Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A.

Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/cationic amino acid transporter 1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via the activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a posttranslational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors, by the inhibition of deoxyhypusine synthase, abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A, and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This affected pathway is critical for eIF5A-regulated erythropoiesis, as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins (RPs) were especially sensitive to the loss of hypusine, and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in chromosome 5q deletions in myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis, and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPCs, synchronizing mitochondrial metabolism with erythroid differentiation.

Location matters: cellular heterogeneity in the hepatic lobule and hepatocellular carcinoma.

Tumor heterogeneity is a hallmark of cancer but a challenging problem to dissect mechanistically. Less recognized is that cells within normal tissues are also remarkably diverse. Hepatocytes are a great example because their spatial positioning and the local microenvironment govern their genetic heterogeneity. Recent studies show that primary liver tumors display heterogeneity similar to that observed in the normal tissue providing clues to the cellular precursor of the tumor and how variations in the lobule microenvironment support tumor formation and aggressiveness. Identifying the principles that control cellular diversity in a healthy liver may highlight potential mechanisms driving hepatic tumor heterogeneity.

Changes in renal function and predictors affecting renal outcome of living kidney donors: a nationwide prospective cohort study.

AIM: The safety of donors is an important issue in living donor kidney transplantation. We investigated serial changes in renal function and predictors affecting the renal outcome of living kidney donors. METHODS: We obtained the data of 456 kidney donors registered to the Korean Organ Transplantation Registry from 2014 to 2016. The estimated glomerular filtration rate (eGFR) changes according to the development of incident chronic kidney disease (CKD) and factors related to CKD were analysed. CKD was defined as an eGFR <60 ml/min/1.73 m2 or the presence of proteinuria or albuminuria. The change in eGFR over time was analysed using a linear mixed model. RESULTS: At 2 years after kidney donation, 21.7% of the donors (99/456) developed CKD. Annual eGFR changes after nephrectomy were 2.2 ml/min/1.73 m2 /year in donors without CKD, and - 0.4 ml/min/1.73 m2 /year in donors with CKD. Higher systolic blood pressure was associated with higher risk of CKD (odds ratio [OR] 1.322 per 10 mmHg increment, 95% confidence interval [CI] 1.036-1.686, p = .025). Higher pre-donation eGFR (OR 0.906 per 1 ml/min/1.73 m2 increment, 95% CI 0.876-0.936, p < .001) and higher ratio of eGFR at discharge to pre-donation (OR 0.603 per 0.1 increment, 95% CI 0.426-0.849, p = .004) were related to lower risk of CKD. CONCLUSION: Kidney donors without incident CKD at 2 years after donation showed gradual increases in eGFR, whereas donors with CKD had relatively constant eGFR. A low ratio of eGFR at discharge after nephrectomy to baseline was a risk factor of CKD.

15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury.

