the present study, Ziyuglycoside II inhibits rotavirus (RV) induced diarrhea
via toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling
pathway. Ziyuglycoside II inhibited the proliferation of MA104 cells infected
with RV via suppressing RV duplication. The combination of Ziyuglycoside II and
Ribavirin protected against RV-induced diarrhea through regulating TLR4/NF-κB
signaling pathway. Moreover, the combined treatment suppressed the level of
pro-inflammation cytokines and overexpressed anti-inflammation cytokine.
Moreover, the combined therapy improved the lesion changes and inhibited the
cell apoptosis in vivo. Thus Ziyuglycoside II may function as protective role
in RV-induced diarrhea.
Polygonatum sibiricum first appeared in ancient Chinese medicine books around 1000 years ago
and is used to tonify the spleen and nourish the lungs. The authors present here a kind of natural polysaccharides (PSP) extracted
from Polygonatum sibiricum were purified, characterized and assayed both
in vitro and in vivo for its immunomodulatory activity and
mechanism. It is of interest to note that PSP not only regulated the immune
function of normal mice, but participated in the protection against
immunosuppression in cyclophosphamide-treated mice, highlighting its potential as an immunostimulant.
(3-(3,4-dihydroxyphenyl)-(2R)-lactic acid) is one of the water-soluble active
ingredients of Salvia miltiorrhizae, a
traditional Chinese medicine for the treatment of cardiovascular diseases. This
study investigated the protective effects of Danshensu on the acute liver
injury induced by iron overload in mice. The results indicated that the underlying
mechanisms at least partly involve anti-oxidation, anti-inflammation,
anti-apoptosis, and decreasing hepatic iron deposition possibly through
down-regulating the expression of iron uptake related proteins, such as DMT1,
TfR, and L-type Ca2+ CP α1C. Therefore, they
conclude Danshensu could be a promising prophylactic or therapeutic agent
for iron overload diseases.
interaction of human leukocyte antigen (HLA) with specific drugs induces
structural alteration in HLA and delayed-type hypersensitivity reactions, which
cause severe cutaneous toxicity. Shirayanagi et al. selected
specific phage antibodies able to recognize HLA-B*57:01 and evaluated
structural alterations in HLA-B*57:01 complexes induced by abacavir. The
affinity of selected phage antibodies increased because of structural
alterations in HLA-B*57:01 following exposure to abacavir, indicating that specific
phage antibodies can identify drug-mediated structural changes in HLA
complexes. These results suggest that phage
display technology is a useful method for detecting structural changes in HLA
and animal welfare are important factors in the development of new drugs.
Considering this, Nakamura et al.
propose a new way of predicting human PK for mAbs that is more efficient than
conventional methods. By collecting mAb PK data on linear elimination and
analyzing a two-compartment model, they revealed that half-life during
elimination is the main contributor to plasma clearance. Based on this feature,
they developed a novel method that uses easy-to-obtain parameters from humans
and non-human primates to predict human PK. Called the half-life method, it can
improve animal welfare and potentially accelerate the drug development process.
(ETZ) is widely used as an OTC pain reliever, however, its site of action and
mechanism underlying its analgesic action had not yet been fully elucidated.
The article by Nikaido et al. provides evidence suggesting that the
analgesic effect of ETZ in the rat formalin test was mediated by multiple
mechanisms of action including the 5-hydroxytryptamine2B receptor
blockade at the spinal cord.
angiogenesis is a leading cause of blindness in several retinal diseases. Kondo
et al. demonstrated that only a 2-day treatment of neonatal rats with the VEGF
receptor tyrosine kinase inhibitor at different time points could induce
abnormal blood vessels with different vascular pathological features (intravitreal
neovascularization vs. tortuous arteries) in the retina. Pharmacological agents
targeting the VEGF signaling pathway are useful for creating an abnormal
retinal vasculature with various pathological features in order to study the
mechanisms underlying abnormal retinal angiogenesis and evaluate the efficacy
of anti-angiogenic compounds.
fentanyl patch (FP) has been used worldwide to relieve cancer pain. However, no
previous studies have examined the influence of cancer cachexia on pain control
in cancer patients receiving FP treatment. Chiba et al. found that cancer
cachexia may be a risk factor for poor pain control in patients receiving FP
treatment, and that uncontrolled pain in FP treatment may be caused by the
inhibition of fentanyl transdermal absorption due to dry skin.
To discover small molecules that affect
osteoclastogenesis, Kumagai et al designed and synthesized styrylpyrone
analogs, and discovered (E)-6-(2-fluorostyryl)-4-methoxy-2H-pyran-2-one (22) has osteoclast-inhibitory activities in murine RAW264 cells. A
partial structure-activity relationship revealed that fluorine and its position
within the styrylpyrone skeleton were important. Authors also revealed that compound
22 prevents osteoclastic bone
resorption by inhibiting osteoclastogenesis. Compound 22 downregulated mRNA expression levels of RANKL-induced nuclear
factor of activated T cells c1 (NFATc1) and osteoclastogenesis-related genes.
These findings may be useful for the desigh of antiresorptive agents for the
treatment of bone disorders characterized by excessive osteoclastic activity .
The 34th Annual Meeting of the Academy of
Pharmaceutical Sciences and Technologies, Japan (APSTJ) was held in Toyama,
Japan, May 16–18, 2019. In this meeting, a joint
symposium was held with the Pharmaceutical Society of Japan and APSTJ.
