As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. Methods: We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. Results: During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. Conclusion: Myo-inositol can be used as an additive biomarker of ESRD progression in DKD.

Alopecia is a distressing condition caused by the dysregulation of anagen, catagen, and telogen in the hair cycle. Dermal papilla cells (DPCs) regulate the hair cycle and play important roles in hair growth and regeneration. Myristoleic acid (MA) increases Wnt reporter activity in DPCs. However, the action mechanisms of MA on the stimulation of anagen signaling in DPCs is not known. In this study, we evaluated the effects of MA on anagen-activating signaling pathways in DPCs. MA significantly increased DPC proliferation and stimulated the G2/M phase, accompanied by increasing cyclin A, Cdc2, and cyclin B1. To elucidate the mechanism by which MA promotes DPC proliferation, we evaluated the effect of MA on autophagy and intracellular pathways. MA induced autophagosome formation by decreasing the levels of the phospho-mammalian target of rapamycin (phospho-mTOR) and increasing autophagy-related 7 (Atg7) and microtubule-associated protein 1A/1B-light chain 3II (LC3II). MA also increased the phosphorylation levels of Wnt/β-catenin proteins, such as GSK3β ( Ser9 ) and β-catenin (Ser 552 and Ser675 ). Treatment with XAV939, an inhibitor of the Wnt/β-catenin pathway, attenuated the MA-induced increase in β-catenin nuclear translocation. Moreover, XAV939 reduced MA-induced effects on cell cycle progression, autophagy, and DPC proliferation. On the other hand, MA increased the levels of phospho (Thr202 /Tyr204 )-extracellular signal regulated kinases (ERK). MA-induced ERK phosphorylation led to changes in the expression levels of Cdc2, Atg7 and LC3II, as well as DPC proliferation. Our results suggest that MA promotes anagen signaling via autophagy and cell cycle progression by activating the Wnt/β-catenin and ERK pathways in DPCs.

Objective: Autologous bone grafting for cranioplasty is associated with a high infection rate and bone absorption. Synthetic implant materials for cranioplasty have been developed. In this study, we evaluated the efficacy of titanium mesh-type patient-specific implants (PSIs) for patients with skull defects using the dice similarity coefficient (DSC), clinical outcomes, and artifacts caused by implants. Methods: This retrospective study included 40 patients who underwent cranioplasty with a titanium mesh PSI at our institution. Based on preoperative and postoperative computed tomography scans, we calculated DSC and artifacts. Results: The calculated DSC of 40 patients was 0.75, and the noise was 13.89% higher in the region of interest (ROI) near the implanted side (average, 7.64 hounsfield unit [HU]±2.62) than in the normal bone (average, 6.72 HU±2.35). However, the image signal-to-noise ratio did not significantly differ between the ROI near the implanted side (4.77±1.78) and normal bone (4.97±1.88). The patients showed no significant perioperative complications that required a secondary operation. Conclusion Titanium mesh-type PSIs for cranioplasty have excellent DSC values with lower artifacts and complication rates.

Purpose: Use of cyclin-dependent kinase 4/6 inhibitors improved survival outcome of hormone receptor (HR) positive metastatic breast cancer (MBC) patients, including Asian population. However, Asian real-world data of palbociclib is limited. We analyzed the real-world clinical practice patterns and outcome in HR-positive, MBC Asian patients treated with palbociclib. Materials and Methods: Between April 2017 to November 2019, 169 HR-positive, human epidermal growth factor-2–negative MBC patients treated with letrozole or fulvestrant plus palbocilib were enrolled from eight institutions. Survival outcome (progression-free survival [PFS]), treatment response and toxicity profiles were analyzed. Results: Median age of letrozole plus palbociclib (145 patients, 85.8%) and fulvestrant plus palbociclib (24 patients, 14.2%) was 58 and 53.5 years, with median follow-up duration of 14.63 months (range 0.2 to 33.9 months). Median PFS (mPFS) of letrozole plus palbociclib and fulvestrant plus palbociclib was 25.6 (95% confidence interval [CI], 19.1 to not reached) and 6.37 months (95% CI, 5.33 to not reached), comparable to previous phase 3 trials. In letrozole plus palbociclib arm, luminal A (hazard ratio, 2.86; 95% CI, 1.20 to 6.80; p=0.017) and patients with good performance (Eastern Cooperative Oncology Group 0-1 [hazard ratio, 3.68; 95% CI, 1.70 to 7.96]) showed better mPFS. In fulvestrant plus palbociclib group, chemotherapy naïve patients showed better mPFS (hazard ratio, 12.51, 95% CI, 1.59 to 99.17; p=0.017). The most common grade 3 or 4 adverse event was neutropenia (letrozole 86.3%, fulvestrant 88.3%). Conclusion To our knowledge, this is the first real-world data of palbociclib reported in Asia. Palbociclib showed comparable benefit to previous phase 3 trials in Asian patients during daily clinical practice.

