(−)-Epigallocatechin-3-gallate (EGCg), a major constituent of green tea extract, is well-known to exhibit many beneficial actions for human health by interacting with numerous proteins. In this study we identified synaptic vesicle membrane protein VAT-1 homolog (VAT1) as a novel EGCg-binding protein in human neuroglioma cell extracts using a magnetic pull-down assay and LC–tandem mass spectrometry. We prepared recombinant human VAT1 and analyzed its direct binding to EGCg and its alkylated derivatives using surface plasmon resonance. For EGCg and the derivative NUP-15, we measured an association constant of 0.02–0.85 ×103 M−1s−1 and a dissociation constant of nearly 8 × 10−4 s−1. The affinity Km(affinity) of their binding to VAT1 was in the 10–20 µM range and comparable with that of other EGCg-binding proteins reported previously. Based on the common structure of the compounds, VAT1 appeared to recognize a catechol or pyrogallol moiety around the B-, C- and G-rings of EGCg. Next, we examined whether VAT1 mediates the effects of EGCg and NUP-15 on expression of neprilysin (NEP). Treatments of mock cells with these compounds upregulated NEP, as observed previously, whereas no effect was observed in the VAT1-overexpressing cells, indicating that VAT1 prevented the effects of EGCg or NUP-15 by binding to and inactivating them in the cells overexpressing VAT1. Further investigation is required to determine the biological significance of the VAT1–EGCg interaction.
(-)-Epigallocatechin-3-gallate (EGCg) is known to upregulate neprilysin, an Aβ-degrading enzyme. To clarify the mechanism underlying this process, the authors screened catechin-binding proteins by pull-down assay with magnetic beads and LC-tandem mass spectrometry and identified synaptic vesicle membrane protein VAT-1 homolog (VAT1). Surface plasmon resonance analysis revealed a direct binding of recombinant VAT1 protein to EGCg or its alkylated derivative NUP-15 with comparable affinity to the other EGCg binding proteins reported previously. Furthermore, the authors found that VAT1 prevented the upregulation of neprilysin by EGCg or NUP-15 through binding to and inactivating them in the cells overexpressing VAT1.
Oxygen is pivotal for survival of animals. Their cellular activity and cognitive behavior are impaired when atmospheric oxygen is insufficient, called hypoxia. However, concurrent effects of hypoxia on physiological signals are poorly understood. To address this question, we simultaneously recorded local field potentials in the primary motor cortex, primary somatosensory, and anterior cingulate cortex, electrocardiograms, electroolfactograms, and electromyograms of rats under acute hypoxic conditions (i.e., 5.0% O2). Exposure to acute hypoxia significantly attenuated alpha oscillations alone in the primary motor cortex, while we failed to find any effects of acute hypoxia on the oscillatory power in the somatosensory cortex or anterior cingulate cortex. These area- and frequency-specific effects by hypoxia may be accounted for by neural innervation from the brainstem to each cortical area via thalamic relay nuclei. Moreover, we found that heart rate and respiratory rate were increased during acute hypoxia and high heart rate was maintained even after the oxygen level returned to the baseline. Altogether, our study characterizes a systemic effect of atmospheric hypoxia on neural and peripheral signals from physiological viewpoints, leading to bridging a gap between cellular and behavioral levels.
The authors investigated concurrent effects of hypoxia on physiological signals by simultaneously recording local field potentials in the primary motor, primary somatosensory and anterior cingulate cortices as well as electrocardiograms, electroolfactograms, and electromyograms of rats in acutely hypoxic environment. When they were exposed to acute hypoxia, alpha oscillations in the primary motor cortex were impaired. Moreover, the authors demonstrated that heart rate and respiratory rate were increased during acute hypoxia and high heart rate was maintained even after the oxygen level returned to the baseline. Altogether, this study characterizes a systemic effect of atmospheric hypoxia from physiological viewpoints.
