Identification of novel Nrf2-activating neuroprotective agents: Elucidation of structural congeners of (-)-galiellalactone and congener-based novel Nrf2 activators.

Herein, (-)-galiellalactone 1 congeners responsible for the nuclear factor erythroid 2-related factor 2 (Nrf2)-activating neuroprotective effects were elucidated. Additionally, novel congener-based Nrf2 activators were identified using a drug repositioning strategy. (-)-Galiellalactone, which comprises a tricyclic lactone skeleton, significantly activates antioxidant response element (ARE)-mediated transcription in neuroblastoma SH-SY5Y cells. Interestingly, two cyclohexene-truncated [3.3] bicyclic lactone analogs, which possess an exocyclic α-methylene-γ-butyrolactone moiety, exhibited higher Nrf2/ARE transcriptional activities than the parent (-)-galiellalactone. We confirmed that the cyclohexene moiety embedding the [3.3] bicyclic lactone congener does not play the essential role of (-)-galiellalactone for Nrf2/ARE activation. Nrf2/ARE activation by novel analogs resulted in the upregulation of downstream antioxidative and phase II detoxifying enzymes, heme oxygenase-1, and NAD(P)H quinone oxidoreductase 1, which are closely related to the cytoprotective effects on neurodegenerative diseases. (-)-Galiellalactone and its [3.3] bicyclic variants 3l and 3p increased the expression of antioxidant genes and exhibited neuroprotective effects against 6-hydroxydopamine-mediated neurotoxicity in the neuroblastoma SH-SY5Y cell line.

Ursolic acid enhances autophagic clearance and ameliorates motor and non-motor symptoms in Parkinson's disease mice model.

Protein aggregation and the abnormal accumulation of aggregates are considered as common mechanisms of neurodegeneration such as Parkinson's disease (PD). Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has shown a protective activity in several experimental models of brain dysfunction through inhibiting oxidative stress and inflammatory responses and suppressing apoptotic signaling in the brain. In this study, we investigated whether UA promoted autophagic clearance of protein aggregates and attenuated the pathology and characteristic symptoms in PD mouse model. Mice were injected with rotenone (1 mg · kg-1 · d-1, i.p.) five times per week for 1 or 2 weeks. We showed that rotenone injection induced significant motor deficit and prodromal non-motor symptoms accompanied by a significant dopaminergic neuronal loss and the deposition of aggregated proteins such as p62 and ubiquitin in the substantia nigra and striatum. Co-injection of UA (10 mg · kg-1 · d-1, i.p.) ameliorated all the rotenone-induced pathological alterations. In differentiated human neuroblastoma SH-SY5Y cells, two-step treatment with a proteasome inhibitor MG132 (0.25, 2.5 µM) induced marked accumulation of ubiquitin and p62 with clear and larger aggresome formation, while UA (5 µM) significantly attenuated the MG132-induced protein accumulation. Furthermore, we demonstrated that UA (5 µM) significantly increased autophagic clearance by promoting autophagic flux in primary neuronal cells and SH-SY5Y cells; UA affected autophagy regulation by increasing the phosphorylation of JNK, which triggered the dissociation of Bcl-2 from Beclin 1. These results suggest that UA could be a promising therapeutic candidate for reducing PD progression from the prodromal stage by regulating abnormal protein accumulation in the brain.

Discovery of new ERRγ agonists regulating dopaminergic neuronal phenotype in SH-SY5Y cells.

The discovery of small molecules that regulate specific neuronal phenotypes is important for the development of new therapeutic candidates for neurological diseases. Estrogen-related receptor γ (ERRγ), an orphan nuclear receptor widely expressed in the central nervous system (CNS), is closely related to the regulation of neuronal metabolism and differentiation. We previously reported that upregulation of ERRγ could enhance dopaminergic neuronal phenotypes in the neuroblastoma cell line, SH-SY5Y. In this study, we designed and synthesized a series of new ERRγ agonists using the X-ray crystal structure of the GSK4716-bound ERRγ complex and known synthetic ligands. Our new ERRγ agonists exhibited increased transcriptional activities of ERRγ. In addition, our molecular docking results supported the experimental findings for ERRγ agonistic activity of the potent analogue, 5d. Importantly, 5d not only enhanced the expression of dopaminergic neuronal-specific molecules, TH and DAT but also activated the relevant signaling events, such as the CREB-mediated signaling pathway. The results of the present study may provide useful clues for the development of novel ERRγ agonists for neurological diseases related to the dopaminergic nervous system.

