INFLAMMATION RESEARCH
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2024
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IF 4.8
Su Pan,Li Zibo,Yan Xiangli,Wang Baoying,Bai Ming,Li Yucheng,Xu Erping
Objective and design Mast cells (MCs), as the fastest immune responders, play a critical role in the progression of neuroinflammation-related diseases, especially in depression. Quercetin (Que) and kaempferol (Kae), as two major diet-derived flavonoids, inhibit MC activation and exhibit significant antidepressant effect due to their anti-inflammatory capacity. The study aimed to explore the mechanisms of inhibitory effect of Que and Kae on MC activation, and whether Que and Kae suppress hippocampal mast cell activation in LPS-induced depressive mice. Subjects and treatment In vitro assays, human mast cells (HMC-1) were pretreated with Que or Kae for 1 h, then stimulated by phorbol 12-myristate 13-acetate (PMA) and 2,5-di-t-butyl-1,4-benzohydroquinone (tBHQ) for 3 h or 12 h. In vivo assays, Que or Kae was administered by oral gavage once daily for 14 days and then lipopolysaccharide (LPS) intraperitoneally injection to induce depressive behaviors. Methods The secretion and expression of TNF-α were determined by ELISA and Western blotting. The nuclear factor of activated T cells (NFAT) transcriptional activity was measured in HMC-1 stably expressing NFAT luciferase reporter gene. Nuclear translocation of NFATc2 was detected by nuclear protein extraction and also was fluorescently detected in HMC-1 stably expressing eGFP-NFATc2. We used Ca 2+ imaging to evaluate changes of store-operated calcium entry (SOCE) in HMC-1 stably expressing fluorescent Ca 2+ indicator jGCamP7s. Molecular docking was used to assess interaction between the Que or Kae and calcium release-activated calcium modulator (ORAI). The hippocampal mast cell accumulation and activation were detected by toluidine blue staining and immunohistochemistry with β-tryptase. Results In vitro assays of HMC-1 activated by PtBHQ (PMA and tBHQ), Que and Kae significantly decreased expression and secretion of TNF-α. Moreover, NFAT transcriptional activity and nuclear translocation of NFATc2 were remarkably inhibited by Que and Kae. In addition, the Ca 2+ influx mediated by SOCE was suppressed by Que, Kae and the YM58483 (ORAI inhibitor), respectively. Importantly, the combination of YM58483 with Que or Kae had no additive effect on the inhibition of SOCE. The molecular docking also showed that Que and Kae both exhibit high binding affinities with ORAI at the same binding site as YM58483. In vivo assays, Que and Kae significantly reversed LPS-induced depression-like behaviors in mice, and inhibited hippocampal mast cell activation in LPS-induced depressive mice. Conclusions Our results indicated that suppression of SOCE/NFATc2 pathway-mediated by ORAI channels may be the mechanism of inhibitory effect of Que and Kae on MC activation, and also suggested Que and Kae may exert the antidepressant effect through suppressing hippocampal mast cell activation.
研究领域:
药理学
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神经科学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
·
IF 5.195
Lin Niu,Jie Wang,Fukui Shen,Jie Gao,Min Jiang,Gang Bai
Ethnopharmacological relevance Magnolia officinalis Cortex ( M. officinalis ) is a classical traditional Chinese medicine (TCM) widely used to treat digestive system diseases . It effectively regulates gastrointestinal motility to improve abdominal pain, abdominal distension and other symptoms. Magnolol (MAG) and honokiol (HON) are the main pharmacodynamic components responsible for the gastrointestinal activity of M. officinalis . Aim of the study The transient receptor potential (TRP) family is highly expressed in the gastrointestinal tract and participates in the regulation of gastrointestinal motility, visceral hypersensitivity, visceral secretion and other physiological activities. In this study, the calcium-lowering mechanisms of MAG and HON contributing to the smooth muscle relaxation associated with TRP are discussed. Materials and methods The relaxation smooth muscle effects of MAG and HON were tested by the isolated intestine tone tests. A synthetic MAG probe (MAG-P) was used to target fishing for their possible target. The distribution of MAG on the smooth muscle was identified by a molecular tracer based on chemical biology. Ca 2+ imaging and dual-luciferase reporter assays were used to determine the effects on the target proteins. Finally, the calcium-mediating effects of MAG and HON on smooth muscle cells and TRPC4-knockdown cells were compared to verify the potential mechanism. Results After confirming the smooth muscle relaxation in the small intestine induced by MAG and HON, the relaxation effect was identified mainly due to the downregulation of intracellular calcium by controlling external calcium influx. Although MAG and HON inhibited both TRPV4 and TRPC4 channels to reduce calcium levels, the inhibitory effect on TRPC4 channels is an important mechanism of their smooth muscle relaxation effect, since TRPC4 is widely expressed in the small intestinal smooth muscle cells. Conclusions The inhibition of MAG and HON on TRPC4 channels contributes to the relaxation of intestinal smooth muscle.
