Search Results (204)

Cardiovascular and metabolic disorders significantly reduce healthspan and lifespan, with oxidative stress being a major contributing factor. Oxidative stress, marked by elevated reactive oxygen species (ROS), disrupts cellular and systemic functions. One proposed mechanism involves TRPM2 (Transient Receptor Potential Melastatin2)-dependent Ca²⁺ dysregulation. These channels, activated by ROS (via ADP-ribose), not only respond to ROS but also amplify it, creating a self-sustaining cycle. Recent studies suggest that TRPM2 activation triggers a cascade of signals from intracellular organelles, enhancing ROS production and affecting cell physiology and viability. This review examines the role of TRPM2 channels in oxidative stress-associated cardiovascular and metabolic diseases. Oxidative stress induces TRPM2-mediated Ca²⁺ influx, leading to lysosomal damage and the release of Zn²⁺ from lysosomal stores to the mitochondria. In mitochondria, Zn²⁺ facilitates electron leakage from respiratory complexes, reducing membrane potential, increasing ROS production, and accelerating mitochondrial degradation. Excess ROS activates PARP1 in the nucleus, releasing ADP-ribose, a TRPM2 agonist, thus perpetuating the cycle. Lysosomes act as Ca²⁺-sensitive signalling platforms, delivering toxic Zn²⁺ signals to mitochondria. This represents a paradigm shift, proposing that the toxic effects of Ca²⁺ on mitochondria are not direct, but are instead mediated by lysosomes and subsequent Zn²⁺ release. This cycle exhibits a ‘domino’ effect, causing sequential and progressive decline in the function of lysosomes, mitochondria, and the nucleus—hallmarks of ageing and oxidative stress-related cardiovascular and metabolic diseases. These insights could lead to new therapeutic strategies for addressing the widespread issue of cardiovascular and metabolic diseases. Full article

Cutaneous malignant melanoma remains one of the most aggressive forms of skin cancer, characterized by high metastatic potential and resistance to standard therapies. Emerging evidence suggests that transient receptor potential (TRP) channels, non-selective cation channels involved in calcium homeostasis, and cellular stress responses play a pivotal role in melanoma development and progression. This review highlights the physiological expression of key TRP subfamilies (TRPM1, TRPM7, TRPM8, TRPV1, TRPV4, and TRPM2) in melanocytes and discusses their dysregulation in melanoma cells. TRPM1 is implicated as a tumor suppressor, whereas TRPM7, TRPV1, and TRPV4 often function as both melanoma suppressor or oncogenic drivers, modulating proliferation, apoptosis, and metastasis. TRPM2, which is responsive to oxidative stress, supports melanoma cell survival under metabolic stress. The potential of TRP channels as diagnostic biomarkers and therapeutic targets is evaluated, with attention paid to current pharmacological approaches and research challenges. The complexity and context-dependency of TRP function in melanoma underscore the need for isoform-specific modulation and personalized therapeutic strategies. Full article

Inorganic polyphosphate (iPolyP) is a ubiquitous molecule composed of a variable number of orthophosphate units. Recent studies have highlighted its involvement in colorectal cancer (CRC) cell proliferation. However, further investigations are needed to elucidate its role in CRC cell progression and migration, as well as its influence on the tumor microenvironment. This study focuses on the inorganic polyphosphate (iPolyP)/transient receptor potential cation channel subfamily M member 8 (TRPM8) axis and its impact on CRC progression. To investigate these issues, western blotting, fixed and live cells immunofluorescence, 2D and 3D cell culture on CRC-patient derived tissues, ELISA, and wound healing assays were performed. Our results show that inorganic polyphosphate induces the expression of epithelial-to-mesenchymal transition (EMT) markers in CRC cells. Furthermore, the iPolyP/TRPM8 axis indirectly promotes tumor growth through activation of the Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain-containing protein 3 (NLRP3) inflammasome in immune cells, leading to increased levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the tumor microenvironment (TME), thereby advancing CRC. These findings suggest that targeting the iPolyP/TRPM8 pathway may be a promising strategy to inhibit CRC progression and metastasis. Full article