The two primary mechanisms by which iodinated contrast media (CM) causes contrast-induced acute kidney injury (CIAKI) are the hemodynamic effect causing intrarenal vasoconstriction and the tubular toxic effect causing acute tubular necrosis. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades prostaglandin E2 (PGE2), promotes tissue repair and regeneration in many organs. PGE2 causes intrarenal arterial vasodilation. In this study, we investigated whether a 15-PGDH inhibitor can act as a candidate for blocking these two major mechanisms of CIAKI. We established a CIAKI mouse model by injecting a 10 gram of iodine per body weight (gI/kg) dose of iodixanol into each mouse tail vein. A 15-PGDH inhibitor (SW033291), PGE1, or PGE2 were administered to compare the renal functional parameters, histologic injury, vasoconstriction, and renal blood flow changes. In addition, human renal proximal tubular epithelial cells were cultured in a CM-treated medium. SW033291, PGE1, or PGE2 were added to compare any changes in cell viability and apoptosis rate. CIAKI mice that received SW033291 had lower serum levels of creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 (p < 0.001); lower histologic injury score and TUNEL positive rates (p < 0.001); and higher medullary arteriolar area (p < 0.05) and renal blood flow (p < 0.001) than CM + vehicle group. In cell culture experiments, Adding SW033291 increased the viability rate (p < 0.05) and decreased the apoptosis rate of the tubular epithelial cells (p < 0.001). This 15-PGDH inhibitor blocks the two primary mechanisms of CIAKI, intrarenal vasoconstriction and tubular cell toxicity, and thus has the potential to be a novel prophylaxis for CIAKI. Abbreviations: 15-PGDH: 15-hydroxyprostaglandin dehydrogenase; AMP: adenosine monophosphate; CIAKI: contrast-induced acute kidney injury; CM: contrast media; EP: prostaglandin E2 receptor; hRPTECs: human-derived renal proximal tubule epithelial cells; KIM-1: kidney injury molecule-1; MTT: 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NGAL: neutrophil gelatinase-associated lipocalin; PBS: phosphate-buffered saline; PGE1: prostaglandin E1; PGE2: prostaglandin E2; RBF: renal blood flow; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; α-SMA: α-Smooth muscle actin.

Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway.

The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population.

Purpose: Epidermal growth factor (EGF) has been found to be associated with the development and repair mechanisms of several renal diseases. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in EGF or its receptor genes might have an association with end-stage renal disease (ESRD) or acute renal allograft rejection (AR) in a Korean population.Methods: Three-hundred and forty seven recipients of the first renal transplants for ESRD, including 63 AR patients along with 289 healthy adults were included in the study. Five EGF gene SNPs (rs11568835, rs11568943, rs2237051, rs11569017, and rs3756261) and four EGFR gene SNPs (rs1140475, rs2293347, rs1050171, and rs6965469) were analyzed. The genotypes of these SNPs were analyzed using the AxiomTM genome-wide human assay. Statistical analysis was performed using SNPStats and Haploview version 4.2 software. Multiple logistic regression models (codominant, dominant, recessive, and Log-additive) were used to estimate the odds ratio (OR), 95% confidence interval (CI), and P value.Results: One SNP (rs11569017) in the EGF gene showed significant association with ESRD but not with AR. Another SNP (rs11568835) in the EGF gene showed significant association with susceptibility to AR but not with ESRD. One SNP (rs1050171) in the EGFR gene showed significant association with susceptibility to AR but not with ESRD.Conclusion: Our findings suggest that SNPs in the EGF and EGFR gene may be associated with the risk of ESRD and AR development in the Korean population.

Effects of mealworm (Tenebrio molitor) larvae hydrolysate on nutrient ileal digestibility in growing pigs compared to those of defatted mealworm larvae meal, fermented poultry by-product, and hydrolyzed fish soluble.

OBJECTIVE: To investigate effect of mealworm (Tenebrio molitor) larvae hydrolysate on nutrient ileal digestibility compared to those of dried mealworm larvae meal, fermented poultry by-product, and hydrolyzed fish soluble in growing pigs. METHODS: A total of 12 crossbred ([Landrace×Yorkshire]×Duroc) growing pigs with average body weight of 28.70±0.32 kg were surgically equipped with simple T-cannulas. A total of 12 pigs were assigned to individual metabolic crates and allotted to one of four treatments with 3 replicates in a fully randomized design. RESULTS: Apparent ileal digestibility (AID) of dry matter (DM) was the highest in pigs fed HML diet. AIDs of crude protein (CP) were higher in pigs fed HML and DMLM diets than those in pigs fed the other two diets. AID of total amino acid was higher (p = 0.06) in pigs fed HML diet. AIDs of lysine (Lys), methionine (Met), and threonine (Thr) were similar in pigs fed DMLM and HML diets, but were higher (p = 0.05, p<0.05, and p = 0.05, respectively) than those in pigs fed FPBM or HFS diet. Pigs fed HML diet had higher standardized ileal digestibilities (SIDs) of DM and CP (p<0.05 and p<0.05, respectively) compared to pigs fed the other FPBM and HFS diets. SIDs of total amino acid were not different (p = 0.06) between treatments. For SIDs of Lys, Met, and Thr, pigs fed HML and DMLM diets showed higher SIDs (p = 0.05, p<0.05, and p<0.05, respectively) than pigs fed FPBM and HFS diets. SIDs of non-essential amino acids (aspartic acid, glycine, and alanine) were higher (p<0.05, p< 0.05, and p<0.05, respectively) in pigs fed HML, FPBM, and DMLM diets than those in pigs fed the HFS diet. AID and SID of glutamic acid were higher in pigs fed HML and FPBM diets. CONCLUSION: In conclusion, dietary supplementation of mealworm larvae hydrolysate had higher digestibility in DM, CP, Lys, Met, and Thr compared to dietary supplementation with fermented poultry by-product and hydrolyzed fish soluble.

