ± 0.76 vs. 2.65 ± 0.62 cm, 21.71 ± 9.68 vs. 16.04 ± 8.49 mmHg, 7.30 ± 4.42 vs. 4.12 ± 2.92 mmHg, all p < 0.05). There was no significant difference between the two groups in terms of the distal wave amplitude, mean wave duration, distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL), integrated relaxation pressure (IRP) and UES basal pressure. The incidence of esophageal dysmotility in the globus GERD group (33.3%) was higher than in the typical GERD group (23.3%). There was no significant difference in esophageal acid exposure of the non-erosive gastroesophageal reflux disease (NERD) patients between the two groups. CONCLUSIONS: Globus GERD patients have a higher UES residual pressure, longer LES length, higher LES basal pressure and greater esophageal dysmotility than typical GERD patients. HRM is useful in evaluating esophageal motility of GERD patients.

Role of the potassium chloride cotransporter isoform 2-mediated spinal chloride homeostasis in a rat model of visceral hypersensitivity.

Visceral hypersensitivity represents an important hallmark in the pathophysiology of irritable bowel syndrome (IBS), of which the mechanisms remain elusive. The present study was designed to examine whether cation-chloride cotransporter (CCC)-mediated chloride (Cl(-)) homeostasis of the spinal cord is involved in chronic stress-induced visceral hypersensitivity. Chronic visceral hypersensitivity was induced by exposing male Wistar rats to water avoidance stress (WAS). RT-PCR, Western blotting, and immunohistochemistry were used to assess the expression of CCCs in the spinal cord. Patch-clamp recordings were performed on adult spinal cord slices to evaluate Cl(-) homeostasis and Cl(-) extrusion capacity of lamina I neurons. Visceral sensitivity was estimated by measuring the abdominal withdrawal reflex in response to colorectal distension (CRD). After 10 days of WAS exposure, levels of both total protein and the oligomeric form of the K(+)-Cl(-) cotransporter isoform 2 (KCC2), but not Na(+)-K(+)-2Cl(-) transporter isoform 1 (NKCC1), were significantly decreased in the dorsal horn of the lumbosacral spinal cord. The downregulation of KCC2 resulted in a depolarizing shifted equilibrium potential of GABAergic inhibitory postsynaptic current and impaired Cl(-) extrusion capacity in lamina I neurons of the lumbosacral spinal cord from WAS rats. Acute noxious CRD disrupted spinal KCC2 expression and function 2 h after the final distention in sham rats, but not in WAS rats. Pharmacological blockade of KCC2 activity by intrathecal injection of a KCC2 inhibitor [(dihydroindenyl)oxy] alkanoic acid enhanced visceral nociceptive sensitivity in sham rats, but not in WAS rats. These results suggest that KCC2 downregulation-mediated impairment of spinal cord Cl(-) homeostasis may play an important role in chronic stress-induced visceral hypersensitivity.

Alcohol drinking and the risk of colorectal adenoma: a dose-response meta-analysis.

The International Agency for Research on Cancer concluded that alcohol consumption was positively related to colorectal cancer. However, the association between alcohol consumption and colorectal adenoma (CRA), the established precancerous lesion of colorectal cancer, remains unclear. We identified studies from a literature search of MEDLINE, EMBASE, and ISI Web of Science through 31 October 2013, and by searching reference lists of pertinent articles. Summary relative risks with 95% confidence intervals were calculated using a random-effects model. A total of 30 studies with 26,145 incident CRA cases were included. Overall, an increase of 25 g (two drinks) per day of alcohol consumption was related to an increased risk of CRA (summary relative risk=1.27, 95% confidence interval: 1.17-1.37). There was considerable heterogeneity between studies not explained by study design, sex, geographic location, publication year, site or size of the lesions, type of adenoma, number of cases, endoscopic assessment, or adjustment for main confounders. The positive association was evident for both men and women and for colonic adenoma, but not for rectal adenoma. Increased alcohol consumption is associated with an increased risk of CRA for both men and women and for adenoma in the colon, but not in the rectum.

Emodin has a protective effect in cases of severe acute pancreatitis via inhibition of nuclear factor­κB activation resulting in antioxidation.

Severe acute pancreatitis (SAP) accounts for up to 20% of acute pancreatitis (AP) cases. The absence of effective treatment options has resulted in a high rate of morbidity and mortality. Emodin is a major component of the Chinese herb rhubarb, which has been widely used in the treatment of numerous diseases, including inflammation and cancer. There are a limited number of studies however, that have investigated the effectiveness of emodin in the treatment of SAP. The present study used a rat model of SAP, to investigate the effect and molecular mechanisms of emodin treatment. Administration of emodin was identified to significantly attenuate SAP, as determined by serum amylase analysis and histological assessment of edema, vacuolization, inflammation and necrosis (P<0.01). Furthermore, treatment with emodin markedly inhibited nuclear factor (NF)­κB DNA­binding activity (P<0.01) and the serum expression levels of tumor necrosis factor­α, interleukin (IL)­6 and IL­1ß (P<0.05). This attenuation was associated with decreased malondialdehyde and increased superoxide dismutase levels in the pancreatic tissues and serum (P<0.05). This study indicated that administration of exogenous emodin had therapeutic effects on the severity of SAP. The mechanism may be due to inhibition of NF­κB activation resulting in an antioxidation response, which can subsequently suppress the expression of cytokines.