研究领域:
药理学
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胃肠病学
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传统中药
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2023
·
IF 1.6
Zhou Liping,Lao Zishan,Fan Xinsheng,Hao Mengyang,Yang Yubing
This study aimed to investigate the effects of sulfur dioxide (SO2) derivatives on asthma induced by ovalbumin (OVA). Sprague Dawley rats were sensitized to and challenged with OVA and SO2 derivatives (NaHSO3 and Na2SO3, 1:3 M/M) to establish 28-day (short-term) and 42-day (long-term) asthma models. Exposure to SO2 derivatives aggravated asthma and hence, promoted lung injury in OVA-induced asthma. In addition, it upregulated the protein expression of TRPV1 and downregulated the expression of tight junctions (TJs). These changes were dose-dependent and were more pronounced in the presence of a high concentration of SO2 derivatives. In vitro, SO2 derivatives also increased the calcium influx and TRPV1 protein expression, and decreased TJ expression. Besides, no significant difference in the TJ expression was found between the WT and TRPV1−/- mice. The underlying mechanism might be related to regulating the effects of TRPV1 and TJs.
研究领域:
肺科学
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免疫学
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毒理学
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产品关联
DOI
PubMed
高影响因子
eLife
·
2023
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IF 7.7
Yang He,Taohui Liu,Quansheng He,Wei Ke,Xiaoyu Li,Jinjin Du,Suixin Deng,Zhenfeng Shu,Jialin Wu,Baozhi Yang,Yuqing Wang,Ying Mao,Yanxia Rao,Yousheng Shu,Bo Peng
General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.
研究领域:
神经科学
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麻醉学
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免疫学
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产品关联
DOI
PubMed
高影响因子
MEDIATORS OF INFLAMMATION
·
2016
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IF 3.418
Xin Liu,Ning Wang,Yuanfeng Zhu,Yongjun Yang,Xiaoli Chen,Shijun Fan,Qian Chen,Hong Zhou,Jiang Zheng
Activated macrophages are the primary sources of IL-12, a key cytokine bridging innate and adaptive immunity. However, macrophages produce low amounts of IL-12 upon stimulation and the underlying regulatory mechanism remains unclear. In this study, we found a new calcium-dependent mechanism that controlled IL-12 production in LPS-treated murine macrophages. First, LPS was demonstrated to induce extracellular calcium entry in murine peritoneal macrophages and inhibition of calcium influx resulted in marked enhancement in IL-12 production. Then, withdrawal of extracellular calcium was found to suppress CaMKK and AMPK activation triggered by LPS while chemical inhibition or genetic knockdown of these two kinases augmented LPS induced IL-12 production. AMPK activation increased the NAD+/NADH ratio and activated Sirtuin 1 (SIRT1), a NAD+-dependent deacetylating enzyme and negative regulator of inflammation. Chemical inhibitor or siRNA of SIRT1 enhanced IL-12 release while its agonist suppressed IL-12 production. Finally, it was found that SIRT1 selectively affected the transcriptional activity of NF-κB which thereby inhibited IL-12 production. Overall, our study demonstrates a new role of transmembrane calcium mobilization in immunity modulation such that inhibition of calcium influx leads to impaired activation of CaMKKβ-AMPK-SIRT1 signaling pathway which lifts restriction on NF-κB activation and results in enhanced IL-12 production.
