TRPM7 Mediates Neuropathic Pain by Activating mTOR Signaling in Astrocytes after Spinal Cord Injury in Rats.

In this study, we investigated whether transient receptor melastatin 7 (TRPM7), known as a non-selective cation channel, inhibits neuropathic pain after spinal cord injury (SCI) and how TRPM7 regulates neuropathic pain. Neuropathic pain was developed 4 weeks after moderate contusive SCI and TRPM7 was markedly upregulated in astrocytes in the lamina I and II of L4-L5 dorsal horn. In addition, both mechanical allodynia and thermal hyperalgesia were significantly alleviated by a TRPM7 inhibitor, carvacrol. In particular, carvacrol treatment inhibited mechanistic target of rapamycin (mTOR) signaling, which was activated in astrocytes. When rats were treated with rapamycin, an inhibitor of mTOR signaling, neuropathic pain was significantly inhibited. Furthermore, blocking TRPM7 and mTOR signaling by carvacrol and rapamycin inhibited astrocyte activation in lamina I and II of dorsal spinal cord and reduced the level of p-JNK and p-c-Jun, which are known to be activated in astrocytes. Finally, inhibiting TRPM7/mTOR signaling also downregulated the production of pain-related factors such as tumor necrosis factor-α, interleukin-6, interleukin-1ß, chemokine (C-C motif) ligand (CCL) 2, CCL-3, CCL-4, CCL-20, chemokine C-X-C motif ligand 1, and matrix metalloproteinase 9 which are known to be involved in the induction and/or maintenance of neuropathic pain after SCI. These results suggest an important role of TRPM7-mediated mTOR signaling in astrocyte activation and thereby induction and/or maintenance of neuropathic pain after SCI.

Cannabigerolic Acid (CBGA) Inhibits the TRPM7 Ion Channel Through its Kinase Domain.

Cannabinoids are a major class of compounds produced by the plant Cannabis sativa. Previous work has demonstrated that the main cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) can have some beneficial effects on pain, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting. While CBD and THC represent the two major plant cannabinoids, some hemp varieties with enzymatic deficiencies produce mainly cannabigerolic acid (CBGA). We recently reported that CBGA has a potent inhibitory effect on both Store-Operated Calcium Entry (SOCE) via inhibition of Calcium Release-Activated Calcium (CRAC) channels as well as currents carried by the channel-kinase TRPM7. Importantly, CBGA prevented kidney damage and suppressed mRNA expression of inflammatory cytokines through inhibition of these mechanisms in an acute nephropathic mouse model. In the present study, we investigate the most common major and minor cannabinoids to determine their potential efficacy on TRPM7 channel function. We find that approximately half of the tested cannabinoids suppress TRPM7 currents to some degree, with CBGA having the strongest inhibitory effect on TRPM7. We determined that the CBGA-mediated inhibition of TRPM7 requires a functional kinase domain, is sensitized by both intracellular Mg⋅ATP and free Mg2+ and reduced by increases in intracellular Ca2+. Finally, we demonstrate that CBGA inhibits native TRPM7 channels in a B lymphocyte cell line. In conclusion, we demonstrate that CBGA is the most potent cannabinoid in suppressing TRPM7 activity and possesses therapeutic potential for diseases in which TRPM7 is known to play an important role such as cancer, stroke, and kidney disease.

TRPM7 Mediates BSCB Disruption After Spinal Cord Injury by Regulating the mTOR/JMJD3 Axis in Rats.

