Cell Reports
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2019
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IF 7.815
Peilin Yu,Zhenming Liu,Xiafei Yu,Peiwu Ye,Huan Liu,Xiwen Xue,Lixin Yang,Zhongtang Li,Yang Wu,Cheng Fang,Yong Juan Zhao,Fan Yang,Jian Hong Luo,Lin-Hua Jiang,Liangren Zhang,Lihe Zhang,Wei Yang
Summary cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca 2+ signaling mechanism.
研究领域:
细胞生物学
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分子生物学
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生理学
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DOI
高影响因子
Diabetes Metabolic Syndrome and Obesity-Targets and Therapy
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2019
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IF 3.319
Qi Feng,Chen Liu,Wei Gao,Xiao-ling Geng,Ning Dai
Purpose Oxidative stress plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). TRPM2 ion channel functions as a molecular sensor for oxidative stress. The aim of this study was to examine the protective effects of Salidroside, a powerful antioxidative plant, on TRPM2 in an established in vitro model of NAFLD. Methods NAFLD model was established by palmitic acid (PA) in hepatic L02 cell lines and was added to the media at a final concentration of 400 μM. Cells were used as normal group, PA group and PA receiving varied concentrations of Salidroside (75μg/mL, 150μg/mL, 300μg/mL). After treating 24 hrs, MTT assay was used to detect cell viability, and ALT level was measured using an appropriate kit assay. Intracellular lipid accumulation was observed by Oil red O staining. Cytosolic Ca 2+ concentrations were evaluated by flow cytometer with Fluo-3/AM. Quantitative RT-PCR was used to measure the mRNA expression of TRPM2, IL-1β and IL-6, and the protein expressions of TRPM2, p-CaMKII and autophagy (LC3B, p62) were determined using Western blot. Results Treatment with Salidroside effectively restored liver injury and alleviated lipid droplet deposition in a dose-dependent manner, which was associated with inhibition of TRPM2/Ca 2+ /CaMKII pathway. Additionally, autophagic clearance was enhanced by intervention with Salidroside in a dose-dependent manner. Further investigation indicated that Salidroside down-regulated the mRNA expression of IL-1β and IL-6-pro-inflammatory cytokines. Conclusion These results suggest that Salidroside could alleviate inflammatory injury and steatosis via autophagy activation mediated by downregulation of the TRPM2/Ca 2+ /CaMKII pathway. Targeting the TRPM2 ion channel is a novel treatment strategy for oxidative stress-induced liver in NAFLD.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Chao Ma,Chunran Zhu,Yajun Zhang,Mei Yu,Yizhi Song,Yulong Chong,Yan Yang,Chan Zhu,Yucui Jiang,Changming Wang,Shuo Cheng,Keke Jia,Guang Yu,Jia Li,Zongxiang Tang
Background Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. Purpose Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. Methods/results After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca 2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca 2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. Conclusion This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.
研究领域:
神经科学
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药理学
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代谢
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产品关联
DOI
PubMed
高影响因子
HUMAN & EXPERIMENTAL TOXICOLOGY
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2026
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IF 3.5
Mengying Fan,Yangyang Chen,Pingping Yin,Peng Li
ObjectiveCerebral ischemia-reperfusion injury (CIRI) remains a major challenge in clinical practice, without effective and targeted approaches to address it. Curculigoside has been reported to exert beneficial effects in CIRI, yet the underlying novel mechanisms remain unclear. In this work, we aimed to explore whether Curculigoside exerted its protective role by regulating transient receptor potential melastatin 2 (TRPM2)-mediated microglial polarization.MethodsA well-established middle cerebral artery occlusion (MCAO) model was constructed in Sprague-Dawley rats, with Curculigoside administrated via the caudal vein. In vitro, LPS/IFN-γ-stimulated BV2 microglial cells were used to investigate the effects of Curculigoside on polarization and neuroinflammation. High-throughput mRNA sequencing was used to predict key targets of Curculigoside. TRPM2 overexpression and autophagy inhibition assays were conducted to verify the underlying mechanism.ResultsCurculigoside treatment significantly alleviated neurological deficits, reduced cerebral infarction volume, and decreased brain edema, accompanied by inhibited M1 polarization of microglia and mitigated inflammatory injury during CIRI. Curculigoside reduced pro-inflammatory M1 polarization in LPS/IFN-γ–stimulated BV2 microglia, thereby reducing neuronal apoptosis. RNA-seq functional enrichment analysis identified TRPM2 as a key target, and Curculigoside was found to downregulate TRPM2 expression and regulate the mTOR-mediated autophagy pathway. Notably, the protective effects of Curculigoside on microglial polarization were reversed by TRPM2 overexpression or autophagy inhibition.ConclusionCurculigoside mitigates CIRI by promoting beneficial microglial polarization through the TRPM2/mTOR-autophagy axis, supporting its potential as a therapeutic agent for CIRI.
