The article by Nomura et al. suggested a
novel mechanism of radiation-induced DNA damage repair contributing to
radioresistance in melanoma. Authors have shown that the transient receptor
potential melastatin 8 (TRPM8) channel is involved in radiation-induced DNA
damage response, cell death, and cell cycle regulation. Furthermore, TRPM8
channel inhibitor enhanced tumor growth-inhibitory effect by gamma-ray in
vivo. These findings proposed that the TRPM8 channel contributes to the resistance
of the growth-inhibitory effect of radiation in melanoma and could be a novel
molecular target to improve the efficiency of radiation therapy for melanoma.
proliferator-activated receptor ɤ (PPARɤ) agonists, such as pioglitazone, are
anti-diabetic drugs, but they cause PPARɤ-related adverse effects such as body weight
gain, cardiac hypertrophy, and bone loss. The authors found that
a novel PPARɤ modulator,
KY-903, has similar anti-diabetic
effects without PPARɤ-related adverse effects in diabetic mice, possibly due
to increases in adiponectin without adipogenesis. KY-903 also has anti-obesity
effects with slight bone loss in obese rats, possibly by PPARɤ antagonism against endogenous or diet-derived
ligands. These findings are useful for research on PPARɤ, and KY-903 is a potential candidate of
anti-diabetic and/or anti-obesity drugs.
The authors investigated the effects of
rivaroxaban on right ventricular (RV) remodeling in a rat model of pulmonary
arterial hypertension (PAH), created with Sugen5416 and chronic hypoxia (SuHx).
The Fulton index, RV systolic pressure, and RV Tei index increased by SuHx were
significantly decreased when treated with rivaroxaban. Rivaroxaban has the
potential of improving RV remodeling in PAH model rats through the suppression
of multiple signaling pathways, including ERK, JNK, and NF-kB,
associated with protease-activated receptor-2. These findings suggest the
additive effects that rivaroxaban may have on the RV remodeling in PAH.
The authors indicated
that the protonation of the histidine residue at the extracellular site in human
oligopeptide transporter (hPEPT1) results in a decrease in the efflux activity,
which is distinct from the sites of proton coupling for transport operation and
substrate binding. Furthermore, they found that the decrease in extracellular
pH reduced the turnover rate of transporters; in other words, the number of
available transporters in the cycle was reduced. The protonation/deprotonation state
of histidine determines the transport activity; the deprotonated histidine
residue can participate in the transport cycle, whereas the protonated histidine
residue can cease the transport.
fibrillation (AF) is one of the most frequent arrhythmias in patients with hypertension.
The authors found that an L/N-type calcium channel blocker cilnidipine exerts anti-AF
effects in the remodeled atria of Dahl salt-sensitive rats more potently than
amlodipine. Since plasma catecholamine levels is lower in the cilnidipine-treated
animals than those in amlodipine-treated ones, blockade of N-type calcium
channels presumably contributes to the superior cardioprotective effect of
cilnidipine. These findings provide important information for considering
treatment of hypertension complicating AF.
(FOS), typical nondigestible oligosaccharides, change the composition and/or
activity of microbiota in the large intestine. Intestinal microbiota has
important roles in the decomposition and fecal excretion of methylmercury
(MeHg). Fecal Hg excretion was markedly higher in FOS-fed mice than in controls
after oral administration of MeHg, but urinary Hg excretion was not. FOS-fed
mice had lower total Hg levels in all tissues (including the brain) than
possible mechanism on function of FOS is accelerated MeHg demethylation
by intestinal bacteria and reduced MeHg absorption in the large intestine.
Psoriasis is an
inflammatory skin disease characterized by red scaly papules or plaques. It has
been suggested that activation of immune cells such as T cells and abnormal
differentiation and proliferation of keratinocytes are involved in the
pathogenesis of psoriasis. IL-2-inducible T cell kinase (ITK) is a tyrosine
kinase expressed in T cells that regulates T cell activation. Authors showed
that topical application of BMS-509744, a selective ITK inhibitor, ameliorates
psoriasis-like inflammation in the skin of mice. This study suggests that ITK
inhibition in skin lesion is a promising candidate treatment for psoriasis.
Ketamine is known as a dissociative anesthetic that
suppresses the cerebral cortex and activates the limbic system, and is unique
as an anesthetic, since it induces blood pressure increase. Author examined the
effect of ketamine, applied directly to the amygdala, on blood pressure. The results showed that the blood
pressure was increased by ketamine injection into the basolateral and central nuclei of the amygdala, endopiriform nucleus and piriform
cortex. Elucidation of the mechanism of ketamine-induced blood pressure
increase will lead to understanding
of the mechanism of side effects of ketamine, and will contribute to its appropriate use.
The malignant potential of
neuroblastoma is associated with elevated expression of β4-galactosyltransferase (β4GalT) 3. The transcription of
gene is regulated by transcription factor Sp3 in SH-SY5Y human neuroblastoma
cell line, and Sp3 activates the β4GalT3 gene promoter. In this study, the authors demonstrated that the
transcriptional activation of the β4GalT3 gene is mediated by the mitogen-activated protein kinase
signaling, and the phosphorylation of the serine residues in Sp3 is important
for the transcriptional activation. The findings propose a therapeutic strategy
for the regulation of the β4GalT3 gene in neuroblastoma by controlling the phosphorylation of Sp3.
The authors evaluated the predictability of
various methods used to assess clinical CYP3A induction risk based on various
in vitro parameters, and demonstrated that correlation methods were better at
predicting clinical induction risk than direct methods recommended in guidance/guidelines.
