Relationship of urinary liver-type fatty acid-binding protein with cardiovascular risk factors in the Japanese population without chronic kidney disease: Sasayama study.

BACKGROUND: Urinary liver-type fatty acid-binding protein (L-FABP) is a well-known marker of proximal tubular impairment. We evaluated the relationship between cardiovascular disease (CVD) risk factors and levels of L-FABP in a cross-sectional community-based study. Participants with normoalbuminuria and normal estimated glomerular filtration rate (eGFR), that is, non-chronic kidney disease (non-CKD), were enrolled in this study. To the best of our knowledge, this is the first study to focus on the association between CVD risk factors and a proximal tubular marker in the Japanese general population with normoalbuminuria and normal eGFR. METHODS: The present study is part of the Sasayama study. The participants included 1000 community residents (447 men and 553 women) aged 40-64 years without a history of CVD or renal dysfunction. Out of these participants 375 men and 477 women, defined as non-CKD, were included for further analysis. In each sex, the highest quintile group was considered to have high-normal L-FABP levels. A multiple logistic regression model was used to evaluate the relationship between risk factors for CVD and high-normal L-FABP levels in the non-CKD participants. We performed a similar analysis using the high-normal urinary albumin to creatinine ratio (UACR) as a dependent variable instead of L-FABP. RESULTS: Among the non-CKD participants, in the highest quintile group (Q5, top 20%), L-FABP was ≥2.17 µg/gCre in men and ≥ 2.83 µg/gCre in women. In women, the multivariate odds ratio was 3.62 (1.45-9.00) for high-normal L-FABP in the presence of diabetes mellitus (DM) compared with that in the group without DM. However, the relationship between DM and the UACR level was not significant. In men, DM was significantly associated with high-normal UACR. However, the relationship with L-FABP levels was not significant. CONCLUSIONS: The presence of DM was more strongly related to high-normal L-FABP levels than to high-normal UACR in women even at the stage of normoalbuminuria and normal eGFR. Our results were also consistent with the findings of a previous study where women were more prone to nonalbuminuric renal impairment compared to men, although further studies are required to confirm the results.

Detection of Subclinical Peripheral Artery Ischemia in Healthy Male Smokers by an Ankle-Brachial Index After Exercise: Sasayama Study.

We investigated the relationship between smoking and the risk of nonnormal (≤0.99) ankle-brachial index (ABI) at rest and after ankle plantar flexion exercise in healthy male community dwellers. A cross-sectional study was performed including 228 Japanese men aged 40 to 64 years without a history of cardiovascular diseases. Participants were classified as never, ex-, and current smokers. We estimated the multivariate-adjusted odds ratios (ORs) for nonnormal ABI of ex- and current smokers in relation to never smokers after adjusting for age and other confounding factors. At rest, the prevalence of nonnormal ABI was not significantly different by smoking status. After exercise, the prevalence of nonnormal ABI increased from 1.8% to 11.5% in ex-smokers and from 3.8% to 17.0% in current smokers, while the prevalence did not significantly change in never smokers. The multivariate-adjusted OR for nonnormal ABI after ankle plantar flexion exercise, in relation to never smokers, was 3.85 (95% confidence interval [CI]: 0.79-18.9) for ex-smokers and 6.97 (95% CI: 1.32-36.7) for current smokers. Our results suggest that ABI after ankle plantar flexion exercise is useful for early detection of subclinical peripheral artery ischemia in male smokers without typical symptoms.

Association between serum long-chain n-3 and n-6 polyunsaturated fatty acid profiles and glomerular filtration rate assessed by serum creatinine and cystatin C levels in Japanese community-dwellers.

BACKGROUND: Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n-3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived long-chain n-3 PUFA intake. METHODS: A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFRcre and eGFRcys). Using multivariate-adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. RESULTS: In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had non-significantly higher eGFRcre and significantly higher eGFRcys (P = 0.016). In addition, eGFRcys in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFRcys, T1: 87 ml/min/1.73 m(2), T2+T3: 91 ml/min/1.73 m(2); P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFRcys. CONCLUSIONS: Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFRcys in Japanese community-dwellers.

Mitochondrial density contributes to the immune response of macrophages to lipopolysaccharide via the MAPK pathway.

We investigated the role of mitochondrial reactive oxygen species (ROS) in the response of macrophages to lipopolysaccharide (LPS) using RAW 264.7 cells and their ρ(o) cells lacking mitochondria. Mitochondrial density, respiratory activity and related proteins in ρ(o) cells were significantly lower than those in RAW cells. LPS rapidly stimulated mitochondrial ROS prior to cytokine secretion, such as TNF-α and IL-6, from RAW 264.7 cells by activating the MAPK pathway, while the response was attenuated in ρ(o) cells. Exposure of ρ(o) cells to H(2)O(2) partially restored the secretion of cytokines induced by LPS. These results suggest that mitochondrial density and/or the respiratory state contribute to intracellular oxidative stress, which is responsible for the stimulation of LPS-induced MAPK signaling to enhance cytokine release from macrophages.

Mitochondria determine the efficacy of anticancer agents that interact with DNA but not the cytoskeleton.

Although chemotherapy is an important method for the treatment of patients with cancer, its efficacy is limited because of different sensitivities of tumor cells to anticancer agents and/or side effects on normal tissues. The present work demonstrates that mitochondria play a crucial role in the apoptosis of cancer cells induced by anticancer agents that interact with DNA but not with the cytoskeleton. Agents that interact with DNA selectively enhanced generation of reactive oxygen species (ROS) in mitochondria, released cytochrome c, and activated caspase-9 and caspase-3 to induce apoptosis of mesothelioma H2052 cells but not their ρ(0) cells, which lack mitochondrial DNA (mtDNA). The sensitivity of a variety of cells to the agents showed positive correlation with the amounts of their mitochondria. In contrast, agents that selectively affect the cytoskeleton activated caspase-8 and caspase-3 and equally induced apoptosis of both H2052 and their ρ(0) cells by a mitochondria-independent mechanism. The results suggest that mtDNA is a potential target for the anticancer agents that interact with DNA to induce ROS-dependent apoptosis of cancer cells, whereas agents that affect the cytoskeleton induce cell death by a mitochondria- and ROS-independent mechanism. The present observation is important for the selection of medicine for chemotherapy of patients with cancer.