The transient receptor potential channels TRPM3 and TRPM8 are cation channels that regulate numerous cellular activities, including thermo- and pain sensation. Stimulation of either TRPM3 or TRPM8 channels induces an intracellular signaling cascade that leads to the activation of stimulus-responsive transcription factors. As part of a search for delayed-response genes that are activated upon TRPM3 or TRPM8 stimulation, we analyzed the gene encoding prostaglandin endoperoxide synthase-2. The expression of this gene is not detectable under basal conditions but is rapidly induced upon stimulation of the cells with numerous extracellular signaling molecules. Here, we show that chromatin-embedded reporter genes under the control of the prostaglandin endoperoxide synthase-2 promoter were activated after stimulation of TRPM3 channels with pregnenolone sulfate or TRPM8 channels with the cooling agent icilin. TRP channel-induced activation of the prostaglandin endoperoxide synthase-2 promoter was attenuated by pharmacological inhibitors of TRPM3 and TRPM8. Mutational analysis of the prostaglandin endoperoxide synthase-2 promoter showed the importance of a cAMP response element within the proximal promoter region of the prostaglandin endoperoxide synthase-2 gene. In summary, our results establish a link between the stimulation of TRPM3 and TRPM8 and the biosynthesis of proinflammatory mediators via the regulation of prostaglandin endoperoxide synthase-2 expression. Full article

Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca²⁺ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M₁R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca²⁺-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M₁R. TRPM3 activation enhanced mitochondrial Ca²⁺ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca²⁺ signaling imbalances in DSPN and presents M₁R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies. Full article

Background/Objectives: We sought to determine if glibenclamide, a sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel blocker, reduces cerebral edema and improves neurological functioning in aneurysmal subarachnoid hemorrhage (aSAH). Methods: Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic search was conducted in PubMed, Cochrane Library, Web of Science, and SCOPUS for studies evaluating glibenclamide in aSAH patients. Primary outcomes included scores on the modified Rankin Scale (mRS) at discharge and the Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) at ten days post-intervention. Secondary outcomes included adverse events, and safety and efficacy endpoints. Random-effects models were employed for meta-analyses. Results: Three studies utilizing oral glibenclamide (n = 245) met inclusion criteria. Oral glibenclamide demonstrated no significant improvements in mRS scores [MD −0.19 with 95% CI (−2.05, 1.66)] at discharge, [MD 0.06, (−0.60, 0.71)] at 3 months, and [MD 0.4, (−0.67, 0.87)] at 6 months; functional independence [risk ratio (RR) 1.05, (0.81, 1.36)]; independent ambulation [RR 1.07, (0.77, 1.48)]; mortality [RR 0.79, (0.42, 1.50)]; or delayed cerebral ischemia [RR 0.58, (0.31, 1.09]). Hypoglycemia risk was significantly higher in the glibenclamide group [RR 3.92, (1.14, 13.49)]. Conclusions: Oral glibenclamide offers a novel approach to addressing cerebral edema in aSAH but shows limited clinical efficacy in improving functional and neurological outcomes in subtherapeutic doses. Its safety profile is acceptable, though hypoglycemia risk necessitates careful monitoring. Further research is required to optimize dosing, timing of intervention, and patient selection to enhance therapeutic outcomes. By contrast, intravenous administration of therapeutic doses of glibenclamide offers a promising avenue for future studies in the management of aSAH by taking advantage of the favorable pharmacokinetics of this route of administration. Full article

This study investigated the effects of potassium magnesium sulfate (PMS) on intestinal dissociation and absorption rate, immune function, and expression of the NOD-like receptor thermal domain-associated protein 3 (NLRP3) inflammasome, aquaporins (AQPs), and potassium and magnesium ion channels in weaned piglets. Experiment 1 involved the assessment of the dissociation rate of PMS in pig digestive fluid and the absorption rate of PMS in the small intestine using an Ussing chamber in vitro. In Experiment 2, 216 healthy 21-day-old weaned piglets were selected and randomly assigned to six groups (0%, 0.15%, 0.30%, 0.45%, 0.60%, and 0.75% PMS), with each group 6 replicates of six piglets per replicate. The in vitro Ussing chamber results indicated that the absorption of K⁺ and Mg²⁺ in the jejunum and ileum was significantly higher than that in the duodenum (p < 0.05). The in vivo study demonstrated that the addition of PMS resulted in a linear increase in serum K⁺, IgG, and interleukin (IL)-2 levels while simultaneously reducing serum IL-1β levels (p < 0.05). Dietary PMS significantly elevated serum IL-10 and Mg²⁺ levels in feces (p < 0.05). Furthermore, supplementation with 0.60% or 0.75% PMS significantly downregulated the mRNA expression of NLRP3 in the jejunum (p < 0.05). Dietary PMS supplementation linearly reduced the mRNA expression levels of cysteine protease 1 (Caspase-1) and IL-1β in both the jejunum and colon as well as the mRNA expression levels of two-pore domain channel subfamily K member 5 (KCNK5) in these regions (p < 0.05). Notably, supplementation with 0.15% PMS significantly decreased the mRNA expression of transient receptor potential channel 6 (TRPM6) in the jejunum and significantly increased the expression of TRPM6 in the colon (p < 0.05). Dietary addition of 0.45% and 0.60% PMS significantly increased the mRNA expression of aquaporin 3 (AQP3) in the colon (p < 0.05), whereas 0.75% PMS significantly increased the mRNA expression of aquaporin 8 (AQP8) in both the jejunum and colon. Moreover, the expression levels of AQP3 and AQP8 were significantly negatively correlated with the diarrhea rate observed between days 29 and 42. In conclusion, dietary PMS supplementation improved immune function, inhibited the activation of intestinal NLRP3, and modulated the expression of water and ion channels in weaned piglets, thereby contributing to the maintenance of intestinal water and ion homeostasis, which could potentially alleviate post-weaning diarrhea in piglets. The recommended supplemental level of PMS in the corn-soybean basal diet for weaned piglets is 0.30%. Full article

