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.
The authors investigated weather difference
ointment bases (absorbent cream, white-, and macrogol-ointment) affect the skin
wound healing rate in normal and diabetic models (streptozotocin-induced rat, STZ
rat). The wound healing rate was similar in the normal rat treated with
three-bases. In contrast of this result, the wound healing in STZ rats treated
with macrogol-ointment was delayed in comparison with other two-bases. These
results indicate that the wound healing in STZ rats is affected by the
properties of ointment base, and the selection of appropriate ointment base
according to the skin condition may be important for the wound healing in
patients with diabetes.
A loop-mediated isothermal amplification
(LAMP)-mediated screening detection method for genetically modified (GM) papaya
was developed using a Genie II real-time fluorometer. The authors also designed
a primer set for the detection of the papaya endogenous reference sequence,
chymopapain, and the species-specificity was confirmed. To enhance the
simplicity, the authors attempted to develop a lateral flow DNA chromatography
to detect LAMP products, and a duplex detection was successfully applied. This
simple and quick method for the screening of GM papaya will be useful for the
prevention of environmental contamination of unauthorized GM crops.
The
author found that bio-ventures established in the 1990s and 2000s played a
crucial role in creating new drugs approved by the FDA from 2017 to 2022 in
regions outside of Japan. In contrast, in Japan, all approved drugs were
created by old incumbent pharmaceutical companies, highlighting the urgent need
to foster drug discovery start-ups in Japan. A case study of the Japanese
company that created the largest number of FDA-approved drugs suggests that
focused investment in modality technology development, strengthening
collaboration with academia in biology, and the reutilizing small-molecule drug
discovery capabilities are essential for improving drug discovery productivity.
High
cholesterol concentration can promote the growth of prostate cancer. Methyl
protodioscin (MPD), a furostanol saponin found in the rhizomes of
Dioscoreaceae, has lipid-lowering and broad anticancer properties. In this
research, MPD decreased expression of SREBP1 and SREBP2 by
inducing FOXO1, lead to the induction of the expression of cholesterol export
pump ABCA1 and reduction of the expression of the rate-limiting enzyme
of cholesterol synthesis HMGCR. Reduced cholesterol caused to disrupted
lipid rafts and MAPK pathway on it, contributing to MPD anti-prostate cancer
activity. Consequently, MPD may be used as an active drug for treatment in
prostate cancer.
The authors described prescription trends
of the antidiabetic agents used to treat type 2 diabetes mellitus (T2DM) in
Japan from 2012 to 2020 using administrative claims data. Noteworthy, this
study examined the prescription trends in every line for T2DM treatment,
including the combinations of antidiabetic agents, and showed that
sodium-glucose cotransporter-2 inhibitors were rapidly introduced into T2DM
treatment from several perspectives. Such a descriptive study revealed how T2DM
treatment changed in accordance with cumulated evidence and can provide
interesting information on public health.
The polyphenol derivative
3,4-dihydroxybenzalacetone (DBL) is the primary antioxidative component of the
medicinal folk mushroom Chaga. The authors investigated whether the antioxidative effect of DBL could propagate to
recipient cells using extracellular vesicles (EVs)-enriched fractions prepared
by sucrose
density gradient ultracentrifugation from conditioned medium of SH-SY5Y cells exposed
to hydrogen peroxide after
pre-exposing DBL. The results obtained from cell-based tests including
the radical scavenging and the fluorescent Paul Karl
Horan-labeled EVs uptake assays suggest that cell-to-cell
communication via bioactive substances, such as EVs propagate
the hydrogen
peroxide-induced radical scavenging effect, whereas
pre-conditioning with DBL inhibits it.
Protection against impaired insulin secretion and β-cell
apoptosis is an important strategy to prevent the progression of type 2 diabetes.
The authors have reported the effects of apigenin, a dietary trihydroxyflavone,
on pancreatic β-cell functions, underlying its anti-diabetic effects. The study
demonstrated that apigenin exerts insulinotropic and anti-apoptotic effects in
the β-cell line INS-1D. The anti-apoptotic effect of apigenin was further supported
by reduced expression of apoptotic signaling proteins and pro-apoptotic protein.