Baseline characteristics of participants enrolled in the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD).

BACKGROUND: We developed the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD) as a subcohort of KNOW-CKD to investigate the different characteristics of pediatric CKD between countries and races. METHODS: Children aged younger than 18 years with stage 1 ~ 5 CKD were recruited at seven major pediatric nephrology centers in Korea. Blood and urine samples, as well as demographic and clinical data, were collected. From 2011 to 2016, 458 children were enrolled, and the baseline profiles of 437 children were analyzed. RESULTS: The median age of the cohort was 10.9 years old, and 68.0% were males. The median estimated glomerular filtration rate was 53.1 mL/min/1.73 m2. The most common etiology of CKD was congenital anomalies of the kidney and urinary tract (42.6%), followed by glomerulopathies (25.6%). CONCLUSION: We report a cross-sectional analysis of the overall baseline characteristics such as age, CKD stage, and underlying kidney disease of the KNOW-Ped CKD. The cohort will be longitudinally followed for ten years. "A higher resolution version of the Graphical abstract is available as Supplementary information."

ERRγ ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype.

Brain derived neurotrophic factor (BDNF) promotes maturation of dopaminergic (DAergic) neurons in the midbrain and positively regulates their maintenance and outgrowth. Therefore, understanding the mechanisms regulating the BDNF signaling pathway in DAergic neurons may help discover potential therapeutic strategies for neuropsychological disorders associated with dysregulation of DAergic neurotransmission. Because estrogen-related receptor gamma (ERRγ) is highly expressed in both the fetal nervous system and adult brains during DAergic neuronal differentiation, and it is involved in regulating the DAergic neuronal phenotype, we asked in this study whether ERRγ ligand regulates BDNF signaling and subsequent DAergic neuronal phenotype. Based on the X-ray crystal structures of the ligand binding domain of ERRγ, we designed and synthesized the ERRγ agonist, (E)-4-hydroxy-N'-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2) (Kd value, 8.35 µmol/L). HPB2 increased BDNF mRNA and protein levels, and enhanced the expression of the BDNF receptor tropomyosin receptor kinase B (TrkB) in human neuroblastoma SH-SY5Y, differentiated Lund human mesencephalic (LUHMES) cells, and primary ventral mesencephalic (VM) neurons. HPB2-induced upregulation of BDNF was attenuated by GSK5182, an antagonist of ERRγ, and siRNA-mediated ERRγ silencing. HPB2-induced activation of extracellular-signal-regulated kinase (ERK) and phosphorylation of cAMP-response element binding protein (CREB) was responsible for BDNF upregulation in SH-SY5Y cells. HPB2 enhanced the DAergic neuronal phenotype, namely upregulation of tyrosine hydroxylase (TH) and DA transporter (DAT) with neurite outgrowth, both in SH-SY5Y and primary VM neurons, which was interfered by the inhibition of BDNF-TrkB signaling, ERRγ knockdown, or blockade of ERK activation. HPB2 also upregulated BDNF and TH in the striatum and induced neurite elongation in the substantia nigra of mice brain. In conclusion, ERRγ activation regulated BDNF expression and the subsequent DAergic neuronal phenotype in neuronal cells. Our results might provide new insights into the mechanism underlying the regulation of BDNF expression, leading to novel therapeutic strategies for neuropsychological disorders associated with DAergic dysregulation.

Incidence of and risk factors for short stature in children with chronic kidney disease: results from the KNOW-Ped CKD.

