preventing the structural destruction of joints, particularly bone and
cartilage, which progresses due to resistance to conventional anti-inflammatory
drugs, is one of the unmet medical needs in the treatment of rheumatoid
arthritis (RA). In this study, the authors investigated the therapeutic effects
of JTE-952, a novel colony-stimulating factor-1 receptor (CSF1R) kinase
inhibitor, on methotrexate-resistant joint destruction using a rat model of RA,
adjuvant-induced arthritis. Blocking CSF1/CSF1R signaling with JTE-952 did not
suppress paw swelling under inflammatory conditions, but it did suppress the
destruction of joint structural components, including bone and cartilage, in
inflamed joints and may improve subsequent joint dysfunction.
Fast-to-slow fiber transition in skeletal muscle occurs
during aging and has been implicated in muscle atrophy in sarcopenia, but the
mechanism is unclear. Authors showed that metallothionein 1 and 2 gene knockout
(MTKO) using the CRISPR-Cas9 system promoted to myogenic differentiation of
C2C12 myoblasts, which was accompanied by an increased number of slow-twitch
myotubes. The increased slow-type myotubes in MTKO cells was inhibited by an
antioxidant N-acetylcysteine, suggesting that MT may be involved in
specification of skeletal muscle fiber-type due to its antioxidant capacity. This
study may help to elucidate the mechanisms of age-related muscle weakness.
In Japan, the move towards
non-prescription emergency contraceptives is under discussion. A nation-wide
survey of 4,631 women conducted by the authors revealed that nearly half of
them lacked accurate knowledge about emergency contraceptives. Total of 43.6%
of women with previous experience needing emergency contraceptives chose not to
use them voluntarily. To address this, the authors emphasize the importance of
comprehensive sex education, and promoting understanding of emergency
contraceptives among women in Japan.
Microneedles are microscopic needle
structures with lengths of several hundred micrometers, and have
attracted attention as one way to improve skin barrier and moisturizing
functions as cosmetic product. However, conventional
microneedles are thought to work by penetrating the stratum corneum, which carries
the risk of side effects. Therefore, in this study, the authors applied
microneedles non-invasively without penetrating the stratum corneum and
investigated their effects on the skin. The results showed that microneedles
can improve skin barrier and moisturizing functions even when applied non-invasively.
This study provides valuable insights for the development of new cosmetic techniques
The activity of Cav3.2 T-type calcium channels expressed
in the sensory neurons is reduced by physiological concentrations of zinc. Sulfides
including hydrogen sulfide (H2S), a gasotransmitter, enhance the channel
activity by removing zinc from Cav3.2, leading to the increased pain
sensitivity. Dietary zinc deficiency causes Cav3.2-dependent mechanical
allodynia in mice. Exogenously applied sulfides produce Cav3.2-dependent
allodynia in the mice fed with normal diet, but do not affect the already
developed allodynia in the mice fed with zinc-deficient diet. Thus, the authors
suggest that the enhanced Cav3.2 activity participates in the development of
pathological pain associated with zinc deficiency.
Bortezomib-induced peripheral neuropathy
(BIPN), an adverse effect of chemotherapy, can cause patients to suffer from
neuropathic pain and lead to drug withdrawal. The authors attempted to explore
effective therapeutic targets for BIPN by combining real-world data analysis
with in vivo experiments. In the analysis of self-reported adverse event data, mechanistic
target of rapamycin (mTOR) inhibitors reduced the incidence of peripheral
neuropathy in bortezomib-treated patients. In bortezomib-treated mice, mTOR
inhibitors or an inhibitor of ribosomal protein S6 kinase 1 (S6K1), a
downstream molecule of mTOR complex 1, showed transient analgesic effects.
These results suggest that S6K1 may be a therapeutic target for BIPN.
