Association between transient receptor potential melastatin genotypes and the prostate surface antigen levels in BPH patients

Background: Benign Prostate Hyperplasia (BPH) is a prevalent condition among older males, characterized by an enlarged prostate gland leading to lower urinary tract symptoms and impacting quality of life. Transient receptor potential melastatin (TRPM) genes regulate various physiological processes. Methods: We studied 194 BPH patients and 194 healthy controls, genotyping six selected TRPM gene SNPs. PSA levels were measured using the Cobas® e411 analyzer. Results: Prostate-specific antigen (PSA) levels were significantly higher in BPH patients (135.76±578.03 ng/mL) than in controls (2.01±1.09 ng/mL). TRPM2 (rs168355) and TRPM7 (rs2362295) genotypes were significantly associated with elevated PSA levels. The TRPM2 GG genotype was associated with decrease in the likelihood of severe PSA levels (OR=0.34, 95% CI: 0.12-0.96, P=0.034), while the TRPM7 CC genotype showed increased odds for severe PSA levels (OR=1.48, 95% CI: 1.08-3.56, P=0.041). Conclusions: Our findings suggest a potential link between TRPM gene variants and the severity of prostatic changes reflected in PSA secretions, indicating the need for further research to understand the underlying mechanisms and clinical implications.

Effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension in mice and its mechanism / 中国药理学通报

Aim To study the effect of menthol on hypobaric hypoxia-induced pulmonary arterial hypertension and explore the underlying mechanism in mice. Methods 10 to 12 weeks old wild type (WT) mice and TRPM8 gene knockout (TRPM8

Effect of selenium against doxorubicin-induced oxidative stress, inflammation, and apoptosis in the brain of rats: Role of TRPM2 channel

Doxorubicin (DOX) is widely used as an anticancer drug in humans' various solid and haematological tumours. Although many studies on the toxic effect of DOX are used in different organs, its impact on brain tissue has yet to be adequately studied. This study investigated the protective effect of selenium (Se) and the role of transient receptor potential melastatin?2 (TRPM2) channel activation against brain damage caused by DOX administration. Sixty rats were randomly divided into the sham, dimethyl sulfoxide (DMSO), DOX, DOX?+?Se, DOX?+?N-(p-amylcinnamoyl) anthranilic acid (ACA), and DOX?+?Se?+?ACA groups. The reactive oxygen species (ROS), poly [ADP-ribose] polymerase 1 (PARP1), and TRPM2 channel levels in brain tissues were measured by ELISA. In addition, a histopathological examination was performed in the cerebral cortex and hippocampal areas, and the TRPM2 channel, NF-?B, and caspase-3 expression were determined immunohistochemically. The levels of ROS, PARP1 and TRPM2 channel in the DOX group were higher than in the sham and DMSO groups (P <?0.05). However, these parameters were decreased in the in DOX+Se and DOX+ACA groups by the treatments of Se and ACA (P?<?0.05). Also, we determined that Se and ACA treatment decreased the NF-?B, caspase-3, and TRPM2 channel expression in the cerebral cortex and hippocampal areas in the DOX-induced rats. The data showed that Se and/or ACA administration together with DOX administration could be used as a protective agent against DOX-induced brain damage.

Lianmei Qiwu Decoction relieves diabetic cardiac autonomic neuropathy by regulating AMPK/TrkA/TRPM7 signaling pathway / 中国中药杂志

