Liver fibrosis is a major consequence of chronic liver disease, where excess extracellular matrix is deposited, due caused by the activation of hepatic stellate cells (HSCs). The suppression of ...collagen production in HSCs is therefore regarded as a therapeutic target of liver fibrosis. The present study investigated effects of harmine, which is a β-carboline alkaloid and known as an inhibitor of dual-specificity tyrosine-regulated kinases (DYRKs), on the production of collagen in HSCs. LX-2 cells, a human HSC cell line, were treated with harmine (0–10 μM) for 48 h in the presence or absence of TGF-β1 (5 ng/ml). The expression of collagen type I α1 (COL1A1) and DYRK isoforms was investigated by Western blotting, quantitative RT-PCR, or immunofluorescence. The influence of knockdown of each DYRK isoform on the COL1A1 expression was further investigated. The expression of COL1A1 was markedly increased by treating with TGF-β1 for 48 h in LX-2 cells. Harmine (10 μM) significantly inhibited the increased expression of COL1A1. LX-2 cells expressed mRNAs of DYRK1A, DYRK1B, DYRK2, and DYRK4, although the expression of DYRK4 was much lower than the others. Knockdown of DYRK1B, but not DYRK1A or DYRK2, with siRNA significantly suppressed TGF-β1-induced increase in COL1A1 expression. These results suggest that harmine suppresses COL1A1 expression via inhibiting DYRK1B in HSCs and therefore might be effective for the treatment of liver fibrosis.
•Harmine suppressed the production of collagen induced by TGF-β1 in LX-2 cells.•LX-2 cells expressed mRNAs of DYRK1A, DYRK1B, and DYRK2.•DYRK1B knockdown suppressed the production of collagen 1A1 induced by TGF-β1 in LX-2 cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Liver fibrosis is a significant consequence of chronic liver diseases, where excess deposition of extracellular matrix is caused by the activation of hepatic stellate cells (HSCs). The suppression of ...HSC activation is therefore regarded as a therapeutic target of liver fibrosis. The present study investigated the involvement of protein arginine methyltransferase 5 (PRMT5), which mediates genome organization and cell cycle regulation, in HSC activation. LX-2 cells, a human HSC cell line, were treated with TGF- β1 for 48 h in the presence of PRMT5 inhibitors (EPZ015666 and JNJ64619178). The expression of α-smooth muscle actin (α-SMA) and type I collagen α1 (COL1A1), activated HSC markers, were markedly increased by the TGF-β1 treatment. PRMT5 inhibitors suppressed the increased expression of α-SMA and COL1A1 in a concentration-dependent manner. Knockdown of PRMT5 also suppressed the TGF-β1-induced COL1A1 expression in LX-2 cells. RNA-sequencing analysis showed that GO terms related to ECM production and SMAD signaling were enriched with RNA of LX-2 cells treated with the PRMT5 inhibitor JNJ64619178. These results suggest that PRMT5 promotes HSC activation, possibly depending on the SMAD signaling pathway, and therefore might be a target for the prevention and treatment of liver fibrosis.
Liver fibrosis is a significant consequence of chronic liver diseases, where excess deposition of extracellular matrix is caused by the activation of hepatic stellate cells (HSCs). The suppression of ...HSC activation is therefore regarded as a therapeutic target of liver fibrosis. The present study investigated the involvement of protein arginine methyltransferase 5 (PRMT5), which mediates genome organization and cell cycle regulation, in HSC activation. LX-2 cells, a human HSC cell line, were treated with TGF- β1 for 48 h in the presence of PRMT5 inhibitors (EPZ015666 and JNJ64619178). The expression of α-smooth muscle actin (α-SMA) and type I collagen α1 (COL1A1), activated HSC markers, were markedly increased by the TGF-β1 treatment. PRMT5 inhibitors suppressed the increased expression of α-SMA and COL1A1 in a concentration-dependent manner. Knockdown of PRMT5 also suppressed the TGF-β1-induced COL1A1 expression in LX-2 cells. RNA-sequencing analysis showed that GO terms related to ECM production and SMAD signaling were enriched with RNA of LX-2 cells treated with the PRMT5 inhibitor JNJ64619178. These results suggest that PRMT5 promotes HSC activation, possibly depending on the SMAD signaling pathway, and therefore might be a target for the prevention and treatment of liver fibrosis.
Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint ...swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients' quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Digoxin toxicity (plasma digoxin concentration ≥0.9 ng/mL) is associated with worsening heart failure (HF). Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where ...users can easily predict the risk of adverse drug reactions. The present study aimed to construct a flowchart using DT analysis that can be used by medical staff to predict digoxin toxicity. We conducted a multicenter retrospective study involving 333 adult patients with HF who received oral digoxin treatment. In this study, we employed a chi-squared automatic interaction detection algorithm to construct DT models. The dependent variable was set as the plasma digoxin concentration (≥ 0.9 ng/mL) in the trough during the steady state, and factors with p < 0.2 in the univariate analysis were set as the explanatory variables. Multivariate logistic regression analysis was conducted to validate the DT model. The accuracy and misclassification rates of the model were evaluated. In the DT analysis, patients with creatinine clearance <32 mL/min, daily digoxin dose ≥1.6 µg/kg, and left ventricular ejection fraction ≥50% showed a high incidence of digoxin toxicity (91.8%; 45/49). Multivariate logistic regression analysis revealed that creatinine clearance <32 mL/min and daily digoxin dose ≥1.6 µg/kg were independent risk factors. The accuracy and misclassification rates of the DT model were 88.2 and 46.2 ± 2.7%, respectively. Although the flowchart created in this study needs further validation, it is straightforward and potentially useful for medical staff in determining the initial dose of digoxin in patients with HF.
