About
the cover: Cellular Ca2+ signaling functions as one of the most
common second messengers
of various signal transduction pathways in cells and mediates various physiological
roles depending on cell-types and their excitability. Among ion channels, Ca2+-permeable
channels in the plasma membrane as well as endo- and sarcoplasmic reticulum
membranes play important roles in cellular Ca2+ signaling. Ca2+-gated
ion channels indicated by the star (★) often crosstalk reciprocally with Ca2+
signals and are central to the regulation of cellular functions. Ca2+-gated ion channel works as a converter
of Ca2+ signals to propagative electrical signals and plays key
roles in the opposite feedback regulation of Ca2+ signaling in
excitable and non-excitable cells.
Imatinib mesylate is a potent tyrosine kinase
inhibitor. It is known that in addition to targeting the oncogenic
drivers, the immune system plays an important role in exerting therapeutic
effects of imatinib and restraining the emergence of escape mechanisms. However, its influence on the recruitment of effector
T cells into the tumors has not been investigated. Authors found that imatinib
significantly enhanced the expression of CD8 T cell-recruiting cytokine genes,
leading to antitumor effects, which was dependent on the tumor type. This study
elucidated a
new mechanism of antitumor immunity induced by imatinib.
Glycosides are often included as active ingredients
in natural medicines. Many glycosides are highly water-soluble, and they are
metabolized by intestinal bacteria before being absorbed in the digestive
tract. Glycyrrhizic acid (GL), one of the main components of yokukansan, is a
glycoside that is metabolized by intestinal bacteria to glycyrrhetinic acid
(GA). This study investigated the gut microbiota compositions and
pharmacokinetics of GL in yokukansan. The results suggest that oral antibiotics
affect the plasma level of GA, and that the blood level of GA changes depending
on the gut microbiota composition.
Toxicological profiles of chemicals have been investigated in rodents, but
new alternative methods to evaluate compound safety are being developed
worldwide using in silico approaches. Physiologically based
pharmacokinetic (PBPK) modeling has the potential to play significant roles in
estimating internal chemical exposures. The authors generated three major PBPK
model input parameters (i.e., absorption rate constants, volumes of the systemic
circulation, and hepatic intrinsic clearances) for chemicals using machine
learning algorithms. The input
parameters for humans of compounds can be reliability estimated using chemical
descriptors calculated using in silico tools for illustrating virtual maximum
plasma concentrations and areas under the curve.
This report reveals that
monolayers of human liver-derived cell lines grown on a membrane exhibit
directional transport, i.e. efflux transport of a substrate of multidrug
resistance-associated protein 2 (MRP2). The transport was suppressed by an MRPs
inhibitor, supporting the idea that MRP2 is the primary mediator of directional
transport. The advantage of this system is its potential to quantitatively
evaluate biliary excretion of MRP2 substrates in vitro. The assay system may
therefore be utilized for the screening of biliary excretion drugs and for
investigating the hepatotoxicity of candidate drugs.