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Energy expenditure and energy intake need to be balanced to maintain proper energy homeostasis. Energy homeostasis is tightly regulated by the central nervous system, and the hypothalamus is the primary center for the regulation of energy balance. The hypothalamus exerts its effect through both humoral and neuronal mechanisms, and each hypothalamic area has a distinct role in the regulation of energy expenditure. Recent studies have advanced the understanding of the molecular regulation of energy expenditure and thermogenesis in the hypothalamus with targeted manipulation techniques of the mouse genome and neuronal function. In this review, we elucidate recent progress in understanding the mechanism of how the hypothalamus affects basal metabolism, modulates physical activity, and adapts to environmental temperature and food intake changes.

Gut microbiota provide numerous types of metabolites that humans cannot produce and have a huge influence on the host metabolism. Accordingly, gut bacteria-derived metabolites can be employed as a resource to develop anti-obesity and metabolism-modulating drugs.This study aimed to examine the anti-adipogenic effect of 3-phenylpropionylglycine (PPG), which is a glycine conjugate of bacteria-derived 3-phenylpropionic acid (PPA).The effect of PPG on preadipocyte-to-adipocyte differentiation was evaluated in 3T3-L1 differentiation models and the degree of the differentiation was estimated by Oil red O staining. The molecular mechanisms of the PPG effect were investigated with transcriptome analyses using RNA-sequencing and quantitative real-time PCR.PPG suppressed lipid droplet accumulation during the adipogenic differentiation of 3T3-L1 cells, which is attributed to down-regulation of lipogenic genes such as acetyl CoA carboxylase 1 (Acc1) and fatty acid synthase (Fasn). However, other chemicals with chemical structures similar to PPG, including cinnamoylglycine and hippuric acid, had little effect on the lipid accumulation of 3T3-L1 cells. In transcriptomic analysis, PPG suppressed the expression of adipogenesis and metabolism-related gene sets, which is highly associated with downregulation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Protein-protein association network analysis suggested adiponectin as a hub gene in the network of genes that were differentially expressed genes in response to PPG treatment.PPG inhibits preadipocyte-to-adipocyte differentiation by suppressing the adiponectin-PPAR pathway. These data provide a potential candidate from bacteria-derived metabolites with anti-adipogenic effects.

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase Sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT-NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ contents show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibited the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, systemic administration of NAMPT peptide increased hypothalamic NAD+ levels during the physically-inactive daytime and stimulated LMA and EE through the hypothalamic NAD+-SIRT2-FOXO1-melanocortin pathway. Notably, obese humans and animals displayed a markedly blunted diurnal oscillation in blood eNAMPT and hypothalamic NAD+-FOXO1 levels as well as LMA and EE. Our findings indicate that the eNAMPT-mediated interorgan regulation of NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.

N6-Methyladenosine (m6A) RNA modification plays a critical role in the posttranscriptional regulation of gene expression. Alterations in cellular m6A levels and m6A-related genes have been reported in many cancers, but whether they play oncogenic or tumor-suppressive roles is inconsistent across cancer types. We investigated common features of alterations in m6A modification and m6A-related genes during carcinogenesis by analyzing transcriptome data of 11 solid tumors from The Cancer Genome Atlas database and our in-house gastric cancer cohort. We calculated m6A writer (W), eraser (E), and reader (R) signatures based on corresponding gene expression. Alterations in the W and E signatures varied according to the cancer type, with a strong positive correlation between the W and E signatures in all types. When the patients were divided according to m6A levels estimated by the ratio of the W and E signatures, the prognostic effect of m6A was inconsistent according to the cancer type. The R and especially the R2 signatures (based on the expression of IGF2BPs) were upregulated in all cancers. Patients with a high R2 signature exhibited poor prognosis across types, which was attributed to enrichment of cell cycle- and epithelial–mesenchymal transition-related pathways. Our study demonstrates common features of m6A alterations across cancer types and suggests that targeting m6A R proteins is a promising strategy for cancer treatment.