This study aimed to investigate whether the approved sequence of vedolizumab and ustekinumab impacts the results of previous observational studies conducted in the European Union (EU), comparing the effectiveness of these drugs in Crohn’s disease (CD) patients who failed anti-tumor necrosis factor-α (TNFα) treatment. We conducted this study in Japan, where the approved sequence of drugs is different from that of the EU. We extracted 256 patients diagnosed with CD, who had a history of anti-TNFα treatment and were prescribed either vedolizumab or ustekinumab, from JMDC claims database. The patients’ backgrounds were adjusted by inverse probability of treatment weighting using propensity score. The primary outcome was treatment persistence. Secondary outcomes were a steroid-free period, time to hospitalization, and time to CD-related surgery. The hazard ratios (HR) for survival times were estimated using the Cox proportional hazard model. The treatment persistence (primary endpoint) was significantly longer for ustekinumab than vedolizumab (HR, 0.32; 95% confidence interval (CI), 0.15–0.72). The results of the secondary endpoints were as follows: steroid-free period (HR, 0.38; 95% CI, 0.10–1.48), time to hospitalization (HR, 1.07; 95% CI, 0.60–1.91), or time to CD-related surgery (HR, 0.33; 95% CI, 0.11–0.97). There were no outcomes indicating the superiority of vedolizumab. Our findings suggest that ustekinumab is a more effective treatment option than vedolizumab for CD patients who failed to anti-TNFα treatment, and this finding remains consistent across both Japan and the EU.
This study examined whether the approved sequence of vedolizumab and ustekinumab impacts the results of studies conducted in the EU, comparing the effectiveness of these drugs in Crohn's disease (CD) patients who failed anti-TNFα treatment. The authors conducted this study in Japan, where the approved sequence of drugs is different from that of the EU. They analyzed data from 256 CD patients from the Japanese claims database. The results suggested that ustekinumab is a more effective treatment option than vedolizumab for CD patients who failed anti-TNFα treatment, and this finding remains consistent across both Japan and the EU.
Metastases and drug resistance are the major risk factors associated with breast cancer (BC), which is the most common type of tumor affecting females. Icariin (ICA) is a traditional Chinese medicine compound that possesses significant anticancer properties. Long non-coding RNAs (lncRNAs) are involved in a wide variety of biological and pathological processes and have been shown to modulate the effectiveness of certain drugs in cancer. The purpose of this study was to examine the potential effect of ICA on epithelial mesenchymal transition (EMT) and stemness articulation in BC cells, as well as the possible relationship between its inhibitory action on EMT and stemness with the NEAT1/transforming growth factor β (TGFβ)/SMAD2 pathway. The effect of ICA on the proliferation (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony assays), EMT (Western blotting, immunofluorescence, and wound healing), and stemness (mammosphere formation assays, Western blotting) of BC cells were examined. According to the findings, ICA suppressed the proliferation, EMT, and stem cell-like in MDA-MB-231 cells, and exerted its inhibitory impact by downregulating the TGFβ/SMAD2 signaling pathway. ICA could significantly downregulate the expression of lncRNA NEAT1, and silencing NEAT1 enhanced the effect of ICA in suppressing EMT and expression of different stem cell markers. In addition, silencing NEAT1 was found to attenuate the TGFβ/SMAD2 signaling pathway, thereby improving the inhibitory impact of ICA on stemness and EMT in BC cells. In conclusion, ICA can potentially inhibit the metastasis of BC via affecting the NEAT1/TGFβ/SMAD2 pathway, which provides a theoretical foundation for understanding the mechanisms involved in potential application of ICA for BC therapy.
[Highlighted Paper selected
by Editor-in-Chief]
Icariin(ICA)
affects the EMT and cancer stem cell-like character of breast cancer cells. The
main mechanism is to influence the characteristics of EMT and cancer stem
cell-like character of breast cancer cells by regulating the TGFβ/SMAD2
signaling pathway, which in turn affects the migration of breast cancer cells. In addition, we have found not only ICA inhibits proliferation, EMT and
stem cell-like character of breast cancer cells by silencing lncRNA NEAT1, but NEAT1
can exert anti-breast cancer effects through TGFβ/SMAD2 signaling pathway. Overall, we
hypothesized that ICA could inhibit the proliferation, EMT and cancer stem
cell-like character of breast cancer cells through the NEAT1/TGFβ/SMAD2 axis
and suppress breast cancer migration.