BACKGROUND: Preserving optimal growth has long been a significant concern for children with chronic kidney disease (CKD). We aimed to examine the incidence of and risk factors for short stature in Asian pediatric patients with CKD. METHODS: We analyzed growth status by height, weight, and body mass index (BMI) standard deviation scores (SDSs) for 432 participants in the KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease. RESULTS: The median height, weight, and BMI SDSs were - 0.94 (interquartile range (IQR) - 1.95 to 0.05), - 0.58 (IQR - 1.46 to 0.48), and - 0.26 (IQR - 1.13 to 0.61), respectively. A high prevalence of short stature (101 of 432 patients, 23.4%) and underweight (61 of 432 patients, 14.1%) was observed. In multivariable logistic regression analysis, CKD stages 4 and 5 (adjusted odds ratio (aOR) 2.700, p = 0.001), onset before age 2 (aOR 2.928, p < 0.0001), underweight (aOR 2.353, p = 0.013), premature birth (aOR 3.484, p < 0.0001), LBW (aOR 3.496, p = 0.001), and low household income (aOR 1.935, p = 0.030) were independent risk factors associated with short stature in children with CKD. CONCLUSIONS: Children with CKD in Korea were shorter and had lower body weight and BMI than the general population. Short stature in children with CKD was most independently associated with low birth weight, followed by premature birth, onset before age 2, CKD stages 4 and 5, underweight, and low household income. Among these, underweight is the only modifiable factor. Therefore, we suggest children with CKD should be carefully monitored for weight, nutritional status, and body composition to achieve optimal growth.

How can we improve patients' access to new drugs under uncertainties? : South Korea's experience with risk sharing arrangements.

BACKGROUND: New drugs including cancer drugs and orphan drugs are becoming increasingly more expensive. Risk sharing arrangements (RSAs) could manage the risk based on both financial impact and the health outcome of new drugs if reimbursed. To improve patients' access to new drugs under uncertainties, many developed countries have adopted RSAs. In this study, we aimed to understand the effects of RSAs in South Korea on patients' access. METHODS: We reviewed current status of RSA drugs in South Korea. The number of appraisals and time gap between market approval and reimbursement per RSA drug were considered to quantify improvement of patients' access as they showed how rapidly decisions on reimbursement of RSA drugs were derived. Then, we applied a comparative analysis to determine whether the RSA drugs in South Korea were reimbursed in the UK, Italy, and Australia. Most data for this study were obtained from websites of the governmental department/agencies responsible for appraisal of drug reimbursement in each country. And literatures related to RSAs were investigated as well. RESULTS: The eligibility for Korean RSAs had two key components - drugs for cancer and rare diseases and not having other alternative treatments. As of the first half of 2019, there were 39 RSA drugs reimbursed in South Korea, the majority of which were financial-based schemes. Refund and expenditure cap were the representative types (89.7%). After introduction of RSAs, the time gap and number of appraisals were decreased. Based on the indications of RSA drugs, the level of drug coverage in South Korea was found lower than Italy, similar to the UK, and higher than Australia. CONCLUSIONS: RSAs in South Korea significantly enhanced patients' access to new drugs and led to the alleviation of patients' out-of-pocket expenses. The drug coverage of South Korea had a level comparable to that of other countries. This study provides implications for countries that have a dual mission of containing pharmaceutical expenditure and improving access to new drugs.

Collective Syntheses of Guaiane Sesquiterpenes: Stereoselective Syntheses of (+)-Dysodensiol F, (+)-10ß,14-Dihydroxy-allo-aromadendrane, and (-)-Dendroside C Aglycon.

A collective synthetic route for tricyclic guaiane sesquiterpenes and total syntheses of (+)-dysodensiol F, (+)-10ß,14-dihydroxy-allo-aromadendrane, and (-)-dendroside C aglycon starting from a versatile hydroazulene intermediate were accomplished. The key features of these syntheses involve late-stage carbene-mediated diastereoselective cyclopropanation, construction of an unusual cis-fused-hydroazulene skeleton via intramolecular Dieckmann condensation, and highly stereoselective tandem conjugate addition/intramolecular allylic alkylation to afford a 5/7/3 tricyclic skeleton of guaiane natural products. The synthesis of (-)-dendroside C aglycon and the first total synthesis of (+)-dysodensiol F and (+)-10ß,14-dihydroxy-allo-aromadendrane are described in detail. Activation of the Nrf2/ARE signaling pathway by (-)-dendroside C aglycon is also disclosed via our synthesis.

