Hewage, Susara Ruwan Kumara Madduma;Piao, Mei Jing;Kang, Kyoung Ah;Ryu, Yea Seong;Fernando, Pattage Madushan Dilhara Jayatissa;Oh, Min Chang;Park, Jeong Eon;Shilnikova, Kristina;Moon, Yu Jin;Shin, Dae O;Hyun, Jin Won
Biomolecules & Therapeutics
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v.25
no.4
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pp.427-433
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2017
Previously, we demonstrated that galangin (3,5,7-trihydroxyflavone) protects human keratinocytes against ultraviolet B (UVB)-induced oxidative damage. In this study, we investigated the effect of galangin on induction of antioxidant enzymes involved in synthesis of reduced glutathione (GSH), and investigated the associated upstream signaling cascades. By activating nuclear factor-erythroid 2-related factor (Nrf2), galangin treatment significantly increased expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS). This activation of Nrf2 depended on extracellular signal-regulated kinases (ERKs) and protein kinase B (AKT) signaling. Inhibition of GSH in galangin-treated cells attenuated the protective effect of galangin against the deleterious effects of UVB. Our results reveal that galangin protects human keratinocytes by activating ERK/AKT-Nrf2, leading to elevated expression of GSH-synthesizing enzymes.
To elucidate the mechanism underlying the embryotropic effect of extracellular matrix(ECM) on the preimplantation development of mammalian embryos, the involvement of mitogen-activated protein kinase(MAPK) downstream the integrin signaling was examined in mouse blastocysts. Blastocysts were cultured in the presence of growth factor-reduced(GFR) Matrigel(0.5%, v/v). MAPK activity was measured by in vitro phosphorylation of myelin basic protein by the Erk1/2 antibody immunoprecipitates of embryonic extract following the Matrigei treatment. MAPK activity of the early blastocysts rapidly increased within 10 min fo1lowing the Matrigel treatment. When the embryos were cultured for 12 h in the presence of Matrigel, the MAPK activity was significantly higher than that ot the control embryos. PD098059, a MAPK kinase(MEK) inhibitor, attenuated the effect of Matrigel on the change in MAPK activity. Taken together, it suggested that the embryotropic effect of ECM proteins might be mediated by the activation of MAPK cascade.
This study aimed to investigate the analgesic effect of substance P (SP) in an animal model of neuropathic pain. An experimental model of neuropathic pain, the chronic constriction injury (CCI) model, was established using ICR mice. An intravenous (i.v.) injection of SP (1 nmole/kg) was administered to the mice to examine the analgesic effects of systemic SP on neuropathic pain. Behavioral testing and immunostaining was performed following treatment of the CCI model with SP. SP attenuated mechanical allodynia in a time-dependent manner, beginning at 1 h following administration, peaking at 1 day post-injection, and decaying by 3 days post-injection. The second injection of SP also increased the threshold of mechanical allodynia, with the effects peaking on day 1 and decaying by day 3. A reduction in phospho-ERK and glial fibrillary acidic protein (GFAP) accompanied the attenuation of mechanical allodynia. We have shown for the first time that i.v. administration of substance P attenuated mechanical allodynia in the maintenance phase of neuropathic pain using von Frey's test, and simultaneously reduced levels of phospho-ERK and GFAP, which are representative biochemical markers of neuropathic pain. Importantly, glial cells in the dorsal horn of the spinal cord (L4-L5) of SP-treated CCI mice, expressed the anti-inflammatory cytokine, IL-10, which was not seen in vehicle saline-treated mice. Thus, i.v. administration of substance P may be beneficial for improving the treatment of patients with neuropathic pain, since it decreases the activity of nociceptive factors and increases the expression of anti-nociceptive factors.