Taste sensation is the gatekeeper for direct decisions on feeding behavior and evaluating the quality of food. Nutritious and beneficial substances such as sugars and amino acids are represented by sweet and umami tastes, respectively, whereas noxious substances and toxins by bitter or sour tastes. Essential electrolytes including Na+ and other ions are recognized by the salty taste. Gustatory information is initially generated by taste buds in the oral cavity, projected into the central nervous system, and finally processed to provide input signals for food recognition, regulation of metabolism and physiology, and higher-order brain functions such as learning and memory, emotion, and reward. Therefore, understanding the peripheral taste system is fundamental for the development of technologies to regulate the endocrine system and improve whole-body metabolism. In this review article, we introduce previous widely-accepted views on the physiology and genetics of peripheral taste cells and primary gustatory neurons, and discuss key findings from the past decade that have raised novel questions or solved previously raised questions.

Angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) expression levels are increased by exercise in skeletal muscle. We have previously shown that Angptl4 regulates food intake and energy expenditure via modulation of hypothalamic AMP-activated protein kinase (AMPK) activity. AMPK is an important signaling molecule that integrates skeletal muscle metabolism during exercise. Therefore, we investigated the involvement of Angptl4 in exercise-induced AMPK activation in skeletal muscle. Angptl4 protein and mRNA expression levels were significantly increased in the gastrocnemius and soleus muscles of mice following a 50-min running bout. Treatment of C2C12 myotubes with Angptl4 increased phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), which were markers of AMPK activation, and the mitochondrial maximum respiratory capacity. Treadmill exercise increased AMPK and ACC phosphorylation in the gastrocnemius of normal mice; this phosphorylation increase was attenuated in mice lacking Angptl4. Endurance to swimming and hanging was also reduced in Angptl4 knockout mice. Taken together, our current data demonstrate that exercise-induced upregulation of skeletal muscle Angptl4 is critical for AMPK activation and exercise tolerance. These findings unveil a new role for skeletal muscle Angptl4 in exercise physiology. NEW & NOTEWORTHY 1) Angiopoietin-like protein 4 (Angptl4) treatment activates AMP-activated protein kinase (AMPK) signaling in skeletal muscle cells. 2) Angptl4 increases the maximum mitochondrial oxidative capacity through AMPK activation in skeletal muscle cells. 3) Lack of Angptl4 mitigates exercise-induced skeletal muscle AMPK activation. 4) Angptl4-deficient mice show a lower endurance to exercise.

Context Serotonin acts as a neurotransmitter in the central and enteric nervous systems, modulating psychological, metabolic and gastrointestinal functions. Serotonin is also found in the serum or plasma, indicating its potential role as a hormone. Objective We aimed to assess the 24-hour diurnal profile of serum serotonin in relation to meal ingestion in healthy adult men. Methods Ten healthy (5 lean and 5 obese) male subjects were enrolled in this study. Blood samples were drawn every 30-60 minutes throughout a 24-hour period to determine the serotonin levels. Three meals were provided on a fixed schedule. To confirm the effect of meal intake on serum serotonin levels, 4 subjects underwent fasting until 1500 h and were then provided a meal without notice. Results Serum serotonin levels had distinct diurnal variations, with the highest levels early in the morning and the lowest levels in the midafternoon and during sleep. Notably, these diurnal oscillations were markedly reduced in obese subjects. Fluctuations in serum serotonin levels were associated with meal intake, and the levels peaked 30 minutes before meals and exhibited a trough during the postprandial period. Fasting blunted the meal-related oscillations in serum serotonin levels. Moreover, unexpected meal intake did not lead to a premeal increase in serum serotonin levels. Conclusions Serum serotonin levels displayed meal-related diurnal oscillations, which were disrupted by fasting and obesity. These findings suggest the possibility that circulating serotonin modulates metabolic function in humans.

Insulin secretion from pancreatic islet β-cells is primarily regulated by the blood glucose level, and also modulated by a number of biological factors produced inside the islets or released from remote organs. Previous studies have shown that angiopoietin-like protein 4 (Angptl4) controls glucose and lipid metabolism through its actions in the liver, adipose tissue, and skeletal muscles. In this present study, we investigated the possible role of Angptl4 in the regulation of insulin secretion from pancreatic islets. Angptl4 was found to be highly expressed in the α-cells but not β-cells of rodent islets. Moreover, treatment of rodent islets with Angptl4 peptide potentiated glucose-stimulated insulin secretion through a protein kinase A-dependent mechanism. Consistently, Angptl4 knockout mice showed impaired glucose tolerance. In the cultured islets from Angptl4 knockout mice, glucose-stimulated insulin secretion was significantly lower than in islets from wild type mice. Angptl4 peptide replacement partially reversed this reduction. Moreover, Angptl4 knockout mice had dysmorphic islets with abnormally distributed α-cells. In contrast, the β-cell mass and distribution were not significantly altered in these knockout mice. Our current data collectively suggest that Angptl4 may play a critical role in the regulation of insulin secretion and islet morphogenesis.

Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways.

Background We evaluated the effects of two dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin and vildagliptin, on metabolic parameters in patients with type 2 diabetes mellitus. Methods A total of 170 type 2 diabetes patients treated with sitagliptin or vildagliptin for more than 24 weeks were selected. The patients were separated into two groups, sitagliptin (100 mg once daily, n=93) and vildagliptin (50 mg twice daily, n=77). We compared the effect of each DPP-4 inhibitor on metabolic parameters, including the fasting plasma glucose (FPG), postprandial glucose (PPG), glycated hemoglobin (HbA1c), and glycated albumin (GA) levels, and lipid parameters at baseline and after 24 weeks of treatment. Results The HbA1c, FPG, and GA levels were similar between the two groups at baseline, but the sitagliptin group displayed a higher PPG level (P=0.03). After 24 weeks of treatment, all of the glucose-related parameters were significantly decreased in both groups (P=0.001). The levels of total cholesterol and triglycerides were only reduced in the vildagliptin group (P=0.001), although the sitagliptin group received a larger quantity of statins than the vildagliptin group (P=0.002).The mean change in the glucose- and lipid-related parameters after 24 weeks of treatment were not significantly different between the two groups (P=not significant). Neither sitagliptin nor vildagliptin treatment was associated with a reduction in the high sensitive C-reactive protein level (P=0.714). Conclusion Vildagliptin and sitagliptin exert a similar effect on metabolic parameters, but vildagliptin exerts a more potent beneficial effect on lipid parameters.

Objective The aim of this study was to examine the association between common polymorphisms of the adiponectin gene (ADIPOQ) and microvascular complications in patients with type 2 diabetes mellitus (T2DM). Research design and methods Rs2241766 and rs1501299 of ADIPOQ were genotyped in 708 patients with T2DM. Fundus photography, nerve conducting velocity, and urine analysis were performed to check for the presence of microvascular complications including diabetic nephropathy, retinopathy and neuropathy. Results The prevalence of diabetic nephropathy tended to be different according to rs2241766 genotype (p = 0.057) and the GG genotype of rs2241766 was associated with diabetic nephropathy [urine albumin/creatinine ratio (UACR) greater than 30 mg/g] after adjusting for age, sex, body mass index, duration of diabetes, HDL-cholesterol, smoking status, and blood pressure (odds ratio = 1.96; 95% confidence interval = 1.01–3.82, p = 0.049). Also, the G allele of rs2241766 demonstrated a trend to be associated with an increase in UACR (p = 0.087). Rs2241766 genotype was not associated with diabetic retinopathy (p = 0.955) and neuropathy (p = 0.104) or any diabetic microvascular complications (p = 0.104). There was no significant association between the rs1501299 genotype of ADIPOQ and the prevalence of diabetic retinopathy and neuropathy or any diabetic microvascular complications even after adjustment. Conclusion These data suggest that the GG genotype at rs2241766 is implicated in the pathogenesis of risk for diabetic nephropathy defined as UACR greater than 30 mg/day in patients with T2DM.