Purpose: Use of cyclin-dependent kinase 4/6 inhibitors improved survival outcome of hormone receptor (HR) positive metastatic breast cancer (MBC) patients, including Asian population. However, Asian real-world data of palbociclib is limited. We analyzed the real-world clinical practice patterns and outcome in HR-positive, MBC Asian patients treated with palbociclib. Materials and Methods: Between April 2017 to November 2019, 169 HR-positive, human epidermal growth factor-2–negative MBC patients treated with letrozole or fulvestrant plus palbocilib were enrolled from eight institutions. Survival outcome (progression-free survival [PFS]), treatment response and toxicity profiles were analyzed. Results: Median age of letrozole plus palbociclib (145 patients, 85.8%) and fulvestrant plus palbociclib (24 patients, 14.2%) was 58 and 53.5 years, with median follow-up duration of 14.63 months (range 0.2 to 33.9 months). Median PFS (mPFS) of letrozole plus palbociclib and fulvestrant plus palbociclib was 25.6 (95% confidence interval [CI], 19.1 to not reached) and 6.37 months (95% CI, 5.33 to not reached), comparable to previous phase 3 trials. In letrozole plus palbociclib arm, luminal A (hazard ratio, 2.86; 95% CI, 1.20 to 6.80; p=0.017) and patients with good performance (Eastern Cooperative Oncology Group 0-1 [hazard ratio, 3.68; 95% CI, 1.70 to 7.96]) showed better mPFS. In fulvestrant plus palbociclib group, chemotherapy naïve patients showed better mPFS (hazard ratio, 12.51, 95% CI, 1.59 to 99.17; p=0.017). The most common grade 3 or 4 adverse event was neutropenia (letrozole 86.3%, fulvestrant 88.3%). Conclusion To our knowledge, this is the first real-world data of palbociclib reported in Asia. Palbociclib showed comparable benefit to previous phase 3 trials in Asian patients during daily clinical practice.

BACKGROUND: Tauopathies, a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase (JHDM) genes, which have yet to be studied in AD pathology. METHODS: To examine alterations of several JHDM genes in AD pathology, we performed bioinformatics analyses of JHDM gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in JHDM gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of JHDM Drosophila homologs (kdm) can affect tauR406W-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system. RESULTS: The expression levels of JHDM1A, JHDM2A/2B, and JHDM3A/3B were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas JHDM1B mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of kdm2 (homolog to human JHDM1), kdm3 (homolog to human JHDM2), kdm4a (homolog to human JHDM3A), or kdm4b (homolog to human JHDM3B) genes in the eye ameliorated the tauR406W-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tauR406W-induced locomotion defects by restoring heterochromatin. CONCLUSION: Our results suggest that downregulation of kdm4a expression may be a potential therapeutic target in AD.
Acetylation ; Alzheimer Disease ; Brain ; Central Nervous System ; Computational Biology ; Diptera ; Down-Regulation ; Drosophila melanogaster ; Drosophila ; Heterochromatin ; Histones ; Humans ; Locomotion ; Methylation ; Neurodegenerative Diseases ; Neurofibrillary Tangles ; Pathology ; Phenotype ; RNA, Messenger ; tau Proteins ; Tauopathies ; Transcriptome

Post-menopausal osteoporosis (PMO) is a major global human health concern. Owing to the need for therapeutic drugs without side effects, natural extracts containing various polyphenolic compounds that may exert estrogenic effects have been studied in depth. Rhus verniciflua Stokes (RVS), which has been used as a traditional herbal medicine for centuries in Korea, was recently revealed to exert estrogenic effects attributable to its bioactive ingredients sulfuretin and butein, which have strong estrogen receptor–binding affinities. In this study, the protective potential of RVS in PMO was evaluated by using an experimental animal model of PMO, which was established by ovariectomy (OVX) of female Sprague Dawley rats. The oral administration of RVS at 20 mg/kg or 100 mg/kg for 8 weeks markedly protected against OVX-induced atrophy of the uterine tube and reversed the elevation in the ratio of serum receptor activator of nuclear factor-κB ligand to osteoprotegerin, which is a marker of disease severity. In addition, RVS inhibited OVX-induced tibia bone loss, activated osteogenic activity, and suppressed osteoclastic activity in the tibial epiphyseal plate, a region of bone remodeling. Collectively, these factors indicated that the oral intake of RVS might be beneficial for the prevention of PMO.
Administration, Oral ; Atrophy ; Bone Remodeling ; Estrogens ; Fallopian Tubes ; Female ; Growth Plate ; Herbal Medicine ; Humans ; Korea ; Models, Animal ; Models, Theoretical* ; Osteoclasts ; Osteoporosis, Postmenopausal* ; Osteoprotegerin ; Ovariectomy ; Rats, Sprague-Dawley ; Rhus* ; Tibia

