PPAR Ligands for Cancer Chemoprevention

Peroxisome proliferators-activated receptors (PPARs) that are members of the nuclear receptor superfamily have three different isoforms: PPARα, PPARδ, and PPARγ. PPARs are ligand-activated transcription factors, and they are implicated in tumor progression, differentiation, and apoptosis. Activation of PPAR isoforms lead to both anticarcinogenesis and anti-inflammatory effect. It has so far identified many PPAR ligands including chemical composition and natural occurring. PPAR ligands are reported to activate PPAR signaling and exert cancer prevention and treatment in vitro and/or in vivo studies. Although the effects depend on the isoforms and the types of ligands, biological modulatory activities of PPARs in carcinogenesis and disease progression are attracted for control or combat cancer development. This short review summarizes currently available data on the role of PPAR ligands in carcinogenesis

Chlamydia pneumoniae CPj0783 interaction with Huntingtin-protein14

Chlamydia pneumoniae is a Gram-negative, obligate intracellular pathogen that causes community-acquired respiratory infections. After C. pneumoniae invades host cells, it disturbs the vesicle transport system to escape host lysosomal or autophagosomal degradation. By using a yeast mis-sorting assay, we found 10 C. pneumoniae candidate genes involved in aberrant vesicular trafficking in host cells. One of the candidate genes, CPj0783, was recognized by antibodies from C. pneumoniae-infected patients. The expression of CPj0783 was detected at mid to late-cycle time points and increased during the inclusion maturation. Two-hybrid screening in yeast cells revealed that CPj0783 interacted with Huntingtin-interacting protein 14 (HIP14). The specific interaction between CPj0783 and HIP14 could be demonstrated by an in vivo co-immunoprecipitation assay and an in vitro GST pull-down assay. It was also demonstrated that HIP14 was localized in the Golgi apparatus and colocalized with CPj0783. HIP14 has a palmitoyl transferase activity that is involved in the palmitoylation-dependent vesicular trafficking of several acylated proteins. These findings suggest that CPj0783 might cause abnormal vesicle-mediated transport by interacting with HIP14. [Int Microbiol 18(4):225-233 (2015)]Keywords: Chlamydia pneumoniae · intracellular pathogens · yeast two-hybrid screening CPj0783–HIP14 · protein mis-sorting · vesicle transpor

The effects of exogenous ghrelin on dextran sodium sulfate-induced colitis in lean and obese mice

Ghrelin is a peptide hormone possessing a variety of physiological and pharmacological actions. This study aims to investigate the anti-inflammatory effects of exogenous ghrelin on chemically induced colitis in genetically predisposed lean (TSNO) and obese (TSOD) mice after different schedule of administration. To induce colitis, animals were given drinking water containing 2% dextran sodium sulfate (DSS) for 5 days. The TSOD and TSNO mice received daily intraperitoneal injections with saline (100 μl/day) or ghrelin (70 nmol/kg/day) for 5 days simultaneously or after DSS treatment. The severity of colitis was assessed by measuring body weight, colon length, histological analysis, plasma tumor necrosis factorα (TNFα) concentration and expression of pro-inflammatory cytokines in the colonic mucosa. At day 10, ghrelin administered after the DSS treatment slightly enhanced colonic inflammation in TSNO mice. On the other hand, ghrelin administration resulted in the partial improvement of colonic inflammation in TSOD mice. Furthermore, ghrelin administered simultaneously with DSS treatment might have slightly ameliorated some inflammation, as indicated by values compared with the after-treatment mice. Our findings suggested that the effects of ghrelin on chemically induced colitis were different between lean and obese mice, and depend on the timing of ghrelin treatment. Therefore, we should consider these points when using ghrelin as an anti-inflammatory agent in inflammation models