研究领域:
免疫学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Guoqing Li,Caiyun Sun,Le Zhu,Yan Zeng,Jinquan Li,Yufei Mei
Cadmium (Cd) is a neurotoxicant that gradually accumulates in the human body with age. High Cd burden is correlated with adult hippocampal neurogenesis (AHN) and memory deficits in mammals. However, little knowledge is known about the mechanism by which Cd exposure impairs neurogenesis and cognition. Here, we investigated the roles of store-operated calcium entry (SOCE)-mediated calcium dyshomeostasis in Cd-induced AHN and memory deficits as well as therapeutic potential for the prevention of Cd-induced neurotoxicity. To achieve this goal, 8 weeks-old C57BL/6 J mice were subjected to different concentrations of cadmium chloride (0, 5, 10, 20 ppm) in drinking water for 8 weeks, we then examined the AHN, calcium homeostasis, SOCE channel and memory in Cd-exposed mice by using immunohistochemistry, calcium imaging, Y-maze and fear conditioning test. Our results indicated that chronic Cd exposure markedly increased Cd levels in serum and cerebrospinal fluid by almost 10-fold, and inhibited the proliferation and differentiation of hippocampal adult neural stem cells in a dose-dependent manner. Additionally, Cd exposure impaired the maturation of hippocampal neural stem cells without inducing gliosis. Transcriptome analysis revealed that Cd exposure inhibited the proliferation of neuroblastoma via alteration of calcium signaling pathway, and attenuated SOCE channels played a pivotal role in mediating Cd-induced cytoplasmic calcium overload and depletion of endoplasmic reticulum calcium stores. Activation of SOCE by hyperforin, a natural derivative from medicinal plant, restored intracellular calcium homeostasis and improved AHN and memory in Cd-exposed mice. Together, this study provided novel insights into the mechanism that Cd exposure impaired AHN and memory by prompting neuronal SOCE-mediated calcium dyshomeostasis, and offered a new therapeutic approach for prevention of Cd-induced neurotoxicity.
研究领域:
神经科学
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药理学
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毒理学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
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
ANALYTICAL CHEMISTRY
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2020
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IF 6.785
Shu Zeng,Shuo Wang,Xuan Xie,Si-hui Yang,Jia-hui Fan,Zhou Nie,Yan Huang,Hong-hui Wang
Neurotransmitters are essential chemical mediators for neuronal communication in variable neuromodulations. However, the progress of neuroscience is hampered by the shortage of suitable sensors to track neurotransmitters with high spatial and temporal resolution. Here, we introduce a self-assembled DNA-nanoprism fluorescent probe capable of nongenetically engineering the cell surface for ultrasensitive imaging of the neurotransmitter release at a single live-cell level. The DNA-nanoprism structure conjugated with three cholesterol tails enables the probe to rapidly and stably anchor on the cell surface within 10 min. The in situ detection of neurotransmitters is achieved by equipping the DNA-nanoprism with an aptamer-based “turn-on” fluorescent sensory module for the transmitter of interest. In a proof-of-concept study, we directly visualized the transient dopamine (DA) release on the cell surface with selective responsivity and high spatiotemporal precision and further explored the dynamic correlation between DA release and calcium influx triggered by high K+. This study provides a robust and sensitive tool for cell-surface-targeted imaging of neuromodulations, which might open up a new avenue to improve the understanding of neurochemistry and advance neuroscience research.
研究领域:
神经科学
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分子生物学
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生物物理学
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纳米技术
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DOI
PubMed
高影响因子
Scientific Reports
·
2023
·Vol. 13
·期 1
·1-13
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IF 4.6
Xu Rui-Qi,Ma Ling,Chen Timson,Zhang Wei-Xiong,Chang Kuan,Wang Jing
Biosurfactants are attracting much interest due to their potential application as therapeutic agents in the medical and cosmetic field. Previous studies have demonstrated that biosurfactant such as sophorolipid (SL) exhibits immunomodulatory effects. In this article, we found the potential of sophorolipid for inhibiting histamine-induced itch and preliminarily explored its molecular basis. First, behavioral tests indicated that SL can remit the histamine-induced scratching behaviors of mice. Second, SL can suppress the the calcium influx induced by histamine, HTMT and VUF8430 in HaCaT cells. RT-PCR analysis showed that the histamine-induced upregulation of mRNA levels of phospholipase Cγ1, 1,4,5-trisphosphate receptor (IP3R), and protein kinase Cα can be inhibted by SL, suggesting that SL may impede the PLC/IP3R signaling pathway activated by histamine. In further tests, the capsaicin-induced calcium influx can also be inhibited by SL. The immunofluorescence and molecular docking analysis indicated that SL acts as an inhibitor of transient receptor potential vanilloid-1 (TRPV1) activation to decrease calcium influx against stimuli. In summary, these results revealed that SL may inhibit histamine-induced itch by decreasing PLC/IP3R signaling pathway activation and modulating TRPV1 activity. This paper indicates that SL can be a useful treatment for histamine-dependent itch.
