This review describes the chronotherapeutic
strategies based on molecular clock system of chronopharmacokinetic,
chronopharmacodynamic and cancer chronopathological factors in the xenobiotic
detoxification, transporter, receptor and molecular target. Chronotherapeutic strategies focus on the monitoring of rhythm, overcoming rhythm disruption,
manipulation of rhythm, chrono-therapeutic drug monitoring, chrono-drug delivery system and chrono-drug discovery. The screening for small molecules targeting
the clock genes is now in progress to stabilize circadian phase and enhance
circadian amplitude, thereby consolidating and coordinating circadian
The academic research along with a combination of chemical and biological
information is essential to promote the research and development of new
modality drug discovery such as clock genes.
a melatonin receptor agonist, has a sleep-promoting effect by modulating sleep-wake
rhythms. To examine the effect of ramelteon on cardiac function, authors simultaneously
recorded electrocardiograms, electromyograms, and electrocorticograms in the
frontal cortex and the olfactory bulb of unrestrained rats treated with
ramelteon. Authors demonstrated that during non-REM sleep, heartrate
variability was maintained by ramelteon treatment. Analysis of the
electromyograms confirmed that neither microarousal during non-REM sleep nor
the occupancy of phasic periods during REM sleep was altered by ramelteon. Thus,
authors propose a remedial effect of ramelteon on cardiac activity by keeping
Numerous studies have confirmed that the
sFlt1/PlGF ratio is a good predictor of the signs and symptoms of Pre-Eclampsia.
However, its usefulness is limited to diagnosis after 20 weeks of gestation. To
address this issue, in the present study the authors used plasma samples
collected at gestational weeks 14-24 weeks from subjects who were subsequently
diagnosed as Pre-Eclampsia. By employing SWATH-based proteomics for
comprehensive discovery and SRM-based target quantification using in silico
peptide selection criteria for validation, the authors were able to identify a
3-protein combination biomarker (AFAM, FINC and SHBG) that can predict
effectively during gestational weeks 14-24 whether pregnant women would
subsequently develop Pre-Eclampsia.
Cisplatin is an
effective anti-cancer drug. A serious major side effect of cisplatin is an
acute kidney injury. The authors demonstrated that panduratin A, a bioactive
flavonoid, ameliorates cisplatin-induced nephrotoxicity by inhibition of cell
apoptosis. The renoprotective effect of panduratin A is mediated by reducing
oxidative stress and inhibiting ERK1/2 and caspase 3 activations. The
protective effect of panduratin A did not impair the anti-cancer activity of
cisplatin in cancer cells. Panduratin A might be a good candidate agent to
alleviate cisplatin’s nephrotoxicity.
Influenza causes nosocomial outbreaks in healthcare
settings. Post-exposure prophylaxis (PEP) for healthcare workers is one of the
effective strategies for preventing outbreaks of influenza. However, PEP
adherence in healthcare workers is rarely analysed. This retrospective questionnaire-based study showed
that the adherence to PEP among healthcare workers was low, especially among
physicians, and that the primary factor for preventing PEP adherence was misguided
self-decision that continuation of PEP was unnecessary. This study emphasized
that medication education should be provided to ensure treatment compliance and
maximize the therapeutic benefits of PEP when PEP is administered.
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.