A comparative study of routing protocols of heterogeneous wireless sensor networks.

Recently, heterogeneous wireless sensor network (HWSN) routing protocols have drawn more and more attention. Various HWSN routing protocols have been proposed to improve the performance of HWSNs. Among these protocols, hierarchical HWSN routing protocols can improve the performance of the network significantly. In this paper, we will evaluate three hierarchical HWSN protocols proposed recently--EDFCM, MCR, and EEPCA--together with two previous classical routing protocols--LEACH and SEP. We mainly focus on the round of the first node dies (also called the stable period) and the number of packets sent to sink, which is an important aspect to evaluate the monitoring ability of a protocol. We conduct a lot of experiments and simulations on Matlab to analyze the performance of the five routing protocols.

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels.

BACKGROUND AND PURPOSE: Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARß , is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. EXPERIMENTAL APPROACH: We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. KEY RESULTS: LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. CONCLUSIONS AND IMPLICATIONS: This blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels.

Dietary fiber intake reduces risk for colorectal adenoma: a meta-analysis.

BACKGROUND & AIMS: Reports on the association between dietary fiber intake and risk of colorectal adenoma (CRA), the precursor of colorectal cancer, have been inconsistent. We conducted a meta-analysis of case-control and cohort studies to analyze this association. METHODS: We searched the MEDLINE and EMBASE databases to identify relevant studies published through July 2013. A random-effects model was used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for associations between fiber intake and CRA risk. Heterogeneity among studies was assessed using the Cochran Q and I(2) statistics. RESULTS: Our meta-analysis included 20 studies involving 10,948 subjects with CRA. The SRRs of CRA for total dietary fiber were 0.72 (95% CI, 0.63-0.83) in a high- vs low-intake analysis and 0.91 (95% CI, 0.87-0.95) per 10-g/day increase in fiber intake in a dose-response model. Subgroup analyses indicated a significant inverse association between total fiber intake and CRA risk in case-control studies (SRR, 0.66; 95% CI, 0.56-0.77), but not in cohort studies (SRR, 0.92; 95% CI, 0.76-1.10). The SRRs of CRA were 0.84 for fruit fiber (95% CI, 0.76-0.94; n = 6 studies), 0.93 for vegetable fiber (95% CI, 0.84-1.04; n = 6 studies), and 0.76 for cereal fiber (95% CI, 0.62-0.92; n = 9 studies) in high- vs low-intake analyses. CONCLUSIONS: Our findings support the hypothesis that high dietary fiber intake is associated inversely with CRA risk. Further studies with prospective designs that use validated questionnaires and control for important confounders are warranted.

Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity.

Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid-induced sensory hypersensitivity.

Role of voltage gated Ca2+ channels in rat visceral hypersensitivity change induced by 2,4,6-trinitrobenzene sulfonic acid.

BACKGROUND: Visceral pain is common symptom involved in many gastrointestinal disorders such as inflammatory bowel disease. The underlying molecular mechanisms remain elusive. We investigated the molecular mechanisms and the role for voltage gated calcium channel (VGCC) in the pathogenesis in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced visceral inflammatory hypersensitivity. RESULTS: Using Agilent cDNA arrays, we found 172 genes changed significantly in dorsal root ganglia (DRG) of TNBS treated rats. Among these changed genes, Cav1.2 and Cav2.3 were significantly up-regulated. Then the RT-PCR and Western blot further confirmed the up-regulation of Cav1.2 and Cav2.3. The whole cell patch clamp recording of acutely dissociated colonic specific DRG neurons showed that the peak IBa density was significantly increased in colonic neurons of TNBS treated rats compared with control rats (-127.82 ± 20.82 pA/pF Vs -91.67 ± 19.02 pA/pF, n = 9, *P < 0.05). To distinguish the different type of calcium currents with the corresponding selective channel blockers, we found that L-type (-38.56 ± 3.97 pA/pF Vs -25.75 ± 3.35 pA/pF, n = 9, * P < 0.05) and R-type (-13.31 ± 1.36 pA/pF Vs -8.60 ± 1.25 pA/pF, n = 9, * P < 0.05) calcium current density were significantly increased in colonic DRG neurons of TNBS treated rats compared with control rats. In addition, pharmacological blockade with L-type antagonist (nimodipine) and R-type antagonist (SNX-482) with intrathecal injection attenuates visceral pain in TNBS induced inflammatory visceral hypersensitivity. CONCLUSION: Cav1.2 and Cav2.3 in colonic primary sensory neurons play an important role in visceral inflammatory hyperalgesia, which maybe the potential therapeutic targets.