scholarly journals HIF-1α Dependent Upregulation of ZIP8, ZIP14, and TRPA1 Modify Intracellular Zn2+ Accumulation in Inflammatory Synoviocytes

2021 ◽  
Vol 22 (12) ◽  
pp. 6349
Author(s):  
Noriyuki Hatano ◽  
Masaki Matsubara ◽  
Hiroka Suzuki ◽  
Yukiko Muraki ◽  
Katsuhiko Muraki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Expression ◽  
Nuclear Factor Κb ◽  
Expression Vectors ◽  
Inflammatory Conditions ◽  
Hek Cells ◽  
Tnf Α ◽  
Transient Receptor ◽  
Factor Α

Intracellular free zinc ([Zn2+]i) is mobilized in neuronal and non-neuronal cells under physiological and/or pathophysiological conditions; therefore, [Zn2+]i is a component of cellular signal transduction in biological systems. Although several transporters and ion channels that carry Zn2+ have been identified, proteins that are involved in Zn2+ supply into cells and their expression are poorly understood, particularly under inflammatory conditions. Here, we show that the expression of Zn2+ transporters ZIP8 and ZIP14 is increased via the activation of hypoxia-induced factor 1α (HIF-1α) in inflammation, leading to [Zn2+]i accumulation, which intrinsically activates transient receptor potential ankyrin 1 (TRPA1) channel and elevates basal [Zn2+]i. In human fibroblast-like synoviocytes (FLSs), treatment with inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1α (IL-1α), evoked TRPA1-dependent intrinsic Ca2+ oscillations. Assays with fluorescent Zn2+ indicators revealed that the basal [Zn2+]i concentration was significantly higher in TRPA1-expressing HEK cells and inflammatory FLSs. Moreover, TRPA1 activation induced an elevation of [Zn2+]i level in the presence of 1 μM Zn2+ in inflammatory FLSs. Among the 17 out of 24 known Zn2+ transporters, FLSs that were treated with TNF-α and IL-1α exhibited a higher expression of ZIP8 and ZIP14. Their expression levels were augmented by transfection with an active component of nuclear factor-κB P65 and HIF-1α expression vectors, and they could be abolished by pretreatment with the HIF-1α inhibitor echinomycin (Echi). The functional expression of ZIP8 and ZIP14 in HEK cells significantly increased the basal [Zn2+]i level. Taken together, Zn2+ carrier proteins, TRPA1, ZIP8, and ZIP14, induced under HIF-1α mediated inflammation can synergistically change [Zn2+]i in inflammatory FLSs.

scholarly journals Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson’s Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Maurício dos Santos Pereira ◽  
Gabriel Henrique Dias Abreu ◽  
Jeremy Rocca ◽  
Sabah Hamadat ◽  
Rita Raisman-Vozari ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Dorsal Striatum ◽  
Receptor Potential ◽  
Neuronal Cultures ◽  
Transient Receptor Potential Vanilloid ◽  
Tnf Α ◽  
Activated State ◽  
Transient Receptor ◽  
6 Hydroxydopamine ◽  
Factor Α

Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-α levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-α secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-α release in glutamate-activated astrocytes. TNF-α, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-α by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism.

scholarly journals Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation

2022 ◽  
Vol 15 (1) ◽  
pp. 57
Author(s):  
Katalin Szabó ◽  
Ágnes Kemény ◽  
Noémi Balázs ◽  
Esam Khanfar ◽  
Zoltán Sándor ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Lymphocyte Function ◽  
Targeted Deletion ◽  
Flow Cytometric ◽  
Cd8 T Lymphocyte ◽  
Tnf Α ◽  
Mrna And Protein Expression ◽  
Transient Receptor

Transient Receptor Potential Ankyrin 1 (TRPA1) has been reported to influence neuroinflammation and lymphocyte function. We analysed the immune phenotype and activation characteristics of TRPA1-deficient mice (knockout—KO) generated by targeted deletion of the pore-loop domain of the ion channel. We compared TRPA1 mRNA and protein expression in monocyte and lymphocyte subpopulations isolated from primary and secondary lymphatic organs of wild type (WT) and KO mice. qRT-PCR and flow cytometric studies indicated a higher level of TRPA1 in monocytes than in lymphocytes, but both were orders of magnitude lower than in sensory neurons. We found lower CD4+/CD8+ thymocyte ratios, diminished CD4/CD8 rates, and B cell numbers in the KO mice. Early activation marker CD69 was lower in CD4+ T cells of KO, while the level of CD8+/CD25+ cells was higher. In vitro TcR-mediated activation did not result in significant differences in CD69 level between WT and KO splenocytes, but lower cytokine (IL-1β, IL-6, TNF-α, IL-17A, IL-22, and RANTES) secretion was observed in KO splenocytes. Basal intracellular Ca2+ level and TcR-induced Ca2+ signal in T lymphocytes did not differ significantly, but interestingly, imiquimod-induced Ca2+ level in KO thymocytes was higher. Our results support the role of TRPA1 in the regulation of activation, cytokine production, and T and B lymphocytes composition in mice.

