Lecithin reverse wormlike micelles (LRWs) are highly viscoelastic bodies
and
potentially useful for transdermal applications. The authors prepared LRWs with
6-carboxyfluorescein (CF) as a model for a hydrophilic drug, and investigated
the effect of the rheological properties and composition of LRWs on the skin
permeation of CF. The highest skin permeability of CF was observed when IPM was
used as the oil, and the penetration of CF into hair follicles is influenced
not only by the rheology of the formulation but also by the interaction between
IPM and sebum in the hair follicles.
[Highlighted Paper selected
by Editor-in-Chief]
Chronic cerebral hypoperfusion can cause
white matter lesions, leading to vascular dementia. Recently, these diseases
have been reported to be associated with lipid peroxidation. In this research,
the authors revealed that ethoxyquin, a lipid-soluble antioxidant, had a
protective effect against a glutamate-stimulated mouse hippocampal cell line
and was comparable to the ferroptosis inhibitor. Additionally, when applied to
a mouse model of chronic cerebral hypoperfusion, ethoxyquin suppressed white
matter lesions and inflammatory responses. Overall, the authors demonstrated
that inhibiting lipid peroxidation could be a helpful therapy for chronic
cerebrovascular disease.
The authors revealed that changes in gastrointestinal fluid volume due to solution osmolality can explain the differences in the magnitude of beverage-drug interactions depending on the type of beverage. Osmolality-dependent fluid secretion and consequent decrease in luminal concentrations and absorption of drugs were observed in the rat intestine after administration of apple juice, orange juice, and grapefruit juice. Further, in vivo oral experiments showed that plasma concentrations of atenolol, a low-permeability drug, after oral administration decreased in dependence upon the magnitude of osmolality of ingested beverages, while the plasma concentrations of antipyrine, a high-permeability drug, did not change.
The article by Oyama et al. suggested a novel mechanism of radiation-induced acquisition of malignant profile in lung cancer. Authors have shown that activation of adenosine A2B receptor and cannabinoid receptors (CB1, CB2 and GPR55) are involved in enhancement of cell migration after g-irradiation in A549 cells. And authors have shown that enhancement of cell migration by activation of adenosine A2B receptor is mediated by activation of CB2 and GPR55 receptor. These findings proposed that the A2B-CB2 and A2B-GPR55 pathways contributes to the radiation-induced acquisition of malignant profile in lung cancer and could be a novel molecular target to improve the efficiency of radiation therapy for lung cancer.
Pyroptosis is a type of regulated cell death, and its dysregulation is detrimental and implicated in various diseases. The authors screened chemical compounds and identified azalamellarin N (AZL-N), a hexacyclic pyrrole alkaloid, as an inhibitor of pyroptosis induced by the intracellular multiprotein complex NLRP3 inflammasome. The inhibitory effects of AZL-N differed depending on the type of stimulus, which was different from those of MCC950, a well-established NLRP3 inhibitor. Considering that many studies have been focusing on the general mechanisms of NLRP3 inflammasome-dependent pyroptosis, AZL-N is a unique tool for uncovering the differential mechanisms of pyroptosis depending on the type of inflammatory stimulus.
Genetic engineering now enables generation of artificially modified antibodies having higher diagnostic utilities. The authors
developed single-chain Fv fragments (scFvs) against cortisol with >55-fold
improved affinity (Ka, 2.0-2.2 ´ 1010
M-1) by inserting additional amino acid(s) site-directedly
into the framework region 1 of the VH domain. These scFvs were fused
with NanoLuc luciferase for the use in an enzyme-linked immunosorbent assay
(ELISA) system. The resulting luminescent
ELISAs generated dose-response curves with >150-fold higher sensitivity than
the colorimetric ELISAs using the scFv without insertion and >8,000-fold
higher sensitivity than the ELISA using the mouse antibody from which the scFvs
were derived.
E. coli is
often employed for the cost-effective production of large quantities of recombinant
proteins. Conventionally, it is believed that post-translational modifications,
including glycosylation, do not transpire during protein expression in E.
coli. However, in the course of preparing recombinant galectin-2 protein
using E. coli, the authors discovered that phosphogluconoylation of Lys
residues and mistranslation of termination codons occurred. The authors have
elucidated strategies to mitigate these occurrences, proposing the addition of
tags, substitution of Lys residues, and modification of termination codons. These
methods offer valuable means to prevent undesired modifications, ensuring the production
of homogeneous recombinant proteins in E. coli.