The theme of the symposium was “Recent Advances in Research on Particulate
Formulations such as Lipoproteins, Liposomes, Extracellular Vesicles, and iPS
Derived Cells.” The four invited speakers provide their review articles in the Current Topics of this
Interactions between drugs and
pharmaceutical additives can cause problems when mixing multiple drugs in
clinical settings. One example is aggregate formation between levoﬂoxacin
hydrate tablets and lansoprazole orally disintegrating tablets. Nakagawa et al
investigated the factors involved in this aggregation, focusing on the role of
pharmaceutical additives and electrostatic interaction. Levoﬂoxacin, which is
zwitterionic, formed aggregates with methacrylic acid copolymer LD, one of the pharmaceutical
additives of lansoprazole orally disintegrating tablet. Other zwitterionic
ingredients, including ampicillin, meropenem, cefepime, and cephalexin, also formed
aggregates with methacrylic acid copolymer LD.
Sesamin is a
major lignan in sesame seeds, and a
recent meta-analysis of controlled trials showed that sesamin consumption reduces blood pressure. The
antihypertensive effect of sesamin was suggested to
be caused by suppression of cytochrome P450 4F2 (CYP4F2)-mediated 20-hydroxyeicosatetraenoic
acid production. However, the detailed mechanism underlying inhibition
of CYP4F2 function by sesamin was
unclear. The article by Watanabe et al.
characterized the in vitro inhibitory effects of sesamin on human CYP4F2 activity. The results indicated
that sesamin is a
mechanism-based inactivator of CYP4F2.
5-Aminosalicylic acid (5-ASA) is used as
first line therapy for inflammatory bowel disease (IBD). However, a very high
5-ASA dose is required for IBD treatment because 5-ASA formula is relatively
low delivery efficacy to local inflamed colonic sites. In this report, Yuri et
al. focused on an intestinal H+-coupled oligopeptide transporter
1 (PEPT1) which is induced in the colon under IBD condition, and demonstrated
that the newly synthesized dipeptide-like 5-ASA derivatives, which are coupling
glycine, glutamic acid and valine to amino group of 5-ASA, were transportable
substrates for PEPT1.
Cutting-edge contributions from invited poster
presentations providing significant research works in the fifth International
Symposium for Medicinal Sciences (ISMS) in the 139th Chiba annual meeting in
2019 are assembled for the Current Topics section in this issue of the Biological
and Pharmaceutical Bulletin.
Mao et al. found that
resveratrol can significantly inhibit the expression of SUMO1. They demonstrate
that resveratrol alleviates inflammatory bowel disease (IBD) in mice by inhibiting
the expression of SUMO1 molecule, and by modulating the activation of wnt/β-catenin
signaling pathway. Clinical analysis also proves that the expression of SUMO1
and β-catenin molecules increased with the worsening of the disease, which also
provides a new method for clinical diagnosis and treatment of IBD.
Edoxaban is an oral
anticoagulant used for preventing and treating stroke or systemic embolism. Bleeding
is the most common complication associated with anticoagulants. In particular,
severe bleeding is assumed to be related to
mortality in patients treated with anticoagulation
therapy. However, few studies have examined the risk factors for bleeding in
Japanese patients receiving edoxaban. The article by Takase et al. revealed
that a low baseline hemoglobin level was a significant risk factor for major and clinically relevant bleeding in Japanese patients receiving edoxaban.
The article by Tanaka et al. proposed a novel
mechanism of radioresistance and candidate for use as radiosensitizers in
radiation therapy of melanoma. A2B receptor was involved in radioresistance via
DNA damage response in B16 cells. A2B receptor antagonist enhances tumor growth-inhibitory
effect by gamma-ray and shows radiosensitizing effect in vivo. These
findings proposed that A2B receptor contributes to radioresistance, and could be a new target for the development of
agents to increase the efficacy of radiotherapy.
is important for regulating biological processes such as B cell receptor
signaling and B cell differentiation. However, little is known about degradation
mechanism of CD81. Hosokawa et al. demonstrated that CD81 on the cell surface is
degraded by lysosome via K63- and K29-linked poly-ubiquitination. The poly-ubiquitinated
CD81 is translocated from the cell surface into endosomes and is degraded by
lysosomes. This is the first report showing that the lysosomal degradation of
CD81 requires poly-ubiquitination
and clathrin-mediated endocytosis.
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is undoubtedly a
well-recognized and highly used antipyretic/analgesic in the world. However, some
experts have misunderstood that APAP is a type of non-steroidal
anti-inflammatory drugs (NSAIDs) with weak-to-moderate effects, since the
adverse reaction profiles of APAP described in package insert in Japan are
almost the same as classical NSAIDs. Even clinicians and researchers might
actually have a wrong perception regarding it. The review by Ishitsuka et al. the
safety profiles of APAP particularly in terms of respiratory tract and ductus
arteriosus-related toxicity. We also introduce some recent findings about
molecular mechanisms of APAP hepatotoxicity.
Microbes are important for pharmacists,
biologists, and chemists, because some environmental microbes cause infectious
diseases, but also produce beneficial compounds for our health. Understanding
environmental microbes are necessary to live with them and also contributes to
preventing infectious diseases. This current topic summarized the recent
progress on controlling environmental pathogenic microbes by disinfection
methods, sterilization methods, vaccines, antibiotics, and developing new