Ion channel regulation of gut immunity

Mounting evidence indicates that gastrointestinal (GI) homeostasis hinges on communications among many cellular networks including the intestinal epithelium, the immune system, and both intrinsic and extrinsic nerves innervating the gut. The GI tract, especially the colon, is the home base for gut microbiome which dynamically regulates immune function. The gut\u27s immune system also provides an effective defense against harmful pathogens entering the GI tract while maintaining immune homeostasis to avoid exaggerated immune reaction to innocuous food and commensal antigens which are important causes of inflammatory disorders such as coeliac disease and inflammatory bowel diseases (IBD). Various ion channels have been detected in multiple cell types throughout the GI tract. By regulating membrane properties and intracellular biochemical signaling, ion channels play a critical role in synchronized signaling among diverse cellular components in the gut that orchestrates the GI immune response. This work focuses on the role of ion channels in immune cells, non-immune resident cells, and neuroimmune interactions in the gut at the steady state and pathological conditions. Understanding the cellular and molecular basis of ion channel signaling in these immune-related pathways and initial testing of pharmacological intervention will facilitate the development of ion channel-based therapeutic approaches for the treatment of intestinal inflammation

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

Modification of neurogenic colonic motor behaviours by chemogenetic ablation of calretinin neurons

How the enteric nervous system determines the pacing and propagation direction of neurogenic contractions along the colon remains largely unknown. We used a chemogenetic strategy to ablate enteric neurons expressing calretinin (CAL). Mice expressing human diphtheria toxin receptor (DTR) in CAL neurons were generated by crossin

MrgprA3-expressing pruriceptors drive pruritogen-induced alloknesis through mechanosensitive Piezo2 channel

Although touch and itch are coded by distinct neuronal populations, light touch also provokes itch in the presence of exogenous pruritogens, resulting in a phenomenon called alloknesis. However, the cellular and molecular mechanisms underlying the initiation of pruritogen-induced mechanical itch sensitization are poorly understood. Here, we show that intradermal injections of histamine or chloroquine (CQ) provoke alloknesis through activation of TRPV1- and MrgprA3-expressing prurioceptors, and functional ablation of these neurons reverses pruritogen-induced alloknesis. Moreover, genetic ablation of mechanosensitive Piezo2 channel function from MrgprA3-expressing prurioceptors also dampens pruritogen-induced alloknesis. Mechanistically, histamine and CQ sensitize Piezo2 channel function, at least in part, through activation of the phospholipase C (PLC) and protein kinase C-δ (PKCδ) signaling. Collectively, our data find a TRPV

Construction of a mortality risk prediction model for elderly people at risk of lobectomy for NSCLC

BackgroundAn increasing number of lung cancer patients are opting for lobectomy for oncological treatment. However, due to the unique organismal condition of elderly patients, their short-term postoperative mortality is significantly higher than that of non-elderly patients. Therefore, there is a need to develop a personalised predictive tool to assess the risk of postoperative mortality in elderly patients.MethodsInformation on the diagnosis and survival of 35,411 older patients with confirmed lobectomy NSCLC from 2009 to 2019 was screened from the SEER database. The surgical group was divided into a high-risk mortality population group (≤90 days) and a non-high-risk mortality population group using a 90-day criterion. Survival curves were plotted using the Kaplan-Meier method to compare the differences in overall survival (OS) and lung cancer-specific survival (LCSS) between the two groups. The data set was split into modelling and validation groups in a ratio of 7.5:2.5, and model risk predictors of postoperative death in elderly patients with NSCLC were screened using univariate and multifactorial logistic regression. Columnar plots were constructed for model visualisation, and the area under the subject operating characteristic curve (AUC), DCA decision curve and clinical impact curve were used to assess model predictiveness and clinical utility.ResultsMulti-factor logistic regression results showed that sex, age, race, histology and grade were independent predictors of the risk of postoperative death in elderly patients with NSCLC. The above factors were imported into R software to construct a line graph model for predicting the risk of postoperative death in elderly patients with NSCLC. The AUCs of the modelling and validation groups were 0.711 and 0.713 respectively, indicating that the model performed well in terms of predictive performance. The DCA decision curve and clinical impact curve showed that the model had a high net clinical benefit and was of clinical application.ConclusionThe construction and validation of a predictive model for death within 90 days of lobectomy in elderly patients with lung cancer will help the clinic to identify high-risk groups and give timely intervention or adjust treatment decisions

A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain

Microglia, resident macrophages of the CNS, are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases, including neuropathic pain. However, molecular mechanisms that govern the spinal neuroimmune axis in the setting of neuropathic pain remain incompletely understood. Here, we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuroimmune axis in the spinal cord, which transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a potential new target for the treatment of chronic pain

Unusual Deep Water sponge assemblage in South China-Witness of the end-Ordovician mass extinction.

There are few sponges known from the end-Ordovician to early-Silurian strata all over the world, and no records of sponge fossils have been found yet in China during this interval. Here we report a unique sponge assemblage spanning the interval of the end-Ordovician mass extinction from the Kaochiapien Formation (Upper Ordovician-Lower Silurian) in South China. This assemblage contains a variety of well-preserved siliceous sponges, including both Burgess Shale-type and modern type taxa. It is clear that this assemblage developed in deep water, low energy ecosystem with less competitors and more vacant niches. Its explosion may be related to the euxinic and anoxic condition as well as the noticeable transgression during the end-Ordovician mass extinction. The excellent preservation of this assemblage is probably due to the rapid burial by mud turbidites. This unusual sponge assemblage provides a link between the Burgess Shale-type deep water sponges and the modern forms. It gives an excellent insight into the deep sea palaeoecology and the macroevolution of Phanerozoic sponges, and opens a new window to investigate the marine ecosystem before and after the end-Ordovician mass extinction. It also offers potential to search for exceptional fossil biota across the Ordovician-Silurian boundary interval in China

An Overview of Antitumour Activity of Polysaccharides

Cancer incidence and mortality are rapidly increasing worldwide; therefore, effective therapies are required in the current scenario of increasing cancer cases. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, and they have become the focus of current antitumour drug research owing to their significant antitumour effects. In addition to the direct antitumour activity of some natural polysaccharides, their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in natural polysaccharides and polysaccharide-based nanomedicines for cancer therapy