After spinal cord injury (SCI), secondary injuries including blood cells infiltration followed by the production of inflammatory mediators are led by blood-spinal cord barrier (BSCB) breakdown. Therefore, preventing BSCB damage could alleviate the secondary injury progresses after SCI. Recently, we reported that transient receptor potential melastatin 7 channel (TRPM7) expression is increased in vascular endothelial cells after injury and thereby mediates BSCB disruption. However, the mechanism by which TRPM7 regulates BSCB disruption has not been examined yet. In current research, we show that TRPM7 mediates BSCB disruption via mammalian target of rapamycin (mTOR) pathway after SCI in rats. After contusion injury at T9 level of spinal cord, mTOR pathway was activated in the endothelial cells of blood vessels and TRPM7 was involved in the activation of mTOR pathway. BSCB disruption, MMP-2/9 activation, and blood cell infiltration after injury were alleviated by rapamycin, a mTOR signaling inhibitor. Rapamycin also conserved the level of tight junction proteins, which were decreased after SCI. Furthermore, mTOR pathway regulated the expression and activation of histone H3K27 demethylase JMJD3, known as a key epigenetic regulator mediating BSCB damage after SCI. In addition, rapamycin inhibited JMJD3 expression, the loss of tight junction molecules, and MMP-2/9 expression in bEnd.3, a brain endothelial cell line, after oxygen-glucose deprivation/reoxygenation. Thus, our results suggest that TRPM7 contributes to the BSCB disruption by regulating JMJD3 expression through the mTOR pathway after SCI.

Altered TRPM7-Dependent Calcium Influx in Natural Killer Cells of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling multisystemic condition. The pathomechanism of ME/CFS remains unestablished; however, impaired natural killer (NK) cell cytotoxicity is a consistent feature of this condition. Calcium (Ca2+) is crucial for NK cell effector functions. Growing research recognises Ca2+ signalling dysregulation in ME/CFS patients and implicates transient receptor potential ion channel dysfunction. TRPM7 (melastatin) was recently considered in the pathoaetiology of ME/CFS as it participates in several Ca2+-dependent processes that are central to NK cell cytotoxicity which may be compromised in ME/CFS. TRPM7-dependent Ca2+ influx was assessed in NK cells isolated from n = 9 ME/CFS patients and n = 9 age- and sex-matched healthy controls (HCs) using live cell fluorescent imaging techniques. Slope (p < 0.05) was significantly reduced in ME/CFS patients compared with HCs following TRPM7 activation. Half-time of maximal response (p < 0.05) and amplitude (p < 0.001) were significantly reduced in the HCs compared with the ME/CFS patients following TRPM7 desensitisation. Findings from this investigation suggest that TRPM7-dependent Ca2+ influx is reduced with agonism and increased with antagonism in ME/CFS patients relative to the age- and sex-matched HCs. The outcomes reported here potentially reflect TRPM3 dysfunction identified in this condition suggesting that ME/CFS is a TRP ion channelopathy.

Severity of Hepatocyte Damage and Prognosis in Cirrhotic Patients Correlate with Hepatocyte Magnesium Depletion.

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation, we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes of 15 CIRs using synchrotron-based X-ray fluorescence microscopy. In 31 CIRs and 10 CTRLs, we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content (117.2 (IQR 110.5-132.9) vs. 162.8 (IQR 155.9-169.8) µg/g; p < 0.001) and a higher percentage of TRPM7 positive hepatocytes (53.0 (IQR 36.8-62.0) vs. 20.7 (10.7-32.8)%; p < 0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: (a) inversely with the magnesium content both in liver tissue and hepatocytes; and (b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with the worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

TRPM7 mediates endoplasmic reticulum stress and ferroptosis in sepsis-induced myocardial injury.

Transient receptor potential melastatin 7 (TRPM7), a non-selective cation channel, was significantly upregulated in the blood of patients with sepsis. This study focuses on the preliminary exploration of the probable regulatory mechanism of TRPM7 in sepsis-induced myocardial injury (SIMI). HL-1 cardiac muscle cell line was treated with lipopolysaccharide (LPS) to mimic SIMI in vitro, and TRPM7 level was assessed. The impacts of TRPM7 knockdown on cellular inflammation response, oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, and ferroptosis were identified. In order to explore the mechanism, ER stress agonist tunicamycin (TM) or ferroptosis inducer erastin was applied to treat HL-1 cells. The influences of TM and erastin on the aforementioned aspects were evaluated. TRPM7 was elevated in response to LPS stimulation, and its knockdown reduced the secretion of inflammatory factors and oxidative stress degree. Moreover, TRPM7 knockdown significantly suppressed cell apoptosis, ER stress, and ferroptosis. TM and erastin reversed the functions of TRPM7 knockdown, indicating ER stress and ferroptosis mediated in the regulation of TRPM7. This research proposes the possibility of TRPM7 as a marker or target for SIMI, and provides theoretical support for follow-up research.