scholarly journals Functional characterization of transient receptor potential channels in mouse urothelial cells

2010 ◽  
Vol 298 (3) ◽  
pp. F692-F701 ◽  
Author(s):  
Wouter Everaerts ◽  
Joris Vriens ◽  
Grzegorz Owsianik ◽  
Giovanni Appendino ◽  
Thomas Voets ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Patch Clamp ◽  
Calcium Imaging ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Functional Expression ◽  
Sensory Function ◽  
Trp Channel ◽  
Urothelial Cells ◽  
Transient Receptor

The bladder urothelium is currently believed to be a sensory structure, contributing to mechano- and chemosensation in the bladder. Transient receptor potential (TRP) cation channels act as polymodal sensors and may underlie some of the receptive properties of urothelial cells. However, the exact TRP channel expression profile of urothelial cells is unclear. In this study, we have performed a systematic analysis of the molecular and functional expression of various TRP channels in mouse urothelium. Urothelial cells from control and trpv4−/− mice were isolated, cultured (12–48 h), and used for quantitative real-time PCR, immunocytochemistry, calcium imaging, and whole cell patch-clamp experiments. At the mRNA level, TRPV4, TRPV2, and TRPM7 were the most abundantly expressed TRP genes. Immunohistochemistry showed a clear expression of TRPV4 in the plasma membrane, whereas TRPV2 was more prominent in the cytoplasm. TRPM7 was detected in the plasma membrane as well as cytoplasmic vesicles. Calcium imaging and patch-clamp experiments using TRP channel agonists and antagonists provided evidence for the functional expression of TRPV4, TRPV2, and TRPM7 but not of TRPA1, TRPV1, and TRPM8. In conclusion, we have demonstrated functional expression of TRPV4, TRPV2, and TRPM7 in mouse urothelial cells. These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction.

Abstract 232: Role of Transient Receptor Potential Melastatin 2 in Cardiomyocyte Apoptosis Induced by TNF-α

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Shuzhuang Li ◽  
Xuan Liu ◽  
Deqin Yu ◽  
Chong Chen ◽  
Xiaolong Chen
Keyword(s):  
Myocardial Injury ◽  
Caspase 3 ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cardiomyocyte Apoptosis ◽  
Mechanical Trauma ◽  
Causative Role ◽  
Transient Receptor Potential Melastatin ◽  
Tnf Α ◽  
Transient Receptor

Mechanical trauma, such as that induced by motor vehicle crashes, represents a major medical and economic problem in the world. Identifying the mechanisms responsible for post-traumatic secondary myocardial injury is critical in order to reduce overall mortality and improve quality of life after trauma. We have previously demonstrated that mechanical trauma-induced overproduction of TNF-α plays a causative role in cardiomyocyte apoptosis via oxidative/nitrative stress. Transient receptor potential melastatin 2 (TRPM2) is a Ca 2+ permeable non-selective cation channel activated by oxidative stress, expressed in the cardiomyocytes. The present study attempted to identify whether TRPM2 is involved in TNF-α-induced cardiomyocyte apoptosis. Cardiomyocytes were isolated from adult male Sprague Dawley rats and cultured with TNF-α (10 ng/ml) for 12h. RT-PCR and semi-quantitative immunohistochemistry were used to quantify TRPM2 mRNA and protein levels respectively. Significant increases in TRPM2 mRNA and protein expression were observed in TNF-α-treated cardiomyocytes, suggesting that TRPM2 may contribute to TNF-α-induced cardiomyocyte apoptosis. To identify the effect of TRPM2 on TNF-α-induced cardiomyocyte apoptosis, cardiomyocytes were cultured with TNF-α or TNF-α + TRPM2 inhibitor (flufenamic acid (FFA) 100uM or clotrimazole 30uM), respectively. Exposure of cardiomyocytes to TNF-α for 12h induced significant apoptosis as determined by caspase-3 activation (1.7-fold increase vs. control, P < 0.01). In contrast, TNF-α-induced caspase-3 activity increases were significantly depressed by FFA and clotrimazole, respectively (P < 0.05). To further confirm the effect of TRPM2 on TNF-α-induced cardiomyocyte apoptosis, we tested the effects of TRPM2-specific small interfering RNA (siRNA). As a result, impressively, TNF-α-induced increases of caspase-3 activity and lysate nucleosomes were significantly reduced in TRPM2-specific siRNA-treated cardiomyocytes (P < 0.01). These results indicate that TRPM2 plays an important role in TNF-α-induced cardiomyocyte apoptosis. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating mechanical trauma-induced secondary myocardial injury.

