No abstract

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.

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.

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.

A new model for chronic visceral hypersensitivity following a diluted AA stimulus in the neonatal period is described. The hypersensitivity may be associated with mast cell hyperplasia in the colon and increased excitability of IB4-positive colonic neurons as a result of suppression of I(A) density and a shift in the inactivation curves of I(A) and I(K) in a hyperpolarizing direction in these cells. This study identifies for the first time a specific molecular mechanism in subpopulations of colonic DRG neurons that underlies chronic visceral hypersensitivity.

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 DNA‑binding activity (P<0.01) and the serum expression levels of tumor necrosis factor‑α, interleukin (IL)‑6 and IL‑1β (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 NF‑κB activation resulting in an antioxidation response, which can subsequently suppress the expression of cytokines.

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. 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.

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.