Heme and non-heme iron transporters in non-polarized and polarized cells

<p>Abstract</p> <p>Background</p> <p>Heme and non-heme iron from diet, and recycled iron from hemoglobin are important products of the synthesis of iron-containing molecules. In excess, iron is potentially toxic because it can produce reactive oxygen species through the Fenton reaction. Humans can absorb, transport, store, and recycle iron without an excretory system to remove excess iron. Two candidate heme transporters and two iron transporters have been reported thus far. Heme incorporated into cells is degraded by heme oxygenases (HOs), and the iron product is reutilized by the body. To specify the processes of heme uptake and degradation, and the reutilization of iron, we determined the subcellular localizations of these transporters and HOs.</p> <p>Results</p> <p>In this study, we analyzed the subcellular localizations of 2 isoenzymes of HOs, 4 isoforms of divalent metal transporter 1 (DMT1), and 2 candidate heme transporters--heme carrier protein 1 (HCP1) and heme responsive gene-1 (HRG-1)--in non-polarized and polarized cells. In non-polarized cells, HCP1, HRG-1, and DMT1A-I are located in the plasma membrane. In polarized cells, they show distinct localizations: HCP1 and DMT1A-I are located in the apical membrane, whereas HRG-1 is located in the basolateral membrane and lysosome. 16Leu at DMT1A-I N-terminal cytosolic domain was found to be crucial for plasma membrane localization. HOs are located in smooth endoplasmic reticulum and colocalize with NADPH-cytochrome P450 reductase.</p> <p>Conclusions</p> <p>HCP1 and DMT1A-I are localized to the apical membrane, and HRG-1 to the basolateral membrane and lysosome. These findings suggest that HCP1 and DMT1A-I have functions in the uptake of dietary heme and non-heme iron. HRG-1 can transport endocytosed heme from the lysosome into the cytosol. These localization studies support a model in which cytosolic heme can be degraded by HOs, and the resulting iron is exported into tissue fluids via the iron transporter ferroportin 1, which is expressed in the basolateral membrane in enterocytes or in the plasma membrane in macrophages. The liberated iron is transported by transferrin and reutilized for hemoglobin synthesis in the erythroid system.</p

日本维持性血液透析患者蛋白质能量消耗的患病率和诊断标准评估

Background and Objectives: The International Society of Renal Nutrition and Metabolism (ISRNM) has recently recommended the use of the term “protein-energy wasting” (PEW). PEW is a state of malnutrition with decreased body stores of protein and energy fuel in hemodialysis patients and is known as a risk factor for morbidity and mortality. We examined the prevalence of PEW and the characteristics of PEW patients in a hemodialysis center in Japan. Methods and Study Design: Fifty-nine outpatients undergoing maintenance hemodialysis at Iga City General Hospital were evaluated. We observed their biochemical data, body composition, dietary intake, and the number of steps prospectively. PEW was defined according to ISRNM criteria. Results: Nine patients (15% of total) were diagnosed as having PEW. Among indicators of PEW criteria, the relevance ratios of “reduced muscle mass” and “unintentional low dietary energy intake” were significantly higher in PEW than in non-PEW. The number of steps was lower, and serum levels of glucose and C-reactive protein were higher in PEW. Conclusion: About 15% of Japanese hemodialysis patients are estimated to have PEW. Our results suggested that major contributing factors to PEW were reduced muscle mass, unintentional low dietary energy intake, lower amount of exercise, insulin resistance, and chronic inflammation.背景与目的：国际肾营养与代谢协会（ISRNM）最近推荐使用术语“蛋白质能量消耗（PEW）”。PEW 是血液透析患者体内蛋白质和能量储存减少的一种营养不良状态，并且被认为是患病率和死亡率的危险因素。我们在日本的一个血液透析中心研究了PEW 的患病率和PEW 患者的特征。方法与研究设计：我们评估了58 名在伊贺市综合医院做维持性血液透析的门诊患者，并观察了他们的生化数据、体成分、膳食摄入量和行走的步数。根据ISRNM 标准诊断PEW。结果：9 名（占总数的15%）患者被诊断为PEW。在PEW 诊断标准指标中，PEW 患者“肌肉量减少”和“无意识的低膳食能量摄入”的比例高于非PEW 患者。PEW 患者中行走的步数较低，而血清葡萄糖和C-反应蛋白水平较高。结论：约有15%的日本血液透析患者患有PEW。我们的研究结果表明：引起PEW 的主要因素是肌肉量减少、无意识的低膳食能量摄入、运动量低、胰岛素抵抗和慢性炎症