Background: Taste disorders in patients with type 2 diabetes mellitus (T2DM) have a negative impact on their quality of life and glycemic control, and treatment options are limited. Buzhong yiqi formula (BZYQF) improves T2DM symptoms but its effects on T2DM-induced taste disorders have not been sufficiently studied. Methods: Molecular docking was utilized to evaluate binding activity between the compounds in BZYQF and the sweet taste receptors (STRs). T2DM was induced in rats through the administration of high-fat diet and streptozotocin, and the rats were then treated with BZYQF for 8 weeks. Daily indicators and serum biochemical factors were monitored. Taste preferences for sweet, bitter, salty, and sour solutions were assessed using a two-bottle test. The morphology of lingual papillae and the numbers of taste buds were examined using HE staining. A high-glucose (HG) model of taste bud organoids was established to measure sucrose-evoked ATP release. The expression of signaling molecules in the sweet taste receptors (STRs) pathway was determined via RT-qPCR, Western blot, and immunofluorescence in lingual papillae and organoids. Results: A total of 508 compounds in BZYQF indicated good binding activity to T1R2, T1R3 or heterodimers of T1R2/T1R3, and 60 compounds had good binding activity to all three forms of STRs. BZYQF alleviated T2DM symptoms and improved taste perception for maltose (10 mM, 50 mM), quinine (0.03 mM, 0.1 mM), and citric acid (1 mM) solutions. BZYQF improved the morphological structure of lingual papillae and increased taste bud numbers in T2DM rats. BZYQF enhanced ATP release responses to sucrose solution in the taste bud organoids of the HG model. Gene expression determination showed that BZYQF upregulated the expression of signaling molecules in the STRs pathway (T1R2, T1R3, IP3R, α-gustducin, TRPM5) in the lingual papillae of the T2DM rats and in the taste bud organoids of the HG model. Conclusions: BZYQF alleviates T2DM-induced taste disorders by increasing the numbers of taste buds and upregulating STR signaling molecules, in which various compounds, especially flavonoids, exhibit a synergistic effect. Full article

Calcium movement and concentration in the cell plays significant roles in normal physiology and in diseases such as cancer. The significance of this ion in oncogenesis suggests that membrane-relevant proteins are involved in its regulation and are deregulated in various cancers. These channels and transporters could be targets for therapeutic interventions. An evaluation of the expression of transient receptor potential (TRP) channels in prostate cancer was performed using publicly available genomic and proteome data. Two TRP family members with high expression in prostate cancers, TRPML2 and TRPM4, were chosen for further analysis the uncover the associations of their level of expression with clinical and pathologic prostate cancer characteristics. Several TRP channels were expressed in prostate cancers at the protein level including TRPM4, TRPML1, TRPML2, TRPC1 and TRPP3. At the mRNA level, MCOLN2 and TRPM4 were strongly expressed in a sub-set of prostate cancers. Cases with high MCOLN2 mRNA expression were associated with frequent ERG fusions and a trend for better survival outcomes. In contrast, prostate cancer cases with high TRPM4 mRNA expression were associated with lower ERG fusion frequency than cases with low TRPM4 mRNA expression. The prognosis of prostate cancers with high TRPM4 expression was not different from the prognosis with counterparts having low TRPM4 mRNA expression. TRP channels were expressed in sub-sets of prostate cancers. The two well-expressed channels of the super family, TRPML2 and TRPM4, have divergent associations with the most prevalent prostate cancer molecular aberrations, ERG fusions. These results imply diverse regulations of the TRP channels that would have to be taken into consideration when devising therapeutic interventions targeting individual channels. Full article