This study investigated the effect of Lianmei Qiwu Decoction(LMQWD) on the improvement of cardiac autonomic nerve remodeling in the diabetic rat model induced by the high-fat diet and explored the underlying mechanism of LMQWD through the AMP-activated protein kinase(AMPK)/tropomyosin receptor kinase A(TrkA)/transient receptor potential melastatin 7(TRPM7) signaling pathway. The diabetic rats were randomly divided into a model group, an LMQWD group, an AMPK agonist group, an unloaded TRPM7 adenovirus group(TRPM7-N), an overexpressed TRPM7 adenovirus group(TRPM7), an LMQWD + unloaded TRPM7 adenovirus group(LMQWD+TRPM7-N), an LMQWD + overexpressed TRPM7 adenovirus group(LMQWD+TRPM7), and a TRPM7 channel inhibitor group(TRPM7 inhibitor). After four weeks of treatment, programmed electrical stimulation(PES) was employed to detect the arrhythmia susceptibility of rats. The myocardial cell structure and myocardial tissue fibrosis of myocardial and ganglion samples in diabetic rats were observed by hematoxylin-eosin(HE) staining and Masson staining. The immunohistochemistry, immunofluorescence, real-time quantitative polymerase chain reaction(RT-PCR), and Western blot were adopted to detect the distribution and expression of TRPM7, tyrosine hydroxylase(TH), choline acetyltransferase(ChAT), growth associated protein-43(GAP-43), nerve growth factor(NGF), p-AMPK/AMPK, and other genes and related neural markers. The results showed that LMQWD could significantly reduce the arrhythmia susceptibility and the degree of fibrosis in myocardial tissues, decrease the levels of TH, ChAT, and GAP-43 in the myocardium and ganglion, increase NGF, inhibit the expression of TRPM7, and up-regulate p-AMPK/AMPK and p-TrkA/TrkA levels. This study indicated that LMQWD could attenuate cardiac autonomic nerve remodeling in the diabetic state, and its mechanism was associated with the activation of AMPK, further phosphorylation of TrkA, and inhibition of TRPM7 expression.

Role of TRPM2 in sevoflurane anesthesia-induced necroptosis in hippocampal neurons of aged rats / 中华麻醉学杂志

Objective:To evaluate the role of transient receptor potential melastatin2 (TRPM2) in sevoflurane anesthesia-induced necroptosis in hippocampal neurons of aged rats.Methods:Sixty SPF-grade healthy male Sprague-Dawley rats, aged 22 months, weighing 550-600 g, were divided into 3 groups ( n=20 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group M) and sevoflurane anesthesia+ TRPM2 inhibitor group (group M+ A). M and M+ A groups inhaled 2% sevoflurane for 5 h. In group M+ A, TRPM2 inhibitor ACA 20 mg/kg was intraperitoneally injected at 1 h before sevoflurane inhalation, and the equal volume of dimethyl sulfoxide was intraperitoneally injected in group C and group M. Morris water maze test was performed at 1 day after sevoflurane anesthesia. The escape latency, times of crossing the original platform and time spent in the original platform quadrant were collected. The expression of TRPM2 and necroptosis-related proteins (mixed lineage kinase domain-like protein [MLKL], receptor-interacting protein kinase-1 [RIPK1], phosphorylated MLKL [p-MLKL], and phosphorylated RIPK1 [p-RIPK1]) was detected by Western blot. The cytosolic Ca 2+ concentration in and necroptosis rate of hippocampal neurons were determined by flow cytometry. Results:Compared with group C, the escape latency was significantly prolonged, the times of crossing the original platform were decreased and the time spent in the original platform quadrant was shortened, the expression of TRPM2, MLKL, RIPK1, p-MLKL and p-RIPK1 was up-regulated, and the cytosolic Ca 2+ concentrations in hippocampal neurons and necroptosis rate of hippocampal neurons were increased in group M and group M+ A ( P<0.05). Compared with group M, the escape latency was significantly shortened, the times of crossing the original platform were increased, and the time spent in the original platform quadrant was prolonged, the expression of TRPM2, MLKL, RIPK1, p-MLKL and p-RIPK1 was down-regulated, and the cytosolic Ca 2+ concentrations in hippocampal neurons and necroptosis rate of hippocampal neurons were decreased in group M+ A ( P<0.05). Conclusions:Hippocampal TRPM2 is involved in the process of sevoflurane anesthesia-induced necroptosis in hippocampal neurons of aged rats.