The mechanisms of several drugs remain unclear, limiting our understanding of how they exert their effects. Receptor affinities have not been comprehensively measured during drug development, and the safety investigations in humans are limited. Therefore, numerous unknown adverse and beneficial effects of drugs in humans persist. In this review, I highlight our achievements in identifying the unexpected beneficial effects of drugs through the analysis of real-world clinical data, which can contribute to drug repositioning and target finding. (1) Through the analysis of real-world data, we found that the anti-arrhythmic amiodarone induced interstitial lung disease, leading to fibrosis. Surprisingly, concurrent use of an anti-thrombin drug, dabigatran mitigated these adverse events. Pharmacological studies using animal models have mimicked this phenomenon and revealed the molecular mechanisms associated with the platelet-derived growth factor-alpha receptors. (2) The antidiabetic dipeptidyl-peptidase 4 inhibitors increased the risk of an autoimmune disease, bullous pemphigoid, which was reduced by the concomitant use of lisinopril. Pharmacological studies using human peripheral blood mononuclear cells have revealed that lisinopril suppressed the skin disorders by inhibiting the expression of cutaneous matrix metalloproteinase 9 in macrophages. (3) The antimicrobial fluoroquinolones increased the risk of tendinopathy, which was reduced by the concomitant use of dexamethasone. However, clinical guidelines have suggested that corticosteroid increases the risk of tendinopathy. Our investigation demonstrated that fluoroquinolones impaired tendon cells through DNA damage by generating reactive oxygen species. In contrast, dexamethasone exhibited an acute beneficial effect on tendon tissue by upregulating the expression of a radical scavenger, glutathione peroxidase 3.
Recently, large amount of real-world data (RWD), such as insurance claims data and self-reports of adverse drug reactions become available. Statistical analysis of RWD has made it possible to identify novel and unexpected confounding factors that influence the occurrence of adverse events or spontaneous disease in humans. Such drug-drug interactions lead to the elucidation of adverse event mechanisms and the discovery of new drug targets. In addition, hypotheses derived from RWD may have high clinical predictive value. In this review, the author shows how RWD analysis can lead to the discovery of drug targets, by introducing examples of research reports.
Total Purine and Purine Base Content of Common Foodstuffs for Facilitating Nutritional Therapy for Gout and Hyperuricemia
Released on J-STAGE: May 01, 2014 | Volume 37 Issue 5 Pages 709-721
Kiyoko Kaneko, Yasuo Aoyagi, Tomoko Fukuuchi, Katsunori Inazawa, Noriko Yamaoka
Views: 4,480
Electron Paramagnetic Resonance Study of the Free Radical Scavenging Capacity of Curcumin and Its Demethoxy and Hydrogenated Derivatives
Released on J-STAGE: October 01, 2015 | Volume 38 Issue 10 Pages 1478-1483
Noppawan Phumala Morales, Srisuporn Sirijaroonwong, Paveena Yamanont, Chada Phisalaphong
Views: 3,198
Anti-inflammatory Effects of Etodolac : Comparison with Other Non-steroidal Anti-inflammatory Drugs
Released on J-STAGE: April 10, 2008 | Volume 17 Issue 12 Pages 1577-1583
Kichiro INOUE, Hiroshi FUJISAWA, Asahiko MOTONAGA, Yoshie INOUE, Takashi KYOI, Fusao UEDA, Kiyoshi KIMURA
Views: 1,190
Protocatechuic Acid Inhibits Rat Pheochromocytoma Cell Damage Induced by a Dopaminergic Neurotoxin
Released on J-STAGE: November 01, 2009 | Volume 32 Issue 11 Pages 1866-1869
Hong-Ning Zhang, Chun-Na An, Man Xu, De-An Guo, Min Li, Xiao-Ping Pu
Views: 1,164