The results suggest and provide a basis for the development of apigenin as a
potential therapeutic for type 2 diabetes through promoting β-cell survival and
function.
Studies have reported an association
between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis in
patients with melanoma treated with ipilimumab. However, it remains unclear
whether NLR is useful in Japanese. Authors retrospectively examined 38 patients,
and found that baseline NLR>3.4 was an independent risk factor for
ipilimumab discontinuation that was significantly associated with shorter
progression-free survival. Because the NLR cut-off value in this study was lower
than values in American and European studies, it possibly differs by race.
Hence, it should be extrapolated to Japanese patients with caution.
This investigation of the impact of
antiseizure medications (ASMs) on hospital transfer was undertaken because
chronic-care hospitals have refused to accept several post-stroke epilepsy
patients using novel ASMs from acute-care hospitals. Patients with stroke
receiving novel ASMs, i.e., perampanel and lacosamide, had longer times to
hospital transfer than patients receiving other ASMs. Furthermore, a weak
correlation was found between the cost of a patient's daily medications and the
number of days to hospital transfer. These results indicate that considering
the availability and cost of ASMs in the transfer destination hospital is
important when choosing medications for patients requiring hospital transfer.
The authors found that
amentoflavone, apigenin, kaempferol, and chrysin enhanced the activity and
expression of neprilysin, one of the major Aβ-degrading enzymes, by screening a
polyphenol library, and that chemical structures involving a double bond
between positions 2 and 3 in the C ring of flavones were important for neprilysin
enhancement. Moreover, natural compounds, such as quercetin, were not effective
per se, but were changed to effective compounds by adding a lipophilic
moiety. These findings provide a basis for the development of novel small
molecules as disease-modifying drugs for Alzheimer’s disease.
Oxaliplatin is a platinum (Pt)-based chemotherapeutic
drug that is widely used to treat gastrointestinal and pancreatic cancers. The
authors hypothesized that the DNA-binding capacity
is one of the properties of reactive Pt species and aimed to evaluate the
contribution of the kidney to the plasma levels of DNA-reactive Pt in an animal
model and a hemodialysis patient. The results of this
study showed that severe renal dysfunction has a limited effect on the plasma
levels of DNA-reactive Pt after oxaliplatin administration.
Vascular damage is often seen in patients
with diabetes and is thought to be caused by oxidative stress. Xanthine
oxidoreductase exists both intracellularly and extracellularly and causes
vascular injury by producing reactive oxygen species. The authors investigated
the effects of topiroxostat, a xanthine oxidase inhibitor, and its mechanism of
action in a rodent model of diabetes. They found that topiroxostat inhibited
anchored xanthine oxidase bound to the surface of vascular endothelial cells in
the thoracic aorta and suppressed damage to these cells, suggesting that
topiroxostat could potentially have a vasoprotective effect in patients with
diabetes-induced macrovascular disease.
mRNA has
many challenges including insufficient delivery owing to the high molecular
weight and high negative charge. Authors chemically synthesized a minimal mRNA
vaccine encoding human gp10025-33 peptide (KVPRNQDWL), as a
potential treatment for melanoma and iontophoresis (IP) was used for its
delivery into the skin. After combining IP with the newly synthetized minimal
mRNA vaccine, successful intradermal and intracellular delivery of the minimal mRNA
was achieved. Results showed stimulation of the immune system which led to tumor
inhibition and infiltration of cytotoxic CD8+ T cells in the
tumor tissue. This is the first report combining IP and chemically synthesized minimal
mRNA vaccine.
Cholinergic
neurons in the basal forebrain are known to degenerate early stage of
Alzheimer's disease (AD), and amyloid-β (Aβ) oligomers are suggested to be deeply
involved in AD pathogenesis. Authors
here established an Aβ oligomer-induced neurodegeneration model using human
induced pluripotent stem cell-derived cholinergic neurons and demonstrated the
neuroprotective effect of plantainoside B identified from herbal extracts as an
Aβ-binding small molecule. Radioisotope-labeled plantainoside B showed
affinities to Aβ oligomers and brain sections from a mouse model of AD. Results
suggest the potential of developing “theranostics” in AD that simultaneously performs
diagnoses (Aβ detection) and therapy (neuroprotection).
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. 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.
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.
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.