Role of corneal cold thermoreceptors in the occurrence and development of dry eye / 中华实验眼科杂志

Dry eye is a multifactorial disease caused by changes in tear quality, volume and dynamics.Disturbance of tear film as the main character is accompanied by discomfort, visual disorder, and damage to the ocular surface and nerves.Cold thermoreceptors existing on the ocular surface are sensitive to alterations in corneal temperature and tear osmolality.They can give rise to the sensations of cold and pain, and regulate tear secretion, and are considered to be associated with the clinical manifestations of dry eye in some ways.This article reviewed the progress of corneal cold thermoreceptors in the regulation of corneal sensation and tear secretion, the related factors of corneal sensory regulation, and the clinical applications of TRPM8-related drugs, so as to provide ideas for the treatment of dry eye.

Disseminated intravascular coagulation phenotype is regulated by the TRPM7 channel during sepsis

BACKGROUND: Sepsis is an uncontrolled inflammatory response against a systemic infection that results in elevated mortality, mainly induced by bacterial products known as endotoxins, producing endotoxemia. Disseminated intravascular coagulation (DIC) is frequently observed in septic patients and is associated with organ failure and death. Sepsis activates endothelial cells (ECs), promoting a prothrombotic phenotype contributing to DIC. Ion channel mediated calcium permeability participates in coagulation. The transient reception potential melastatin 7 (TRPM7) non-selective divalent cation channel that also contains an α-kinase domain, which is permeable to divalent cations including Ca2+, regulates endotoxin-stimulated calcium permeability in ECs and is associated with increased mortality in septic patients. However, whether endothelial TRPM7 mediates endotoxemia-induced coagulation is not known. Therefore, our aim was to examine if TRPM7 mediates coagulation during endotoxemia. RESULTS: The results showed that TRPM7 regulated endotoxin-induced platelet and neutrophil adhesion to ECs, dependent on the TRPM7 ion channel activity and by the α-kinase function. Endotoxic animals showed that TRPM7 mediated neutrophil rolling on blood vessels and intravascular coagulation. TRPM7 mediated the increased expression of the adhesion proteins, von Willebrand factor (vWF), intercellular adhesion molecule 1 (ICAM-1), and P-selectin, which were also mediated by the TRPM7 α-kinase function. Notably, endotoxin-induced expression of vWF, ICAM-1 and P-selectin were required for endotoxin-induced platelet and neutrophil adhesion to ECs. Endotoxemic rats showed increased endothelial TRPM7 expression associated with a procoagulant phenotype, liver and kidney dysfunction, increased death events and an increased relative risk of death. Interestingly, circulating ECs (CECs) from septic shock patients (SSPs) showed increased TRPM7 expression associated with increased DIC scores and decreased survival times. Additionally, SSPs with a high expression of TRPM7 in CECs showed increased mortality and relative risk of death. Notably, CECs from SSPs showed significant results from the AUROC analyses for predicting mortality in SSPs that were better than the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores. CONCLUSIONS: Our study demonstrates that sepsis-induced DIC is mediated by TRPM7 in ECs. TRPM7 ion channel activity and α-kinase function are required by DIC-mediated sepsis-induced organ dysfunction and its expression are associated with increased mortality during sepsis. TRPM7 appears as a new prognostic biomarker to predict mortality associated to DIC in SSPs, and as a novel target for drug development against DIC during infectious inflammatory diseases.