Transient receptor potential melastatin-3 (TRPM3) channels are cation channels activated by heat and chemical ligands. TRPM3 regulates heat sensation, secretion, neurotransmitter release, iris constriction, and tumor promotion. Stimulation of TRPM3 triggers an influx of Ca²⁺ ions into the cells and the initiation of an intracellular signaling cascade. TRPM3 channels are regulated by phosphatidylinositol 4,5-bisphosphate, the βγ subunit of G-protein-coupled receptors, phospholipase C, and calmodulin. Extracellular signal-regulated protein kinase ERK1/2 and c-Jun N-terminal protein kinase (JNK) function as signal transducers. The signaling cascade is negatively regulated by the protein phosphatases MKP-1 and calcineurin and increased concentrations of Zn²⁺. Stimulation of TRPM3 leads to the activation of stimulus-responsive transcription factors controlled by epigenetic regulators. Potential delayed response genes encoding the pro-inflammatory regulators interleukin-8, calcitonin gene-related peptide, and the prostaglandin-synthesizing enzyme prostaglandin endoperoxide synthase-2 have been identified. Elucidating the TRPM3-induced signaling cascade provides insights into how TRPM3 stimulation alters numerous biochemical and physiological parameters within the cell and throughout the organism and offers intervention points for manipulating TRPM3 signaling and function. Full article

Prostate cancer (PC) remains a significant health challenge, with androgen receptor (AR) signaling playing a pivotal role in its progression. This study investigates the expression and functional implications of the transient receptor potential melastatin 8 (TRPM8) channel in PC, focusing on its interaction with AR and its impact on oncogenic pathways. We analyzed mRNA expression levels of TRPM8 and AR in PC tissues, revealing that TRPM8 is upregulated in benign and early-stage tumors but significantly downregulated in metastatic samples. This decline correlates with increased AR expression, suggesting a compensatory mechanism that enhances AR-driven tumorigenesis. RNA sequencing and pathway enrichment analyses demonstrated that TRPM8 knockout (KO) prostates exhibited significant alterations in gene expression, particularly in pathways related to extracellular matrix (ECM) remodeling, cell proliferation, and survival signaling. Notably, genes associated with metastasis, such as MMP2 and FAP, were upregulated in TRPM8 KO samples, indicating a potential role for TRPM8 in inhibiting tumor invasion. Furthermore, Gene Set Enrichment Analysis (GSEA) revealed positive enrichment of androgen response, angiogenesis, and epithelial–mesenchymal transition (EMT) pathways in TRPM8 KO prostates, reinforcing the notion that TRPM8 loss creates a pro-tumorigenic environment. Our findings suggest that TRPM8 functions as a molecular brake on PC progression, and its loss may contribute to the development of aggressive disease phenotypes. This study underscores the importance of TRPM8 as a potential therapeutic target and biomarker in PC, warranting further investigation into its role in cancer biology and treatment response. Full article

Phytocannabinoids (pCBs) from Cannabis sativa represent an important class of bioactive molecules, potentially useful for the treatment of a wide range of diseases. Their efficacy is due to their ability to interact with multiple targets of the endocannabinoid system, including the thermosensitive transient receptor potential (Thermo-TRPs), namely TRPV1-4, TRPA1, and TRPM8 channels. Previously, we demonstrated a shift in selectivity toward TRPA1 in the activity profile of the main pCBs, that is, CBD, ∆⁸-THC, CBG, CBC, and CBN, by swapping the pentyl chain with the α,α-dimethylheptyl (DMH) one. Using these derivatives as a starting point, here we investigate the effects on the thermo-TRPs activity profile of the integration of a quinone group into the resorcinol scaffold. We found that, while the activity on TRPA1 is substantially retained, an increase in potency/efficacy on the TRPV3 modulation is observed. Docking studies were used to elucidate the binding modes of the most active compounds toward this receptor, providing a rationale for this biological activity. In summary, we show that the quinone derivatives of DMH-pCBs are endowed with a TRPA1/TRPV3 desensitizing activity, potentially useful for the treatment of skin diseases sustained by inflammatory conditions. Full article

