Perceived stress, depressive symptoms, and cortisol-to-cortisone ratio in spot urine in 6878 older adults.

BACKGROUND: Late life depression and perceived stress could influence disease pathways via reduced 11ß-HSD2 activity, particularly given suggestions that reduced 11ß-HSD2 activity, which is reflected in the cortisol-to-cortisone ratio, is a risk factor of disease. To date, however, examination of the relationship between the cortisol-to-cortisone ratio and perceived stress or depressive symptoms is insufficient. METHODS: We examined the cross-sectional association of the cortisol-to-cortisone ratio with perceived stress and depressive symptoms, and analyzed whether cortisol levels modify this association, in 6878 participants aged 45-74 years. Cortisol and cortisone in spot urine were measured using liquid chromatography-mass spectrometry. Perceived stress during the past year was measured using a self-reported questionnaire. Depressive symptoms were evaluated using the Zung Self-Rating Depression Scale. Analyses were performed with adjustment for age, sex, lifestyle factors (smoking habit, alcohol consumption, physical activity, and sleeping hours), and physical health factors (body mass index [kg/m2] and medical history [diabetes, hypertension, and medication for hyperlipidemia or corticosteroids]). RESULTS: Cortisol-to-cortisone ratio and cortisol were positively associated with perceived stress (% change: 2.33, Ptrend = 0.003; and 4.74, Ptrend = 0.001, respectively), but were not significantly associated with depressive symptoms. Further, the relationship between cortisol-to-cortisone ratio and perceived stress was modified by cortisol level and sex: the positive association between perceived stress and the cortisol-to-cortisone ratio was more evident in subjects with lower cortisol levels (Pinteraction = 0.009) and in men (Pinteraction = 0.026). CONCLUSIONS: These findings suggest that the cortisol-to-cortisone ratio in spot urine may be a useful marker for non-acute perceived stress in daily life against a possible background of reduced 11ß-HSD2 in older adults.

Ethanol induces skin hyperpigmentation in mice with aldehyde dehydrogenase 2 deficiency.

Alcohol induces various cutaneous changes, such as palmar erythema and jaundice. However, alcohol-induced skin hyperpigmentation due to melanin deposition has not been reported. Aldehyde dehydrogenase 2 (ALDH2), one of 19 human ALDH isozymes, metabolizes endogenous and exogenous aldehydes to their respective carboxylic acids. Reduced ALDH2 greatly affects acetaldehyde metabolism, leading to its accumulation in the body after the consumption of alcohol and the consequent development of a wide range of phenotypes. In the present study, we report a novel phenotype manifesting in a mouse model with the altered expression of ALDH2. Aldh2 knockout (Aldh2+/- and Aldh2-/-) and wild-type (Aldh2+/+) mice were fed a standard solid rodent chow and a bottle of ethanol solution at concentrations of 0%, 3%, 10%, or 20% (v/v) for more than 10 weeks. The intensity of their skin pigmentation was evaluated by macroscopic observation. Ethanol-exposed Aldh2+/- and Aldh2-/- mice exhibited dose-dependent skin pigmentation in areas of hairless skin, including the soles of the paws and tail; no such changes were observed in wild-type mice. The intensity of skin pigmentation correlated with the number of Aldh2 alleles that were altered in the mice (i.e., 0, 1 and 2 for Aldh2+/+, Aldh2+/-, Aldh2-/-, respectively). Interestingly, the skin pigmentation changes reversed upon the discontinuation of ethanol. The histological examination of the pigmented skin demonstrated the presence of melanin-like deposits, mainly in the epidermis. In conclusion, we report a novel finding that the intake of ethanol induces skin hyperpigmentation in an ALDH2 activity-dependent manner.

Potential Use of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugate as an NF-κB siRNA Carrier for the Treatment of Fulminant Hepatitis.