Multiple cellular pathways regulate lipid droplet homeostasis for the establishment of polarity in collagen sandwich-cultured hepatocytes.

Hepatocyte polarization is energy dependent. The establishment of polarization in collagen sandwich culture of hepatocytes requires utilization of lipid droplets and mitochondrial ß-oxidation to supply ATP. Multiple cellular pathways are involved in lipid droplet homeostasis; however, mechanistic insights of how hepatocytes utilize lipid droplets during polarization remain elusive. The current study investigated the effects of various pathways involved in lipid droplet homeostasis on bioenergetics during hepatocyte polarization. The results showed that hepatocytes were dependent on lipolysis of lipid droplets to release fatty acids for ß-oxidation. Inhibition of lipolysis significantly decreased cellular fatty acid and ATP levels and inhibited hepatocyte polarization, revealing that lipolysis was an important mechanism for providing energy for hepatocyte polarization. The results also demonstrated that autophagic degradation of lipid droplets (lipophagy) was not essential for breaking down lipid droplets. Conversely, autophagy contributed to lipid droplet formation and played a key role in sustaining lipid droplet stores for energy production. In addition, cholesterol biosynthesis/cholesterol esterification and de novo fatty acid synthesis also contributed to maintaining lipid droplet stores for bioenergetics during hepatocyte polarization. In summary, multiple cellular pathways are coordinated to maintain lipid droplet homeostasis and sustain fatty acid ß-oxidation during hepatocyte polarization.

Bioenergetics for Hepatocyte Polarization: Coordination of Multiple Cellular Organelles and the Master Regulator AMPK.

Hepatocytes have well-defined polarized morphological structure. Establishment and maintenance of cellular polarity is crucial to the function and viability of hepatocytes. Many disorders, both genetic and acquired, and drugs can impair hepatocyte polarization resulting in liver dysfunction and injury. Hepatocyte polarization is an energy-dependent cellular process. Hence, cellular energy metabolism can significantly affect the polarized morphology and function of hepatocytes. Recent in vitro studies have demonstrated that multiple cellular organelles, including mitochondria, auto-phagosomes and lipid droplets, are involved in the utilization of energy for hepatocyte polarization; also, AMP-dependent kinase (AMPK), a key cellular energy sensor, regulates the function and activities of these cellular organelles and thus plays an important role in bioenergetics for hepatocyte polarization. This review provides the latest understanding on how mitochondria, autophagosomes, and lipid droplets coordinate energy production, and it addresses how AMPK activation regulates these key cellular organelles for energy production during hepatocyte polarization. Furthermore, the review suggests potential directions for future research.

Comparative efficacy and safety of gemigliptin versus linagliptin in type 2 diabetes patients with renal impairment: A 40-week extension of the GUARD randomized study.

