We investigated the effect of the rheological properties and composition of lecithin reverse wormlike micelles (LRWs) on the skin permeation of a model of a hydrophilic drug to determine whether LRWs support uniform hydrophilic drug/oil-based formulations and good drug penetrate into skin. Here, we prepared LRWs with D (−)-ribose (RI) or glycerol (GL) as polar compounds, liquid paraffin (LP) or isopropyl myristate (IPM) as oils, and 6-carboxyfluorescein (CF) as a model for a hydrophilic drug, and evaluated the rheological properties and skin penetration characteristics of the preparations. The LRWs showed moderate viscosity at 25 °C, a typical storage temperature, but decreasing viscosity at 32 °C, the surface temperature of human skin, suggesting that the LRWs would penetrate the microstructure of skin (e.g., wrinkles and hair follicles). The highest skin permeability of CF was observed when IPM was used as the oil, suggesting that both the stratum corneum and hair follicle routes are involved in drug permeation. 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.
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.
White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood–brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.
[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.
We recently reported that the gastrointestinal (GI) fluid volume is influenced by the solution osmolality, and proposed that this effect may play a role in beverage–drug interactions. Here, we investigated whether osmolality-dependent fluid secretion can explain the difference in the magnitudes of fruit juice–drug interactions depending on the type of fruit juice (grapefruit juice (GFJ), orange juice (OJ), and apple juice (AJ)). The osmolality of GFJ, OJ, and AJ used in this study was found to be 552, 686, and 749 mOsm/kg, respectively. Measurements of intestinal fluid movement following beverage administration by the in situ closed-loop technique revealed the following rank order for fluid volume in rat ileum: AJ > OJ > GFJ > purified water, suggesting that water movement is dependent on the osmolality of these beverages. Such changes in GI fluid volume are expected to alter the luminal drug concentration, potentially contributing to the magnitude of beverage–drug interactions. Indeed, in vivo pharmacokinetic study in rats revealed that the plasma concentration of atenolol, a low-permeability drug, was the highest after oral administration in purified water, followed by GFJ and OJ, and was the lowest after administration in AJ. In contrast, antipyrine, a high-permeability drug, showed no significant difference in plasma concentration after administration in purified water and fruit juices, suggesting that the absorption of high-permeability drugs is less affected by solution osmolality. Our findings indicate that differences in the magnitude of beverage–drug interactions can be at least partly explained by differences in the osmolality of the beverages ingested.
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.
Residual cancer cells after radiation therapy may acquire malignant phenotypes such as enhanced motility and migration ability, and therefore it is important to identify targets for preventing radiation-induced malignancy in order to increase the effectiveness of radiotherapy. G-Protein-coupled receptors (GPCRs) such as adenosine A2B receptor and cannabinoid receptors (CB1, CB2, and GPR55) may be involved, as they are known to have roles in proliferation, invasion, migration and tumor growth. In this study, we investigated the involvement of A2B and cannabinoid receptors in γ-radiation-induced enhancement of cell migration and actin remodeling, as well as the involvement of cannabinoid receptors in cell migration enhancement via activation of A2B receptor in human lung cancer A549 cells. Antagonists or knockdown of A2B, CB1, CB2, or GPR55 receptor suppressed γ-radiation-induced cell migration and actin remodeling. Furthermore, BAY60-6583 (an A2B receptor-specific agonist) enhanced cell migration and actin remodeling in A549 cells, and this enhancement was suppressed by antagonists or knockdown of CB2 or GPR55, though not CB1 receptor. Our results indicate that A2B receptors and cannabinoid CB1, CB2, and GPR55 receptors all contribute to γ-radiation-induced acquisition of malignant phenotypes, and in particular that interactions of A2B receptor and cannabinoid CB2 and GPR55 receptors play a role in promoting cell migration and actin remodeling. A2B receptor-cannabinoid receptor pathways may be promising targets for blocking the appearance of malignant phenotypes during radiotherapy of lung cancer.
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 form of regulated cell death that promotes inflammation; it attracts much attention because its dysregulation leads to various inflammatory diseases. To help explore the precise mechanisms by which pyroptosis is regulated, in this study, we searched for chemical compounds that inhibit pyroptosis. From our original compound library, we identified azalamellarin N (AZL-N), a hexacyclic pyrrole alkaloid, as an inhibitor of pyroptosis induced by R837 (also called imiquimod), which is an agonist of the intracellular multiprotein complex nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, whereas the effect of AZL-N on R837-induced pyroptosis was relatively weak, AZL-N strongly inhibited pyroptosis induced by extracellular ATP or nigericin, which are different types of NLRP3 inflammasome agonists. This was in contrast with the results that MCC950, a well-established NLRP3 inhibitor, consistently inhibited pyroptosis irrespective of the type of stimulus. We also found that AZL-N inhibited activation of caspase-1 and apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC), which are components of the NLRP3 inflammasome. Analysis of the structure–activity relationship revealed that a lactam ring of AZL-N, which has been shown to contribute to the strong binding of AZL-N to its known target protein kinases, is required for its inhibitory effects on pyroptosis. These results suggest that AZL-N inhibits pyroptosis by targeting molecule(s), which may be protein kinase(s), that act upstream of NLRP3 inflammasome activation, rather than by directly targeting the components of the NLRP3 inflammasome. Further identification and analysis of target molecule(s) of AZL-N will shed light on the regulatory mechanisms of pyroptosis, particularly those depending on proinflammatory stimuli.
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.
Total Purine and Purine Base Content of Common Foodstuffs for Facilitating Nutritional Therapy for Gout and Hyperuricemia
Released on J-STAGE: May 01, 2014 | Volume 37 Issue 5 Pages 709-721
Kiyoko Kaneko, Yasuo Aoyagi, Tomoko Fukuuchi, Katsunori Inazawa, Noriko Yamaoka
Views: 4,480
Electron Paramagnetic Resonance Study of the Free Radical Scavenging Capacity of Curcumin and Its Demethoxy and Hydrogenated Derivatives
Released on J-STAGE: October 01, 2015 | Volume 38 Issue 10 Pages 1478-1483
Noppawan Phumala Morales, Srisuporn Sirijaroonwong, Paveena Yamanont, Chada Phisalaphong
Views: 3,198
Anti-inflammatory Effects of Etodolac : Comparison with Other Non-steroidal Anti-inflammatory Drugs
Released on J-STAGE: April 10, 2008 | Volume 17 Issue 12 Pages 1577-1583
Kichiro INOUE, Hiroshi FUJISAWA, Asahiko MOTONAGA, Yoshie INOUE, Takashi KYOI, Fusao UEDA, Kiyoshi KIMURA
Views: 1,190
Protocatechuic Acid Inhibits Rat Pheochromocytoma Cell Damage Induced by a Dopaminergic Neurotoxin
Released on J-STAGE: November 01, 2009 | Volume 32 Issue 11 Pages 1866-1869
Hong-Ning Zhang, Chun-Na An, Man Xu, De-An Guo, Min Li, Xiao-Ping Pu
Views: 1,164