Development and Validation of Cutoff Value for Reduced Muscle Mass for GLIM Criteria in Patients with Gastrointestinal and Hepatobiliary–Pancreatic Cancers

The Global Leadership Initiative on Malnutrition (GLIM) criteria recommends using race- and sex-adjusted cutoff values for reduced muscle mass (RMM), but the only cutoff values available for Asians are the skeletal muscle mass index (SMI) established by the Asian Working Group for Sarcopenia (AWGS). This retrospective study aimed to develop and validate cutoff values for the fat-free mass index (FFMI) and arm circumference (AC) of Asians, and to investigate the association between GLIM malnutrition and prognosis. A total of 660 patients with primary gastrointestinal (GI) and hepatobiliary–pancreatic (HBP) cancers who underwent their first resection surgery were recruited and randomly divided into development and validation groups. The FFMI and AC cutoff values were calculated by receiver operating characteristic curve analysis for the AWGS SMI as the gold standard. The cutoff values for each RMM were used to diagnose malnutrition on the basis of GLIM criteria, and the survival rates were compared. The optimal FFMI cutoff values for RMM were 17 kg/m2 for men and 15 kg/m2 for women, and for AC were 27 cm for men and 25 cm for women. In the validation group, the accuracy of the FFMI and AC cutoff values to discriminate RMM were 85.2% and 68.8%, respectively. Using any of the three measures of RMM, overall survival rates were significantly lower in the GLIM malnutrition group. In conclusion, the cutoff values for the FFMI and AC in this study could discriminate RMM, and GLIM malnutrition using these cutoff values was associated with decreased survival

Cancer Chemopreventive Ability of Conjugated Linolenic Acids

Conjugated fatty acids (CFA) have received increased interest because of their beneficial effects on human health, including preventing cancer development. Conjugated linoleic acids (CLA) are such CFA, and have been reviewed extensively for their multiple biological activities. In contrast to other types of CFAs including CLA that are found at low concentrations (less than 1%) in natural products, conjugated linolenic acids (CLN) are the only CFAs that occur in higher quantities in natural products. Some plant seeds contain a considerably high concentration of CLN (30 to 70 wt% lipid). Our research group has screened CLN from different plant seed oils to determine their cancer chemopreventive ability. This review describes the physiological functions of CLN isomers that occur in certain plant seeds. CLN are able to induce apoptosis through decrease of Bcl-2 protein in certain human cancer cell lines, increase expression of peroxisome proliferator-activated receptor (PPAR)-γ, and up-regulate gene expression of p53. Findings in our preclinical animal studies have indicated that feeding with CLN resulted in inhibition of colorectal tumorigenesis through modulation of apoptosis and expression of PPARγ and p53. In this review, we summarize chemopreventive efficacy of CLN against cancer development, especially colorectal cancer

Body fat mass is correlated with serum transthyretin levels in maintenance hemodialysis patients

Serum transthyretin (TTR), also known as prealbumin, is a reliable nutritional indicator and an independent prognostic factor for maintenance hemodialysis patients. However, we recently reported that serum TTR levels did not affect protein−energy wasting (PEW). In this study, we investigated factors affecting serum TTR levels in 60 maintenance hemodialysis patients. The patients were divided into High-TTR and Low-TTR groups according to the median serum TTR level. Albumin levels were significantly higher and C-reactive protein (CRP) levels were significantly lower in the High-TTR group than in the Low-TTR group. Although body fat mass was significantly higher in the High-TTR group than in the Low-TTR group, no significant difference in body fat ratio were observed. These findings suggest that body fat mass is related to serum TTR levels, apart from factors such as albumin and CRP levels, which showed correlations with serum TTR levels. Because body fat mass is related to better survival in maintenance hemodialysis patients, it may contribute to the prognostic value of serum TTR levels. In addition, in such patients, it may be important to evaluate body fatmass rather than body fat ratio and to maintain the minimum necessary body fat mass