Type 2 diabetes (T2D) in Asian populations is characterized by a lower body mass index (BMI) than in Caucasian cases. This pilot study investigated antidiabetic outcomes after a Roux-en-Y gastric bypass (RYGB) in Asian subjects with T2D and BMI

Supplemental Digital Content is available in the text, Incretin hormone-based therapy in type 2 diabetes has been widely used, and dipepdityl peptidase-4 (DPP-4) inhibitors, which prevent incretin degradation, have become popular oral hypoglycemic agents. The efficacy of DPP-4 inhibitors varies from individuals, and factors determining responses to DPP-4 inhibitors have not been fully established. We aimed to investigate whether genetic variations in glucagon-like peptide (GLP-1) receptor are associated with responses to DPP-4 inhibitors in patients with type 2 diabetes. Genetic variations of rs3765467 in GLP-1 receptor were explored in 246 patients with type 2 diabetes who received DPP-4 inhibitors treatment for 24 weeks in addition to previous medication. Patients with glycated hemoglobin (HbA1c) > 7% and who were naive to any DPP-4 inhibitors were enrolled. Responders were defined as those who showed a > 10% reduction in HbA1c after DPP-4 inhibitor treatment. DPP-4 inhibitors improved glycemic parameters and lipid profiles. Compared to the major genotype (GG), a larger proportion of patients with the minor allele genotype (GA/AA) were responders (P = 0.018), and also showing greater HbA1c reductions (1.3 ± 1.1 vs 0.9 ± 1.2%; P = 0.022). This genetic effect remained significant even after adjustment for other confounding factors (OR = 2.00, 95% CI = 1.03–3.89). Polymorphism in the GLP-1 receptor may influence DPP-4 inhibitor response. Further studies in larger population will help determine the association between genetic variation and interindividual differences in DPP-4 inhibitor therapy.

SUMMARY Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS inhibition completely abrogates macrophage accumulation and activation, proinflammatory cytokine overproduction, reactive astrogliosis, blood-brain-barrier permeability, and lipid accumulation in the ARC of obese mice. Moreover, central iNOS inhibition improves obesity-induced alterations in systemic glucose metabolism without affecting adiposity. Our findings suggest a critical role for hypothalamic macrophage-expressed iNOS in hypothalamic inflammation and abnormal glucose metabolism in cases of overnutrition-induced obesity., In Brief Lee et al. demonstrate in mice that, upon prolonged high-fat diet feeding, hypothalamic macrophages proliferate, expand their pool, and sustain hypothalamic inflammation. Moreover, they show that hypothalamic macrophage iNOS inhibition diminishes macrophage activation, astrogliosis, blood-brain-barrier permeability, and impaired glucose metabolism in diet-induced obese mice., Graphical Abstract

Presensitization to human leukocyte antigen (HLA) tends to decrease renal graft survival. During the pregnancy, fetal blood is frequently exposed to the maternal circulation possibly inducing maternal immunization to paternal HLA inherited by the fetus. In this way, pregnancy may occasionally present a hazard to renal graft survival. In this study, we compared retrospectively graft survivals according to living related donor-recipient pairs.From July 1979 to January 2011, 374 patients underwent living related renal transplantation sharing at least one HLA haplotype with their donor. We compared acute rejection and complication rates as well as long-term graft survival according to the donor-recipient paring: child-to-mother, child-to-father, mother-to-child, father-to-child, and one haplotype-matched siblings. All patients received immunosuppressive therapy, consisting of a calcineurin inhibitor, mycophenolate mofetil, or azathioprine and prednisolone.Twenty-one cases (5.6%) were child-to-father paring; 28 (7.5%), child-to-mother; 179 (47.9%), one-haplotype-matched siblings; 46 (12.3%), father-to-child; and 100 (26.7%), mother-to-child paring. Child-to-father pairing displayed the best graft survival; child-to-mother (hazard ratio [HR] = 1.709, P = .662) and one-haplotype-matched siblings (HR = 6.589, P = .062) showed no significant difference. Father-to-child pares experienced poorer outcomes than child-to-father pairs (HR = 11.579, P = .017) and mother-to-child, the poorest graft survival (HR 17.188, P = .005).Pregnancy continues to be a significant source of presensitization in the course of gestation and after parturition. Graft failure can result from an anamnestic reaction subsequent to intrauterine exposure of the mother to HLA of a fetus due to sensitization.

