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"Hwang, Soojin"
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Water-stable perovskite-loaded nanogels containing antioxidant property for highly sensitive and selective detection of roxithromycin in animal-derived food products
Luminescent inorganic lead halide perovskite nanoparticles lack stability in aqueous solutions, limiting their application to optical sensors. Here, hybrid CsPbBr
3
-loaded MIP nanogels were developed with enhanced stability in aqueous media. Multifunctional MIP nanogels with antioxidant function and hydrophobic cavities were synthesized from HEMA derivatives in the presence of roxithromycin as a template. The CsPbBr
3
nanoparticles were loaded into pre-synthesized MIP nanogels via in-situ synthesis with a size distribution of 200 nm. The developed CsPbBr
3
-nanogel exhibits excellent stability to air/moisture and enhanced stability toward an aqueous solvent. The developed CsPbBr
3
-loaded MIP nanogels showed a selective and sensitive detection of ROX with a limit of detection calculated to be 1.7 × 10
–5
μg/mL (20.6 pM). The developed CsPbBr
3
-loaded MIP antioxidant-nanogels were evaluated on practical application for the quantitative determination of ROX antibiotic in animal-derived food products with excellent analytical performance. The detection of ROX in animal-derived food products showed good recovery results, making them an ideal candidate for sensing ROX.
Journal Article
Drosophila DJ-1 Decreases Neural Sensitivity to Stress by Negatively Regulating Daxx-Like Protein through dFOXO
DJ-1, a Parkinson's disease (PD)-associated gene, has been shown to protect against oxidative stress in Drosophila. However, the molecular mechanism underlying oxidative stress-induced phenotypes, including apoptosis, locomotive defects, and lethality, in DJ-1-deficient flies is not fully understood. Here we showed that Daxx-like protein (DLP), a Drosophila homologue of the mammalian Death domain-associated protein (Daxx), was upregulated under oxidative stress conditions in the loss-of-function mutants of Drosophila DJ-1β, a Drosophila homologue of DJ-1. DLP overexpression induced apoptosis via the c-Jun N-terminal kinase (JNK)/Drosophila forkhead box subgroup O (dFOXO) pathway, whereas loss of DLP increased resistance to oxidative stress and UV irradiation. Moreover, the oxidative stress-induced phenotypes of DJ-1β mutants were dramatically rescued by DLP deficiency, suggesting that enhanced expression of DLP contributes to the DJ-1β mutant phenotypes. Interestingly, we found that dFOXO was required for the increase in DLP expression in DJ-1β mutants and that dFOXO activity was increased in the heads of DJ-1β mutants. In addition, subcellular localization of DLP appeared to be influenced by DJ-1 expression so that cytosolic DLP was increased in DJ-1β mutants. Similarly, in mammalian cells, Daxx translocation from the nucleus to the cytosol was suppressed by overexpressed DJ-1β under oxidative stress conditions; and, furthermore, targeted expression of DJ-1β to mitochondria efficiently inhibited the Daxx translocation. Taken together, our findings demonstrate that DJ-1β protects flies against oxidative stress- and UV-induced apoptosis by regulating the subcellular localization and gene expression of DLP, thus implying that Daxx-induced apoptosis is involved in the pathogenesis of DJ-1-associated PD.
Journal Article
Endocrine manifestations and long-term outcomes of patients with mitochondrial diseases
Background
Endocrine dysfunctions are commonly associated with mitochondrial diseases. This study aimed to investigate clinical characteristics and outcomes of endocrine manifestations in patients with mitochondrial diseases.
Methods
This study included 54 patients from 47 families with mitochondrial diseases who were genetically confirmed; 49 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), four with Pearson syndrome, and one with Kearns–Sayre syndrome (KSS). Clinical and endocrine findings were retrospectively reviewed.
Results
The median age at diagnosis was 18.5 years (range, 0.1 − 49 years). In 49 patients with MELAS, the mean height and weight standard deviation scores were − 2.0 ± 1.3 and − 2.6 ± 1.6, respectively, with 44.9% (
n
= 22) of the patients exhibiting short stature at diagnosis. Twenty-three (46.9%) patients with MELAS were diagnosed with diabetes mellitus (DM) at a median age of 26 years (range, 12 − 50 years). Interestingly, papillary thyroid cancer was observed in 10.2% of patients (
n
= 5) with MELAS at a mean age of 34.1 ± 6.9 years. One patient with MELAS and one with KSS exhibited hypoparathyroidism. Patients with Pearson syndrome and KSS exhibited more severe short stature. Adrenal insufficiency was noted in 50% of the patients with Pearson syndrome.
Conclusions
In 20% of patients with MELAS, endocrine dysfunctions including having a short stature, DM, and hypoparathyroidism preceded the onset of neurological manifestations. Papillary thyroid cancer occurred in 10% of patients with MELAS. Patients with Pearson syndrome and KSS showed profound growth retardation and multisystem dysfunctions, such as chronic kidney disease and neurological defects, which contributed to increased mortality.