AIMS: The long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period. METHODS: The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m2 were enrolled in the main study. After 12 weeks, patients in the gemigliptin group continued to receive gemigliptin (N = 50), whereas patients in the placebo group were transitioned from placebo to linagliptin (N = 52). Each group received the indicated treatment over the subsequent 40-week period. A total of 102 patients consented to participate in the extension study, and 79 patients ultimately completed the study. RESULTS: The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00% ± 0.21% and 0.65% ± 0.22% lower at week 52 than at baseline (P < .001 and P = .003), respectively. No significant difference in the change in HbA1c level was found between the 2 groups (P = .148). Trends in fasting plasma glucose, fructosamine and glycated albumin levels in the 2 groups were similar to trends in HbA1c levels. The eGFR of both groups was also significantly lower at week 52 than at baseline, and no significant difference in change in eGFR was found between the 2 groups. In contrast, both drugs had little effect on urinary albumin excretion, although both drugs significantly reduced the urinary type IV collagen level. The overall rates of adverse events were similar between the 2 groups. CONCLUSIONS: Gemigliptin and linagliptin did not differ with respect to safety and efficacy in patients with T2DM and renal impairment. The 2 drugs had similar glucose-lowering effects, and the changes in eGFR and albuminuria were also similar. Additionally, the risk of side effects, including hypoglycaemia, was similar between the 2 groups.

Normal body mass index with central obesity has increased risk of coronary artery calcification in Korean patients with chronic kidney disease.

In chronic kidney disease (CKD), overweight and mild obesity have shown the lowest cardiovascular (CV) risk. However, central obesity has been directly associated with CV risk in these patients. This bidirectional relationship of body mass index (BMI) and central obesity prompted us to evaluate CV risk based on a combination of BMI and waist-to-hip ratio (WHR) in nondialysis CKD patients. We included 1078 patients with CKD stage 2 through 5 (nondialysis) enrolled in a nationwide prospective cohort of Korea. Patients were divided into 3 groups by BMI (normal BMI, 18.5-22.9; overweight, 23.0-27.4; and obese, 27.5 and over kg/m2) and were dichotomized by a sex-specific median WHR (0.92 in males and 0.88 in females). Coronary artery calcification (CAC) was determined by multislice computed tomography. CAC (score above 10 Agatston units) was found in 477 patients. Multivariate logistic regression analysis indicated that BMI was not independently associated with CAC. However, WHR showed an independent linear and significant association with CAC (odds ratio, 1.036; 95% confidence interval, 1.007-1.065 per 0.01 increase). Furthermore, when patients were categorized into 6 groups according to a combination of BMI and WHR, normal BMI but higher WHR had the highest risk of CAC compared with the normal BMI with lower WHR group (2.104; 1.074-4.121). Thus, a normal BMI with central obesity was associated with the highest risk of CAC, suggesting that considering BMI and WHR, 2 surrogates of obesity, can help to discriminate CV risk in Korean nondialysis CKD patients.

Serial interferon-gamma release assays for latent tuberculosis in dialysis patients with end stage renal disease in a Korean population.

BACKGROUND: Serial interferon-gamma-release-assay (IGRA) result can show variance due to within-subject variation and difference in host immune status, and may be affected by latent tuberculosis infection (LTBI) treatment. We aimed to know the changes in QFT-IT (QuantiFERON-TB Gold In-Tube) results measured at a 4 month interval in end stage renal disease patients and whether these changes were influenced by dialysis method or LTBI treatment. METHODS: We prospectively performed serial QFT-IT tests at 4 month interval in 93 end stage renal disease (ESRD) patients on HD (hemodialysis) or PD (peritoneal dialysis). LTBI treatment was given to 18 of 39 patients with initial positive QFT-IT result. Agreement between the two results was estimated for all 93 patients and reversion rates were estimated among the 39 patients with initial positive QFT-IT. RESULTS: Positive QFT-IT at the first and 2(nd) tests were 41.9 and 34.4 %, respectively. The concordance rate between baseline QFT-IT and 2(nd) QFT in 93 ESRD patients was excellent (90.3 %, kappa = 0.80, p < 0.001). Agreement between the first QFT-IT and 2(nd) QFT-IT in HD (95.3 %, kappa = 0.91, p < 0.001) was higher than in PD patients (86.0 %, kappa = 0.69, p < 0.001). Among all ESRD patients, the odds of reversion of QFT-IT was not different in those who were, or were not treated for LTBI [odds ratio = 2.3 (0.5-11.4), p = 0.43]. CONCLUSIONS: In a group of 93 dialyzed ESRD patients 8.6 % showed reversion of initial positive QFT to negative within 4 months. Reversion seemed not to be associated with LTBI treatment. Further study with larger numbers of patients is needed to investigate the variation of QFT-IT tests in dialyzed ESRD patients.