Clinical management of primary hypomagnesemia with secondary hypocalcemia / 中华内分泌代谢杂志

Primary hypomagnesemia with secondary hypocalcemia(HSH) is a rare cause of hypoparathyroidism. This article presents a case of a 26-year-old male with recurrent generalized weakness and tetany, and a literature review of diagnosis and treatment of primary HSH. The biochemical tests revealed the patient had severe hypomagnesemia, mild hypocalcemia, hypokalemia, and hypoparathyroidism. Transient receptor potential melastatin-6(TRPM6) gene mutation were detected by gene test, which confirmed the diagnosis of primary HSH. The patient had been treated with long term oral magnesium supplementation, who remained asymptomatic during the follow-up. Primary HSH is a rare autosomal-recessive disorder caused by mutations in the TRPM6 gene which encoding a magnesium permeable channel expressed in the intestine and the kidney. The primary defect is impaired intestinal absorption of magnesium with secondary renal excretion, leading to a series of clinical symptoms. The treatment is mainly through lifelong magnesium supplementation.

Tyrosine phosphorylation of TRPM3 ion channel mediates diabetes-induced heat hyperalgesia / 中国临床药理学与治疗学

AIM: To investigate the relationship between TRPM3 and diabetes-induced painful peripheral neuropathy. METHODS: Treptozotocin (STZ) was intraperitoneal injected for establishment of diabetic mice model, behavioral tests of paw withdraw thresholds (PWTs) and paw withdraw latencies (PWLs) were conducted; Protein contents and tyrosine phosphorylation levels of TRPM3 were detected by immunoprecipitation and immunoblotting. RESULTS: The PWTs and PWLs in diabetic mice were significantly reduced; TRPM3 tyrosine phosphorylation in the dorsal root ganglia (DRG) of diabetic mice significantly increased compared with control, while the protein expression shows no statistical significance; Enhanced tyrosine phosphorylation of TRPM3 by BPV can evoke heat hyperalgesia in intact mice; Reduce of the tyrosine phosphorylation levels of TRPM3 through PP2 significantly alleviates diabetes-induced heat hyperalgesia, without affecting mechanical allodynia. CONCLUSION: The upregulation of tyrosine phosphorylation of TRPM3 plays a key role in heat related painful diabetic peripheral neuropathy.

Effects of 2-APB in skin wound healing in mice through down-regulation of TRPM7 / 中国临床药理学与治疗学

AIM: To explore the promoting effect of 2-APB on skin wound healing in mice and its potential mechanism. METHODS: KM mice were divided into 5 groups: control group, DMSO group, low (50 mg/L), medium (100 mg/L) and high (200 mg/L) concentration 2-APB group. On the back of each mouse's skin use a circular punch about 1 cm on both sides of the midline of the spine to make a skin wound with a diameter of 10 mm and as deep as the fascia. The control group was only wrapped with gauze and no drugs were applied; the DMSO group was applied 1 g DMSO/Vaseline ointment per day; in the 2-APB group, apply 1 g of 2-APB/Vaseline ointment at a corresponding concentration every day. Pictures were taken the next day to observe the healing, and the material was taken on the 21st day, HE staining was used to observe the pathological morphology of the wound and western blot to detect TRPM7, TGF-β, collagen-I and IL-1β expression. RESULTS: Compared with the control group and the DMSO group, different concentrations of 2-APB could significantly promote skin wound healing in mice (P<0.01), but there was no significant difference in wound healing rate between the DMSO group and the control group group. The results of HE staining showed that, compared with the control group group and the DMSO group, 2-APB could increase the collagen content of the wound and the thickness of the dermis (P<0.01), but there was no significant difference between the DMSO group and the control group group. At the same time, 2-APB could also significantly increase the expression of TGF-β and Col-I on the wound, and inhibit the expression of TRPM7 and IL-1β. CONCLUSION: Different concentrations of 2-APB (50, 100 and 200 mg/L) can promote skin wound healing, and its mechanism may be related to the inhibition of TRPM7.