研究领域:
药理学
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皮肤病学
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2024
·
IF 5.2
Fang Chen,Huyan Shen,Gang Liu,Pingping Zhang,Lin Zhang,Siyu Lin,Han Gao,Hong Peng,Yan-Fei Qi,Yan Chen,Yinhui Jiang,Jiandong Huang,Xiangchun Shen,Yu-Si Luo,Ke Zhang
Aims The study evaluated the antiviral effect of Verapamil against respiratory syncytial virus (RSV) and investigated its underlying mechanism. Materials and methods RSV-infected BALB/c mice were treated with Verapamil. Body weight, survival rates, viral load, lung damage, inflammatory factors, and the expression of RSV fusion (F) protein were analyzed. In cellular studies, intracellular Ca 2+ and viral titers were measured in the presence of Verapamil, Calcium Chloride, and EGTA. A time-of-addition assay assessed the antiviral effect of Verapamil. Key findings Mice infected with RSV and treated with Verapamil exhibited a significant decrease in weight loss, an increase in survival rates, and reductions in viral titers, RSV F protein expression, inflammatory responses, and lung tissue injury. Verapamil reduced intracellular calcium levels, which correlated with reduced viral titers. The addition of calcium chloride reversed the anti-viral effects mediated by Verapamil, while EGTA potentiated them. The antiviral activity of Verapamil was observed during the early phase of RSV infection, likely by blocking Ca 2+ channels and inhibiting virus replication. Significance Verapamil effectively inhibits RSV infection by blocking calcium channels and reducing intracellular calcium levels, thereby impeding viral replication. Thus, Verapamil shows promise as a treatment for RSV.
研究领域:
药理学
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病毒学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Yizhou Zhu,Chaofeng Wang,Can Ai,Yiming Xiang,Congyang Mao,Wei Qiao,Jun Wu,John Akrofi Kubi,Xiangmei Liu,Shuilin Wu,Xin Zhao,Bin Li,Kelvin W. K. Yeung
Early osteoimmune microenvironment disorder at the interface between bone and implant can lead to implant loosening, which prolongs patient convalescence, exacerbates postoperative complications, and potentially results in implant failure. The timely regulation of macrophages primarily orchestrates the entire long-term regeneration process. Here, it is proposed to precisely direct macrophage polarization using localized photoelectrical signals generated by an excitable surface in response to remote stimulation via near-infrared light (NIR). The photocurrent generated from the n–n heterojunction between calcium titanate (CaTiO 3 ) and defective titanium dioxide (TiO 2 -V o ) on the excitable surface can accurately direct macrophage polarization, suppressing acute inflammation at the early stage of post-implantation and establishing a favorable osteoimmune microenvironment that promotes bone-to-implant integration. Mechanistic study reveals that photoelectric signals initiate increased calcium influx via voltage-gated calcium ion channels, subsequently modulating calcium/calmodulin-dependent protein kinase kinase 2 (Camkk2) and calcium/calmodulin-dependent protein kinase I (Camk1) expression to regulate macrophage polarization. This optimization of the osteoimmune microenvironment results in enhanced mesenchymal stem cells (MSCs) recruitment and osteogenesis, ultimately accelerating bone-to-implant integration within 14 days post-implantation. This research presents a novel method for adjusting in vivo spatiotemporal immune responses through the use of noninvasive and externally-controlled targeted stimulations.
研究领域:
生物医学工程
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免疫学
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组织工程
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材料科学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
·
2019
·Vol. 74
·期 6
·549
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IF 2.371
Huang Yue,Wu Xiangyan,Wu Meizhu,Chu Jianfeng,Yu Na,Shen Aling,Shen Zhiqing,Chen Youqin,Peng Jun
The Qingda granule (QDG) formulation was simplified from the Qingxuan Jiangya Decoction, which has been used in China to treat hypertension for decades. However, the molecular mechanisms of QDG in antihypertension remain largely unknown. Therefore, we evaluated the therapeutic efficacy of QDG against elevated blood pressure and explored its underlying mechanism. QDG treatment decreased elevated blood pressure and increased the vascular elasticity of thoracic aortic rings to KCl stimulation in spontaneously hypertensive rats. QDG treatment increased the relaxation of isolated thoracic aortic rings precontracted with norepinephrine (NE) or KCl in an endothelium-independent manner, which was attenuated by treatment with verapamil, but not by treatment with TEA, 4-AP, Gli, or BaCl 2 . Moreover, QDG pretreatment attenuated the CaCl 2 -induced constriction of isolated thoracic aortic rings in K + - or NE-containing Ca 2+ -free solutions. In addition, QDG pretreatment significantly inhibited the influx of Ca 2+ in A7r5 cells induced by a K + - or NE-containing Ca 2+ solution and decreased the levels of p-AKT but had no effect on levels of total AKT protein in isolated thoracic aortic rings. Considering these results, QDG treatment attenuated elevated blood pressure and promoted the vasorelaxation of thoracic aortic rings by inhibiting the influx of Ca 2+ and activating the AKT pathway .
研究领域:
药理学
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心血管研究
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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