Involvement of TRPM7 in Alcohol-Induced Damage of the Blood-Brain Barrier in the Presence of HIV Viral Proteins.

Ethanol (EtOH) exerts its effects through various protein targets, including transient receptor potential melastatin 7 (TRPM7) channels, which play an essential role in cellular homeostasis. We demonstrated that TRPM7 is expressed in rat brain microvascular endothelial cells (rBMVECs), the major cellular component of the blood-brain barrier (BBB). Heavy alcohol drinking is often associated with HIV infection, however mechanisms underlying alcohol-induced BBB damage and HIV proteins, are not fully understood. We utilized the HIV-1 transgenic (HIV-1Tg) rat to mimic HIV-1 patients on combination anti-retroviral therapy (cART) and demonstrated TRPM7 expression in rBMVECs wass lower in adolescent HIV-1Tg rats compared to control animals, however control and HIV-1Tg rats expressed similar levels at 9 weeks, indicating persistent presence of HIV-1 proteins delayed TRPM7 expression. Binge exposure to EtOH (binge EtOH) decreased TRPM7 expression in control rBMVECs in a concentration-dependent manner, and abolished TRPM7 expression in HIV-1Tg rats. In human BMVECs (hBMVECs), TRPM7 expression was downregulated after treatment with EtOH, HIV-1 proteins, and in combination. Next, we constructed in vitro BBB models using BMVECs and found TRPM7 antagonists enhanced EtOH-mediated BBB integrity changes. Our study demonstrated alcohol decreased TRPM7 expression, whereby TRPM7 could be involved in the mechanisms underlying BBB alcohol-induced damage in HIV-1 patients on cART.

Carvacrol Inhibits Expression of Transient Receptor Potential Melastatin 7 Channels and Alleviates Zinc Neurotoxicity Induced by Traumatic Brain Injury.

Carvacrol is a monoterpenoid phenol produced by aromatic plants such as oregano. Although the exact mechanism by which carvacrol acts has not yet been established, it appears to inhibit transient receptor potential melastatin 7 (TRPM7), which modulates the homeostasis of metal ions such as zinc and calcium. Several studies have demonstrated that carvacrol has protective effects against zinc neurotoxicity after ischemia and epilepsy. However, to date, no studies have investigated the effect of carvacrol on traumatic brain injury (TBI)-induced zinc neurotoxicity. In the present study, we investigated the therapeutic potential of carvacrol for the prevention of zinc-induced neuronal death after TBI. Rats were subjected to a controlled cortical impact, and carvacrol was injected at a dose of 50 mg/kg. Histological analysis was performed at 12 h, 24 h, and 7 days after TBI. We found that carvacrol reduced TBI-induced TRPM7 over-expression and free zinc accumulation. As a result, subsequent oxidative stress, dendritic damage, and neuronal degeneration were decreased. Moreover, carvacrol not only reduced microglial activation and delayed neuronal death but also improved neurological outcomes after TBI. Taken together, these findings suggest that carvacrol administration may have therapeutic potential after TBI by preventing neuronal death through the inhibition of TRPM7 expression and alleviation of zinc neurotoxicity.

Clinical and Prognostic Values of TRPM7 in Colon and Rectal Cancers.

