Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
46 巻, 1 号
選択された号の論文の17件中1~17を表示しています
Regular Articles
  • Mingzhi Luo, Kai Ni, Rong Gu, Youyuan Qin, Jia Guo, Bo Che, Yan Pan, J ...
    2023 年 46 巻 1 号 p. 1-11
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Inspired by the well-known phenomenon of stretch-induced airway dilation in normal lungs and the emerging stretch-responsive Piezo1 channels that can be chemically activated by specific agonists such as Yoda1, we attempted to investigate whether chemical activation of Piezo1 by Yoda1 can modulate the biomechanical behaviors of airway smooth muscle cells (ASMCs) so that it may be exploited as a novel approach for bronchodilation. Thus, we treated in vitro cultured rat ASMCs with Yoda1, and examined the cells for calcium signaling, cell stiffness, traction force, cell migration, and the mRNA expression and distribution of molecules relevant to cell biomechanics. The data show that ASMCs expressed abundant mRNA of Piezo1. ASMCs exposed to 1 µM Yoda1 exhibited a potent but transient Ca2+ signaling, and treatment with 1 µM Yoda1 for 24 h led to decreased cell stiffness and traction force, all of which were partially reversed by Piezo1 inhibitor GsMTx4 and Piezo1 knockdown, respectively. In addition, ASMCs treated with 1 µM Yoda1 for 24 h exhibited impaired horizontal but enhanced vertical cell migration, as well as significant changes in key components of cells’ contractile machinery including the structure and distribution of stress fibers and alpha-smooth muscle actin (α-SMA) fibrils, the mRNA expression of molecules associated with cell biomechanics. These results provide the first evidence that chemical activation of Piezo1 by Yoda1 resulted in marked pro-relaxation alterations of biomechanical behaviors and contractile machinery of the ASMCs. These findings suggest that Piezo1-specific agonists may indeed have great potential as alternative drug agents for relaxing ASMCs.

    Editor's pick

    Inspired by the well-known phenomenon of stretch-induced airway dilation in normal lung and the emerging stretch-responsive Piezo1 channels, the authors in this study demonstrated that chemical activation of Piezo1 channels by agonist YODA1 dramatically reduced the contractility of cultured ASMCs in terms of cells stiffness, traction force, migration, and expression of molecules associated with cell mechanics. These findings indicate that chemical activation of Piezo1 can indeed modulate biomechanical behaviors of ASMCs towards relaxation. And this novel regulatory mechanism as alternative to the conventional b2-adrenergic receptor for relaxation of ASMCs may provide a potentially new target for bronchodilation in asthma therapy.

  • DoYeong Jeon, Nackhyoung Kim, Soo-Jong Um
    2023 年 46 巻 1 号 p. 12-18
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Although bromodomain and extraterminal (BET) inhibitors (BETis) have anti-tumor potential, the underlying molecular mechanism is poorly understood. We found that BETis effectively repressed cell growth via G1/S arrest and migration of HCT116 cells in a p53-independent manner. BETis increased the expression of p21WAF1 and repressed the expression of E2F target genes. Consistent with this, retinoblastoma protein (Rb) phosphorylation was downregulated by BETis, supporting E2F inactivation. To investigate the epigenetic mechanism, chromatin immunoprecipitation (ChIP) assays were employed using the E2F1 target gene c-MYC. Following BETi treatment, recruitment of phosphorylated Rb, BRD2, and MLL2 to the c-MYC promoter was reduced, whereas recruitment of unphosphorylated Rb and EZH2 was increased. Consequently, decreased H4K5/K12ac and H3K4me3 accumulation but increased H3K27me3 accumulation were observed. Overall, this study suggests that BETis may be useful for the treatment of colorectal cancer via epigenetic regulation of the E2F1/c-MYC axis, leading to growth arrest in a p53-independent manner.