Association studies of cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene polymorphisms with acute rejection in kidney transplantation recipients.

Recent studies have shown that single-nucleotide polymorphisms (SNPs) are associated with allograft rejection in kidney transplantation recipients. We evaluated the possible association between SNPs of the cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene, and acute rejection (AR) among renal transplant patients in a Korean population. We conducted a case-control association study in 63 AR and 284 non-AR kidney transplant recipients. The SNPs of CYP2E1 were genotyped by direct sequencing. Recipient sex (p = 0.023) and the use of tacrolimus (p = 0.017) were significantly different between the two groups. The use of mycophenolate mofetil (MMF) and antibody induction therapy was significantly lower in the AR group. Multiple logistic regression models (codominant, dominant, recessive, and log-additive models) adjusted by sex and type of immunosuppressive regimens were applied to determine the odds ratios (ORs), 95% confidence intervals (CIs), and p-values. The rs2515641 of CYP2E1 showed significant differences between the AR patient group and non-AR group (p = 0.003, OR = 2.55, 95% CI = 1.37-4.75 in the codominant 1 model; p = 0.002, OR = 2.61, 95% CI = 1.43-4.77 in the dominant model; p = 0.0035, OR = 2.13, 95% CI = 1.29-3.50 in the log-additive model). The allele of the rs2515641 SNP also showed a significant association (p = 0.004, OR = 1.99, 95% CI = 1.24-3.21). This study suggests that the CYP2E1 polymorphism may be related to the development of AR in Korean kidney transplantation recipients.

KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease): design and methods.

BACKGROUND: The progression and complications of chronic kidney disease should differ depending on the cause (C), glomerular filtration rate category (G), and albuminuria (A). The KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease), which is a prospective cohort study, enrolls subjects with chronic kidney disease stages 1 to 5 (predialysis). METHODS/DESIGN: Nine nephrology centers in major university hospitals throughout Korea will enroll approximately 2,450 adults with chronic kidney disease over a 5-year period from 2011 to 2015. The participating individuals will be monitored for approximately 10 years until death or until end-stage renal disease occurs. The subjects will be classified into subgroups based on the following specific causes of chronic kidney disease: glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, polycystic kidney disease, and others. The eligible subjects will be evaluated at baseline for socio-demographic information, detailed personal/family history, office BP, quality of life, and health behaviors. After enrollment in the study, thorough assessments, including laboratory tests, cardiac evaluation and radiologic imaging, will be performed according to the standardized protocol. The biospecimen samples will be collected regularly. A renal event is defined by >50% decrease in estimated GFR (eGFR) from the baseline values, doubling of serum creatinine, or end-stage renal disease. The primary composite outcome consists of renal events, cardiovascular events, and death. As of September 2013, 1,470 adult chronic kidney disease subjects were enrolled in the study, including 543 subjects with glomerulonephritis, 317 with diabetic nephropathy, 294 with hypertensive nephropathy and 249 with polycystic kidney disease. DISCUSSION: As the first large-scale chronic kidney disease cohort study to be established and maintained longitudinally for up to 10 years, the KNOW-CKD will help to clarify the natural course, complication profiles, and risk factors of Asian populations with chronic kidney disease. TRIAL REGISTRATION: No. NCT01630486 at http://www.clinicaltrials.gov.