Background and Objectives: Transient receptor potential melastatin 7 (TRPM7) is a unique channel protein, and functionally responsible for transportation of calcium and magnesium. Physiologically, the TRPM7 channel is involved in homeostasis of calcium and magnesium, and cell survival. TRPM7 expression is up-regulated in many cancers as malignant behaviors of cancer cells, and its deficiency suppresses their growth. Materials and Methods: In this study, we aimed to analyze clinical and prognostic characteristics of TRPM7 expression in colorectal cancers (CRC) using The Cancer Genome Atlas. Results: High expression of TRPM7 was observed in younger patients with rectal cancer (p = 0.0002). By quantitative correlation analysis, TRPM7 was negatively correlated with age (R = −0.239, p = 0.003) and p53 (R = −0.240, p = 0.002). Furthermore, it was positively correlated with APC expression (R = 0.534, p < 0.001) and KRAS expression (R = 0.319, p < 0.001). In colon cancer, there were no variables that showed a significant correlation with TRPM7. Survival analysis found that TRPM7 expression did not have any prognostic value in colon and rectal cancers. Conclusions: Our study highlights that TRPM7 expression in CRC, particularly in rectal cancer, may be a potential marker. Future studies are needed to provide deeper insights into the role of TRPM7 in rectal cancer.

Low-intensity pulsed ultrasound/nanomechanical force generators enhance osteogenesis of BMSCs through microfilaments and TRPM7.

BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) has been reported to accelerate fracture healing, but the mechanism is unclear and its efficacy needs to be further optimized. Ultrasound in combination with functionalized microbubbles has been shown to induce local shear forces and controllable mechanical stress in cells, amplifying the mechanical effects of LIPUS. Nanoscale lipid bubbles (nanobubbles) have high stability and good biosafety. However, the effect of LIPUS combined with functionalized nanobubbles on osteogenesis has rarely been studied. RESULTS: In this study, we report cyclic arginine-glycine-aspartic acid-modified nanobubbles (cRGD-NBs), with a particle size of ~ 500 nm, able to actively target bone marrow mesenchymal stem cells (BMSCs) via integrin receptors. cRGD-NBs can act as nanomechanical force generators on the cell membrane, and further enhance the BMSCs osteogenesis and bone formation promoted by LIPUS. The polymerization of actin microfilaments and the mechanosensitive transient receptor potential melastatin 7 (TRPM7) ion channel play important roles in BMSCs osteogenesis promoted by LIPUS/cRGD-NBs. Moreover, the mutual regulation of TRPM7 and actin microfilaments promote the effect of LIPUS/cRGD-NBs. The extracellular Ca2 + influx, controlled partly by TRPM7, could participated in the effect of LIPUS/cRGD-NBs on BMSCs. CONCLUSIONS: The nanomechanical force generators cRGD-NBs could promote osteogenesis of BMSCs and bone formation induced by LIPUS, through regulation TRPM7, actin cytoskeleton, and intracellular calcium oscillations. This study provides new directions for optimizing the efficacy of LIPUS for fracture healing, and a theoretical basis for the further application and development of LIPUS in clinical practice.

Transient receptor potential melastatin 7 and their modulators.

TRPM (transient receptor potential melastatin) 7, a member of the TRPM subfamily, is a nonselective cation channel located on the cell membrane that regulates mammalian cell intracellular Mg2+ balance. TRPM7 is widely expressed in vivo and is characterized by a unique domain structure comprised of cation channel and protein kinase. TRPM7 primarily controls the cellular influx of Mg2+ and Ca2+. As such TRPM7 plays an important role in the physiological processes of cell proliferation, adhesion, migration, and differentiation, as well as phenotypic transformation. Changes in TRPM7 expression and activity are directly related to diseases such as tissue fibrosis, vascular injury, as well as the occurrence and development of tumors. The structure and function of TRPM7 has been previously described, but regulation of TRPM7 has been limited to Mg2+ and laboratory pharmacological compounds. Hence, in this review, we summarized the endogenous and exogenous regulation of TRPM7, clarified its internal regulatory mechanisms and molecular signaling pathways, and emphasized the regulation of TRPM7 activity as an important target for disease treatment.

Mechanism of Stat1 in the neuronal Ca2+ overload after intracerebral hemorrhage via the H3K27ac/Trpm7 axis.