The authors focused on cell-penetrating
peptides (CPPs) as penetration enhancers for ocular drug delivery. This study suggested
that the CPPs evaluated in this study can be penetration enhancers based on in
vitro intracellular uptake using a reconstructed human corneal epithelial
model. The CPPs could enhance the penetration of drug molecules into the cornea
in cases of coexistence as well as conjugation between CPPs and drug molecules.
The result of surface plasmon resonance showed that the electrostatic
interaction plays an important role. The authors expect that this fundamental
information in this article will support the development of new penetration
enhancers in eye drop formulations for ocular drug delivery.
Inflammation is responsible for the development of
various kidney diseases. Plasminogen activator
inhibitor-1 (PAI-1) is
involved in the
pathogenesis of inflammatory kidney injury; however, the regulatory mechanism
of PAI-1 in injured kidneys remains unclear. The authors
found that PAI-1 expression was increased in endothelial cells after
lipopolysaccharide (LPS, an inflammation inducer) treatment, and
pharmacological inhibition of PAI-1 reduced LPS-induced kidney injury.
Moreover, IL-6 exacerbated kidney injury concomitant with increased PAI-1
expression, and Arid5a deficiency partially suppressed the expression of IL-6
and PAI-1 in the kidneys after LPS treatment. These findings indicate that the
Arid5a/IL-6/PAI-1 signaling is involved in LPS-induced kidney injury.
Hericium
erinaceus
secretes an acidic ribonuclease (RNase) He1 belonged to RNase T1 family. The authors
decided on the structure of He1 apo form and He1/guanosine complex. The
mechanism of acidification of optimal pH in He1 was, in neutral environment, to
form the hydrogen bond between Asp 31 on α1β3- loop and His 34 (catalytic
residue), and repulsive each other Glu 92 and Asp 93 on β6,7- loop. Structure
comparison of He1 with other acidic RNases, Ms and U2, suggested that the
acidic residues on α1β3- and β6,7- loop may contribute to the acidification of
optimal pH in Ms and U2.
Although most previous studies in this area used
recombinant adiponectin, herein, the author used native high-molecular-weight
(HMW) adiponectin purified from human plasma, which is considered the most
active form of circulating adiponectin. The current results clearly demonstrate
that native HMW adiponectin preferentially inhibits lipopolysaccharide-induced interleukin-1β expression but not tumor
necrosis factor-α
expression by inhibiting the Akt-C/EBPβ inflammatory signaling pathway in macrophages. Furthermore, HMW
adiponectin preconditioning is essential for achieving the anti-inflammatory
effects of adiponectin. Thus, these findings highlight
the regulatory mechanisms underlying the anti-inflammatory function of adiponectin.
Authors suggest that plant extracts, including
quercetin and oenothein B, reduce the amount of virus in the cell supernatants
and induce cytotoxicity in HIV-1-infected T cells but not HTLV-1-infected T
cells. The large amount of oenothein B were detected in Onagraceae. Thus, the plant
extracts might block the HIV-1 release and kill the HIV-1-infected cells.
Consequently, the plant extracts from the plant library of Turkey might be
suitable candidates to develop novel anti-retroviral drugs that target the late
phase of the HIV-1 life cycle.
Citrus
sudachi is a popular fruit in Tokushima
Prefecture, Japan, and its peel contains high amounts of polymethoxyflavones
with the most abundant being sudachitin (SDC) followed by demethoxysudachitin (DMSDC).
The effects of SDC and DMSDC on the cardiovascular system have not been
investigated. The present study aimed to investigate the effects of SDC and
DMSDC on vascular tonus and to investigate mechanism of action of SDC using aorta
preparations isolated from rats. The results demonstrated that SDC and DMSDC
cause endothelial-independent relaxation, and that the mechanism of
vasorelaxation by SDC is associated with the enhancement of cAMP- and
cGMP-dependent pathways.
