Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can ...permeate the blood–brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer’s disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.
In a previous study, we found that carnosic acid (CA) protected cortical neurons by activating the Keap1/Nrf2 pathway, which activation was initiated by
S-alkylation of the critical cysteine thiol of ...the Keap1 protein by the “electrophilic”
quinone-type of CA T. Satoh, K. Kosaka, K. Itoh, A. Kobayashi, M. Yamamoto, Y. Shimojo, C. Kitajima, J. Cui, J. Kamins, S. Okamoto, T. Shirasawa, S.A. Lipton, Carnosic acid, a
catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via
S-alkylation of targeted cysteines on Keap1. J Neurochem., in press. In the present study, we used HT22 cells, a neuronal cell line, to test CA derivatives that might be more suitable for
in vivo use, as an electrophile like CA might react with other molecules prior to reaching its intended target. CA and carnosol protected the HT22 cells against oxidative glutamate toxicity. CA activated the transcriptional antioxidant-responsive element of phase-2 genes including hemeoxygenase-1, NADPH-dependent quinone oxidoreductase, and γ-glutamyl cysteine ligase, all of which provide neurorprotection by regulating cellular redox. This finding was confirmed by the result that CA significantly increased the level of glutathione. We synthesized a series of its analogues in which CA was esterified at its catechol hydroxyl moieties to prevent the oxidation from the
catechol to
quinone form or esterified at those moieties and its carbonic acid to stop the conversion from CA to carnosol. In both cases, the conversion and oxidation cannot occur until the alkyl groups are removed by an intracellular esterase. Thus, the most potent active form as the activator of the Keap1/Nrf2 pathway, the
quinone-type CA, will be produced inside the cells. However, neither chemical modulation potentiated the neruroprotective effects, possibly because of increased lipophilicity. These results suggest that the neuroprotective effects of CA critically require both free carboxylic acid and
catechol hydroxyl moieties. Thus, the hydrophilicity of CA might be a critical feature for its neuroprotective effects.
Electrophilic compounds are a newly recognized class of redox-active neuroprotective compounds with electron deficient, electrophilic carbon centers that react with specific cysteine residues on ...targeted proteins via thiol (S-)alkylation. Although plants produce a variety of physiologically active electrophilic compounds, the detailed mechanism of action of these compounds remains unknown. Catechol ring-containing compounds have attracted attention because they become electrophilic quinones upon oxidation, although they are not themselves electrophilic. In this study, we focused on the neuroprotective effects of one such compound, carnosic acid (CA), found in the herb rosemary obtained from Rosmarinus officinalis. We found that CA activates the Keap1/Nrf2 transcriptional pathway by binding to specific Keap1 cysteine residues, thus protecting neurons from oxidative stress and excitotoxicity. In cerebrocortical cultures, CA-biotin accumulates in non-neuronal cells at low concentrations and in neurons at higher concentrations. We present evidence that both the neuronal and non-neuronal distribution of CA may contribute to its neuroprotective effect. Furthermore, CA translocates into the brain, increases the level of reduced glutathione in vivo, and protects the brain against middle cerebral artery ischemia/reperfusion, suggesting that CA may represent a new type of neuroprotective electrophilic compound.
Prevalence of diabetes mellitus type 2 (DM-II) is increasing in Japan. Brown alga Ecklonia kurome Okamura (Laminariaceae) (kurome in Japanese) is rich in phlorotannins, a kind of polyphenol. ...Phlorotannins have been reported to possess various bioactivities; however, few studies have reported its effect on DM-II.
The present study was conducted to investigate the antidiabetic effect of polyphenols from E. kurome (KPP) on KK-A(y) mice, the animal model for human DM-II.
Inhibitory activities of KPP against α-amylase and α-glucosidase in vitro, and effects on oral carbohydrate tolerance test in vivo were investigated. KK-A(y) mice were fed with 0.1% KPP containing water for 5 weeks. A glucose tolerance test was conducted at week 4 of the 5-week period. At the end of experiment, blood biochemical parameters, including blood glucose, insulin, glycoalbumin, and fructosamine were determined. Furthermore, the kidneys and pancreatic islets were histologically examined.