Intracerebral hemorrhage (ICH) is classified as a subtype of stroke and calcium (Ca2+) overload is a catalyst for ICH. This study explored the mechanisms of Stat1 (signal transducer and activator of transcription 1) in the neuronal Ca2+ overload after ICH. ICH mouse models and in vitro cell models were established. Stat1 and transient receptor potential melastatin 7 (Trpm7) were detected upregulated in ICH models. Afterward, the mice were infected with the lentivirus containing sh-Stat1, and HT22 cells were treated with si-Stat1 and the lentivirus containing pcDNA3.1-Trpm7. The neurological functional impairment, histopathological damage, and Nissl bodies in mice were all measured. HT22 cell viability and apoptosis were identified. The levels of Ca2+, Trpm7 mRNA, H3K27 acetylation (H3K27ac), CaMKII-α, and p-Stat1 protein in the tissues and cells were determined. We found that silencing Stat1 alleviated ICH damage and repressed the neuronal Ca2+ overload after ICH. H3K27ac enrichment in the Trpm7 promoter region was examined and we found that p-Stat1 accelerated Trpm7 transcription via promoting H3K27ac in the Trpm7 promoter region. Besides, Trpm7 overexpression increased Ca2+ overload and aggravated ICH. Overall, p-Stat1 promoted Trpm7 transcription and further aggravated the Ca2+ overload after ICH.NEW & NOTEWORTHY We found Stat1 promotes Trpm7 transcription by promoting H3K27 acetylation and thus promotes calcium overload of neurons after intracerebral hemorrhage.

Suppression of Transient Receptor Potential Melastatin 7 by Carvacrol Protects against Injured Spinal Cord by Inhibiting Blood-Spinal Cord Barrier Disruption.

When the blood-spinal cord barrier (BSCB) is disrupted after a spinal cord injury (SCI), several pathophysiological cascades occur, including inflammation and apoptotic cell death of neurons and oligodendrocytes, resulting in permanent neurological deficits. Transient receptor potential melastatin 7 (TRPM7) is involved in the pathological processes in many neuronal diseases, including traumatic brain injury, amyotrophic lateral sclerosis, parkinsonism dementia, and Alzheimer's disease. Further, carvacrol (CAR), a TRPM7 inhibitor, is known to protect against SCI by reducing oxidative stress and inhibiting the endothelial nitric oxide synthase pathway. However, the functions of TRPM7 in the regulation of BSCB homeostasis after SCI have not been examined. Here, we demonstrated that TRPM7, a calcium-mediated non-selective divalent cation channel, plays a critical role after SCI in rats. Rats were contused at T9 and given CAR (50 mg/kg) intraperitoneally immediately and 12 h after SCI, and then given the same dose once a day for 7 days. TRPM7 was found to be up-regulated after SCI in both in vitro and in vivo studies, and it was expressed in blood vessels alongside neurons and oligodendrocytes. Additionally, CAR treatment suppressed BSCB disruption by inhibiting the loss of tight junction (TJ) proteins and preserved TJ integrity. CAR also reduced apoptotic cell death and improved functional recovery after SCI by preventing BSCB disruption caused by blood infiltration and inflammatory responses. Based on these findings, we propose that blocking the TRPM7 channel can inhibit the destruction of the BSCB and it is a potential target in therapeutic drug development for use in SCI.

Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases.

An autoimmune disease is an inappropriate response to one's tissues due to a break in immune tolerance and exposure to self-antigens. It often leads to structural and functional damage to organs and systemic disorders. To date, there are no effective interventions to prevent the progression of autoimmune diseases. Hence, there is an urgent need for new treatment targets. TRPM7 is an enzyme-coupled, transient receptor ion channel of the subfamily M that plays a vital role in pathologic and physiologic conditions. While TRPM7 is constitutively activated under certain conditions, it can regulate cell migration, polarization, proliferation and cytokine secretion. However, a growing body of evidence highlights the critical role of TRPM7 in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and diabetes. Herein, we present (a) a review of the channel kinase properties of TRPM7 and its pharmacological properties, (b) discuss the role of TRPM7 in immune cells (neutrophils, macrophages, lymphocytes and mast cells) and its upstream immunoreactive substances, and (c) highlight TRPM7 as a potential therapeutic target for autoimmune diseases.