  • Kousuke Nishikiori, Kentaro Tanaka, Takashi Ozawa, Yoshihiro Uesawa
    2023 年 46 巻 1 号 p. 19-25
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Various factors affect the prognosis of dialysis patients. Analysis of the drugs used and clinical and demographic characteristics of the patient at the time of dialysis initiation is a useful means of estimating prognosis. In this study, we investigated the drugs used by dialysis patients during the induction phase of dialysis and performed a detailed analysis of variables predictive of prognosis. Patients who underwent dialysis between June 1998 and January 2019 and died during this period were included in the study (n = 118). The induction phase of dialysis was defined as the first month after dialysis began. Dialysis duration was defined as the time between dialysis initiation and death. A univariate regression analysis was performed, with dialysis duration as the objective variable and the drugs used during the induction phase of dialysis, blood laboratory values, age at start of dialysis, sex, body height, body weight, medical history and cause of death as the explanatory variables. In addition, multiple logistic regression analysis with stepwise variable selection of significant factors was performed to determine the factors related to dialysis duration. Antihypertensives, hemoglobin (Hb), and age at start of dialysis were found to have significant effects on dialysis duration. It was posited that antihypertensives prolong dialysis duration, thereby improving life expectancy. The regression model developed allowed estimation of prognosis based on the drugs used during the induction phase of dialysis and patient characteristics. These findings may be used to improve drug adherence in dialysis patients and guide physicians in their treatment.

    Editor's pick

    Various factors affect the prognosis of dialysis patients. Analysis of the drugs used and clinical and demographic characteristics of the patient at the time of dialysis initiation is a useful means of estimating prognosis. The authors investigated the drugs used by dialysis patients during the induction phase of dialysis and performed a detailed analysis of variables predictive of prognosis. As a result, antihypertensives, hemoglobin, and age at start of dialysis were found to have significant effects on dialysis duration. It was posited that antihypertensives prolong dialysis duration, thereby improving life expectancy. These findings may be used to improve drug adherence in dialysis patients and guide physicians in their treatment.

  • Chen Huang, Tao Zhou, Lihua Ma, Shipeng Zhao
    2023 年 46 巻 1 号 p. 26-34
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Oxaliplatin (OXA) is a usual chemotherapeutic agent applied in the colorectal cancer (CRC) clinical treatment. Interferon-alpha inducible protein 6 (IFI6) has been proved to promote proliferation and suppress apoptosis in several tumor cells, while the impacts of IFI6 on OXA resistance in CRC still need exploration. HCT116 and SW620 cells were used as the parental to obtain OXA-resistant cells. The influence of IFI6 on OXA sensitivity, cell proliferation and apoptosis were evaluated by overexpression or knockdown IFI6 in cells. In this work, we found that the level of IFI6 was significantly enhanced in HCT116/OXA and SW620/OXA cells as compared to the parental cells. Overexpression of IFI6 decreased the sensitivity of HCT116 and SW620 cells to OXA. However, knockdown of IFI6 enhanced the sensitivity of HCT116/OXA and SW620/OXA cells to OXA. And upregulated IFI6 promoted the proliferation and repressed apoptosis in HCT116 cells, while suppressed IFI6 markedly reduced proliferation and increased apoptosis in HCT116/OXA cells. Additionally, IFI6 suppressed the phosphorylation level of p38, and silenced IFI6 enhanced it. The addition of the p38 kinase inhibitor, SB203580, alleviated the decreased cell proliferation and increased apoptosis in HCT116/OXA cells. Suppressed IFI6 enhanced the reactive oxygen species (ROS) level in HCT116/OXA cells, and blockade of ROS with N-acetyl-L-cysteine (NAC) decreased the enhancement level of ROS and the phosphorylation level of the p38, which was induced by IFI6 down-regulation. We, therefore, implied that suppressed IFI6 reverses OXA-resistance of CRC cells via promoting the ROS-induced p38 mitogen-activated protein kinase (MAPK) signaling pathway.