Fibroblast-like synoviocytes (FLS) play a crucial role in initiating rheumatoid arthritis. B-cell activating factor (BAFF) plays a role in FLS survival as well as in B cell maturation and maintenance. Here, we investigated whether tumor necrosis factor (TNF)-α-induced BAFF expression controls FLS migration and whether BAFF expression in FLS could be regulated by KR33426 which is the inhibitor of BAFF binding to BAFF receptors (BAFF-R) by using MH7A synovial cells transfected with the SV40 T antigen. More TNF-α-treated cells migrated compared to the control. TNF-α increased BAFF expression in FLS, significantly. FLS migration was inhibited by the transfection with BAFF-siRNA. KR33426 also inhibited BAFF expression increased by TNF-α treatment in FLS as judged by western blotting, PCR, and transcriptional activity assay. Kinases including JNK, p38 and Erk were activated by TNF-α treatment. While JNK and p38 were inhibited by KR33426 treatment, no changes in Erk were observed. Transcription factors including p65, c-Fos, CREB and SP1 were enhanced by TNF-α treatment. Among them, c-Fos was inhibited by KR33426 treatment. Small interference(si)-RNA of c-fos decreased BAFF transcriptional activity. FLS migration induced by TNF-α was inhibited by the transfection with BAFF-siRNA. KR33426 increased Twist, Snail, Cadherin-11 and N-Cadherin. In contrast, KR33426 decreased E-cadherin and TNF-α-enhanced CCL2. Taken together, our results demonstrate that synovial cell migration via CCL2 expression could be regulated by BAFF expression which is decreased by KR33426 and c-Fos-siRNA. It suggests for the first time that the role of BAFF-siRNA on FLS migration might be matched in the effect of KR33426 on BAFF expression.
Objective: Transient receptor potential vanilloid subfamily type 1 (TRPV1), a most specific marker of the nociceptive primary afferent, is expressed in peptidergic and non-peptidergic primary afferents innervating skin and viscera. However, its expression in sensory fibers to skeletal muscle is not well known. In this study, we studied the neurochemical characteristics of TRPV1-positive primary afferents to skeletal muscles. Methods: Sprague-Dawley rats were injected with total $20{\mu}l$ of 1% fast blue (FB) into the gastrocnemius and erector spinae muscle and animals were perfused 4 days after injection. FB-positive cells were traced in the L4-L5 (for gastrocnemius muscle) and L2-L4 (for erector spinae muscle) dorsal root ganglia. The neurochemical characteristics of the muscle afferents were studied with multiple immunofluorescence with TRPV1, calcitonin gene-related peptide (CGRP) and $P2X_3$. To identify spinal neurons responding to noxious stimulus to the skeletal muscle, 10% acetic acids were injected into the gastrocnemius and erector spinae muscles and expression of phospho extracellular signal-regulated kinase (pERK) in spinal cords were identified with immunohistochemical method. Results: TRPVl was expressed in about 49% of muscle afferents traced from gastrocnemius and 40% of erector spinae. Sixty-five to 60% of TRPV1-positive muscles afferents also expressed CGRP. In contrast, expression of $P2X_3$ immnoreaction in TRPV1-positive muscle afferents were about 20%. TRPV1-positive primary afferents were contacted with spinal neurons expressing pERK after injection of acetic acid into the muscles. Conclusion: It is consequently suggested that nociception from skeletal muscles are mediated by TRPV1-positive primary afferents and majority of them are also peptidergic.