Dyslipidemia in pediatric CKD patients: results from KNOW-PedCKD (KoreaN cohort study for Outcomes in patients With Pediatric CKD).

BACKGROUND: Pediatric as well as adult patients with chronic kidney disease (CKD) are susceptible to cardiovascular disease (CVD) events, which increase their mortality. Dyslipidemia is thought to be one of the most important contributing risk factors for developing CVD. This study aimed to evaluate the prevalence of dyslipidemia and assess clinical and laboratory risk factors associated with dyslipidemia in East Asian pediatric patients with CKD. METHODS: From April 2011 to April 2016, 469 patients with CKD aged < 20 years were enrolled in KNOW-PedCKD (the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease); 356 patients were included in the final analysis. Using the baseline data of the cohort cross-sectionally, a multivariable logistic regression analysis was performed to assess the risk factors for dyslipidemia; a subanalysis for each lipid abnormality was also done. RESULTS: The prevalence of dyslipidemia was 61.5% (n = 219). For dyslipidemia, nephrotic range proteinuria and 25-hydroxyvitamin D deficiency significantly increased the adjusted odds ratio. In the subanalysis, glomerulonephropathy as the origin of CKD and nephrotic range proteinuria significantly increased the risks for high total cholesterol and high low-density lipoprotein cholesterol. Overweight or obese body mass index z-score, elevated proteinuria, hypocalcemia, and 1,25-dihydroxyvitamin D deficiency were significantly associated with low high-density lipoprotein cholesterol. Glomerular filtration rate stage 3b or higher and hyperphosphatemia significantly increased the risk for high triglycerides. CONCLUSIONS: Long-term data accumulation and prospective analysis are needed to clarify the relationship between CKD progression and dyslipidemia and to find additional risk factors for dyslipidemia.

Left-ventricular diastolic dysfunction in Korean children with chronic kidney disease: data from the KNOW-Ped CKD study.

BACKGROUND: Cardiovascular disease (CVD) is the most common cause of mortality in pediatric chronic kidney disease (CKD) patients. Left ventricular (LV) hypertrophy (LVH) is associated with LV diastolic dysfunction (LVDD) development and is used as an early marker of CVD in pediatric CKD. This study aimed to assess the prevalence and risk factors of LVDD and the association between LVH and LVDD in Korean pediatric CKD patients. METHODS: Data were collected using the baseline data of the Korean cohort study for outcome in patients with pediatric chronic kidney disease, a nationwide, 10-year, prospective, observational cohort study of pediatric CKD. A total of 244 patients were included in the final analysis. Two-dimensional echocardiography and tissue Doppler images were used to evaluate LVH and LVDD. LVH was defined as an LV mass index (LVMI) ≥38 g/m2.7 and LV-wall thickness z-score > 1.64. LVDD was defined as a mitral peak velocity of early filling to early diastolic mitral annular velocity (E/E') > 14. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors of LVDD. RESULTS: In this study, the male-to-female ratio was 2.2 (168:76) and median age was 11.2 years. The average estimated glomerular filtration rate was 57.4 ml/min/1.73 m2, and no patients received renal replacement therapy. The mean value of LVMI and E/E' was 37.0 g/m2.7 and 7.4, respectively. The prevalence of LVH was 40.1 and 17.4% by LVMI ≥38 g/m2.7 and LV-wall thickness z-score, respectively. The prevalence of LVDD was 4.5%, and patients with LVH showed greater risk of LVDD (odds ratio 7.3, p = 0.012). In the univariate analysis, young age, low hemoglobin level, higher LVMI, and higher LV-wall thickness z-score were associated with LVDD. In the multivariate analysis, young age, low hemoglobin level, and higher LV-wall thickness z-score were independently associated with LVDD. CONCLUSION: This study shows that LVH patients have a greater risk of LVDD and that anemia is the only modifiable risk factor for LVDD in Korean pediatric CKD patients.

