Curcumin effects on age-related changes in oral immunity: an in vivo study.

The current study aimed to investigate the effects of ageing on oral immunity using ß-defensin (DEFB) 1/2 as a marker and evaluate the effects of curcumin (CUR) on these processes. The study sample included thirty male C57BL/6J mice divided into three groups based on the treatment method used. The young control (YC) and old control (OC) groups received 0·5 % methylcellulose-400 (CUR vehicle) orally for 5 days, whereas the CUR group of older mice received a CUR solution suspended in 0·5 % methylcellulose-400 (dose: 3·0 mg/kg body). DEFB1/2 and immune indicator levels were measured in the saliva and salivary glands post-treatment. The saliva volume and protein content were significantly reduced in the OC group compared with the YC group. CUR administration restored these parameters, decreased DEFB1 expression in the salivary gland and increased DEFB1/2 secretion and DEFB2 expression. These findings were supported by epigenetic gene regulation and partial cytokine activation from changes in WD40 repeat protein 5, TNF alpha and IL-1beta. CUR can partially restore age-related changes in oral immune responses and promote oral health, thereby preventing frailty in the older population through a nutritional therapeutic pathway.

Regulation of Chloride Channels by Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced α-Defensin 5.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat non-small cell lung cancer with EGFR mutations. However, first-generation erlotinib and second-generation afatinib often cause diarrhea, which may develop because of the association between EGFR-TKIs and the chloride channel or abnormalities in the intestinal microbiota due to disruption of the intestinal immune system. As reports on the effects of EGFR-TKIs on intestinal immunity are lacking, we aimed to determine whether the intestinal immune system is involved in the molecular effects of EGFR-TKIs on chloride channels using Caco-2 cells. Initially, we evaluated the association of chloride channels with α-defensin 5 (DEFA5), a marker of intestinal immunity. Erlotinib and afatinib significantly increased the extracellularly secreted DEFA5 level and autophagy-related 16-like 1 and X-box binding protein 1 transcript levels, indicative of enhanced granule exocytosis. Conversely, intracellular DEFA5 and Toll-like receptor 4 protein expression and tumor necrosis factor-α transcript levels decreased significantly, suggesting that Toll-like receptor 4 suppression repressed DEFA5 production. Furthermore, among the chloride channels, DEFA5 was found to significantly increase the transcript levels of cystic fibrosis transmembrane conductance regulators. These results indicate that DEFA5 plays a significant role in the mechanism of chloride channel-mediated diarrhea induced by EGFR-TKIs. Therefore, we successfully elucidated the potential host action of DEFA5 in cancer therapy for the first time.

Use of ab initio calculations to predict the biological potency of carboxylesterase inhibitors.

Carboxylesterases are important enzymes responsible for the hydrolysis and metabolism of numerous pharmaceuticals and xenobiotics. These enzymes are potently inhibited by trifluoromethyl ketone containing (TFK) inhibitors. We demonstrated that the ketone hydration state was affected by the surrounding chemical moieties and was related to inhibitor potency, with inhibitors that favored the gem-diol conformation exhibiting greater potency. Ab initio calculations were performed to determine the energy of hydration of the ketone, and the values were correlated with esterase inhibition data for a series of carboxylesterase inhibitors. This system was examined in three different mammalian models (human liver microsomes, murine liver microsomes, and commercial porcine liver esterase) and in an insect enzyme preparation (juvenile hormone esterase). In all cases, the extent of ketone hydration was strongly correlated with biological potency. Our results showed a very strong correlation with the extent of hydration, accounting for 94% of activity for human liver microsome esterase inhibition (p < 0.01). The atomic charge on the carbon atom of the carbonyl group in the TFK also strongly correlated with inhibitor potency, accounting for 94% of inhibition activity in human liver microsomes (p < 0.01). In addition, we provide crystallographic evidence of intramolecular hydrogen bonding in sulfur-containing inhibitors and relate these data to gem-diol formation. This study provides insight into the mechanism of carboxylesterase inhibition and raises the possibility that inhibitors that too strongly favor the gem-diol configuration have decreased potency due to low rate of ketone formation.