Impact of obesity on childhood kidney

Obese patients are known to have greater risks to develop hypertension, coronary vascular disease, and insulin resistance, and more attention has been recently paid to the impact of obesity on kidney. This study was conducted to investigate whether obese children have higher risk of renal injury as well as adults. Eighteen hundred and thirty school children aged 6–14 years with abnormal urinary findings on thrice occasions detected by the screening program for renal disease in Japan were enrolled. Of them, 27 children with nephritis or suspected nephritis diagnosed by persistent proteinuria with hematuria were compared to 588 without urinary abnormalities regarding their body mass index (BMI), blood pressure (BP), and serum level of total cholesterol. BMI and systolic BP (mmHg) were significantly higher in the former than in the latter. As a result, obesity may be associated with the development of renal injury even in childhood

Anthropometrics estimates renal function

In recumbent elderly patients, creatinine clearance (eCCr) estimated by the Cockcroft-Gault (CG) equation may not necessarily reflect renal function. We aimed to develop a novel formula to revise the CG equation using anthropometric measurements in bedridden elderly patients and evaluate its clinical utility. The subjects included 77 bedridden Japanese patients aged ≥ 65, hospitalized at Naruto Yamakami Hospital. The actual CCr (mCCr) value was measured using the 24-hour urine collection method. Anthropometric data, such as skeletal muscle mass, body fat mass (BFM), and triceps skinfold thickness (TSF), were collected. We established a novel formula to estimate CCr(BFM) or CCr(TSF) by correcting the eCCr(Enz + 0.2) value with BFM or TSF. The stage of classification of renal dysfunctions in patients with eGFR(BFM) or eGFR(TSF) was equivalent to the GFR(control) based on the mCCr. Notably, the novel equation for eCCr based on TSF (eCCr(TSF)), dubbed the “Naruto” formula, can be useful to evaluate renal function in bedridden elderly patients without expensive equipment or additional costs. In this study, mCCr was considered to be the true renal function of the patient, but whether and to what extent mCCr correlates with inulin clearance is unknown

Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation

Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type–specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation) and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI) transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA–mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our study demonstrates the utility of FAIRE-seq in providing a global view of cell type–specific regulatory elements in the genome and in identifying transcriptional regulators of adipocyte differentiation

CNS targets of adipokines

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record.Our understanding of adipose tissue as an endocrine organ has been transformed over the last twenty years. During this time a number of adipocyte-derived factors or adipokines have been identified. This paper will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be the focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted

Temperature-controlled and aerosol-assisted synthesis of aluminium organophosphonate spherical particles with uniform mesopores

Spray-drying of clear precursor solution containing inorganic organic hybrid species and EO(n)PO(m)EO(n) triblock copolymer at low temperature, followed by treatment in acetone to remove the triblock copolymer, afforded spherical particles of aluminium organophosphonate (AOP) with uniform mesopores

Low-dose radiation attenuates chemical mutagenesis in vivo - Cross adaptation -

The biological effects of low-dose radiation are not only of social concern but also of scientific interest. The radioadaptive response, which is defined as an increased radioresistance by prior exposure to low-dose radiation, has been extensively studied both in vitro and in vivo. Here we briefly review the radioadaptive response with respect to mutagenesis, survival rate, and carcinogenesis in vivo, and introduce our recent findings of cross adaptation in mouse thymic cells, that is, the suppressive effect of repeated low-dose radiation on mutation induction by the alkylating agent N-ethyl-N-nitrosourea

Role of Exposure Sequence in the Combined Effect of Ionizing Radiation and N-ethyl-N-nitrosourea in Murine T-cell Lymhomagenesis