NF-κB and its associated pathways are complicatedly concerned about hepatic homeostasis. Discriminating inhibition of NF-κB signaling has been expected to treat various liver diseases including fulminant hepatitis. To clarify the potential use of thioalkylated mannose-appended dendrimer (generation 3; G3) conjugates with α-cyclodextrin with average degree of substitution of mannose (DSM4) (Man-S-α-CDE (G3, DSM4)) as a novel antigen presenting cell (APC)-specific siRNA carrier, we evaluated the RNAi effect of NF-κB p65 siRNA (sip65) complex with Man-S-α-CDE (G3, DSM4) both in vitro and in vivo. Man-S-α-CDE (G3, DSM4)/sip65 complex significantly suppressed NF-κB p65 mRNA expression and nitric oxide (NO) production from lipopolysaccharide (LPS)-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and mannose receptor-mediated cellular uptake. Intravenous injection of Man-S-α-CDE (G3, DSM4)/sip65 complex extended the survival rate of LPS-induced fulminant hepatitis model mice. In addition, intravenous administration of Man-S-α-CDE (G3, DSM4)/sip65 complex had the potential to induce the in vivo RNAi effect by significant suppression of mRNA expression of NF-κB p65 and inflammatory cytokines in the liver of fulminant hepatitis model mice induced by LPS/d-galactosamine (d-Gal) without any significant side effects. Also, the serum levels of enzymes were significantly attenuated by injection of Man-S-α-CDE (G3, DSM4)/sip65 complex in fulminant hepatitis model mice. Collectively, these results suggest that Man-S-α-CDE (G3, DSM4) has the potential as a novel APC-selective sip65 carrier for the treatment of LPS/d-Gal-induced fulminant hepatitis in mice.

Design and evaluation of thioalkylated mannose-modified dendrimer (G3)/α-cyclodextrin conjugates as antigen-presenting cell-selective siRNA carriers.

To design and evaluate the potential use of thioalkylated mannose-modified dendrimer (generation 3; G3) conjugates with α-cyclodextrin (Man-S-α-CDE (G3)) as novel antigen-presenting cell (APC)-selective siRNA carriers, we investigated the RNAi effects of siRNA complexes with Man-S-α-CDEs (G3). Man-S-α-CDE (G3, average degree of substitution of mannose (DSM) 4)/siRNA complex had the potent RNAi effects in both NR8383 cells, a rat alveolar macrophage cell line, and JAWSII cells, a mouse dendritic cell line, through adequate physicochemical properties, mannose receptor (MR)-mediated cellular uptake, and efficient phagosomal escape of the siRNA complex. In addition, cytotoxic activities of the siRNA complexes with α-CDE (G3, DS2) and Man-S-α-CDE (G3, DSM4) were almost negligible up to a charge ratio of 100 (carrier/siRNA). Taken together, these results suggest that Man-S-α-CDE (G3, DSM4) has the potential for a novel APC-selective siRNA carrier.

Potential use of fucose-appended dendrimer/α-cyclodextrin conjugates as NF-κB decoy carriers for the treatment of lipopolysaccharide-induced fulminant hepatitis in mice.

The purpose of the present study is to treat lipopolysaccharide (LPS)-induced fulminant hepatitis by NF-κB decoy complex with fucose-appended dendrimer (generation 2; G2) conjugate with α-cyclodextrin (Fuc-S-α-CDE (G2)). Fuc-S-α-CDE (G2, average degree of substitution of fucose (DSF2))/NF-κB decoy complex significantly suppressed nitric oxide and tumor necrosis factor-α (TNF-α) production from LPS-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and fucose receptor-mediated cellular uptake. Intravenous injection of Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex extended the survival of LPS-induced fulminant hepatitis model mice. In addition, Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex administered intravenously highly accumulated in the liver, compared to naked NF-κB decoy alone. Furthermore, the liver accumulation of Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex was inhibited by the pretreatment with GdCl3, a specific inhibitor of Kupffer cell uptake. Also, the serum aspartate aminotransferase, alanine aminotransferase and TNF-α levels in LPS-induced fulminant hepatitis model mice were significantly attenuated by the treatment with Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex, compared with naked NF-κB decoy alone. Taken together, these results suggest that Fuc-S-α-CDE (G2, DSF2) has the potential for a novel Kupffer cell-selective NF-κB decoy carrier for the treatment of LPS-induced fulminant hepatitis in mice.