UNASSIGNED: Osteoarthritis (OA) is a debilitating joint disorder characterized by the progressive degeneration of articular cartilage. Although the role of ion channels in OA pathogenesis is increasingly recognized, diagnostic markers and targeted therapies remain limited.
UNASSIGNED: In this study, we analyzed the GSE48556 dataset to identify differentially expressed ion channel-related genes (DEGs) in OA and normal controls. We employed machine learning algorithms, least absolute shrinkage and selection operator(LASSO), and support vector machine recursive feature elimination(SVM-RFE) to select potential diagnostic markers. Then the gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to explore the potential diagnostic markers\' involvement in biological pathways. Finally, weighted gene co-expression network analysis (WGCNA) was used to identify key genes associated with OA.
UNASSIGNED: We identified a total of 47 DEGs, with the majority involved in transient receptor potential (TRP) pathways. Seven genes (CHRNA4, GABRE, HTR3B, KCNG2, KCNJ2, LRRC8C, and TRPM5) were identified as the best characteristic genes for distinguishing OA from healthy samples. We performed clustering analysis and identified two distinct subtypes of OA, C1, and C2, with differential gene expression and immune cell infiltration profiles. Then we identified three key genes (PPP1R3D, ZNF101, and LOC651309) associated with OA. We constructed a prediction model using these genes and validated it using the GSE46750 dataset, demonstrating reasonable accuracy and specificity.
UNASSIGNED: Our findings provide novel insights into the role of ion channel-related genes in OA pathogenesis and offer potential diagnostic markers and therapeutic targets for the treatment of OA.
As society ages, the incidence of knee osteoarthritis continues to rise, bringing with it a series of social impacts and medical pressure. Despite the increasing recognition of the role of ion channels in the pathogenesis of OA, diagnostic markers and targeted therapies remain limited.This study investigated the role of TRP as possible diagnostic tools for OA.Seven TRP-related genes were identified as the best traits to distinguish OA from healthy samples, and then we constructed and validated risk scores for three key genes (PPP1R3D, ZNF101, and LOC651309) relevant to OA ion channel gene modules.Our findings provide novel insights into the role of ion channel-related genes in OA pathogenesis and offer a reference for further clinical diagnosis.

The thermo- and pain-sensitive Transient Receptor Potential Melastatin 3 and 8 (TRPM3 and TRPM8) ion channels are functionally associated in the lipid rafts of the plasma membrane. We have already described that cholesterol and sphingomyelin depletion, or inhibition of sphingolipid biosynthesis decreased the TRPM8 but not the TRPM3 channel opening on cultured sensory neurons. We aimed to test the effects of lipid raft disruptors on channel activation on TRPM3- and TRPM8-expressing HEK293T cells in vitro, as well as their potential analgesic actions in TRPM3 and TRPM8 channel activation involving acute pain models in mice. CHO cell viability was examined after lipid raft disruptor treatments and their effects on channel activation on channel expressing HEK293T cells by measurement of cytoplasmic Ca2+ concentration were monitored. The effects of treatments were investigated in Pregnenolone-Sulphate-CIM-0216-evoked and icilin-induced acute nocifensive pain models in mice. Cholesterol depletion decreased CHO cell viability. Sphingomyelinase and methyl-beta-cyclodextrin reduced the duration of icilin-evoked nocifensive behavior, while lipid raft disruptors did not inhibit the activity of recombinant TRPM3 and TRPM8. We conclude that depletion of sphingomyelin or cholesterol from rafts can modulate the function of native TRPM8 receptors. Furthermore, sphingolipid cleavage provided superiority over cholesterol depletion, and this method can open novel possibilities in the management of different pain conditions.

Mechanosensitive ion channels are widely distributed in the heart, lung, bladder and other tissues, and plays an important role in exercise-induced cardiovascular function promotion. By reviewing the PubMed databases, the results were summarized using the terms \"Exercise/Sport\", \"Piezo1\", \"Transient receptor potential (TRP)\" and \"Cardiovascular\" as the keywords, 124-related papers screened were sorted and reviewed. The results showed that: (1) Piezo1 and TRP channels play an important role in regulating blood pressure and the development of cardiovascular diseases such as atherosclerosis, myocardial infarction, and cardiac fibrosis; (2) Exercise promotes cardiac health, inhibits the development of pathological heart to heart failure, regulating the changes in the characterization of Piezo1 and TRP channels; (3) Piezo1 activates downstream signaling pathways with very broad pathways, such as AKT/eNOS, NF-κB, p38MAPK and HIPPO-YAP signaling pathways. Piezo1 and Irisin regulate nuclear localization of YAP and are hypothesized to act synergistically to regulate tissue mechanical properties of the cardiovascular system and (4) The cardioprotective effects of exercise through the TRP family are mostly accomplished through Ca2+ and involve many signaling pathways. TRP channels exert their important cardioprotective effects by reducing the TRPC3-Nox2 complex and mediating Irisin-induced Ca2+ influx through TRPV4. It is proposed that exercise stimulates the mechanosensitive cation channel Piezo1 and TRP channels, which exerts cardioprotective effects. The activation of Piezo1 and TRP channels and their downstream targets to exert cardioprotective function by exercise may provide a theoretical basis for the prevention of cardiovascular diseases and the rehabilitation of clinical patients.