  • Feng Jiang, Tieming Zhu, Chunfeng Yang, Yang Chen, Zhidong Fu, Lihui J ...
    2023 年 46 巻 1 号 p. 35-41
    発行日: 2023/01/01
    公開日: 2023/01/01
    [早期公開] 公開日: 2022/10/22
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    Pachymic acid (PA), exacted from Polyporaceae, has been known for its biological activities including diuretic, dormitive, anti-oxidant, anti-aging, anti-inflammatory and anticancer properties in several types of diseases. Recently, studies have demonstrated that PA could suppress cell growth and induce cell apoptosis in different kinds of cancer cells. But the underlying mechanisms remain poorly elucidated. In the current study, we investigated the effect of pachymic acid on liver cancer cells and its underlying mechanisms. Our results evidenced that pachymic acid effectively inhibited the cell growth and metastatic potential in HepG2 and Huh7 cells. Mechanistically, we revealed that pachymic acid triggered cell apoptosis by increasing caspase 3 and caspase 9 cleavage, upregulating Bax and cytochrome c expression, while reducing the expression of Bcl2. Besides, pachymic acid could markedly inhibit the cell invasion and migration and cell metastatic potential by mediating epithelial-to-mesenchymal transition (EMT) markers and metastasis-associated genes in HepG2 and Huh7 cells. In addition, we demonstrated that FAK-Src-Jun N-terminal kinase (JNK)-matrix metalloproteinase 2 (MMP2) axis was involved in PA-inhibited liver cell EMT. Together, these results contribute to our deeper understanding of the anti-cancer effects of pachymic acid on liver cancer cells. This study also provided compelling evidence that PA might be a potential therapeutic agent for liver cancer treatment.

  • Hangtian Zhou, Lingling Xu, Yan Shi, Shihui Gu, Nan Wu, Fei Liu, Yinji ...
    2023 年 46 巻 1 号 p. 42-51
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Lung cancer is the leading cause of cancer-related deaths worldwide, synthesizing and screening of novel anti-cancer drugs provides an alternative therapeutic strategy for renewal of the chemotherapy regimens against lung cancer. To this end, several compounds were synthesized based on the modification of the original myricetin, and their anti-tumor activity against the human non-small cell lung cancer (NSCLC) A549 cells were measured. Among the myricetin derivatives, S4-10 has displayed the highest antitumor efficacy in dose-dependent manner. The proliferation of A549 cells were significantly attenuated by given 6 µM of S4-10 both in vitro and in vivo. Further, the treatment of S4-10 also results in the inhibition of cell migration and invasiveness and the induction of cell apoptosis and G2 cycle arrest of A549 cells. Moreover, we found that S4-10 inhibits the progression of A549 cells through the sterol biosynthetic-cell apoptosis axis. These findings shed the light of developing S4-10 as a promising treatment agent for NSCLC.

  • Chuyu Zhao, Zhou Zhou, Xuehan Wu, Yihan Wang, Li Zuo, Rui Zheng, Yu Li ...
    2023 年 46 巻 1 号 p. 52-60
    発行日: 2023/01/01
    公開日: 2023/01/01
    [早期公開] 公開日: 2022/10/27
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    Vitamin K, a necessary nutritional supplement for human, has been found to exhibit anti-inflammatory activity. In the present study, we investigated the effects of vitamin K family on lipopolysaccharide (LPS) plus nigericin induced pyroptosis and explored the underlying mechanism of its action in THP-1 monocytes. Results showed that vitamin K3 treatment significantly suppressed THP-1 pyroptosis, but not vitamin K1 or K2, as evidenced by increased cell viability, reduced cellular lactate dehydrogenase (LDH) release and improved cell morphology. Vitamin K3 inhibited NLRP3 expression, caspase-1 activation, GSDMD cleavage and interleukin (IL)-1β secretion in pyrophoric THP-1 cells. In addition, vitamin K3 inhibited the pro-inflammatory signaling pathways including nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). Vitamin K3 treatment also attenuated tissue damage and reduced serum LDH, IL-1β and IL-6 levels in LPS-induced systemic inflammation of mice. The reduced myeloperoxidase (MPO) activityand F4/80 expression indicated that vitamin K3 effectively reduced the infiltration of neutrophils and macrophages. Moreover, NLRP3 expression in monocytes/macrophages were also decreased in vitamin K3-treatedmice after LPS challenge. These findings suggest that vitamin K3 potently alleviates systemic inflammation and organ injury via inhibition of pyroptosis in monocytes and may serve as a novel therapeutic strategy for patients with inflammatory diseases.