Background Dystroglycan (DG) is a recently focused adhesion molecule with possible roles in cancer development and progression. We investigated correlations between α-DG expression and prognosis in gastric carcinoma with liver metastasis. Methods For 40 patients with gastric adenocarcinoma and liver-only metastasis, α-DG expression was determined by immunohistochemistry in paraffin-embedded surgical specimens of resected stomach tumor, resected liver metastasis, and their normal counterpart tissues. Correlations between α-DG expression and prognosis were retrospectively analyzed. Results α-DG expression was higher in primary gastric cancer (P = 0.006) and lower in liver metastasis (P = 0.002) than in each normal counterpart. In primary stomach cancer, patients who had lower α-DG expression in tumors than in normal counterparts showed poor overall survival (OS) (P = 0.028). In contrast, in the liver, patients who had higher α-DG expression in tumors than in normal counterparts showed poor OS (P = 0.022). Also, higher α-DG expression in liver metastasis than in stomach tumors led to poor recurrence-free survival (P = 0.023) and OS (P = 0.056). Conclusions This approach may be used to further understanding of the pathogenesis of liver metastasis from gastric cancer. Further studies are warranted to reveal the mechanisms of α-DG dysregulation in liver metastasis. J. Surg. Oncol. 2009;100:459–465. © 2009 Wiley-Liss, Inc.

Objective Estrogen plays an important role in the control of energy balance in the hypothalamus. Leptin-independent STAT3 activation (i.e., tyrosine 705 -phosphorylation of STAT3, pSTAT3) in the hypothalamus is hypothesized as the primary mechanism of the estrogen-induced anorexic response. However, the type of estrogen receptor that mediates this regulation is unknown. We investigated the role of the G protein-coupled receptor 30 (GPR30) in estradiol (E2)-induced STAT3 activation in the hypothalamus. Materials/methods Regulation of STAT3 activation by E2, G-1, a specific agonist of GPR30 and G-15, a specific antagonist of GPR30 was analyzed in vitro and in vivo . Effect of GPR30 activation on eating behavior was analyzed in vivo . Results E2 stimulated pSTAT3 in cells expressing GPR30, but not expressing estrogen receptor ERα and ERβ. G-1 induced pSTAT3, and G-15 inhibited E2-induced pSTAT3 in primary cultures of hypothalamic neurons. A cerebroventricular injection of G-1 increased pSTAT3 in the arcuate nucleus of mice, which was associated with a decrease in food intake and body weight gain. Conclusions These results suggest that GPR30 is the estrogen receptor that mediates the anorectic effect of estrogen through the STAT3 pathway in the hypothalamus.

BACKGROUND Dysglycemia and dyslipidemia are important metabolic complications of organ transplantation. Statins are widely used to control dyslipidemia; however, long-term use of statins is related to diabetes mellitus (DM) and impaired fasting glucose (IFG). The aim of this study was to evaluate the influence of statins on the development of dysglycemia (IFG and/or DM) in renal allograft recipients. METHODS A total of 394 patients without previously known DM or IFG who underwent kidney transplantation were enrolled. Patients were grouped into the two groups according to the use of statin (control, n=149; statin, n=245). The major statins used were fluvastatin (80 mg/d, n=134) and atorvastatin (20 mg/d, n=111). We compared the incidence of IFG or DM during the follow-up period. RESULTS The incidence of IFG was higher in the statin group than that in the control group (28.6% vs. 8.7%, P

Background: The dipeptidyl peptidase-4 (DPP4) inhibitors have become widely used antidiabetic medication. They control glycemia by interacting with serum DPP4 to interfere catalyzation of incretins. The aim of this pilot study was to discover the DPP4 polymorphisms that could affect the efficacy of vildagliptin, a DPP-4 inhibitor in diabetic patients. Methods: Genetic variations in DPP4 were identified in 48 patients with type 2 diabetes who received vildagliptin treatment at least 12 weeks following metformin monotherapy. Luciferase assay was performed to estimate the effect of the regulatory single nucleotide polymorphism (SNP) on expression of DPP4. Results: Eight tagging SNPs were genotyped in a sample of 24 patients. Additional sample of 24 patients was used to discover further regulatory SNPs and coding SNPs. In all 48 patients, responders (degree of HbA1c and/or fasting glucose level decrease greater than 10% of baseline after 12 weeks of vildagliptin add-on treatment) did not show any significant difference in selected six DPP4 polymorphisms from non-responders. DPP4 expression was not different according to g.-234A/C in luciferase assay. Conclusion: Our pilot study could not find any significant genetic variant which is associated with vildagliptin response in patients with type 2 diabetes. Further studies in large population are warranted.