Transient receptor potential melastatin 7 aggravates necrotizing enterocolitis by promoting an inflammatory response in children.

Background: As a rare disease in children, necrotizing enterocolitis (NEC) leads to high morbidity and mortality. However, its pathophysiology is largely unclear. Transient receptor potential melastatin 7 (TRPM7) is a membrane protein, which plays key roles in the inflammatory response. This study sought to examine the promoting effect of TRPM7 on NEC in children and explore the therapeutic effect of a TRPM7 inhibitor NS8593. Methods: First, we detected TRPM7 and NLR family pyrin domain containing 3 (NLRP3) expression and the state of inflammation in children with NEC through quantitative real-time polymerase chain reaction (RT-PCR), Western blot, and enzyme-linked immunosorbent assays. Next, Human intestinal epithelial cell lines were induced to NEC by lipopolysaccharides (LPSs). The level of cytokines and reactive oxygen species (ROS) were tested by RT-PCR and flow cytometry. The TRPM7 mediated calcium flux were determined by fluorescence. In addition, we used the TRPM7 inhibitor NS8593 to treat the in vivo rat model. The mRNA and protein expression were determined by real-time PCR and Elisa analysis, respectively. Results: TRPM7 and NLRP3 expression was more increased in the samples from children with NEC compared to the control samples. Additionally, the elevated secretion of interleukin-1ß, interleukin-6, and tumor necrosis factor alpha was also detected in the serum of children with NEC. These results showed that TRPM7 had a promoting effect on NEC development, possibly via the activation of NLRP3. To test our hypothesis, the TRPM7 inhibitor NS8593 was used to treat the LPS-stimulated IEC-6 cells. We found that the TRPM7 inhibitor NS8593 inhibited LPS-induced cytokine production and exhibited an anti-inflammatory effect by alleviating TRPM7-mediated NLRP3 inflammasome activation. Through in-vivo experiments, we found that TRPM7 was involved in the occurrence of NEC, and its inhibitor NS8593 played a certain therapeutic role in the rat model. Conclusions: Our study revealed TRPM7 inhibitors attenuated LPS-induced ROS and reduced the release of pro-inflammatory cytokines. It also exhibited protective effects on the NEC model.

Protective effect of miR-9-5p regulating transient receptor potential melastatin 7 on myocardial ischemia-reperfusion in rats / 解剖学报

Objective To investigate the effect of microRNA-9-5p (miR-9-5p) regulating transient receptor potential melastatin 7 (TRPM7) on myocardial ischemia-reperfusion (MIR) in rats. Methods Thirty-two SD rats were divided into sham operation group, model group, miR-9-5p overexpression group and empty vector control group. The MIR model was established by ligation of left coronary artery. The sham operation group was not ligated. miR-9-5p agomir and agomir NC were injected into tail vein 24 hours before model establishment in miR-9-5p overexpression group and empty vector control group. The myocardial injury was observed by HE staining. The expression of miR-9-5p was detected by Real-time PCR. The serum levels of interleukin(IL)-6, tumor necrosis factor alpha(TNF-α), IL-1β, creatine kinase isoenzyme MB (CK-MB), cardiac troponin Ⅰ (cTnI), lactate dehydrogenase (LDH) and the contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in myocardium were measured were measured by ELISA. Cardiomyocyte apoptosis was detected by TUNEL. Double luciferase assay verified the relationship between miR-9-5p and TRPM7. The protein expressions of TRPM7, Bcl-2, Bcl-2 associated X (Bax), phosphorylated nuclear factor kappa-B 65 (p-NF-κB p65) and toll like receptor 4 (TLR4) were detected by Western blotting. Results The expression of miR-9-5p was low in myocardial tissue of rats (P<0.05). Overexpression of miR-9-5p could reduce the expression levels of CK-MB, cTnI and LDH, and improve the degree of myocardial injury. Compared with the model group, the apoptosis rate, Bax protein expression, MDA, IL-6, TNF-α and IL-1β contents in myocardial cells of miR-9-5p overexpression group decreased, while Bcl-2 protein expression and SOD content increased (P<0.05). The result of dual luciferase assay showed that TRPM7 was the target gene of miR-9-5p, and the protein expressions of TRPM7, p-NF-κB p65 and TLR4 in miR-9-5p overexpression group were lower than those in model group (P<0.05). Conclusion MiR-9-5p can inhibit myocardial cell apoptosis, oxidative stress and inflammation induced by myocardial ischemia-reperfusion, and inhibit TLR4/NF-κB pathway by regulating TRPM7.

Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder. Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown. This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.

Carvacrol alleviates liver fibrosis by inhibiting TRPM7 and modulating the MAPK signaling pathway.

Liver fibrosis is a compensatory response to the tissue repair process. The activation and proliferation of hepatic stellate cells (HSCs) are thought to be related to the occurrence of hepatic fibrosis. Therefore, inhibiting the activation and proliferation of HSCs is a key step in alleviating liver fibrosis. As a non-specific inhibitor of transient receptor potential melastatin 7 (TRPM7), carvacrol has anti-tumor, anti-inflammatory and anti-hepatic fibrosis activities. This study aimed to explore the protective effect of carvacrol on liver fibrosis and related molecular mechanisms. A CCl4-induced liver fibrosis mouse model and platelet-derived growth factor (PDGF-BB)-activated HSC-T6 cells (a rat hepatic stellate cell line) were employed for in vivo and in vitro experiments. C57BL/6J mice were orally administered different concentrations of carvacrol every day for 6 weeks during the development of CCl4-induced liver fibrosis. The results show that carvacrol could effectively reduce liver damage and the progression of liver fibrosis in mice, which are expressed as fibrotic markers levels were reduced and histopathological characteristics were improved. Moreover, carvacrol inhibited the proliferation and activation of HSC-T6 cells induced by PDGF-BB. In addition, it was found that carvacrol inhibits the expression of TRPM7 and mediated through mitogen-activated protein kinases (MAPK). Collectively, our study shows that carvacrol can reduce liver fibrosis by inhibiting the activation and proliferation of hepatic stellate cells, and the MAPK signaling pathway might be involved in this process.

Expression and prognostic value of TRPM7 in canine mammary tumours.

Canine mammary gland tumour (CMTs) are one of the most commonly found tumours in intact female dogs. A previous study on canine mammary glands demonstrated the presence of the transient receptor potential melastatin 7 (TRPM7) ion channels in healthy canine mammary tissues. However, the significance of TRPM7 in CMT is not yet known. TRPM7 is a Ca2+ and Mg2+ permeable cation channel that contains a protein kinase domain. The aim of this study was to determine TRPM7 expression in 57 benign and malignant CMT tissues of dogs using immunohistochemistry (IHC) and evaluate its correlation with clinicopathological features and explore the potential prognostic value of TRPM7 in a prospective survival study. IHC analysis shows that TRPM7 was expressed in the cytoplasm of neoplastic epithelial cells. Moreover, TRPM7 expression was significantly associated with tumour malignancy (P = .027), Ki-67 index (P < .0001) and metastasis (P < .0001). Survival curve analysis indicates that high TRPM7 expression was significantly associated with poor disease-free (P = .035) and overall survival (P = .011) in malignant CMTs. Our results demonstrate that TRPM7 is expressed in CMTs and that its expression is positively correlated with clinicopathological parameters. Thus, TRPM7 was assumed to be a potential prognostic factor for CMTs.

Transient Receptor Potential Melastatin 7 Promotes Vascular Adventitial Fibroblasts Phenotypic Transformation and Inflammatory Reaction Induced by Mechanical Stretching Stress via p38 MAPK/JNK Pathway.

Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and specific anti-TRPM7 small interfering RNA (si-RNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.