LRRK2 G2019S Induces Anxiety/Depression-like Behavior before the Onset of Motor Dysfunction with 5-HT1A Receptor Upregulation in Mice.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology of LRRK2 mutation-related PD, including increased dopaminergic neurodegeneration and Lewy bodies, is indistinguishable from that of idiopathic PD. The subtle nonmotor phenotypes of LRRK2 mutation-related PD have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S. Through multiple behavioral tests, including light-dark test, elevated plus maze, sucrose preference test, forced swimming test, and tail-suspension test, we found that anxiety/depression-like behavior appeared in middle-aged (43-52 weeks) Tg mice before the onset of PD-like motor dysfunction. These behavioral tests were performed using both male and female mice, and there were no sex-related differences in behavioral changes in the middle-aged Tg mice. Along with behavioral changes, serotonin levels also significantly declined in the hippocampus of Tg mice. Additionally, increases in the expression of the 5-HT1A receptor (5-HT1AR) grew more significant with aging and were detected in the hippocampus, amygdala, and dorsal raphe nucleus. In vitro study using the serotonergic RN46A and hippocampal HT22 cells showed that 5-HT1AR upregulation was related to enhanced expression of LRRK2 G2019S and was attenuated by the LRRK2 inhibitor LRRK2-IN-1. Wild-type LRRK2 had no significant effect on 5-HT1AR transcription. The present study provides the first in vivo and in vitro evidence demonstrating abnormal regulation of 5-HT1AR along with the manifestation of anxiety/depression-like, nonmotor symptom in PD related to LRRK2.SIGNIFICANCE STATEMENT Parkinson's disease (PD), the second most common neurodegenerative disorder, is clinically characterized by motor dysfunctions. In most cases, various nonmotor symptoms present several years before the onset of the classical motor features of PD and severely affect the quality of life of patients. Here, we demonstrate the causative role of leucine-rich repeat kinase 2 (LRRK2), a common PD-linked mutation, in the development of anxiety/depression-like behaviors. We found that age-dependent 5-HT1A receptor upregulation in the hippocampus, amygdala, and dorsal raphe nucleus is accompanied by the expression of the LRRK2 mutant phenotype. Our findings demonstrating a potential mechanism for nonmotor psychiatric symptoms produced by LRRK2 mutation suggest that directly targeting the 5-HT1A receptor can improve the therapeutic efficacy of drugs for PD-associated depression.

CXC chemokine ligand 1 mediates adiponectin-induced angiogenesis in ovarian cancer.

OBJECTIVES: Adiponectin is a cytokine secreted from adipose tissue that regulates energy homeostasis, inflammation, and cell proliferation. Obesity is associated with increased risk of various cancers, including ovarian cancer. Adipokines, including adiponectin, have been implicated as a factor linking obesity and carcinogenesis. The oncogenic role of adiponectin is not known with regard to various cancer types. We sought to determine the role of adiponectin in angiogenesis in ovarian cancer in vitro. METHODS: We transfected SKOV3 cells with vascular endothelial growth factor small interfering RNA in order to identify the independent angiogenic role of adiponectin in ovarian cancer. The vascular endothelial growth factor knockdown SKOV3 cell lines were treated with adiponectin for 48 h. The cytokines involved in adiponectin-mediated angiogenesis were explored using the human angiogenesis cytokine array and were verified with the enzyme-linked immunosorbent assay. The angiogenic effect of adiponectin was evaluated using the human umbilical vein endothelial cell tube formation assay. We also investigated the effects of adiponectin treatment on the migration and invasion of SKOV3 cells. RESULTS: The number of tubes formed by human umbilical vein endothelial cell decreased significantly after knockdown of vascular endothelial growth factor (via transfection of vascular endothelial growth factor small interfering RNA into SKOV3 cells). When these vascular endothelial growth factor knockdown SKOV3 cells were treated with adiponectin, there was an increase in the number of tubes in a tube formation assay. Following adiponectin treatment, the CXC chemokine ligand 1 secretion increased in a cytokine array. This was confirmed by both enzyme-linked immunosorbent assay and Western blot. The increased secretion of CXC chemokine ligand 1 by adiponectin occurred regardless of vascular endothelial growth factor knockdown. In addition, the induction of migration and invasion of SKOV3 cells were significantly stronger with adiponectin treatment than they were without. CONCLUSION: Adiponectin treatment of ovarian cancer cells induces angiogenesis via CXC chemokine ligand 1 independently of vascular endothelial growth factor. These findings suggest that adiponectin may serve as a novel therapeutic target for ovarian cancer.