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DOI
高影响因子
Biomaterials Research
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2025
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IF 9.6
Congrui Zhao,Antian Xu,Jingyao Gong,Yangbo Xu,Ping Sun,Fuming He
Early immune homeostasis at the biomaterial–tissue interface is a critical engineering challenge for osseointegration success. While strontium (Sr)-modified biomaterials exhibit advantages in enhancing osseointegration, the immunomodulatory effects of localized Sr release, particularly on upstream monocytes, remain unelucidated. This study aims to delineate Sr-reprogrammed monocyte subset dynamics and the underlying mechanism. Here, we engineered Sr-doped sandblasted, large-grit, and acid-etched (Sr-SLA) titanium implants. Sr-SLA implants ameliorated the early inflammatory microenvironment and promoted osseointegration. To decipher the Sr-modulated immune microenvironment, we employed single-cell RNA sequencing, which revealed that monocytes constituted the largest proportion of cells surrounding implants, with subset distribution correlating with osteogenic efficiency. Notably, Sr-SLA implants suppressed the activation of pro-inflammatory classical monocytes (Ly6C hi ), with high transient receptor potential melastatin 2 (TRPM2) and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) expression, while promoting the expansion of regenerative nonclassical monocytes (Ly6C lo ), exhibiting low TRPM2 and NLRP3 levels. Further validation demonstrated that Sr ions inhibited NLRP3 inflammasome activation in monocytes via blocking TRPM2 expression and calcium influx, leading to reduced pro-inflammatory cytokine (interleukin-1β and interleukin-18) secretion. Meanwhile, a conditioned medium from Sr-SLA-cultured monocytes exerted robust osteogenic potential by markedly facilitating bone marrow mesenchymal stromal cells’ osteogenic differentiation, due to a Sr-reshaped cytokine profile. Moreover, in vivo study corroborated that monocyte depletion impaired osseointegration, underscoring its indispensable role in implant-mediated bone regeneration. Collectively, Sr-SLA implants reprogrammed monocyte subsets via the TRPM2–Ca 2+ –NLRP3 axis, reshaping the early inflammatory microenvironment to enhance osseointegration. This study establishes a cascade linking material properties, early immune response, and bone regeneration, providing an engineerable target for designing immunomodulatory biomaterials.