Scutellaria baicalensis Georgi has been widely used in China for treatment of various diseases. This study investigated the effect of Scutellaria baicalensis Georgi extracts (SBE) against Coxsackievirus B3 (CVB3)-induced myocarditis in vitro and in vivo. In vitro, Hela cells and primary myocardial cells were infected with CVB3 and treated with SBE ($50-800{\mu}g/ml$) and ribavirin ($200{\mu}M$) for 48 h and then determined by CCK8 assay. Real-time PCR and western blotting assays were performed. In vivo, a myocarditis model was induced in male BALB/c mice by injecting CVB3 suspension intraperitoneally for three times, followed by treatment with SBE (400 and 200 mg/kg) and ribavirin (100 mg/kg) for 28 days. SBE ameliorated the cytotoxicity of CVB3 in Hela cells, especially at $400{\mu}g/ml$ (39.93% vs 65.67%, p < 0.05) without influencing cell growth and also significantly reduced CVB3 replication in primary myocardial cells. The levels of AKT, ERK, and p38 were increased after CVB3 infection. SBE could downregulate the expressions of AKT and p38. In vivo, the mortality rate from CVB3 reached to 66.67%, while 10.00% and 23.33% of this came after 400 and 200 mg/kg SBE treatment, respectively (p < 0.05). The CVB3 replication was obviously reduced after SBE administration from day 5. Similarly, the levels of AKT, ERK, and p38 mRNAs and proteins were increased, and SBE suppressed the expression of AKT and p38. Our study indicates that SBE is a promising potent antiviral agent against CVB3-induced myocarditis by inhibition of virus replication via depressing AKT and p38 expressions.
Objectives : In this study, we investigated the combination effects of Cinnamomi cortex Ethanol Extract (CcEE) and hyperthermia in the human AGS gastric cancer cell line. Methods : AGS cells were treated with the indicated concentrations of CcEE (0, 50 or $60{\mu}g/mL$) for 1h prior to hyperthermia. And then incubated for a further 30 min at the indicated temperatures (37, 42 or $43^{\circ}C$) in a humidified incubator containing 5% $CO_2$ or a thermostatically controlled water bath for hyperthermia. The cell viability was measured by MTT assay, Morphology assay and Trypan blue assay. To investigate the possible molecular signaling pathways, the activation of mitogen-activated protein kinase (MAPK) proteins (ERK, p38 and JNK) and expression of various anti-apoptotic proteins such as Caspase-3, Caspase-9, p53, Cyclin D1 and MMP-2 were assessed by Western blot analysis. In addition, Annexin V and 7-amino-actinomycin D (7-AAD) staining was performed to examine the apoptotic mechanism. Results : Combination of CcEE with hyperthermia effectively suppressed the cell viability and changed cellmorphology compared with CcEE or hyperthermia treatment alone. Combined treatment also abated the expression of Caspase-3, Caspase-9, Cyclin D1 and MMP-2. Whereas, the expression level of p53 was up-regulated by co-treatment. Moreover, combination treatment enhanced phosphorylation of ERK, p38 and JNK. In addition, this combination increased anti-cancer effect by inducing cell death through the apoptosis. Conclusions : Taken together, all these findings suggest that the combination treatment with CcEE and hyperthermia may have therapeutic potential as a promising approach to patients with stomach cancer.
[Purpose] Chronic stress is a precipitating factor for depression, whereas exercise is beneficial for both the mood and cognitive process. The current study demonstrates the anti-depressive effects of regular exercise and the mechanisms linked to hippocampal neurogenesis. [Methods] Mice were subjected to 14 consecutive days of restraint, followed by 3 weeks of treadmill running, and were then subjected to behavioral tests that included the forced swimming and Y-maze tests. Protein levels were assessed using western blot analysis and newborn cells were detected using 5-bromo-2'-deoxyuridine (BrdU). [Results] Three weeks of treadmill running ameliorated the behavioral depression caused by 14 days of continuous restraint stress. The exercise regimen enhanced BrdU-labeled cells and class III β-tubulin levels in the hippocampal dentate gyrus, as well as those of thioredoxin-1 (TRX-1) and synaptosomal β2-adrenergic receptors (β2-AR) under stress. In vitro experiments involving treatment with recombinant human TRX-1 (rhTRX-1) augmented the levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear β-catenin, and proliferating cell nuclear antigens, which were previously inhibited by U0216 and FH535 (inhibitors of ERK1/2 and β-catenin/T cell factor-mediated transcription, respectively). The hippocampal neurogenesis elicited by a 7-day exercise regimen was abolished by a selective inhibitor of β2-AR, butoxamine. [Conclusion] These results suggest that TRX-1-mediated hippocampal neurogenesis by β2-AR function is a potential mechanism underlying the psychotropic effect of exercise.