Mental health and psychosocial adjustment in pediatric chronic kidney disease derived from the KNOW-Ped CKD study.

BACKGROUND: Psychosocial development of pediatric chronic kidney disease (CKD) patients is substantially affected due to growth retardation, frequent school absences, and difficulties engaging in normal peer relationship activities. While many studies focus on specific issues such as depression, anxiety, or neurocognitive function, few evaluate prevalence of various types of mental health and psychosocial adjustment problems among children with CKD. This study aimed to investigate these within the KoreaN cohort study for Outcomes in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD). METHODS: One hundred sixty-six subjects who completed the Korean-Child Behavioral Checklist (K-CBCL) were included. The clinical group comprised subjects with scores indicating psychosocial adjustment or mental health problems using the T scores for the 14 subscales of the K-CBCL. We analyzed associations between mental health or adjustment problems in pediatric CKD and each variable. RESULTS: Mean age was 11.1 (± 3.9) years, number of males was 117 (70.5%), and 20.5% and 22.3% of children had significant mental health problems and psychosocial adjustment problems, respectively. Overall, 33.1% were assigned to the clinical group, and exhibited short stature and higher rates of preterm birth history compared to the non-clinical group. Subjects with adjustment problems had higher comorbidities such as CNS disease, developmental delay, cardiovascular disease, and multi-organ involvement. Logistic regression analysis revealed preterm birth and developmental delay correlated highly with clinical group. CONCLUSIONS: A significant proportion of children and adolescents with CKD experience mental health and adjustment problems. In particular, patients with developmental delay or preterm birth history require screening and targeted follow-up.

CNBP acts as a key transcriptional regulator of sustained expression of interleukin-6.

The transcription of inflammatory genes is an essential step in host defense activation. Here, we show that cellular nucleic acid-binding protein (CNBP) acts as a transcription regulator that is required for activating the innate immune response. We identified specific CNBP-binding motifs present in the promoter region of sustained inflammatory cytokines, thus, directly inducing the expression of target genes. In particular, lipopolysaccharide (LPS) induced cnbp expression through an NF-κB-dependent manner and a positive autoregulatory mechanism, which enables prolonged il-6 gene expression. This event depends strictly on LPS-induced CNBP nuclear translocation through phosphorylation-mediated dimerization. Consequently, cnbp-depleted zebrafish are highly susceptible to Shigella flexneri infection in vivo. Collectively, these observations identify CNBP as a key transcriptional regulator required for activating and maintaining the immune response.

Biotransformed Metabolites of the Hop Prenylflavanone Isoxanthohumol.

A metabolic conversion study on microbes is known as one of the most useful tools to predict the xenobiotic metabolism of organic compounds in mammalian systems. The microbial biotransformation of isoxanthohumol (1), a major hop prenylflavanone in beer, has resulted in the production of three diastereomeric pairs of oxygenated metabolites (2⁻7). The microbial metabolites of 1 were formed by epoxidation or hydroxylation of the prenyl group, and HPLC, NMR, and CD analyses revealed that all of the products were diastereomeric pairs composed of (2S)- and (2R)- isomers. The structures of these metabolic compounds were elucidated to be (2S,2"S)- and (2R,2"S)-4'-hydroxy-5-methoxy-7,8-(2,2-dimethyl-3-hydroxy-2,3-dihydro-4H-pyrano)-flavanones (2 and 3), (2S)- and (2R)-7,4'-dihydroxy-5-methoxy-8-(2,3-dihydroxy-3-methylbutyl)-flavanones (4 and 5) which were new oxygenated derivatives, along with (2R)- and (2S)-4'-hydroxy-5-methoxy-2"-(1-hydroxy-1-methylethyl)dihydrofuro[2,3-h]flavanones (6 and 7) on the basis of spectroscopic data. These results could contribute to understanding the metabolic fates of the major beer prenylflavanone isoxanthohumol that occur in mammalian system.