KPP showed inhibitory activities on carbohydrate-hydrolyzing enzymes and decreased postprandial blood glucose levels. The body weight gain and blood glucose levels in the KPP group were lower than the control group during the experimental period. KPP improved glucose tolerance and decreased the fasting blood glucose and insulin levels, fructosamine and glycoalbumin levels compared with the control group. Furthermore, KPP contracted the pancreatic islet size and decreased renal mesangial matrix in KK-A(y) mice.
These results suggest that KPP is effective against DM-II and might provide a source of therapeutic agents for DM-II.
Context: Prevalence of diabetes mellitus type 2 (DM-II) is increasing in Japan. Brown alga Ecklonia kurome Okamura (Laminariaceae) (kurome in Japanese) is rich in phlorotannins, a kind of polyphenol. ...Phlorotannins have been reported to possess various bioactivities; however, few studies have reported its effect on DM-II.
Objective: The present study was conducted to investigate the antidiabetic effect of polyphenols from E. kurome (KPP) on KK-Ay mice, the animal model for human DM-II.
Materials and methods: Inhibitory activities of KPP against α-amylase and α-glucosidase in vitro, and effects on oral carbohydrate tolerance test in vivo were investigated. KK-Ay mice were fed with 0.1% KPP containing water for 5 weeks. A glucose tolerance test was conducted at week 4 of the 5-week period. At the end of experiment, blood biochemical parameters, including blood glucose, insulin, glycoalbumin, and fructosamine were determined. Furthermore, the kidneys and pancreatic islets were histologically examined.
Results: KPP showed inhibitory activities on carbohydrate-hydrolyzing enzymes and decreased postprandial blood glucose levels. The body weight gain and blood glucose levels in the KPP group were lower than the control group during the experimental period. KPP improved glucose tolerance and decreased the fasting blood glucose and insulin levels, fructosamine and glycoalbumin levels compared with the control group. Furthermore, KPP contracted the pancreatic islet size and decreased renal mesangial matrix in KK-Ay mice.
Discussion and conclusion: These results suggest that KPP is effective against DM-II and might provide a source of therapeutic agents for DM-II.
Aims
In patients with breast cancer, skin assessment is useful for the treatment and prevention of postoperative adverse effects of radiotherapy. This study was designed to clarify the long‐term ...changes in the irradiated skin of patients after breast‐conserving surgery using visual inspection and noninvasive imaging.
Methods
We compared changes in the irradiated skin over time between evaluations, based on visual inspection and noninvasive imaging in 31 patients receiving postmastectomy radiation therapy. The condition of the skin was evaluated by visual inspection of the thermogram, and analysis of skin surface temperature, intensity of erythema, intensity of melanin, and hydration level.
Results
Skin surface temperature remained higher at the irradiation site after 11 months, despite the absence of erythema per visual inspection. The intensity of erythema was higher at the irradiated site until 17–19 months after completion of irradiation. Similarly, the intensity of melanin tended to be higher at the irradiated site compared with the nonirradiated site until 17–19 months. The hydration level at the irradiated site was lower at 6 months but recovered to match the nonirradiated site at 11–13 months. Impaired skin conditions assessed by noninvasive objective procedures persist longer than the assessment made by visual inspection.
Conclusions
Adverse effects should be treated or prevented in the long term in patients receiving postmastectomy radiation therapy.
Hirosaki University has regularly offered health support activities to residents of X town in Fukushima, and thus, some interactive benefits are expected as a service-learning experience for nursing ...students. This study aimed to clarify the experiences of students who participated in service-learning and consider which methods and content were effective. In total, 52 nursing students were recruited into the program, which was held from 2018 to 2021. The roles of students included assisting in health consultations related to a radiation disaster. Questionnaires designed by researchers with experience in risk communication programs were conducted on the students after the program, and included the reasons why they joined, their most memorable experiences, and their opinions regarding required support for residents. The data were analyzed by content analysis. The nursing students thought about the health of residents through health support activities in the affected areas. Furthermore, by communicating with residents via on-site service-learning, they could experience the humanity of the residents and the current status of the affected areas, learn the importance of person-to-person relationships, and think about reconstruction. Thus, service-learning was found to be effective and to offer substantial benefits for both residents and students in affected areas.
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