Caffeic acid phenethyl ester (CAPE) is an active component of propolis obtained from honeybee hives. CAPE possesses anti-mitogenic, anti-carcinogenic, anti-inflammatory, and immunomodulatory activities in diverse systems, which know as displays antioxidant activity and inhibits lipoxygenase activities, protein tyrosine kinase, and nuclear factor kappa B (NF-κB) activation. This study aimed to investigate the effect of CAPE on lipopolysaccharide (LPS)-induced human neutrophil phagocytosis. Human neutrophils were cultured with various concentrations of CAPE (1, 10, and 100 µM) with or without LPS. The pro-inflammatory proteins (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-6 and IL-8) levels were measured after 4 h incubation. To investigate the intracellular signaling pathway, we measured the levels of mitogen-activated protein kinases (MAPK), including phosphorylation of p38, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Next, to evaluate the potential phagocytosis, neutrophils were labeled with iron particles of superparamagnetic iron oxide nanoparticles (SPIONs, 40 nm) for 1 h in culture medium containing 5 mg/mL of iron. The labeling efficiency was determined by Prussian blue staining for intracellular iron and 3T-wighted magnetic resonance imaging. CAPE decreased the activation of intracellular signaling pathways, including ERK1/2 and c-Jun, and expression of pro-inflammatory cytokines, including TNF-α and IL-6, but had no effect on the signaling pathways of p38 and cytokine IL-8. Furthermore, images obtained after mannan-coated SPION treatment suggested that CAPE induced significantly higher signal intensities than the control or LPS group. Together, these results suggest that CAPE regulates LPS-mediated activation of human neutrophils to reduce phagocytosis.
Lee, Chea Yeon;Park, Hyo Sung;Kong, Deok-Hoon;Kim, Young Kwan;Cho, Whajung
Journal of Nutrition and Health
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v.53
no.5
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pp.452-463
/
2020
Purpose: Aster tataricus (AT) is one of the Asteraceae perennial herbs used in traditional Chinese medicine. The herb contains various bioactive substances, such as flavonoids, isoflavonoids, and phenolic compounds in the roots, and exhibits a range of effects including anti-bacterial, anti-oxidant, and anti-inflammatory activities. This study compared the immunomodulatory effects of ethanol and water extracts of whole AT, except the roots, and analyzed the molecular mechanisms for the regulatory effects on cytokine secretion from THP-1 cells. Methods: The effects of AT extract on the cell viability and proliferation of THP-1 cells were analyzed using the Cell Counting Kit-8 method. The concentrations of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the cell culture supernatant of the AT-treated THP-1 cells were measured using an enzyme-linked immunosorbent assay. The protein levels of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), inhibitor of nuclear factor kappa B (IκBα), and mitogen-activated protein kinase (MAPK) phosphorylation in the cell lysates were determined by western blotting. Results: The water extract and the ethanol extract of AT did not affect the cell viability, and increased the proliferation of THP-1 cells significantly compared to the vehicle. The water extract increased the secretion of IL-1β from THP-1 cells in a dose-dependent manner, but the ethanol extract had no effect. The expression of COX-2 and iNOS protein and the phosphorylation of MAPK and Akt were induced in AT-treated cells. In addition, IκBα was degraded by AT in a concentration-dependent manner. IL-1β secretion by AT was reduced by extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) inhibitors, while TNF-α secretion was decreased by inhibitors of ERK, p38 MAPK, and JNK. Interestingly, the p38 MAPK inhibitor increased the production of IL-1β by AT further. Conclusion: The water extract of the above-ground parts of AT contains immunomodulatory bioactive substances that stimulate immune cells through the MAPK signaling pathway.
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