Complement Component 3 Is Regulated by TWIST1 and Mediates Epithelial-Mesenchymal Transition.

We have previously shown that complement component 3 (C3) is secreted by malignant epithelial cells. To understand the mechanism of upregulation of C3 expression in tumor cells, we studied the C3 promoter and identified that twist basic helix-loop-helix transcription factor 1 (TWIST1) binds to the C3 promoter and enhances its expression. Because TWIST1 mediates epithelial-mesenchymal transition (EMT), we studied the effect of C3 on EMT and found that C3 decreased E-cadherin expression on cancer cells and promoted EMT. We showed that C3-induced reduction in E-cadherin expression in ovarian cancer cells was mediated by C3a and is Krüppel-like factor 5 dependent. We investigated the association between TWIST1 and C3 in malignant tumors and in murine embryos. TWIST1 and C3 colocalized at the invasive tumor edges, and in the neural crest and limb buds of mouse embryos. Our results identified TWIST1 as a transcription factor that regulates C3 expression during pathologic and physiologic EMT.

Genotype-Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis.

BACKGROUND/AIMS: Primary distal renal tubular acidosis (dRTA) in children is a rare genetic disorder, and three causative mutated genes have been identified: SLC4A1, ATP6V1B1, and ATP6V0A4. We analyzed the prevalence and phenotypic differences of genetic mutations in children with dRTA. METHODS: A total of 17 children with dRTA were enrolled in the study. All patients underwent genetic testing for all three candidate genes. RESULTS: Pathogenic mutations, including six novel mutations, were detected in 15 (88.2%) patients: dominant SLC4A1 mutations in ten (58.8%) patients, recessive ATP6V0A4 mutations in three (17.6%) patients, and recessive ATP6V1B1 mutations in two (11.8%) patients. Compared to other patients, patients with SLC4A1 mutations showed an older age of onset (3.7 ± 2.6 years) and less severe metabolic acidosis at initial presentation. All patients developed nephrocalcinosis, and sensorineural hearing loss was observed in two patients with ATP6V1B1 mutations. Three (17.6%) patients had decreased renal function (chronic kidney disease stage 2), and five (29.4%) patients had persistent growth retardation at the last follow-up. Long-term prognosis showed no genotype-phenotype correlation. CONCLUSIONS: SLC4A1 is the most common defective gene in Korean children with dRTA. Patients with SLC4A1 mutations show later onset and milder disease severity. Long-term follow-up of hearing ability, renal function, and growth is necessary for patients with dRTA.

Response to Combination Chemotherapy With Paclitaxel/Ifosfamide/Platinum Versus Paclitaxel/Platinum for Patients With Metastatic, Recurrent, or Persistent Carcinoma of the Uterine Cervix: A Retrospective Analysis.

OBJECTIVE: Paclitaxel/ifosfamide/cisplatin triplet has shown a higher response rate than paclitaxel/cisplatin doublet, but the toxicity profile hindered the use of the triplet regimen. In this study, we adjusted the dosage of the triplet regimen and introduced carboplatin in cisplatin-intolerable patients. We tested the efficacy and toxicity of the modified triplet regimen in patients with recurrent or persistent cervical cancer. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients with recurrent or persistent cervical cancer who were treated between 2003 and 2015 at Samsung Medical Center. Response rate, progression-free survival (PFS), overall survival (OS), and toxicity of paclitaxel/ifosfamide/platinum (TIP) and paclitaxel/platinum (TP) were compared. RESULTS: The overall response rate of TIP was significantly higher than that of TP (52.7% vs 36.4%, P = 0.031). In the TP group, response rate was higher in patients with progression-free interval longer than 12 months (P = 0.028) and those with squamous cell histology (P = 0.028). In TIP group, patients with older than 50 years (P = 0.017), progression-free interval longer than 12 months (P = 0.046), and squamous cell carcinoma histology (P < 0.001) showed higher response rates; but TIP showed higher response on all occasions. Median OS and median PFS were similar for TP and TIP (OS, 22.43 months vs 18.5 months, P = 0.44; PFS, 6.37 months vs 8.3 months, P = 0.48). CONCLUSIONS: Paclitaxel/ifosfamide/platinum showed a higher response rate than TP in patients with recurrent cervical cancer without an increase in severe complications. Considering the high response rate, TIP may be an option for persistent or recurrent cervical cancer.