研究领域:
生物材料
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免疫学
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骨再生
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组织工程
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2026
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IF 7.3
Yuhang Zhou,Zhenjie Zang,Xingzu Wang,Yunhao Feng,Zhenqing Wang,Ziyao Li,Tongxiang Diao,Qiang Fu,Hui Zhang
N-(1,3-Dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q) is an oxidation product of the tire rubber antioxidant 6PPD. Recent studies have detected 6PPD-Q in various environmental media, including water, air, and soil, and in human biospecimens such as urine, breast milk, blood and cerebrospinal fluid. These findings highlight its widespread presence in the environment and the potential for multi-route human exposure. Although previous research has demonstrated that 6PPD-Q induces multi-organ toxicity, particularly in the liver and nervous system, its effects on the male reproductive system and the associated molecular mechanisms remain unexplored. We developed a chronic exposure model in male mice to systematically assess the toxic effects of 6PPD-Q on the testes and its potential mechanisms. Our results indicate that 6PPD-Q accumulates in testicular tissue and induces histological damage, which is characterized by reduced serum testosterone levels, impaired sperm quality, sloughing of the spermatogenic epithelium, and disruption of the blood-testis barrier. Mechanistic investigations suggest that these effects are associated with impaired autophagy, elevated oxidative stress, and increased apoptosis in testicular tissue. Through integrated network toxicology and transcriptomics analyses, we identified TRPM2 (transient receptor potential cation channel subfamily M member 2)-mediated autophagy dysfunction as a critical event in 6PPD-Q-induced testicular injury. This study systematically unveils the toxic effects of 6PPD-Q on the male mouse reproductive system and elucidates the underlying molecular mechanisms. It elucidates that TRPM2-mediated autophagy plays a crucial role in the testicular injury induced by 6PPD-Q. This research provides essential evidence for understanding the reproductive health risks posed by emerging environmental pollutants and for developing prevention strategies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Bio Materials
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2025
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IF 4.7
Boying Li,Ran Zhang,Nana Wang,Xiaoning Liu,Ning Li,Jintong Ding,Zhanshuo Cao,Xiongwei Qu,Chengfen Xing
Acute myeloid leukemia (AML) is extremely difficult to cure due to the challenges in accurately targeting it, as it is characterized by rapid progression, high aggressiveness, and high drug resistance. In this study, biomimetic sustained release nanoparticles (PLGA-C-M) were designed and prepared to inhibit the survival and resistance pathways of AML. PLGA-C-M targeted AML cells by wrapping leukemia cell membranes, achieving sustained slow drug release in the blood, and then progressively affecting intracellular Ca2+ signaling by targeting TRPM2 ion channels that were highly expressed in AML in a step-by-step manner. PLGA-C-M can inhibit the growth of AML cells from three aspects: destroying mitochondrial function, reducing autophagy, and overcoming the drug resistance of cancer cells. Biomimetic nanoparticles achieved simultaneous regulation of intracellular ROS and Ca2+ signals to inhibit the growth of leukemia cells and provided ideas for the regulation of ion channel-related signal transduction in AML.
研究领域:
纳米技术
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癌症生物学
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药理学
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生物化学
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材料科学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Behavioral Neuroscience
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2021
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IF 3.558
Zhu Tiantian,Zhu Moli,Qiu Yue,Wu Zeqing,Huang Ning,Wan Guangrui,Xu Jian,Song Ping,Wang Shuangxi,Yin Yaling,Li Peng
Cerebral ischemia triggers vascular dementia (VD), which is characterized by memory loss, cognitive deficits, and vascular injury in the brain. Puerarin (Pur) represents the major isoflavone glycoside of Radix Puerariae, with verified neuroprotective activity and cardiovascular protective effects. However, whether Pur ameliorates cognitive impairment and vascular injury in rats with permanent occlusion of bilateral common carotid arteries (BCCAO) remains unknown. This work aimed to assess Pur’s effects on BCCAO-induced VD and to dissect the underlying mechanisms, especially examining the function of transient receptor potential melastatin-related 2 (TRPM2) in alleviating cognitive deficits and vascular injuries. Rats with BCCAO developed VD. Pur (50, 100, and 150 mg/kg) dose-dependently attenuated the pathological changes, increased synaptic structural plasticity in the dorsal CA1 hippocampal region and decreased oxidative stress, which eventually reduced cognitive impairment and vascular injury in BCCAO rats. Notably, Pur-improved neuronal cell loss, synaptic structural plasticity, and endothelial vasorelaxation function might be mediated by the reactive oxygen species (ROS)-dependent TRPM2/NMDAR pathway, evidenced by decreased levels of ROS, malondialdehyde (MDA), Bax, Bax/Bcl2, and TRPM2, and increased levels of superoxide dismutase (SOD), Bcl2, and NR2A. In conclusion, Pur has therapeutic potential for VD, alleviating neuronal cell apoptosis and vascular injury, which may be related to the ROS-dependent TRPM2/NMDAR pathway.
研究领域:
神经科学
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药理学
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心血管研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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