Short-term exposure to ambient air pollution and injuries due to external causes according to intentions and mechanisms.

Although injuries are a leading cause of death and affect the life expectancy of individuals who live with disabilities globally, the potential role of air pollution exposure on injuries due to external causes has received little scientific attention, especially compared with that given to the association of air pollution and non-external causes of morbidity and mortality. We investigated the association between emergency department visits for externally caused injuries and short-term exposure to major ambient air pollutants, with focus on the intentions and mechanisms of injuries. We identified 2,049,855 injured patients in Seoul, South Korea between 2008 and 2016 using the National Emergency Database. Daily short-term exposure to air pollution including particles <10 µm (PM10) and <2.5 µm (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide (CO), and ozone (O3) was estimated based on hourly concentrations. We employed a time-stratified case-crossover study design using a conditional Poisson regression model adjusted for meteorological variables, influenza epidemics, and holidays. Immediate exposure (lag 0) to most pollutants significantly increased the risk of total injuries (PM2.5, 0.42 %; NO2, 0.68 %; SO2, 1.05 %; CO, 0.57 %; O3, 1.86 % per interquartile range increment), and the associations differed according to the intention and mechanism of injury. Unintentional and assault injuries were significantly associated with air pollution exposure, whereas self-harm injuries showed no association. In mechanism-specific analyses, injuries caused by falls, blunt objects, penetration, traffic accidents, machinery, and slips were associated with specific air pollutants, even in the co-pollutant models. The associations were stronger in injured patients aged <15 years, and in males than in their counterparts. Our results suggest that short-term air pollution exposure might play a role in the risk of externally caused injuries and the association may differ depending on the intention and mechanism of injury, which provide important evidence for injury prevention and air quality strategies.

GPCR Screening Reveals that the Metabolite Receptor HCAR3 Regulates Epithelial Proliferation, Migration, and Cellular Respiration.

Epithelial cells in the skin and other tissues rely on signals from their environment to maintain homeostasis and respond to injury, and GPCRs play a critical role in this communication. A better understanding of the GPCRs expressed in epithelial cells will contribute to understanding the relationship between cells and their niche and could lead to developing new therapies to modulate cell fate. This study used human primary keratinocytes as a model to investigate the specific GPCRs regulating epithelial cell proliferation and differentiation. We identified 3 key receptors-HCAR3, LTB4R, and GPR137-and found that knockdown of these receptors led to changes in numerous gene networks that are important for maintaining cell identity and promoting proliferation while inhibiting differentiation. Our study also revealed that the metabolite receptor HCAR3 regulates keratinocyte migration and cellular metabolism. Knockdown of HCAR3 led to reduced keratinocyte migration and respiration, which could be attributed to altered metabolite use and aberrant mitochondrial morphology caused by the absence of the receptor. This study contributes to understanding the complex interplay between GPCR signaling and epithelial cell fate decisions.

A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.

In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal and pericentral axis. How the mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combine intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We find that periportal and pericentral mitochondria are morphologically and functionally distinct; beta-oxidation is elevated in periportal regions, while lipid synthesis is predominant in the pericentral mitochondria. In addition, comparative phosphoproteomics reveals spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifts mitochondrial phenotypes in the periportal and pericentral regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.

Association between a TGFBR2 gene polymorphism (rs2228048, Asn389Asn) and acute rejection in Korean kidney transplantation recipients.