Influence of the Method of Definition on the Prevalence of Left-Ventricular Hypertrophy in Children with Chronic Kidney Disease: Data from the Know-Ped CKD Study.

BACKGROUND/AIMS: Children with chronic kidney disease (CKD) have a high risk of cardiovascular disease. Left-ventricular (LV) hypertrophy (LVH) is an early marker of cardiovascular disease in pediatric CKD, and the prevalence of LVH in pediatric CKD is approximately 20-30% in pre-dialysis CKD patients. However, there is no consensus on the ideal method of defining LVH in pediatric CKD patients. Previous studies have typically used the LV mass index (LVMI), which is calculated as LV mass in grams divided by height in meters to the 2.7th power ≥ 38 g/m2.7, to diagnose LVH in children with CKD. Recently, age-specific reference values for LVMI ≥ 95th percentile and LV wall-thickness z-score > 1.64 in children were addressed. The aim of this study was to assess the prevalence and contributing factors of LVH in pediatric CKD patients according to each measurement and evaluate the concordance between each measurement. METHODS: We used the baseline data of the KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD), which is a nationwide, 10-year, prospective, observational cohort study of pediatric CKD. A total of 469 patients were enrolled, and 458 patients were included in the final analysis. Univariate and multiple logistic regression analysis were performed to evaluate the association of the variables with LVH. Kappa statistics were used to analyze the concordance. RESULTS: According to an LVH diagnosis of LVMI ≥ 38 g/m2.7, 188 patients (41.0%) were diagnosed with LVH, and the prevalence of LVH was high in younger patients (< 2 years of age). Using the age-specific reference values, 116 patients (25.3%) were diagnosed with LVH, and there was no difference in the prevalence of LVH according to age. Thirty-one patients (6.8%) were diagnosed with LVH using an LV wall-thickness z-score > 1.64. There is poor concordance between the diagnosis of LVH using the LV wall-thickness z-score and the LVMI method. CONCLUSIONS: The results of this study show that there is poor concordance between the diagnosis of LVH using the wall-thickness z-score and the LVMI2.7 criteria. Further investigation is needed to estimate the correlation between LVH and cardiac dysfunction and to find a better method for defining LVH in the pediatric CKD cohort and thereby predicting cardiac dysfunction.

Health-related quality of life of children with pre-dialysis chronic kidney disease.

BACKGROUND: The goal of this study was to evaluate the quality of life (QOL) of Asian children with pre-dialysis chronic kidney disease (CKD) and to reveal the factors influencing the QOL of children with CKD. METHODS: We performed a cross-sectional study of the PedsQL 4.0 Generic Core Scale Module in the KNOW-PedCKD (KoreaN cohort study for Outcome in patients with Pediatric Chronic Kidney Disease) cohort, and compared the child self-reported and parent proxy-reported QOL of the pediatric cohort. From 2011 through 2016, a total of 376 children with CKD were enrolled after informed consent was obtained from parents or caregivers in seven pediatric nephrology centers. RESULTS: In parent proxy-reports, male patients had a better QOL than female patients in the Physical Functioning category. In child self-reports, male patients had better QOL than female patients in the Physical, Emotional, and School Functioning categories. According to CKD stage, there were significant differences in the QOL score in all categories of parent proxy-reports, and patients with higher CKD stage (lower glomerular filtration rate) had a worse QOL. Growth parameters showed a significantly positive correlation with the QOL score in all categories. CONCLUSIONS: The QOL of children with predialysis CKD is affected by various factors, including sex, glomerular filtration rate (GFR), socio-economic status, existence of co-morbidities, anemia, growth retardation, and behavioral disorders. To improve their QOL, it is important to objectively understand the respective effects of these factors and attempt early intervention.