We examined the inhibitory effects of α-linolenic acid (ALA) on the contractions of pig coronary arteries. ALA concentration-dependently inhibited the contractions elicited by U46619 and ...prostaglandin F2α without affecting those elicited by 80 mM KCl, histamine, acetylcholine, and serotonin. ALA rightward shifted the concentration-response curve of U46619, and Schild plot analysis revealed that ALA competitively antagonized U46619. Furthermore, ALA inhibited the increase in intracellular Ca2+ concentration caused by TP receptor stimulation but not that caused by FP receptor stimulation. These results suggest that ALA behaves as a selective antagonist of TP receptors in coronary arteries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Polypharmacy, defined as the concurrent use of over six drugs, is common in the treatment of heart failure (HF); however, unpredictable drug interactions with bepridil may occur. In this study, we ...have elucidated the influence of polypharmacy on plasma bepridil concentrations in patients with HF.
We conducted a multicenter retrospective study involving 359 adult patients with HF who received oral bepridil. Because QT prolongation is an adverse effect following plasma bepridil concentrations ≥800 ng/mL, the risk factors for patients achieving these concentrations at steady state were elucidated via multivariate logistic regression. The correlation between bepridil dose and plasma concentration was examined. The effect of polypharmacy on the value of the concentration-to-dose (C/D) ratio was investigated.
A significant relationship was observed between bepridil dose and plasma concentration (p < 0.001), and the intensity of the correlation was moderate (r = 0.503). Based on multivariate logistic regression, the adjusted odds ratios for a daily dose of bepridil ≥1.6 mg/kg, polypharmacy, and concomitant of aprindine, a cytochrome P450 2D6 inhibitor, were 6.82 (95% coefficient interval: 2.104-22.132, p = 0.001), 2.96 (95% coefficient interval: 1.014-8.643, p = 0.047), and 8.63 (95% coefficient interval: 1.684-44.215, p = 0.010), respectively. Despite the moderate correlation in non-polypharmacy, the correlation was not observed in polypharmacy. Therefore, inhibiting metabolism, along with other mechanisms, may contribute to the polypharmacy-induced increase in plasma bepridil concentrations. Moreover, the C/D ratios in the groups receiving 6-9 and 10≤ concomitant drugs were 1.28- and 1.70-fold higher than in those receiving <6 drugs, respectively.
Plasma bepridil concentrations may be influenced by polypharmacy. Moreover, the plasma bepridil concentration increased in correlation with the number of concomitant drugs used. Although the mechanism of this increase could not be determined, plasma bepridil concentrations should be periodically monitored for safe use in patients with HF.
Retrospectively registered.
Abstract
This study was performed to elucidate whether eicosapentaenoic acid (EPA) suppresses spasm-prone blood vessel contractions induced by a thromboxane mimetic (U46619) and prostaglandin F
2α
...(PGF
2α
) and determine whether the primary target of EPA is the prostanoid TP receptor. Accordingly, we assessed: (1) the tension changes in porcine basilar and coronary arteries, and (2) changes in the Fura-2 (an intracellular Ca
2+
indicator) fluorescence intensity ratio at 510 nm elicited by 340/380 nm excitation (F340/380) in 293T cells expressing the human TP receptor (TP-293T cells) and those expressing the human prostanoid FP receptor (FP-293T cells). EPA inhibited both porcine basilar and coronary artery contractions induced by U46619 and PGF
2α
in a concentration-dependent manner, but it did not affect the contractions induced by 80 mM KCl. EPA also inhibited the increase in F340/380 induced by U46619 and PGF
2
α
in TP-293T cells. In contrast, EPA showed only a marginal effect on the increase in F340/380 induced by PGF
2α
in FP-293T cells. These findings indicate that EPA strongly suppresses the porcine basilar and coronary artery contractions mediated by TP receptor and that inhibition of TP receptors partly underlies the EPA-induced inhibitory effects on these arterial contractions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Thermal conductivity of a 300-nm-thick VO2 thin film and its temperature dependence across the metal-insulator phase transition (TMIT) were studied using a pulsed light heating thermoreflectance ...technique. The VO2 and Mo/VO2/Mo films with a VO2 thickness of 300 nm were prepared on quartz glass substrates: the former was used for the characterization of electrical properties, and the latter was used for the thermal conductivity measurement. The VO2 films were deposited by reactive rf magnetron sputtering using a V2O3 target and an Ar-O2 mixture gas at 645 K. The VO2 films consisted of single phase VO2 as confirmed by X-ray diffraction and electron beam diffraction. With increased temperature, the electrical resistivity of the VO2 film decreased abruptly from 6.3 × 10−1 to 5.3 × 10−4 Ω cm across the TMIT of around 325-340 K. The thermal conductivity of the VO2 film increased from 3.6 to 5.4 W m−1 K−1 across the TMIT. This discontinuity and temperature dependence of thermal conductivity can be explained by the phonon heat conduction and the Wiedemann-Franz law.
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