Natural compounds like flavonoids preserve intestinal mucosal integrity through their antioxidant, anti-inflammatory, and antimicrobial properties. Additionally, some flavonoids show prebiotic abilities, promoting the growth and activity of beneficial gut bacteria. This study investigates the protective impact of Lens culinaris extract (LE), which is abundant in flavonoids, on intestinal mucosal integrity during LPS-induced inflammation. Using Caco-2 cells as a model for the intestinal barrier, the study found that LE did not affect cell viability but played a cytoprotective role in the presence of LPS. LE improved transepithelial electrical resistance (TEER) and tight junction (TJ) protein levels, which are crucial for barrier integrity. It also countered the upregulation of pro-inflammatory genes TRPA1 and TRPV1 induced by LPS and reduced pro-inflammatory markers like TNF-α, NF-κB, IL-1β, and IL-8. Moreover, LE reversed the LPS-induced upregulation of AQP8 and TLR-4 expression. These findings emphasize the potential of natural compounds like LE to regulate the intestinal barrier and reduce inflammation\'s harmful effects on intestinal cells. More research is required to understand their mechanisms and explore therapeutic applications, especially for gastrointestinal inflammatory conditions.

Morphological and structural remodeling of the heart, including cardiac hypertrophy and fibrosis, has been considered a therapeutic target for heart failure for approximately three decades. Groundbreaking heart failure medications demonstrating reverse remodeling effects have contributed significantly to medical advancements. However, nearly 50% of heart failure patients still exhibit drug resistance, posing a challenge to the healthcare system. Recently, characteristics of heart failure resistant to ARBs and β-blockers have been defined, highlighting preserved systolic function despite impaired diastolic function, leading to the classification of heart failure with preserved ejection fraction (HFpEF). The pathogenesis and etiology of HFpEF may be related to metabolic abnormalities, as evidenced by its mimicry through endothelial dysfunction and excessive intake of high-fat diets. Our recent findings indicate a significant involvement of mitochondrial hyper-fission in the progression of heart failure. This mitochondrial pathological remodeling is associated with redox imbalance, especially hydrogen sulfide accumulation due to abnormal electron leak in myocardium. In this review, we also introduce a novel therapeutic strategy for heart failure from the current perspective of mitochondrial redox-metabolic remodeling.

Cisplatin is a platinum-based chemotherapy drug widely used to treat various solid tumours. Although it is effective in anti-cancer therapy, many patients develop peripheral neuropathy during and after cisplatin treatment. Peripheral neuropathy results from lesions or diseases in the peripheral somatosensory nervous system and is a significant cause of debilitation and suffering in patients. In recent years, preclinical studies have been conducted to elucidate the mechanisms involved in chemotherapy-induced peripheral neuropathic pain, as well as to promote new therapeutic targets since current treatments are ineffective and are associated with adverse effects. G-protein coupled receptors and ion channels play a significant role in pain processing and may represent promising targets for improving the management of cisplatin-induced neuropathic pain. This review describes the role of G protein-coupled receptors and ion channels in cisplatin-induced pain, analysing preclinical experimental studies that investigated the role of each receptor subtype in the modulation of cisplatin-induced pain.

Neuropathic pain, a prevalent chronic condition in clinical settings, has attracted widespread societal attention. This condition is characterized by a persistent pain state accompanied by affective and cognitive disruptions, significantly impacting patients\' quality of life. However, current clinical therapies fall short of addressing its complexity. Thus, exploring the underlying molecular mechanism of neuropathic pain and identifying potential targets for intervention is highly warranted. The transient receptor potential (TRP) receptors, a class of widely distributed channel proteins, in the nervous system, play a crucial role in sensory signaling, cellular calcium regulation, and developmental influences. TRP ion channels are also responsible for various sensory responses including heat, cold, pain, and stress. This review highlights recent advances in understanding TRPs in various rodent models of neuropathic pain, aiming to uncover potential therapeutic targets for clinical management.