SummaryContext It was previously reported in Korea that there were 1·4 case per million per year of acromegaly. This was low in comparison with the extrapolated values of Western European countries. We expected that the incidence of acromegaly would be much higher now because of recently improved medical facilities, diagnostic tools and coverage of medical insurance to all the population of South Korea. Objective The purpose of this nationwide survey was to examine the incidence and prevalence of patients with acromegaly, mode of treatment and outcome of surgical treatment of recent 5 years. Design and patients We requested and collected the medical records of all possible patients with acromegaly from 74 secondary or tertiary medical institutes in Korea from 2003 to 2007 retrospectively. Measurements Date of diagnosis and treatment, tumour size, pre- and postoperative hormonal level, treatment modality and usage of medication were collected. Results During 5 years, 1350 patients with acromegaly had been registered. The average annual incidence was 3·9 cases per million during this period, and prevalence had increased up to 27·9 cases per million in 2007. Male/female ratio was 1:1·2, and mean age at diagnosis was 44·1 years. Macroadenoma was dominant (82·9%). Transsphenoidal adenoidectomy was used the most as primary treatment (90·4%). Conclusions This Korean acromegaly survey offers a realistic overview of the predominant epidemiological characteristics of acromegaly in Korea. Annual incidence was at a similar level with western countries. Efforts to diagnose and control the disease earlier are recommended.

Dystroglycan (DG) is a recently focused adhesion molecule with possible roles in cancer development and progression. We investigated correlations between alpha-DG expression and prognosis in gastric carcinoma with liver metastasis.For 40 patients with gastric adenocarcinoma and liver-only metastasis, alpha-DG expression was determined by immunohistochemistry in paraffin-embedded surgical specimens of resected stomach tumor, resected liver metastasis, and their normal counterpart tissues. Correlations between alpha-DG expression and prognosis were retrospectively analyzed.alpha-DG expression was higher in primary gastric cancer (P = 0.006) and lower in liver metastasis (P = 0.002) than in each normal counterpart. In primary stomach cancer, patients who had lower alpha-DG expression in tumors than in normal counterparts showed poor overall survival (OS) (P = 0.028). In contrast, in the liver, patients who had higher alpha-DG expression in tumors than in normal counterparts showed poor OS (P = 0.022). Also, higher alpha-DG expression in liver metastasis than in stomach tumors led to poor recurrence-free survival (P = 0.023) and OS (P = 0.056).This approach may be used to further understanding of the pathogenesis of liver metastasis from gastric cancer. Further studies are warranted to reveal the mechanisms of alpha-DG dysregulation in liver metastasis.

Heme oxygenase (HO)-1 is a key enzyme in cytoprotective mechanisms against oxidative stress in the cardiovascular-renal system. The T(-413)A single nucleotide polymorphism (SNP) and (GT)n microsatellite polymorphism in the HO-1 gene promoter modulate the HO-1 gene transcriptional activity and these polymorphisms are associated with various human diseases. We investigated the association between HO-1 promoter polymorphisms and nephropathy in type 2 diabetes. We sequenced the T(-413)A SNP and (GT)n repeat segments of the HO-1 gene promoter in 536 patients with type 2 diabetes. (GT)n alleles were divided into 2 groups: short (S, ≤25 GT repeats) and long (L, >25 GT repeats) alleles. The presence of albuminuria was used as a marker of diabetic nephropathy. Patients with the TT genotype in the T(-413)A SNP were significantly more susceptible to albuminuria development than those carrying the A allele, with an odds ratio of 1.577 (95% confidence interval, 1.088 − 2.285; P = 0.016). Subgroup analysis showed that patients carrying the TT genotype with long duration of diabetes (≥20 years), poor glycemic control, male gender and without hypertension had higher odds ratios for the development of albuminuria. In vitro, promoter activity of the T(-413)A SNP was higher with A allele than T allele. Regarding to the (GT)n repeats, the LL genotype showed a higher odds ratio for the development of albuminuria only in patients with hypertension when compared to the S allele. In conclusion, the T(-413)A SNP in the HO-1 promoter is significantly associated with albuminuria development in type 2 diabetes patients, especially with longer duration and poor glycemic control.