Antidepressants, such as
milnacipran, a serotonin and noradrenaline reuptake inhibitor, and mirtazapine,
a noradrenergic and specific serotonergic antidepressant attenuate the
induction of scratching events by chloroquine (CQ) or histamine. However, it
remains unclear whether serotonin or noradrenaline is involved in attenuating
effects of these antidepressants. Miyahara and colleagues show that 5-HT4
and 5-HT6 receptors are involved in the amelioration of CQ-induced
scratches, but not histamine-induced scratches, engendered by the antidepressants.
These findings suggest that 5-HT4, 5-HT5, and 5-HT6
receptors play differential roles in acute pruriceptive processing after
administration of CQ or histamine.
The authors validated the
modified Cockcroft-Gault equation, developed previously for aged-oriented
cohort, in a newly obtained dataset and found that good renal function estimates
were obtained for patients exceeding 65 years of age. Using statistical
analysis, estimates for a subset of patients in this cohort were identified to
be inadequate and this deviation from estimates was attributed to a decreased
albumin level. A multivariate linear regression estimating equation was
developed for this region by incorporating body composition parameters. A flow
diagram was proposed to select an appropriate renal function estimating
equation particularly for older patients.
Linezolid (LZD) has been reported
to cause severe hyponatremia, but infection per
se is also a potential cause of hyponatremia by increasing vasopressin
secretion. The author compared the incidence and risk of developing
hyponatremia between LZD and vancomycin (VCM) using propensity score analysis
to demonstrate that hyponatremia is associated with LZD rather than infection.
The analysis indicated a significantly higher incidence and 3.7-fold higher
risk of developing hyponatremia associated with LZD than with VCM, regardless
of patient background characteristics. Regularly monitoring serum sodium and
infusing sodium promptly when the level decreases would be required when
administering LZD.
Despite the fact that liver fibrosis is an
intractable disease with a poor prognosis, effective therapeutic agents are not
available. The authors
focused on bone morphogenetic factor 7 (BMP7) that
inhibits TGF-β signaling. They prepared a long-acting albumin-fused
BMP7 (HSA-BMP7) and evaluated its inhibitory effect on liver fibrosis. In the mice with bile duct ligation, HSA-BMP7 administration suppressed
the infiltration of inflammatory cells and fibrosis area around the bile duct. In the
carbon tetrachloride-induced liver fibrosis mice, HSA-BMP7 administration also decreased
the hepatic fibrosis. HSA-BMP7 has the potential for serving as a
therapeutic agent for the treatment of liver fibrosis.
The yeast strain Saccharomyces cerevisiae is an eukaryotic organism that secrete
extracellular vesicles (EVs). The authors
characterized the biodistribution of locally (intradermally and subcutaneously)
administered Saccharomyces
cerevisiae-derived EVs (S-EVs) and the EV-mediated immune responses to
evaluate their potential use as biocompatible vaccine adjuvants. Locally administered
S-EVs were delivered to the lymph nodes, mainly reaching the B-cell zone. Furthermore,
S-EVs increased the expression of cytokine and costimulatory molecules. Especially,
subcutaneously injected S-EVs showed potent adjuvanticity, indicating that
subcutaneous administration of S-EVs is the desirable approach for achieving
effective immune stimulation. These findings will facilitate the development of
novel EV-based immunotherapies.
Osteoporosis is caused by an imbalance between osteoblast
bone formation and osteoclast bone resorption, thus is treated with oral and
parenteral bone-resorption inhibitors and parenteral bone-formation promoting
drugs. The authors demonstrated that KY-054, a novel coumarin derivative, has osteoblast
differentiation-promoting activities in mouse and rat mesenchymal stem cells, increasing
metaphyseal and diaphyseal cortical bone volume and bone strength parameters without
reducing medullary volume by micro-computed tomography in ovariectomized rats. KY-054
is a potential orally active osteogenic anti-osteoporosis drug candidate with a
unique mode of action by acceleration of osteoblast differentiation.
Authors fabricated 3D-printed contact
lenses composed of polyethylene glycol diacrylate and an antibiotic,
azithromycin. The drug-loaded contact lenses were prepared using vat
photopolymerization 3D printer, and the effect of second curing on 3D printed
object was investigated. The mechanical strength and drug release of contact
lens formulation were evaluated in the present study. The 3D printed contact
lenses exhibited antimicrobial effect in vitro. The current results suggested
that the preparation of antibiotic-loaded contact lenses by 3D printing
provides useful information for manufacture of ophthalmic device and
personalized therapy.