  • Shigeyoshi Honma, Kazuma Komine, Suzuka Ota, Kohei Toriyabe, Yuta Mori ...
    2023 年 46 巻 1 号 p. 61-66
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Suplatast is a T helper 2 (Th2) cytokine inhibitor. Here, we tested its therapeutic effects using a mouse model of renal interstitial fibrosis caused by unilateral ureteral obstruction (UUO). In this model, suplatast was found to prevent the induced fibrosis in the obstructed kidney when given in the drinking water at 100 mg/kg/d. Mechanistically, suplaplast inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) that was otherwise increased by UUO. Similarly, suplaplast reduced the increased accumulation of KIM-1, transforming growth factor β (TGF-β), type I collagen, interleukin-4 (IL-4), janus kinase (JAK)1 and signal transducer and activator of transcription (STAT)3 mRNA seen in the kidneys of UUO-treated mice. Furthermore, STAT3 phosphorylation, which was stimulated by UUO, was also significantly decreased by suplatast. Collectively, these data show that suplatast reduces UUO-induced renal interstitial fibrosis via mechanisms including a reduction of phosphorylation of ERK and JAK/STAT pathway signaling.

  • Jun Jia, Jiaojiao Xia, Weifeng Liu, Fengqin Tao, Jun Xiao
    2023 年 46 巻 1 号 p. 67-73
    発行日: 2023/01/01
    公開日: 2023/01/01
    [早期公開] 公開日: 2022/10/22
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    Osteosarcoma (OS), one of the bone tumors, occurs mainly during childhood and adolescence and has an incidence rate of 5%. Cinnamtannin B-1 (CTB-1) is a natural trimeric proanthocyanidin compound found in plants Cinnamomum zeylanicum and Laurus nobilis. Previously, several articles have demonstrated that CTB-1 exerts a certain effect on melanoma and cervical cancer. However, their role in OS remains unclear. In this study, CTB-1 was found to inhibit the proliferation of OS cancer cells, with the dose of CTB-1 positively correlated to the survival rate of HOS and MG-63 cells. Recently, microRNAs (miRNAs) were also reported to play an important role in tumor proliferation. Hence, we performed the miRNA sequencing analysis after CTB-1 treatment to identify miRNA levels in HOS cells and found that the expression of miR-1281 was significantly upregulated. According to the functional analysis, CTB-1 inhibited the growth and migration of OS by upregulating the expression of miR-1281. Additionally, miR-1281 acted as a sponge for Peptidylprolyl Isomerase F (PPIF), inhibiting its expression levels. The rescue experiments revealed that CTB-1 delayed the development of OS by regulating the miR-1281/PPIF pathway. Hence, our findings suggested that CTB-1 inhibited the cell growth, invasion, and migration of OS by upregulating miR-1281 and inhibiting PPIF expression, thereby providing a possible target drug for OS treatment.

  • Jianchao He, Yuhui Bu, Xiaolong Li, Xiaojun Zhang, Li Ma
    2023 年 46 巻 1 号 p. 74-85
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Breast cancer (BC) is the most generally diagnosed cancer and the driving cause of cancer-related death. Transmembrane (TMEM) proteins have been reported to serve as prognostic indicators in a variety of cancers, and it can offer therapeutic targets for carcinoma. However, the function of TMEM in BC remains unclear. In this study, TMEM9A, a member of TMEM family, was screened as the candidate gene after analyzing the profiles of GSE42568 and GEPIA-BRCA database via bioinformatic method. The upregulated expression of TMEM9A was confirmed in BC samples compared with the paired normal tissues. Hence, we speculated that TMEM9A might promote BC progression. To test the hypothesis, we performed a series of loss/gain-of-function experiments and found that BC cells with TMEM9A deletion inhibited cell proliferation, migration, and invasion along with induced apoptosis. Conversely, TMEM9A overexpression reversed the trend. Mechanically, TMEM9A knockdown blocked the Wnt/β-catenin signaling pathway as evidenced by the increased adenomatous polyposis coli (APC) expression and decreased β-catenin, cyclin D1, and axis inhibition protein 2 (AXIN2) expression. Furthermore, over-activation of the Wnt/β-catenin pathway by transfecting BC cells with β-Catenin-S33Y (β-Catenin tyrosine for serine at codon 33) plasmids reversed the effects caused by TMEM9A knockdown. In conclusion, TMEM9A may play a tumor-promoting role in BC progression via activating the Wnt/β-catenin signaling pathway. Therefore, TMEM9A may be an effective therapeutic option for BC.