scholarly journals The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain

2019 ◽  
Vol 20 (3) ◽  
pp. 526 ◽  
Author(s):  
Mohammad Hossain ◽  
Marina Bakri ◽  
Farhana Yahya ◽  
Hiroshi Ando ◽  
Shumpei Unno ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Glutamate Release ◽  
Receptor Potential ◽  
Functional Expression ◽  
Dental Pain ◽  
Post Translational Modifications ◽  
Transient Receptor ◽  
External Stimuli

Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain.

scholarly journals Standardized Extract of Atractylodis Rhizoma Alba and Fructus Schisandrae Ameliorates Coughing and Increases Expectoration of Phlegm

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3064 ◽  
Author(s):  
Hee-Sung Chae ◽  
Sun Young Kim ◽  
Pisey Pel ◽  
Jungmoo Huh ◽  
Sun-Woo Joo ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Acute Bronchitis ◽  
Chronic Obstructive ◽  
Upper Respiratory Tract ◽  
In Vivo Experiments ◽  
Transient Receptor ◽  
Tract Infections ◽  
Factor Α

Cough and phlegm frequently occur in respiratory diseases like upper respiratory tract infections, acute bronchitis, and chronic obstructive pulmonary diseases. To relieve these symptoms and diseases, various ingredients are being used despite the debates on their clinical efficacy. We aimed to investigate the effects of the extract CKD-497, composed of Atractylodis Rhizoma Alba and Fructus Schisandrae, in relieving cough and facilitating expectoration of phlegm. CKD-497 was found to inhibit inflammatory mediators such as interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α) in lipopolysaccharide (LPS)-treated mouse macrophages and transient receptor potential cation channel 1 (TRPV-1)-overexpressed human bronchial epithelial cells stimulated by capsaicin. CKD-497 decreased the viscosity of the mucin solution. During in vivo experiments, CKD-497 reduced coughing numbers and increased expectoration of phlegm via mucociliary clearance enhancement. Collectively, these data suggest that CKD-497 possesses potential for cough and phlegm expectoration treatment.

scholarly journals Antinociceptive Effects of Emodin on CFA-Induced Inflammatory Pain in Rats

2020 ◽  
Vol 15 (7) ◽  
pp. 1934578X2094200
Author(s):  
Wan Ni ◽  
Nianyun Wang ◽  
Shenglan Tian ◽  
Qingbang Xu
Keyword(s):  
Mrna Expression ◽  
Inflammatory Pain ◽  
Transient Receptor Potential ◽  
Interleukin 1 ◽  
Receptor Potential ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Transient Receptor Potential Vanilloid ◽  
Tnf Α ◽  
Transient Receptor

The effect of emodin on complete Freund’s adjuvant (CFA)-induced inflammatory pain in rats and its potential molecular mechanism was investigated. For this, a rat model of inflammatory pain induced by CFA was established and rats were treated with emodin by intraperitoneal injection. The pain threshold was evaluated by the von Frey, thermo hyperalgesia, and cold plate tests. The mRNA expression of transient receptor potential channel ankyrin type-1 ( Trpa1) and transient receptor potential vanilloid 1 ( Trpv1) was detected by quantitative reverse transcription polymerase chain reaction, and the level of inflammatory cytokines was determined by enzyme-linked immunosorbent assay. The mechanical and thermal pain thresholds of CFA-treated rats were significantly lower than those of the control rats, while the paw withdrawal responses in response to cold stimulation were higher than that of the control group. Emodin treatment significantly improved CFA-induced hyperalgesia. Further results showed that emodin inhibits the upregulation of Trpa1 and Trpv1 mRNA expression in the dorsal root ganglion (DRG) of rats with inflammatory pain compared with the control group. Emodin also significantly reduced the levels of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) in the serum of rats with inflammatory pain. Thus, emodin may inhibit hyperalgesia induced by inflammatory stimulation by downregulating the mRNA expression of Trpa1 and Trpv1 in DRG neurons and reducing the levels of TNF-α, IL-1β, and IL-6.

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