Function of TRPM8 Ion Channel and Regulation Mechanism of Its Post-translational Modification / 中国生物化学与分子生物学报

TRPM8 (transient receptor potential melastatin 8), also known as a cold and menthol receptor and a member of the TRP (transient receptor potential) channel superfamily, locates on the cell membrane or organelle membrane.. TRPM8 is a non-selective cation channel, which can be used as either a cold and heat sensor or cold and pain sensor to conduct signal transduction. It plays an important role in maintaining intracellular homeostasis and controlling ion in cells. It has been found that PTM (post-translational modification) of TRPM8 affects the occurrence and development of many diseases by regulating the function of TRPM8 channel. Therefore, it is necessary to explore the PTM process of TRPM8 to gain a deeper understanding for the function and regulatory mechanism of TRPM8. At present, several types of post-translational modifications of TRPM8 have been reported, including phosphorylation, ubiquitination and glycosylation, which can regulate protein interactions and change the activity of TRPM8 ion channels, leading to modulation of cell proliferation, migration and apoptosis. It is noteworthy that the expression of TRPM8 level is closely related to many kinds of cancers, such as prostate cancer, bladder cancer and breast cancer. This review focus on the structure of TRPM8 ion channels, systematically elaborate the translational modifications, activator and antagonist of TRPM8 protein, and the regulation of some proteins on TRPM8 channel activity. At the same time, we summarize the recent progress of TRPM8 in prostate cancer, bladder cancer and breast cancer, which would provide new directions and new ideas for the treatment of cancer.

Relationship Between TRPV1 and TRPM8 in Reflux Esophagitis Models / 胃肠病学

Background: Studies have shown that transient receptor potential (TRP) channels play important roles in gastroesophageal reflux disease (GERD), however, the relationship between TRPV1 and TRPM8 in reflux esophagitis (RE) remains unclear. Aims: To investigate the expressions of TRPV1, TRPM8 and their correlation in guinea pigs with RE. Methods: Thirty male guinea pigs aged 3⁃4 weeks were randomly divided into 3 groups: blank control group, negative control group and model group, with 10 animals in each group. Guinea pigs in model group and negative control group were given esophageal perfusion with 0.1 mol/L HCl containing 0.5% pepsin and normal saline, respectively, once a day for 14 days; guinea pigs in blank control group were free to drink sterile water for 14 days. On day 15, the esophagus was dissected for macroscopic and histopathological examination, and Western blotting and/or real⁃time PCR were used to detect the expression levels of TRPV1, TRPM8, GNAQ (an isoform of G protein), and the tight junction proteins and proinflammatory cytokines in esophageal tissue. The co⁃localization of TRPV1 and TRPM8 was assessed by immunofluorescence. Results: Esophageal mucosal congestion, hyperplasia of esophageal epithelial cells, infiltration of inflammatory cells, as well as up⁃regulation of proinflammatory cytokines and down⁃regulation of tight junction proteins were observed in esophageal tissue of guinea pigs in model group, which indicated the successful RE model construction. As compared with the negative control group, expression levels of TRPV1 and GNAQ mRNA and protein were significantly increased, while expression levels of TRPM8 mRNA and protein were significantly reduced in esophageal tissue of guinea pigs in model group (all P<0.05). TRPV1 and TRPM8 channels were co ⁃ localized in the lamina propria of esophageal mucosa. Conclusions: There is a certain equilibrium mechanism between TRPV1 and TRPM8 channels in RE models. G protein⁃coupled receptor signaling pathway and the downstream TRPV1/TRPM8 might be involved in the occurrence and development of GERD.

TRPM3/miR-204 in the regulation of ophthalmic diseases / 国际眼科杂志(Guoji Yanke Zazhi)

@#MicroRNAs(miRNAs)are one of the most important regulatory factors of gene expression, which involved in the growth, development, differentiation and apoptosis of various cells, tissues and organs. TRPM3 is located in human chromosome 9 and belongs to M sub-family of the transient receptor potential(TRP)channels. MiR-204 is located on TRPM3 intron 6 and participates in the regulation of post-transcriptional gene expression through cleavage or translation inhibition of target mRNAs. Studies have shown that TRPM3/miR-204 complex locus plays an important role in the occurrence and development of eye diseases such as cataract, glaucoma, corneal neovascularization, corneal wound healing, retinal diseases, optic nerve diseases and so on. In this paper, the biological function of TRPM3/miR-204, its expression and regulation in the eyes and its correlation with a variety of ophthalmic diseases are reviewed.