Background/Objective: Atherosclerosis is one of the leading causes of cardiovascular diseases and mortality around the world. One exciting strategy for atherosclerosis treatment is immunotherapy, especially active immunization. Active immunization relies on the delivery of antigens in a vaccine platform to introduce humoral and cellular immunity, alleviating atherosclerotic progression. Transient receptor potential channel isoform M2 (TRPM2) is an ROS-activated Ca²⁺-permeable ion channel that can promote atherosclerosis via stimulating vascular inflammation. In the present study, we developed a strategy of active immunization with the TRPM2 E3 domain peptide in a vaccine platform, aiming to induce the endogenous production of anti-TRPM2 blocking antibody in mice in vivo, consequently inhibiting TRPM2 channel activity to alleviate atherosclerotic progression. Methods: ApoE knockout mice were fed with a high cholesterol diet to develop atherosclerosis. The mice were injected with or without the E3 peptide vaccines, followed by analysis of atherosclerotic lesion by en face Oil Red O staining of the whole aorta and histologic analysis of thin tissue sections from aortic roots. Results: The results show that immunization with a pig TRPM2 E3 region-based peptide (P1) could effectively alleviate high cholesterol diet-induced atherosclerosis in ApoE knockout mice. We worked out the best vaccine formulation for the most effective atheroprotection, namely P1 at the dose of 67.5 µg per mouse (2.5 mg/kg body weight) with aluminum salts as adjuvant. Conclusions: The present study provides a novel target TRPM2 for peptide vaccine-based anti-atherosclerotic strategy and lays the foundation for future preclinical/clinical trials using TRPM2 E3 P1 vaccine for a potential therapeutic option against atherosclerosis. Full article

Magnesium, the most abundant divalent metal within the cell, is essential for physiological function and critical in cellular signaling. To maintain cellular homeostasis, intracellular magnesium levels are tightly regulated, as dysregulation is linked to numerous diseases, including cancer, diabetes, cardiovascular disorders, and neurological conditions. Over the past two decades, extensive research on magnesium-regulating proteins has provided valuable insight into their pathogenic and therapeutic potential. This review explores an emerging mechanism of magnesium homeostasis involving proteins in the PRL (phosphatase of regenerating liver), ARL (ADP ribosylation factor-like GTPase family), CNNM (cyclin and cystathionine β-synthase domain magnesium transport mediator), and TRPM (transient receptor potential melastatin) families, collectively termed herein as the PACT network. While each PACT protein has been studied within its individual signaling and disease contexts, their interactions suggest a broader regulatory network with therapeutic potential. This review consolidates the current knowledge on the PACT proteins’ structure, function, and interactions and identifies research gaps to encourage future investigation. As the field of magnesium homeostasis continues to advance, understanding PACT protein interactions offers new opportunities for basic research and therapeutic development targeting magnesium-related disorders. Full article

Focal swellings of dendrites (“dendritic blebbing”) together with structural damage of mitochondria and the endoplasmic reticulum (ER) are morphological hallmarks of glutamate neurotoxicity, also known as excitotoxicity. These pathological alterations are generally thought to be caused by the so-called “overactivation” of N-methyl-D-aspartate receptors (NMDARs). Here, we demonstrate that the activation of extrasynaptic NMDARs, specifically when forming a protein–protein complex with TRPM4, drives these pathological traits. In contrast, strong activation of synaptic NMDARs fails to induce cell damage despite evoking plateau-type calcium signals that are comparable to those generated by activation of the NMDAR/TRPM4 complex, indicating that high intracellular calcium levels per se are not toxic to neurons. Using confocal laser scanning microscopy and transmission electron microscopy, we show that disrupting the NMDAR/TRPM4 complex using the recently discovered small-molecule TwinF interface inhibitor FP802 inhibits the NMDA-induced neurotoxicity-associated dendritic blebbing and structural damage to mitochondria and the ER. It also prevents, at least in part, the disruption of ER–mitochondria contact sites. These findings establish the NMDAR/TRPM4 complex as the trigger for the structural damage of dendrites and intracellular organelles associated with excitotoxicity. They also suggest that activation of the NMDAR/TRPM4 complex, in addition to inducing high-amplitude, plateau-type calcium signals, generates a second signal required for glutamate neurotoxicity (“two-hit hypothesis”). As structural damage to organelles, particularly mitochondria, is a common feature of many human neurodegenerative diseases, including Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), TwinF interface inhibitors have the potential to provide neuroprotection across a broad spectrum of these diseases. Full article