Transforming growth factor-ß (TGF-ß) signaling transduction initiates TGF-ß activation, resulting in activation of TGF-ß receptor II (TGFBR2). Any quantitative and qualitative changes in TGFBR2 are expected to affect the TGF-ß signaling pathway, which occupies a central position with respect to the regulation of cell growth, differentiation, apoptosis, immune reaction, angiogenesis and extracellular matrix formation. Recent studies have shown that TGF-ß1 gene polymorphisms may confer susceptibility to early acute and chronic allograft rejection in kidney transplantation recipients. In this study, we assessed whether polymorphisms of the TGFBR2 gene were associated with susceptibility to kidney transplantation rejection. A total of 347 renal allograft recipients transplanted at three centers in Korea were analyzed. Three SNPs (rs764522, rs3087465, rs2228048) of the TGFBR2 gene were genotyped from genomic DNA with direct sequencing. Multiple logistic regression models (codominant, dominant, recessive, and log-additive) were performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and p-values. A total of 63 patients (18%) developed acute rejection (AR). There were no significant differences in age, sex, number of HLA mismatches, cause of renal failure, or immunosuppressant regimen between the AR and non-AR group. The synonymous SNP rs2228048 was significantly associated with AR (p = 0.020 in recessive model, and p = 0.036 in log-additive model. The allele frequencies of rs2228048 were different between the AR and non-AR group (p = 0.026). These results suggest that the synonymous TGFBR2 gene SNP rs2228048 may be associated with the development of AR in Korean kidney transplantation recipients. Authors Yeong-Hoon Kim and Tae Hee Kim contributed equally to this work and are considered co-first authors.

Angiotensinogen polymorphisms and post-transplantation diabetes mellitus in Korean renal transplant subjects.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a common and serious metabolic complication. Genetic polymorphisms of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes have been reported to be related to diabetes mellitus and insulin sensitivity; however, the role of these genes in the development of PTDM is not known. For this purpose, we investigated the association of ACE and AGT genetic polymorphisms with PTDM. METHODS: A total of 302 subjects without previously diagnosed diabetes who had received kidney transplants were included. One ACE single nucleotide polymorphism (SNP) (rs4291) and two AGT SNPs (rs 699 and rs 4762) were genotyped from genomic DNA with direct sequencing. RESULTS: PTDM developed in 49 (16.2%) of 302 subjects. Subjects in the PTDM were older than those in the non-PTDM. There was a significant difference between the two groups in tacrolimus use (p=0.03). Of the three SNPs, the rs4762 of the AGT gene was significantly associated with the development of PTDM in the dominant models (p = 0.03) after adjusting for age and tacrolimus usage. CONCLUSIONS: AGT gene rs4762 polymorphisms may serve as genetic markers for the development of PTDM. The exact molecular mechanisms still need to be clarified.

Effects of dietary trace mineral levels on physiological responses, reproductive performance, litter performance, blood profiles, and milk composition in gestating sows.

OBJECTIVE: This study was conducted to evaluate the effects of optimal trace mineral levels on the physiological responses, reproductive performance, litter performance, blood profiles and milk composition in gestating sows. METHODS: A total of 59 multiparous sows (Yorkshire×Landrace) with similar body weight (BW), backfat thickness (BF), and parity were assigned to one of four treatments with 14 or 15 sows per treatment using a completely randomized design. The treatments were 100% (M1), 300% (M3), 600% (M6), and 900% (M9) of the National Research Council (NRC) Nutrient Requirements of Swine. During lactation period, all the sows were fed the same commercial lactation diet. RESULTS: No significant differences were observed in the BW, BF, reproductive performance, milk composition, or growth performance of the piglets. On day 70 of gestation, the serum zinc concentration showed a quadratic response to M6 treatment (quadratic, p<0.05). Moreover, as the dietary mineral levels increased, the zinc concentration increased linearly at 110 days of gestation (linear, p<0.05). Furthermore, copper and iron concentrations in the serum of sows at 24 h postpartum decreased linearly when high levels of dietary minerals were provided (linear, p<0.05). In the serum of piglets, serum zinc concentrations decreased linearly (linear, p<0.05), and iron concentration showed a quadratic response (quadratic, p<0.05) with an increase in trace mineral premix levels in gestation diets. CONCLUSION: The current trace mineral requirements of NRC (2012) are suitable for gestating sows, and the addition of dietary mineral levels in the gestating diet did not show any improvements during the gestation and lactation periods.