Implications of Transient Receptor Potential Cation Channels in Migraine Pathophysiology / 神经科学通报·英文版

Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive, abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potential (TRP) channels, which transduce noxious stimuli into pain signals, are expressed in trigeminal ganglion neurons and brain regions closely associated with the pathophysiology of migraine. In the trigeminal ganglion, TRP channels co-localize with calcitonin gene-related peptide, a neuropeptide crucially implicated in migraine pathophysiology. Many preclinical and clinical data support the roles of TRP channels in migraine. In particular, activation of TRP cation channel V1 has been shown to regulate calcitonin gene-related peptide release from trigeminal nerves. Intriguingly, several effective anti-migraine therapies, including botulinum neurotoxin type A, affect the functions of TRP cation channels. Here, we discuss currently available data regarding the roles of major TRP cation channels in the pathophysiology of migraine and the therapeutic applicability thereof.

Role of TRPM2-CnA-Drp1 pathway in propofol-induced reduction of renal injury induced by hepatic ischemia-reperfusion in mice / 中华麻醉学杂志

Objective:To evaluate the role of transient receptor potential melastatin 2 (TRPM2)-calcineurin A (CnA)-dynamin-related protein 1 (Drp1) pathway in propofol-induced reduction of renal injury induced by hepatic ischemia-reperfusion (I/R) in mice.Methods:Twenty-four SPF male C57BL6 mice, aged 8 weeks, weighing 20-23 g, were divided into 4 groups ( n=6 each) using a random number table method: sham operation group (group S), hepatic I/R group (group IR), propofol group (group P) and TRPM2 agonist (ADPR) combined with propofol group (AP group). Hepatic I/R injury was induced by occluding the portal vein and hepatic artery supplying the left and middle lobes of the liver for 60 min followed by reperfusion in anesthetized rats.In group P, 0.2 ml normal saline was injected intraperitoneally at 1 h before establishing the model and 1% propofol 30 mg/kg was injected intraperitoneally at 30 min before establishing the model.In group AP, ADPR 10 mg/kg (in 0.2 ml of normal saline) was injected intraperitoneally at 1 h before establishing the model, and 1% propofol 30 mg/kg was injected intraperitoneally at 30 min before establishing the model.The equal volume of normal saline was given intraperitoneally at 1 h and at 30 min before establishing the model in group S and group IR.Blood samples were taken from the eyeballs for determination of the levels of serum urea nitrogen (BUN), creatinine (Cr), aminotransferase (ALT) and aspartate aminotransferase (AST) at 6 h of reperfusion.The animals were then sacrificed and the kidney tissues were taken, the ultrastructure of myocardial mitochondria was observed using transmission electron microscopy, the average diameter of mitochondria was calculated, and the expression of TRPM2, CnA, phospho-Drp1 Ser637 (p-Drp1 Ser637) and cleaved caspase-3 was detected (by Western blot). Results:Compared with group S, the concentrations of serum BUN and Cr were significantly increased, the expression of TRPM2, CnA and cleaved caspase-3 in kidney tissues was up-regulated, the expression of p-Drp1 ser637 was down-regulated, and the average diameter of mitochondria was shortened in IR, P and AP groups ( P<0.05). Compared with group IR, the concentrations of serum BUN and Cr were significantly decreased, the expression of TRPM2, CnA and cleaved caspase-3 in kidney tissues was down-regulated, the expression of p-Drp1 Ser637 was up-regulated, the average diameter of mitochondria was prolonged ( P<0.05), mitochondrial injury was attenuated, and no significant change was found in the serum ALT and AST concentrations in group P, and no significant change was found in concentrations of BUN and Cr in serum in group AP ( P>0.05). Compared with group P, concentrations of BUN and Cr in serum was significantly increased, the expression of TRPM2, CnA and cleaved caspase-3 in kidney tissues was up-regulated, the expression of p-Drp1 Ser637 in kidney tissues was down-regulated, and the average diameter of mitochondria was shortened ( P<0.05), and mitochondrial injury was accentuated in group AP. Conclusion:The mechanism of propofol-induced reduction of renal injury induced by hepatic I/R is related to inhibiting the expression of TRPM2 in kidney tissues, decreasing the level of intracellular CnA and inhibiting dephosphorylation of Drp1 Ser637 in mice.