  • Keiichiro Suzuki, Kazuya Matsumoto, Misa Takenaka, Tetsuya Aiba
    2023 年 46 巻 1 号 p. 86-94
    発行日: 2023/01/01
    公開日: 2023/01/01
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    From our previous observation that the anesthetic effects of phenobarbital potentiate in rats with a decreased cerebral protein expression of the potassium chloride cotransporter KCC2 (SLC12A5), an in vivo study was conducted to clarify whether the pharmacological effect of phenobarbital alters by stimulating the cerebral tropomyosin receptor kinase B (TrkB) that is known to down-regulate the KCC2 protein expression. The stimulation was performed in rats with repetitious intraperitoneal administration of a TrkB agonist, namely 7,8-dihydroxyflavone (DHF). After that, the rats underwent an intraventricular infusion of phenobarbital using a dwelled cannula, and the onset time of the phenobarbital-induced general anesthesia was determined. In addition, their brain tissues were excised and cerebral cortices were collected. Then, subcellular fractions were prepared and the cerebral expression of various proteins involving the anesthetic effects of phenobarbital was examined. It was demonstrated that phenobarbital induced general anesthesia about 2 times faster in rats receiving the DHF treatment than in control rats, and that the phenobarbital amount in the brain tissue at the onset time of anesthesia was lower in rats with the treatment. Western blotting showed that the cerebral protein expression of KCC2 decreases, and the phosphorylation of the TrkB protein increases with the DHF treatment. These observations indicate that the anesthetic effects of phenobarbital potentiate with the TrkB stimulation and the resultant decrease in the cerebral KCC2 protein expression. The results also suggest that the TrkB protein and its phosphorylation status may be a key modulator of the pharmacological efficacy of phenobarbital.

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    Tropomyosin receptor kinase B (TrkB) may be a key modulator of the pharmacological effects of barbiturates. Suzuki, et al., used a TrkB agonist 7,8-dihydroxyflavone (DHF) in the animal study for phenobarbital-induced general anesthesia, demonstrating that rats receiving the DHF pretreatment readily fell into anesthesia in a shorter time than those without the pretreatment. They then showed that DHF promotes the TrkB to be phosphorylated and that the protein expression of the potassium chloride transporter KCC2 was consequently suppressed. It was thus revealed that DHF potentiates the pharmacological effects of phenobarbital as it causes the functional activation of the TrkB.

  • Keisuke Ikegami, Megumi Saito, Shungo Imai, Hayato Kizaki, Osamu Yasum ...
    2023 年 46 巻 1 号 p. 95-101
    発行日: 2023/01/01
    公開日: 2023/01/01
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    To prevent denosumab-induced hypocalcemia in patients with renal dysfunction, combination therapy with 1α,25-dihydroxy-vitamin D3 (active vitamin D) is recommended. We previously developed a risk prediction model for hypocalcemia in patients with cholecalciferol/calcium (natural vitamin D). However, the prescription status and the risk factors of patients with active vitamin D have not been identified, so we designed this retrospective observational study using a large practice database covering June 2013 to May 2020 to analyze prescription status and risk factors. Patients were classified according to vitamin D type. After that, factors associated with development of hypocalcemia in patients with active vitamin D were explored. Univariate analysis was conducted to compare patient backgrounds between the hypocalcemia and non-hypocalcemia groups. Receiver operating characteristic analysis was conducted to evaluate the predictive potential of the extracted factors. Of the 33442 patients who received denosumab, 22347 and 3560 patients were co-administered natural and active vitamin D, respectively. Patients with active vitamin D had significantly lower renal function (estimated glomerular filtration rate (eGFR) median: 74.0 vs. 69.7 mL/min/1.73 m2), but some patients (23.6%) with sufficient renal function (eGFR ≥90) were also receiving active vitamin D. Of the 3560 patients with active vitamin D, non-hypocalcemia (n = 166) and hypocalcemia (n = 17) groups who met the study criteria were analyzed. Renal function was lower in the hypocalcemia group, and alkaline phosphatase gave the best discrimination. High aspartate aminotransferase (AST), renal dysfunction, high alkaline phosphatase (ALP), and low hemoglobin may be significant factors in risk prediction for hypocalcemia in patients with active vitamin D.