Hypoxia-inducible factor 1alpha (HIF-1alpha), which transactivates a variety of hypoxia-induced genes, is rapidly degraded under nomoxia through the hydroxylation-ubiquitination-proteasome pathway. In this study, we addressed how HIF-1alpha is stabilized by proteasome inhibitors. The ubiquitin pool was rapidly reduced after proteasome inhibition, followed by the accumulation of non-ubiquitinated HIF-1alpha. The poly-ubiquitination of HIF-1alpha was resumed by restoration of free ubiquitin, which suggests that the HIF-1alpha stabilization under proteasome inhibition is attributed to depletion of the free ubiquitin pool. Ni2+ and Zn2+ also stabilized HIF-1alpha with depletion of the free ubiquitin pool and these effects of metal ions were attenuated by restoration of free ubiquitin. Ni2+ and Zn2+ may disturb the recycling of free ubiquitin, as MG132 does. Based on these results, the state of the ubiquitin pool seems to be another critical factor determining the cellular level of HIF-1alpha.
Cell Hypoxia/physiology ; Cell Line, Tumor ; HCT116 Cells ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*metabolism ; Leupeptins/pharmacology ; Nickel/chemistry ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors/*pharmacology ; Ubiquitin/*metabolism ; Ubiquitination/*physiology ; Up-Regulation ; Zinc/chemistry

Fetal lung development normally occurs in a hypoxic environment. Hypoxia-inducible factor (HIF)-1alpha is robustly induced under hypoxia and transactivates many genes that are essential for fetal development. Most preterm infants are prematurely exposed to hyperoxia, which can halt hypoxia-driven lung maturation. We were to investigate whether the HIF-1alpha inducer, deferoxamine (DFX) can improve alveolarization in a rat model of bronchopulmonary dysplasia (BPD). A rat model of BPD was produced by intra-amniotic lipopolysaccharide (LPS) administration and postnatal hyperoxia (85% for 7 days), and DFX (150 mg/kg/d) or vehicle was administered to rat pups intraperitoneally for 14 days. On day 14, the rat pups were sacrificed and their lungs were removed and examined. A parallel in vitro study was performed with a human small airway epithelial cell line to test whether DFX induces the expression of HIF-1alpha and its target genes. Alveolarization and pulmonary vascular development were impaired in rats with BPD. However, DFX significantly ameliorated these effects. Immunohistochemical analysis showed that HIF-1alpha was significantly upregulated in the lungs of BPD rats treated with DFX. DFX was also found to induce HIF-1alpha in human small airway epithelial cells and to promote the expression of HIF-1alpha target genes. Our data suggest that DFX induces and activates HIF-1alpha, thereby improving alveolarization and vascular distribution in the lungs of rats with BPD.
Animals ; Bronchopulmonary Dysplasia/*drug therapy/*metabolism/pathology ; Deferoxamine/*administration & dosage ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Male ; Pulmonary Alveoli/drug effects/*growth & development/metabolism/pathology ; Pulmonary Veins/drug effects/*growth & development/pathology ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; Up-Regulation/drug effects

BACKGROUND AND OBJECTIVES: A higher neutrophil to lymphocyte ratio (NLR) has been associated with poor clinical outcomes in various cardiac diseases. However, the clinical availability of NLR in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has not been known. We evaluated the availability of NLR to predict clinical outcomes in patients with STEMI undergoing primary PCI. SUBJECTS AND METHODS: We analyzed 326 consecutive STEMI patients treated with primary PCI. The patients were divided into tertiles according to NLR: NLR< or =3.30 (n=108), 3.316.53 (n=110). We evaluated the incidence of major adverse cardiac events (MACE), a composite of all causes of death, non-fatal MI, and ischemic stroke at the 12-month follow-up. RESULTS: The high NLR group was associated with a significantly higher rate of 12-month MACE (19.1% vs. 3.7%, p<0.001), 12-month death (18.2% vs. 2.8%, p<0.001), in-hospital MACE (12.7% vs. 2.8%, p=0.010) and in-hospital death (12.7% vs. 1.9%, p=0.003) compared to the low NLR group. In the multivariable model, high NLR was an independent predictor of 12-month MACE {hazard ratio (HR) 3.33 (1.09-10.16), p=0.035} and death {HR 4.10 (1.17-14.46), p=0.028} after adjustment for gender, left ventricular ejection fraction, creatinine clearance, angiographic parameters and factors included in the Thrombolysis in Myocardial Infarction risk score for STEMI. There was a significant gradient of 12-month MACE across the NLR tertiles with a markedly increased MACE hazard in the high NLR group (log rank test p=0.002). CONCLUSION: The NLR is a useful marker to predict 12-month MACE and death in patients with STEMI who have undergone primary PCI.
Cause of Death ; Creatinine ; Heart Diseases ; Humans ; Incidence ; Lymphocytes ; Myocardial Infarction ; Neutrophils ; Percutaneous Coronary Intervention ; Stroke ; Stroke Volume