The Effects of Lung Ischaemia/Reperfusion on TRPM Gene Expression

ABSTRACT Objective: Transient receptor potential melastatin (TRPM) are integral membrane proteins that have broad range of cellular functions. Roles of TRPM2, TRPM3, TRPM4 and TRPM7 among these channels are very important, and their roles in lung ischaemia/reperfusion injury have not been evaluated yet. The aim of this study is to investigate the contribution of these genes in lung ischaemia/reperfusion injury and evaluate histopathology of tissues. Methods: A total of 40 Wistar albino rats were enrolled for the study. Ischaemia was performed by the application of an atramvatic clamp to pulmonary artery. Gene expressions were determined by the semi-quantitative reverse transcription-polymerase chain reaction method. Histopatholical evaluations were held by a standard haematoxyline-eosin staining. Results: The major histopathological tissue damage was observed in ischaemia performed groups, and expression of TRPM channels was found to be obviously downregulated. Substantial changes were determined between TRPM2, TRPM3, TRPM4 and TRPM7 and lung ischaemia/reperfusion injury. In particular, expression of TRPM2 and TRPM7 was reversibly downregulated in ischaemia. Yet, the expression of TRPM3 and TRPM4 was irreversibly down-regulated after ischaemia. Conclusion: Consequently, these results indicate that TRPM family of cation channels may have significant roles in the lung ischaemia/reperfusion injury.

Research progress of trpm7 channel and tumor development / 中国药理学通报

Transient receptor potential melastatin-subfamily member 7(TRPM7) is a non-selective cation channel fused with a functional kinase domain. Studies have shown that TRPM7 is aberrantly expressed in tumor cells. TRPM7 plays a variety of functional roles in cancer cells including survival t cell cycle progression, proliferation, invasion, epithelial-mesenchymal transition (EMT) and angiogenesis. The high correlation between TR-PM7 and tumorigcnesis makes TRPM7 a prognostic indicator and a potential therapeutic target for malignant tumors. In this arti cle , we review the research progress of TRPM7 and tumor progression, explore the mechanism of TRPM7-mediated tumor development and the clinical treatment of tumor strategy targeting TRPM7, and provide some reference for follow-up research and clinical treatment.

Research progress of magnesium ion and its transporters in tumors / 肿瘤

In recent years, researchers have found that magnesium ion homeostasis imbalance is common in tumor cells, and the deficiency and supplement of magnesium ion can affect the occurrence and development of tumor. As an abundant divalent cation in cells, magnesium ion plays an important role in maintaining genetic stability, metabolism, cell growth and proliferation, signal transduction and other physiological processes. Magnesium ion homeostasis is regulated by a variety of transporters, and the research reports on the changes of magnesium ion transporters expression leading to the imbalance of magnesium ion homeostasis which affects the occurrence, development and treatment prognosis of tumors are increasing year by year. In this article, magnesium ion and its related transport proteins include magnesium ion transient receptor potential melastatin (TRPM) protein, magnesium transporter (MagT) protein, cyclin and cystathionine beta-synthase (CBS) domain divalent metal cation transport mediator (CNNM) protein and solute carrier (SLC) protein and other related reports in tumors are summarized, with the purpose of providing ideas for exploring whether magnesium ion and its transporters can become new targets for tumor diagnosis, treatment and prognosis.