  • Zijian Zhou, Kazuki Nagayasu, Hisashi Shirakawa, Shuji Kaneko
    2023 年 46 巻 1 号 p. 102-110
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Peripheral neuropathy is one of the major adverse effects that limit the clinical application of bortezomib (BTZ). However, the underlying mechanisms of BTZ-induced peripheral neuropathy (BIPN) remain elusive. To examine cell types potentially involved in the development of BIPN, we used four purified cultures of cells of the peripheral nervous system: Schwann cells (SCs), satellite glial cells (SGCs), macrophages, and dorsal root ganglion (DRG) neurons. Administration of a low BTZ concentration (5 nM; similar to concentrations in clinical use) caused dedifferentiation of cultured SCs, returning mature SCs to an immature state. In cultured SGCs, BTZ increased glial fibrillary acidic protein (GFAP) levels without inducing the release of inflammatory cytokines or chemokines. In macrophages, BTZ caused little inflammatory response. Finally, in DRG neurons, BTZ strongly suppressed the expression levels of sensor and transducer ion channels without affecting cell morphology. Taken together, low concentrations of BTZ can cause SC dedifferentiation (i.e., demyelination), increased GFAP level in SGC, and decreased expression levels of sensor and transducer ion channels in DRG neurons (i.e., numbness feeling). Thus, we have reported, for the first time, specific effects of BTZ on peripheral nervous system cells, thereby contributing to a better understanding of the initiating mechanism of BIPN.

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    Bortezomib is widely used in treating multiple myeloma, but causes serious adverse effects, such as peripheral neuropathy, leading to discontinuation of Bortezomib treatment. To explore the mechanism, the authors, unlike previous reports, applied relatively low concentrations of bortezomib at clinical concentration, to primary cultured Schwann cells, satellite glial cells, macrophages, and dorsal root ganglion neurons. The results showed that bortezomib caused Schwann cell dedifferentiation, increased GFAP levels in satellite glial cells without inducing inflammatory responses, and decreased ion channel expression in dorsal root ganglion neurons. This may explain the mechanism of bortezomib-induced peripheral neuropathy.

  • Takuya Hirao, Beak Gyu Kim, Hinako Habuchi, Kotoku Kawaguchi, Takashi ...
    2023 年 46 巻 1 号 p. 111-122
    発行日: 2023/01/01
    公開日: 2023/01/01
    [早期公開] 公開日: 2022/11/10
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    Ependymal cilia play pivotal roles in cerebrospinal fluid flow. In the primary culture system, undifferentiated glial cells differentiate well into ependymal multiciliated cells (MCCs) in the absence of fetal bovine serum (FBS). However, the substances included in FBS which inhibit this differentiation process have not been clarified yet. Here, we constructed the polarized primary culture system of ependymal cells using a permeable filter in which they retained ciliary movement. We found that transforming growth factor-β1 (TGF-β1) as well as Bone morphogenetic protein (BMP)-2 inhibited the differentiation with ciliary movement. The inhibition on the differentiation by FBS was recovered by the TGF-β1 and BMP-2 inhibitors in combination.