Murine T-cell lymphomas (TL) can be reproducibly induced by ionizing radiation or chemical carcinogens. This animal model is considered useful in the search for characterization of genes involved in the development of human acute lymphoblastic leukemia. We have been studying this lymphoma model, which is induced by X-rays, carbon-ions or alkylating agents such as N-ethyl-N-nitrosourea (ENU). In the study of X-ray induced thymic lymphomas in B6C3F1 mice, we found a unique locus with a high frequency of loss of heterozygosity (LOH) (50%) in the centromeric region of chromosome 11 [1]. LOH at this locus was very rarely observed in ENU-induced or spontaneously developing T-cell lymphomas, suggesting that it was a radiation-associated molecular change. We also showed that Ikaros was mapped in this frequent LOH locus, suggesting Ikaros as a tumor suppressor gene. Ikaros is a transcription factor that plays a critical role in both lineage commitment and differentiation of lymphocytes. The mutation analysis of Ikaros in the X-ray- or ENU-induced lymphomas revealed that Ikaros mutation frequency and spectrum is carcinogen dependent. Mutation frequency in X-ray-induced TL was around 50%, while that in ENU-induced TL was 20%. Inactivation of Ikaros in X-ray-induced TL was caused by transcriptional silencing, unusual splicing, point mutation and small insertion, most of which were associated with LOH [2]. LOH at Ikaros locus was generated by intra-chromosomal deletion [3]. On the other hand, Ikaros inactivation in ENU-induced TLs was caused by only point mutations not accompanied with LOH [4]. Thus, the mutation of Ikaros was distinguished between X-rays-induced TL and ENU-induced one. Recently, we showed that TL induced in mismatch repair gene Mlh1-deficient mice harbored frequent frameshift mutations in mononucleotide sequence in Ikaros, suggesting Ikaros is also a mutational target in Mlh1-dificient mice [5]. Taken together, Ikaros could be inactivated by several mechanisms. Recently our interest is focused on the effect of combined exposure of radiation and chemical carcinogens. Since we are living in the environment with numerous natural and man-made radiation and chemicals, cancer development in human is considered as a result of interaction with these factors. But, the quantitative assessment and mechanistic understanding of combined effects of radiation and chemical carcinogens are still insufficient. The aim of this study is to elucidate the mode and mechanism of the combined effect of X-rays with ENU on mouse T-cell leukemogenesis. Beginning at 4- or 8-weeks of age, female B6C3F1 mice were exposed weekly to whole body X-irradiation (0.2 ? 2.0 Gy) for consecutive 4 weeks or were given ENU (50 ? 400 ppm) in drinking water for consecutive 4 weeks. The dose-response curve for X-ray- or ENU?induced lymphoma had threshold dose. Combined exposure was carried out by X-irradiation followed by ENU or by reverse sequence ENU followed by X-irradiation. The exposure of high dose X-rays followed by ENU resulted in a synergistic effect, while the effect was antagonistic at low or threshold dose of carcinogens. Thus, combined effect is dose dependent. When the order of exposure was reversed, i.e., ENU followed by X-rays, the mode of combined exposure was additive at any doses. Molecular changes such as LOH and Ikaros mutations in TL after X-irradiation followed by ENU were similar to those in ENU-induced TL. In contrast, TL induced by reverse treatment exhibited mutations, which were similar to those found in X-ray-induced TL. It is concluded that the mode of combined effect is dependent upon the dose and the treatment order of carcinogens. \n1. Shimada Y., M. Nishimura, S. Kakinuma, M. Okumoto, T. Shiroishi, K. H. Clifton, S. Wakana: Radiation-associated loss of heterozygosity at the Znfn1a1 (Ikaros) locus on chromosome 11 in murine thymic lymphomas. Radiat Res 2000;154:293-300.?2. Kakinuma S., M. Nishimura, S. Sasanuma, K. Mita, G. Suzuki, Y. Katsura, T. Sado, Y. Shimada: Spectrum of Znfn1a1 (Ikaros) inactivation and its association with loss of heterozygosity in radiogenic T-cell lymphomas in susceptible B6C3F1 mice. Radiat Res 2002;157:331-340.?3. Yoshida M. A., A. Nakata, M. Akiyama, S. Kakinuma, T. Sado, M. Nishimura, Y. Shimada: Distinct structural abnormalities of chromosomes 11 and 12 associated with loss of heterozygosity in X-ray-induced mouse thymic lymphomas. Cancer Genet Cytogenet 2007: in press.?4. Kakinuma S., M. Nishimura, A. Kubo, J. Y. Nagai, Y. Amasaki, H. J. Majima, T. Sado, Y. Shimada: Frequent retention of heterozygosity for point mutations in p53 and Ikaros in N-ethyl-N-nitrosourea-induced mouse thymic lymphomas. Mutat Res 2005;572:132-141.?5. Kakinuma S., Y. Kodama, Y. Amasaki, S. Yi, Y. Tokairin, M. Arai, M. Nishimura, M. Monobe, S. Kojima, Y. Shimada: Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice. Oncogene 2007;26:2945-2949.NIRS-Bfs Internatinal Workshop on Research Applications of the Radiationbiology Archive

Mutation induction and expression of repair genes in thymus lymphomagenesis by combined exposure of X-rays and ENU

Radiation carcinogenesis in human is considered as a result of the combined exposure with other environment factors. The aim of this study is to examine the mechanism of thymic lymphomagenesis induced by combined exposure of radiation and chemical carcinogen. We investigated frequency and spectrum of the mutation, and an expression of repair genes after combined exposure of X-rays with N-ethyl-N-nitrosourea (ENU).B6C3F1gpt-delta transgenic mice were exposed to X irradiation at 0.2 or 1.0 Gy for consecutive 4 weeks, followed by ENU at 200ppm for 4 weeks. Four weeks after the end of ENU treatment, genome DNA was prepared from thymus and determined the mutation frequency and spectrum in gpt gene. The expression of Mgmt and other repair genes during ENU treatment was examined by Real Time PCR or RT-PCR array. We previously reported that irradiation with 0.2 Gy suppressed ENU-induced thymic lymphomagenesis while that with 1.0 Gy enhanced. This study showed that exposure to 0.2Gy dramatically suppressed mutation induction by ENU, especially G to A transition. When combined with 1.0 Gy, mutant frequency was enhanced by 30-folds and accelerated clonal expansion of mutated cells. The expression of Mgmt after exposure of 0.2Gy resulted in a higher expression than that after ENU alone at the initial one week, but increase was smaller thereafter. Other candidate repair genes are now investigated by Real Time PCR Array.1st Asian Conference on Environmental Mutagens, 36th Annual Meeting of the Japanese Environmental Mutagen Societ