The authors established
an ambulatory care pharmacy practice that enables pharmacist–urologist
collaboration for the treatment of patients with urologic cancer taking oral
anti-cancer medications. In this manuscript, the
authors sought to investigate the usefulness of pharmacist-urologist
collaboration, considering the potential confounding factors, for patients with
renal cell carcinoma treating pazopanib monotherapy. The results showed that
the time to pazopanib discontinuation was significantly prolonged after the
implementation of collaborative management by analyzing the multivariate Cox
proportional hazards model. These results clearly indicated that the
effectiveness of pharmacist-led team care in pharmacotherapies.
extracellular vesicles (sEVs) have been of interest as a drug delivery system
(DDS) for various disease treatments, as they possess some advantages in drug
delivery. However, certain issues in drug encapsulation, such as low
encapsulation efficiency and poor reproducibility, are needed to be addressed.
Herein, a new drug encapsulation approach has been developed which utilizes
membrane fusion of sEVs and drug encapsulated liposomes composed of
phosphatidylserine via the calcium fusion method. The fused-nanoparticles
achieved efficient doxorubicin encapsulation as well as increased cellular
uptake of liposomes. The present findings are expected to be applied for
encapsulation of other therapeutic modalities into sEVs and development of
The anticancer drug oxaliplatin (OXA) is associated
with peripheral neuropathy as a side effect accompanied by mechanical and cold
allodynia. Authors aimed to record and compare
the firing of neurons in the deep and superficial layers of the spinal dorsal
horn (SDH) in rats treated with a single dose of OXA. Authors
comparison of neuronal firing frequencies carried out in the present study of a
CIPN rat model treated with a single dose of OXA revealed that pain pathology
is reflected more strongly by the superficial than by the deeper layer of the
(PGx) testing can predict therapeutic responses or adverse effects based on
genetic variants and is expected to be the preemptive precision medicine for patient
management. Tramadol is metabolized by CYP2D6 to an active
metabolite, which in turn acts as an analgesic. From the retrospective cohort
study in Japanese patients with postoperative pain after orthopedic
arthroscopic surgery, the authors demonstrated that the
analgesic effect in the early postoperative period was depended on CYP2D6 gene polymorphism.
These results suggested the clinical utility of preemptive treatment based on
the PGx test, which can consider dose adjustment or drug change in advance.
TRP ankyrin 1 (TRPA1) is present in the
afferent sensory neurons and is activated by food-derived ingredients, such as
Japanese horseradish, cinnamon, and garlic. The present study aimed to
investigate the expression of TRPA1 in taste buds, and determine its functional
roles in taste perception using TRPA1-deficient mice. TRPA1-immunoreactivities
are detectable in the taste nerve. TRPA1 deficiency significantly reduced sweet
sensitivity compared to that in WT mice as per the two-bottle preference tests.
Authors found that TRPA1 in the taste nerve contributes to the sense of sweet
taste in mice.
Allergic contact dermatitis is a common
dermatitis and is induced by contact with allergens. The authors found that
methionine suppressed this dermatitis in some strains of mice. They also found
that the strength of the effect depended on the suppression of liver betaine
homocysteine methyltransferase (Bhmt) expression by the dermatitis.
Although the mechanism has not been elucidated, the authors propose that while
dermatitis suppresses liver Bhmt expression in some strains of mice, the
fact that the metabolic state of the liver affects the suppression of
dermatitis suggests that there is at least a skin-liver interaction, especially
a dermatitis-liver interaction.
This study aimed to investigate the
mechanism underlying the skin pigmentation caused by anticancer drugs using
5-fluorouracil (5-FU), a widely used anticancer drug known to cause this
complication. Authors believe our study makes a significant contribution to the
literature because anticancer drug-induced skin pigmentation remarkably affects
the quality of life of cancer patients, has no established treatment, and has
an unknown mechanism. This result provides new insight into the role of the
ACTH/cAMP/tyrosinase pathway in 5-FU-mediated skin pigmentation and may help
manage this complication.