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    Ependymal cilia on the ventricular surface play pivotal roles in cerebrospinal fluid flow. Authors newly constructed the polarized primary culture system of ependymal multiciliated cells (MCCs) from undifferentiated glial cells using a permeable filter in which they retained ciliary movement. Fetal bovine serum (FBS) on the ventricular side of culture inhibited the differentiation with ciliary movement. Transforming growth factor-b1 (TGF-b1) and Bone morphogenetic protein (BMP)-2 mimic the inhibitory action of FBS. The inhibition on the differentiation by FBS was recovered by the TGF-b1 and BMP-2 inhibitors in combination. Taken together, TGF-b1 and BMP-2 are found to be major inhibitors in the differentiation of ependymal MCCs.

Notes
  • Fumitaka Kawakami, Motoki Imai, Shun Tamaki, Etsuro Ohta, Rei Kawashim ...
    2023 年 46 巻 1 号 p. 123-127
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Mutations in leucine rich-repeat kinase 2 (LRRK2) cause autosomal-dominant, late-onset Parkinson’s disease (PD). Accumulating evidence indicates that PD-associated LRRK2 mutations induce neuronal cell death by increasing cellular reactive oxygen species levels. However, the mechanism of increased oxidative stress associated with LRRK2 kinase activity remains unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects cells from oxidative stress by inducing the expression of antioxidant genes. In the present, it was found that decreased expression of Nrf2 and mRNA expression of its target genes in Lrrk2-transgenic mouse brain and LRRK2 overexpressing SH-SY5Y cells. Furthermore, knockdown of glycogen synthase kinase-3β (GSK-3β) recovered Nrf2 expression and mRNA expression of its target genes in LRRK2 overexpressing SH-SY5Y cells. We concluded that since Nrf2 is transcriptional factor for antioxidative responses, therefore, reduction of Nrf2 expression by LRRK2 may be part of a mechanism that LRRK2-induces vulnerability to oxidative stress in neuronal cells.

  • Asami Funaki, Ikkou Hirata, Hiroki Matsui, Tatsuya Isezaki, Ryohkan Fu ...
    2023 年 46 巻 1 号 p. 128-132
    発行日: 2023/01/01
    公開日: 2023/01/01
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    Biosimilars (BS) are promoted worldwide because of the high cost of biologics. However, patients are apprehensive about switching to BS. For some diseases, several factors, which may be disease-dependent, influence patients’ acceptance of switching to BS. Herein, we evaluated whether factors influencing acceptance for switching were disease-dependent among Japanese patients with different diseases. This cross-sectional study involved pharmacists’ interviews with patients who used or planned to use biologics. Demographic and clinical characteristics were retrospectively investigated using the patients’ medical records. Multivariate logistic regression showed that switch refusal was associated with a history of adverse reactions to biologics (odds ratio [95% confidence interval (CI)] = 3.38 [1.35–8.44]), history of complaints related to disease activity (3.57 [1.53–8.32]), and unacceptability of generic drugs (7.62 [2.70–21.60]). Subgroup analyses suggested that the unacceptability of generic drugs was a common factor, regardless of the disease. Concomitantly, histories of adverse reactions to biologics and complaints related to disease activity were disease-dependent factors. Healthcare professionals should help patients in selecting BS, considering these factors according to the disease.

  • Haruhito Hiiro, Tatsuki Hashimoto, Makoto Mizoguchi, Mika Kaneko, Nano ...
    2023 年 46 巻 1 号 p. 133-137
    発行日: 2023/01/01
    公開日: 2023/01/01
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    The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the contractile force of papillary muscles with different potencies: the potency order was propafenone > aprindine > cibenzoline > flecainide > ranolazine > disopyramide > pilsicainide > mexiletine > GS-458967. The potency of drugs correlated with the reported IC50 values to block the L-type Ca2+ channel rather than the Na+ channel. The effects of drugs were roughly the same when examined under a high extracellular K+ solution, which inactivates the Na+ channel. Furthermore, the attenuation of the extracellular Ca2+-induced positive inotropy was strong with propafenone, moderate with cibenzoline, and weak with pilsicainide. These results indicate that the negative inotropic effects of class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca2+ channel.

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