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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Different Involvement of DNA Methylation and Histone Deacetylation in the Expression of Solute-Carrier Transporters in 4 Colon Cancer Cell Lines
Released on J-STAGE: March 01, 2012 | Volume 35 Issue 3 Pages 301-307
Mika Ikehata, Kumiko Ueda, Seigo Iwakawa
Views: 13,692
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: 3,366
Effects of Ashwagandha (Roots of Withania somnifera) on Neurodegenerative Diseases
Released on J-STAGE: June 01, 2014 | Volume 37 Issue 6 Pages 892-897
Tomoharu Kuboyama, Chihiro Tohda, Katsuko Komatsu
Views: 307