TRPM2 overactivation drives hyperlipidemia-induced dysfunction of myeloid cells and neurovascular units.

Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels.

TRPM7 channel activity promotes the pathogenesis of abdominal aortic aneurysms.

Abdominal aortic aneurysms (AAAs) occur in 1-2% of the elderly. The rupture of an AAA usually causes uncontrollable lethal hemorrhage, and its risk increases with AAA size. However, there is no effective pharmacological therapy for hindering AAA growth.

TRP Channels in Excitotoxicity.

Glutamate excitotoxicity is a central mechanism contributing to cellular dysfunction and death in various neurological disorders and diseases, such as stroke, traumatic brain injury, epilepsy, schizophrenia, addiction, mood disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, pathologic pain, and even normal aging-related changes. This detrimental effect emerges from glutamate binding to glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, -methyl-d-aspartate receptors, kainate receptors, and GluD receptors. Thus, excitotoxicity could be prevented by targeting glutamate receptors and their downstream signaling pathways.

TRP Channels in Stroke.

Ischemic stroke is a devastating disease that affects millions of patients worldwide. Unfortunately, there are no effective medications for mitigating brain injury after ischemic stroke. TRP channels are evolutionally ancient biosensors that detect external stimuli as well as tissue or cellular injury.

Regulation of Presynaptic Calcium Channels.

Voltage-gated calcium channels (VGCCs), especially Ca2.1 and Ca2.2, are the major mediators of Ca influx at the presynaptic membrane in response to neuron excitation, thereby exerting a predominant control on synaptic transmission.

Activation of endothelial TRPM2 exacerbates blood-brain barrier degradation in ischemic stroke.

Aims: Damage of the blood-brain barrier (BBB) is a hallmark of brain injury during the early stages of ischemic stroke. The subsequent endothelial hyperpermeability drives the initial pathological changes and aggravates neuronal death. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable nonselective cation channel activated by oxidative stress.

Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15.

Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg ions on their own and influx of divalent cations when expressed with the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM-binding partner and an inhibitor of divalent cation influx by TRPM7.

Structural insights into regulation of TRPM7 divalent cation uptake by the small GTPase ARL15.

Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg ions on their own or uptake of divalent cations when coupled to the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM binding partner and an inhibitor of divalent cation influx by TRPM7.

Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes.

The vast potential of human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) in preclinical models of cardiac pathologies, precision medicine, and drug screening remains to be fully realized because hiPSC-CMs are immature without adult-like characteristics. Here, we present a method to accelerate hiPSC-CM maturation on a substrate, cardiac mimetic matrix (CMM), mimicking adult human heart matrix ligand chemistry, rigidity, and submicron ultrastructure, which synergistically mature hiPSC-CMs rapidly within 30 days. hiPSC-CMs matured on CMM exhibit systemic transcriptomic maturation toward an adult heart state, are aligned with high strain energy, metabolically rely on oxidative phosphorylation and fatty acid oxidation, and display enhanced redox handling capability, efficient calcium handling, and electrophysiological features of ventricular myocytes.

TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.

Atherosclerosis is the major cause of ischemic heart disease and stroke, the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear.

Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury.

Excitotoxicity induced by NMDA receptor (NMDAR) activation is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical trials. Here, we reveal an unexpected mechanism underlying NMDAR-mediated neurotoxicity, which leads to the identification of a novel target and development of an effective therapeutic peptide for ischemic stroke.

A Systemic Review of the Integral Role of TRPM2 in Ischemic Stroke: From Upstream Risk Factors to Ultimate Neuronal Death.

Ischemic stroke causes a heavy health burden worldwide, with over 10 million new cases every year. Despite the high prevalence and mortality rate of ischemic stroke, the underlying molecular mechanisms for the common etiological factors of ischemic stroke and ischemic stroke itself remain unclear, which results in insufficient preventive strategies and ineffective treatments for this devastating disease. In this review, we demonstrate that transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a non-selective ion channel activated by oxidative stress, is actively involved in all the important steps in the etiology and pathology of ischemic stroke.

Upregulation of transient receptor potential melastatin 4 (TRPM4) in ventricular fibroblasts from heart failure patients.

The transient receptor potential melastatin 4 (TRPM4) is a Ca-activated nonselective monovalent cation channel belonging to the TRP channel superfamily. TRPM4 is widely expressed in various tissues and most abundantly expressed in the heart. TRPM4 plays a critical role in cardiac conduction.

Melatonin promotes sleep by activating the BK channel in .

Melatonin (Mel) promotes sleep through G protein-coupled receptors. However, the downstream molecular target(s) is unknown. We identified the BK channel SLO-1 as a molecular target of the Mel receptor PCDR-1-.

Celastrol attenuates arterial and valvular calcification via inhibiting BMP2/Smad1/5 signalling.

Vascular calcification is an important risk factor for the mortality and morbidity in chronic kidney disease (CKD). Unfortunately, until now there is no certain medication targeting vascular calcification in CKD. In this study, we explored the inhibitory effect of celastrol on high calcium-induced vascular calcification and the underlying molecular mechanisms.

Inhibition of acetylation of histones 3 and 4 attenuates aortic valve calcification.

Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery.

CD47 deficiency protects cardiomyocytes against hypoxia/reoxygenation injury by rescuing autophagic clearance.

To assess the effect of cluster of differentiation (CD47) downregulation on autophagy in hypoxia/reoxygenation (H/R)‑treated H9c2 cardiomyocytes. H9c2 cells were maintained in normoxic conditions (95% air, 5% CO2, 37˚C) without CD47 antibodies, Si‑CD47 or chloroquine (CQ) treatment; H9c2 cells in the H/R group were subjected to 24 h of hypoxia (1% O2, 94% N2, 5% CO2, 37˚C) followed by 12 h of reoxygenation (95% air, 5% CO2, 37˚C). All assays were controlled, triplicated and repeated on three separately initiated cultures.

Distribution, Morphological Characterization, and Resiniferatoxin-Susceptibility of Sensory Neurons That Innervate Rat Perirenal Adipose Tissue.

Perirenal adipose tissue (PrAT) is a visceral adipose tissue involved in the pathogenesis of obesity and cardiovascular diseases via neural pathways. However, the origins, morphological characterization, and resiniferatoxin (RTX)-susceptibility of sensory neurons that innervate rat PrAT are yet unclear. Using neural tracing, an injection of DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) into PrAT revealed that sensory neurons that innervate PrAT reside in T9-L3 dorsal root ganglia (DRG).