Among correlation approaches, the Relative Factor (RF) and AUC/F2 methods showed
an especially good correlation with clinical induction, and can be used to
assess induction risk along with other correlation methods recommended in guidance/guidelines.
These findings may allow researchers to more confidently determine whether or
not a clinical induction study should be performed before clinical trials.
adipose tissue is characterized by increased immune cell infiltration.
Adipocyte-immune cell interaction overproduces inflammatory adipokine, which
contribute to the development of type 2 diabetes mellitus. The regulation of
immune cells infiltration and inflammation in adipose tissue may exert preventive
and therapeutic effects on obesity-related diseases. Flavonoids such as
hesperidin have anti-inflammatory properties, but their low bioavailability
limits their use as drugs and supplements. The authors report that glucosyl
hesperidin (GH), a water-soluble derivative of hesperidin, ameliorated glucose
intolerance and reduced macrophage infiltration into adipose tissue in high-fat
diet-fed mice. These results suggest the usefulness of GH against
transient receptor potential canonical (TRPC) subfamily members, TRPC3 and
TRPC6, reportedly participate in the development of fibrosis in cardiovascular
and renal systems. This study is to investigate whether
TRPC3 and TRPC6 channels also contribute to the formation of nonalcoholic
steatohepatitis (NASH) which includes liver fibrosis, using TRPC3 or TRPC6
systemic knockout mice fed with the choline-deficient, L-amino acid-defined,
high-fat diet. The authors found that systemic deletion of TRPC3 or
TRPC6 gene alone failed to attenuate liver dysfunction and fibrosis in NASH
Aripiprazole (ARP), an antipsychotic
drug, binds strongly to site II on human serum albumin (HSA). In this study, the
issue of how uremic toxins (indoxyl sulfate, indole acetic acid and p-cresyl
sulfate) affect the binding of ARP to HSA were investigated. Authors
demonstrated that these uremic toxins inhibit the binding of ARP to diazepam subsite
within site II, and these inhibitory effects were more significant, comparing
with those on the drug binding to arylpropionic acids subsite. These findings
provide important information for considering the pharmacokinetics of ARP and
the drugs that bind to site II during renal diseases.
combining whole-brain activation mapping of neurons activated in response to
dopamine D1 and D2 receptor antagonists with non-bias analysis, Niu et al.
provide the direct evidence that the orbital
cortex in addition to the striatum are important brain areas associated with DA
antagonists-induced movement abnormality.
Transient receptor potential melastatin 3 (TRPM3)
is Ca2+-permeable channel that is highly expressed in the brain and activated
by the neurosteroid pregnenolone sulfate (PS) and body temperature. Here, it is
shown that TRPM3 was expressed in cultured rat oligodendrocyte precursor cells
(OPCs) and activated by PS, resulting in extracellular Ca2+ influx. Moreover, TRPM3 expression was increased by treatment with tumor
necrosis factor a. In demyelinated lesions
of endothelin-1-induced ischemic rat model (lacunar infarction model), TRPM3
was upregulated in OPCs, a type of glial cells that differentiate into myelinating
oligodendrocytes. These imply that TRPM3 is involved in the regulation of
specific behaviors of OPCs in inflammatory pathological conditions. Scale bar
shows 200 mm.
article by Kitabatake et al. suggested a novel mechanism of radiation resistance
and radiation-induced acquisition of malignant profile in glioblastoma. Authors
have shown that CD73, an enzyme that metabolizes extracellular ATP to adenosine,
and activation of adenosine A2B receptor (CD73-A2B receptor pathway) are
involved in radiation-induced DNA damage response, cell death, and enhancement of
cell migration in A172 cells. These findings proposed that the CD73-A2B
receptor pathway contributes to the resistance of the antitumor effect of
radiation in glioblastoma and could be a novel molecular target to improve the
efficiency of radiation therapy for glioblastoma.
Most of therapeutic peptides like insulin are administered parenteral
because of rapid hydrolysis and enzymatic degradation after oral
administration. Many techniques have been investigated for overcoming the
problems and meeting the shortage of current conventional dosage forms such as
iontophoresis.In this study, authors investigated if iontophoresis can be used to
enhance permeation of insulin nanoparticles across the intestinal membrane and
thus enhance the oral delivery of insulin.Gut iontophoresis is a promising technology that can substantially
improve the transport of insulin nanoparticles across the intestinal membrane
pH (pHe) characterized of tumor microenvironment (TME) impairs the responses of
tumors to anti-cancer chemotherapies. In this study, the authors showed that
daily oral dosing of sodium potassium citrate (K/Na citrate) increased blood bicarbonate
concentrations and then neutralized the tumor pHe. In addition, this tumor neutralization
potentiated the therapeutic effect of anticancer agent TS-1 on Panc-1
pancreatic cancer-xenograft murine model. The authors strongly propose that the
neutralization of acidic TME by oral dosing of K/Na citrate must be a smart
approach for enhancing the therapeutic effects of anticancer agents for
pancreatic cancer in the end stage.
5 has a particularly broad antibacterial spectrum, eliminates pathogenic
microorganisms and regulates intestinal flora. There are few reports of
measuring the secretory capacity of α-defensin 5 in vitro. In this
study, author found Caco-2 cells, which are gastrointestinal model cells, secreted
α-defensin 5 and examined the relationship between α-defensin 5 secretion and
cytokines mRNA levels such as TNF-α. These results suggest that Caco-2 cells
may be a simple model for screening health food components and drugs that
affect α-defensin 5 secretion.