Effects of calcium-binding sites in the S2–S3 loop on human and Nematostella vectensis TRPM2 channel gating processes / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

As a crucial signaling molecule, calcium plays a critical role in many physiological and pathological processes by regulating ion channel activity. Recently, one study resolved the structure of the transient receptor potential melastatin 2 (TRPM2) channel from Nematostella vectensis (nvTRPM2). This identified a calcium-binding site in the S2–S3 loop, while its effect on channel gating remains unclear. Here, we investigated the role of this calcium-binding site in both nvTRPM2 and human TRPM2 (hTRPM2) by mutagenesis and patch-clamp recording. Unlike hTRPM2, nvTRPM2 cannot be activated by calcium alone. Moreover, the inactivation rate of nvTRPM2 was decreased as intracellular calcium concentration was increased. In addition, our results showed that the four key residues in the calcium-binding site of S2–S3 loop have similar effects on the gating processes of nvTRPM2 and hTRPM2. Among them, the mutations at negatively charged residues (glutamate and aspartate) substantially decreased the currents of nvTRPM2 and hTRPM2. This suggests that these sites are essential for calcium-dependent channel gating. For the charge-neutralizing residues (glutamine and asparagine) in the calcium-binding site, our data showed that glutamine mutating to alanine or glutamate did not affect the channel activity, but glutamine mutating to lysine caused loss of function. Asparagine mutating to aspartate still remained functional, while asparagine mutating to alanine or lysine led to little channel activity. These results suggest that the side chain of glutamine has a less contribution to channel gating than does asparagine. However, our data indicated that both glutamine mutating to alanine or glutamate and asparagine mutating to aspartate accelerated the channel inactivation rate, suggesting that the calcium-binding site in the S2–S3 loop is important for calcium-dependent channel inactivation. Taken together, our results uncovered the effect of four key residues in the S2–S3 loop of TRPM2 on the TRPM2 gating process.

Effects of calcium-binding sites in the S2-S3 loop on human and Nematostella vectensis TRPM2 channel gating processes / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

As a crucial signaling molecule, calcium plays a critical role in many physiological and pathological processes by regulating ion channel activity. Recently, one study resolved the structure of the transient receptor potential melastatin 2 (TRPM2) channel from Nematostella vectensis (nvTRPM2). This identified a calcium-binding site in the S2-S3 loop, while its effect on channel gating remains unclear. Here, we investigated the role of this calcium-binding site in both nvTRPM2 and human TRPM2 (hTRPM2) by mutagenesis and patch-clamp recording. Unlike hTRPM2, nvTRPM2 cannot be activated by calcium alone. Moreover, the inactivation rate of nvTRPM2 was decreased as intracellular calcium concentration was increased. In addition, our results showed that the four key residues in the calcium-binding site of S2-S3 loop have similar effects on the gating processes of nvTRPM2 and hTRPM2. Among them, the mutations at negatively charged residues (glutamate and aspartate) substantially decreased the currents of nvTRPM2 and hTRPM2. This suggests that these sites are essential for calcium-dependent channel gating. For the charge-neutralizing residues (glutamine and asparagine) in the calcium-binding site, our data showed that glutamine mutating to alanine or glutamate did not affect the channel activity, but glutamine mutating to lysine caused loss of function. Asparagine mutating to aspartate still remained functional, while asparagine mutating to alanine or lysine led to little channel activity. These results suggest that the side chain of glutamine has a less contribution to channel gating than does asparagine. However, our data indicated that both glutamine mutating to alanine or glutamate and asparagine mutating to aspartate accelerated the channel inactivation rate, suggesting that the calcium-binding site in the S2-S3 loop is important for calcium-dependent channel inactivation. Taken together, our results uncovered the effect of four key residues in the S2-S3 loop of TRPM2 on the TRPM2 gating process.