dehydrogenase type 1 (11β-HSD1) is the only enzyme that converts inactive
glucocorticoids to active forms and plays an important role in regulating
glucocorticoid action in target tissues. Excess glucocorticoids cause insulin
resistance in the liver and adipose tissue. Several 11β-HSD1 inhibitors have
been reported, but all have been evaluated in obese diabetes models. In the
present study, the authors investigated the pharmacological properties of
JTT-654, a selective 11β-HSD1 inhibitor, in cortisone-treated rats and
non-obese Goto-Kakizaki rats with type 2 diabetes, because many Asians,
including Japanese, have non-obese type 2 diabetes. Information gained from
detailed analysis of the mechanism of action of JTT-654 may provide a new therapeutic
approach for the treatment of non-obese type 2 diabetic patients.
typical manifestation of iatrogenic injury associated with intravenous
injection is extravascular leakage. The severity of injury and treatment for
extravascular leakage of cytotoxic agents is well known, however there is
insufficient information on non-cytotoxic agents. The authors reviewed human
and animal studies of extravascular injury induced by non-cytotoxic agents and
classified them based on the severity of injury. The classification of
non-cytotoxic agents in the extravasation is useful information in clinical
practice to provide appropriate warning of the risk of injury and to prevent worsening
Recently, evidence is accumulating on functional
communication between the central nervous system (CNS) and the gut microbiota. Given
this, early prebiotic treatment may assist the development of the CNS through
the gut microbiota. In this study, Araki et al. found that 2'-fucosyllactose (2´-FL),
a human milk oligosaccharide, altered the fecal microbiota and reduced
anxiety-like behavior and amygdala hyperactivity observed in mice exposed to
early weaning stress. These findings suggest that prebiotic treatment with
2´-FL may alleviate the adverse effects of early life stress in the CNS such as
anxiety and amygdala hyperactivity.
It is believed that
15-lipoxygenase plays a role in tissue damage under conditions of low oxygen
levels through lipid-derived radical chain reactions. The authors of this study
discovered that when a
higher content of linoleate than oxygen content was stood with 15-lipoxygenase
in the presence of hydrogen polysulfides, which are believed to be endogenous
bioactive substance in cells, the conjugated diene moiety of the oxidized
linoleate derivatives was isomerized from E/Z form to E/E form.
Based on these findings, authors proposed a hypothesis that hydrogen
polysulfides scavenge lipid-derived radicals, generating thiyl radicals, which
then isomerized the conjugated diene moiety.
Lactic acid bacteria (LABs) are well known
as beneficial microorganisms to maintain human health. Although LABs are recognized
as probiotics, these bacteria produce many kinds of bioactive compounds. The
mechanisms how LABs produce these bioactive substances are not well known. Additionally,
unlike the cases of E. coli and yeast, there are not enough commercially
available tools for a genetic approach of LABs. Therefore, in the present
study, the authors have constructed a new plasmid as an efficient genetic
engineering tool for random insertional mutagenesis in LABs using a combination
of transposon Tn10 and the temperature-sensitive replication system.
the potential for cytochrome P450 2C9 (CYP2C9) to cause drug interactions,
there are few cases of information
related to the influence of CYP2C9 polymorphism on drug labeling
recommendations in Japan. Among the various
factors related to adverse events in the database associated with the
prescription of celecoxib or diclofenac alone, variations in the in vivo intrinsic
clearance of the drug may exist. Virtual hepatic and plasma exposures estimated
modeling in patients harboring impaired CYP2C9*3 could represent a
causal factor for adverse events induced by celecoxib or diclofenac in a manner
similar to that for drug interactions.
Recent improvement of pharmacotherapy on
cancer is remarkable, however cancer is still one of the most devastating
diseases for patients and their caregivers. The authors compared the
development and approval status of first-in-class (FIC) anticancer drugs
between the US, EU, and Japan, and found that approval in Japan lagged
substantially behind compared to the other regions (more than 1 year vs the EU
and more than 2 years vs the US). Considering the high impact of anticancer
drugs on society worldwide, we should work together to reduce drug lag among
regions using an improved international cooperative framework.