UNASSIGNED: Mechanosensation is an important trigger of physiological processes in the gastrointestinal tract. Aberrant responses to mechanical input are associated with digestive disorders, including visceral hypersensitivity. Transient Receptor Potential Vanilloid 4 (TRPV4) is a mechanosensory ion channel with proposed roles in visceral afferent signaling, intestinal inflammation, and gut motility. While TRPV4 is a potential therapeutic target for digestive disease, current mechanistic understanding of how TRPV4 may influence gut function is limited by inconsistent reports of TRPV4 expression and distribution.
UNASSIGNED: In this study we profiled functional expression of TRPV4 using Ca2+ imaging of wholemount preparations of the mouse, monkey, and human intestine in combination with immunofluorescent labeling for established cellular markers. The involvement of TRPV4 in colonic motility was assessed in vitro using videomapping and contraction assays.
UNASSIGNED: The TRPV4 agonist GSK1016790A evoked Ca2+ signaling in muscularis macrophages, enteric glia, and endothelial cells. TRPV4 specificity was confirmed using TRPV4 KO mouse tissue or antagonist pre-treatment. Calcium responses were not detected in other cell types required for neuromuscular signaling including enteric neurons, interstitial cells of Cajal, PDGFRα+ cells, and intestinal smooth muscle. TRPV4 activation led to rapid Ca2+ responses by a subpopulation of glial cells, followed by sustained Ca2+ signaling throughout the enteric glial network. Propagation of these waves was suppressed by inhibition of gap junctions or Ca2+ release from intracellular stores. Coordinated glial signaling in response to GSK1016790A was also disrupted in acute TNBS colitis. The involvement of TRPV4 in the initiation and propagation of colonic motility patterns was examined in vitro.
UNASSIGNED: We reveal a previously unappreciated role for TRPV4 in the initiation of distension-evoked colonic motility. These observations provide new insights into the functional role of TRPV4 activation in the gut, with important implications for how TRPV4 may influence critical processes including inflammatory signaling and motility.

The combustion of fossil fuels contributes to air pollution (AP), which was linked to about 8.79 million global deaths in 2018, mainly due to respiratory and cardiovascular-related effects. Among these, particulate air pollution (PM2.5) stands out as a major risk factor for heart health, especially during vulnerable phases. Our prior study showed that premature exposure to 1,2-naphthoquinone (1,2-NQ), a chemical found in diesel exhaust particles (DEP), exacerbated asthma in adulthood. Moreover, increased concentration of 1,2-NQ contributed to airway inflammation triggered by PM2.5, employing neurogenic pathways related to the up-regulation of transient receptor potential vanilloid 1 (TRPV1). However, the potential impact of early-life exposure to 1,2-naphthoquinone (1,2-NQ) on atrial fibrillation (AF) has not yet been investigated. This study aims to investigate how inhaling 1,2-NQ in early life affects the autonomic adrenergic system and the role played by TRPV1 in these heart disturbances. C57Bl/6 neonate male mice were exposed to 1,2-NQ (100 nM) or its vehicle at 6, 8, and 10 days of life. Early exposure to 1,2-NQ impairs adrenergic responses in the right atria without markedly affecting cholinergic responses. ECG analysis revealed altered rhythmicity in young mice, suggesting increased sympathetic nervous system activity. Furthermore, 1,2-NQ affected β1-adrenergic receptor agonist-mediated positive chronotropism, which was prevented by metoprolol, a β1 receptor blocker. Capsazepine, a TRPV1 blocker but not a TRPC5 blocker, reversed 1,2-NQ-induced cardiac changes. In conclusion, neonate mice exposure to AP 1,2-NQ results in an elevated risk of developing cardiac adrenergic dysfunction, potentially leading to atrial arrhythmia at a young age.

Nociception and pain sensation are important neural processes in humans to avoid injury. Many proteins are involved in nociception and pain sensation in humans; however, the evolution of these proteins in animals is unknown. Here, we chose nociception- and pain-related proteins, including G protein-coupled receptors (GPCRs), ion channels (ICs), and neuropeptides (NPs), which are reportedly associated with nociception and pain in humans, and identified their homologs in various animals by BLAST, phylogenetic analysis and protein architecture comparison to reveal their evolution from protozoans to humans. We found that the homologs of transient receptor potential channel A 1 (TRPA1), TRAPM, acid-sensing IC (ASIC), and voltage-dependent calcium channel (VDCC) first appear in Porifera. Substance-P receptor 1 (TACR1) emerged from Coelenterata. Somatostatin receptor type 2 (SSTR2), TRPV1 and voltage-dependent sodium channels (VDSC) appear in Platyhelminthes. Calcitonin gene-related peptide receptor (CGRPR) was first identified in Nematoda. However, opioid receptors (OPRs) and most NPs were discovered only in vertebrates and exist from agnatha to humans. The results demonstrated that homologs of nociception and pain-related ICs exist from lower animal phyla to high animal phyla, and that most of the GPCRs originate from low to high phyla sequentially, whereas OPRs and NPs are newly evolved in vertebrates, which provides hints of the evolution of nociception and pain-related proteins in animals and humans.