Journal Article
Two novel genetic variants in the WFDC2 gene from patients with bronchiectasis
Background
Bronchiectasis is a chronic respiratory condition characterized by irreversible dilation and damage of the bronchial walls, leading to impaired mucociliary clearance and recurrent infections. Its etiology is diverse; however, genetic factors are critical in its congenital and severe forms. Therefore, we aimed to identify two novel variants of the
WFDC2
gene, known as antiprotease, from patients with bronchiectasis and/or related phenotypes using trio-based whole-genome sequencing analysis.
Methods
Patients with bronchiectasis were recruited as trio or quad, and their genomic DNA was isolated. The whole genome sequence was produced and analyzed to find causative genetic variants through an internal pipeline using GATK-DRAGEN-Hail. Variant interpretation and pathogenicity assessment using various in-silico tools were performed to identify causative variants. Clinical characteristics were collected from the patients with identified variants.
Results
In this discovery study involving four patients from three families, two novel variants in the
WFDC2
gene were identified and suggested as causative pathogenic variants for bronchiectasis. The first variant (c.291 C > G, p.(Cys97Trp)) is a homozygous variant that was not found in the population genome data. However, the second variant (c.278G > C, p.(Cys93Ser)) was identified in another patient as a heterozygous variant, forming a compound heterozygous state with the first variant. Notably, both variants, located at cysteine residues that are conserved across many species, are crucial in forming disulfide bonds essential for protein structure and function. In-silico analyses classified both variants as pathogenic; they were also identified as likely pathogenic according to the American College of Medical Genetics and Genomic guidelines. Furthermore, in an expansion study, the homozygous variant was also found in two unrelated patients.
Conclusion
We identified two novel bi-allelic variants located at cysteine residues in the
WFDC2
gene from patients with bronchiectasis who had previously not received a genetic diagnosis. Therefore, considering prior research on the pivotal role of the WFDC2 protein in the respiratory system, these two novel variants may serve as potential diagnostic markers and therapeutic targets for bronchiectasis.
Clinical trial number
Not Applicable
Journal Article
Clinical and molecular characteristics of Korean patients with Kabuki syndrome
Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS.
This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing.
The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation.
This study enhances the understanding of the clinical and genetic characteristics of KS.
Journal Article
Ataluren‐Induced Functional Restoration of Neurofibromin in Fibroblasts From Neurofibromatosis Type 1 Patients With Nonsense Mutations
Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder caused by heterogeneous mutations in the tumor suppressor gene NF1. Neurofibromin, encoded by NF1, predominantly acts as a negative regulator of the RAS‐MEK signaling pathway. Up to 30% of NF1 patients harbor nonsense mutations (NS) that introduce premature termination codons (PTCs). Ataluren is a well‐characterized small molecule that acts as a nonsense suppressor by enhancing the ribosomal readthrough of PTCs. Here, we isolated primary fibroblasts from 22 Korean NF1NS/+ patients and comprehensively evaluated the efficacy of ataluren treatment. The results demonstrate that hyperactivated GTP‐bound RAS was significantly alleviated in approximately 23% of NF1NS/+ fibroblasts, and the cellular levels of phosphorylated ERK also decreased in approximately 24% after ataluren treatment. Through transcriptome‐wide profiling based on ataluren responsiveness, we analyzed a subset of genes in ataluren‐treated NF1NS/+ fibroblasts whose expression was significantly altered in ataluren‐responsive cells, but not in nonresponsive cells. Furthermore, both AMPD3 and TGFBR3 were notably identified as feasible biomarkers for monitoring functional neurofibromin. Interestingly, AMPD3 can be an effective therapeutic target for NF1‐associated diseases. Together, our study suggests that ataluren can be considered a therapeutic agent for some NF1NS/+ patients and contributes to expanding insights into NF1 therapy. The therapeutic potential of ataluren for NF1 nonsense mutations was assessed by a comprehensive evaluation of the RAS/MEK/ERK pathway activity in 22 NF1NS/+ patient‐derived fibroblasts. The whole‐transcriptomic profiles between ataluren responders and nonresponders, and further analysis and validation revealed novel biomarkers, AMPD3 and TGFBR3, for monitoring NF1 therapy and highlighted AMPD3 as a new therapeutic target for NF1‐associated diseases.
Journal Article
A Randomized, Double‐Blind, 2‐Treatment, 2‐Period, Crossover Phase 1 Study to Compare the Pharmacokinetics, Safety and Tolerability of 60 IU/Kg of Abcertin and Cerezyme in Healthy Volunteers Following a Single Intravenous Administration
Background Imiglucerase (Cerezyme; Sanofi, Paris, France), an analogue of β‐glucocerebrosidase produced by recombinant DNA technology, has been a safe and effective treatment for Gaucher disease (GD) for over 25 years. A new imiglucerase, Abcertin (Seongnam‐si, Gyeonggi‐do, Republic of Korea) has shown a similar safety and efficacy profile in previous clinical studies. This study compared the pharmacokinetics, immunogenicity, safety, and tolerability to EU‐sourced Cerezyme following a single 60 IU/kg dose. Methods This phase 1, single‐center, randomized, double‐blind, two‐way crossover study enrolled 36 healthy volunteers aged 18–45 years. Participants were randomly assigned to receive either Abcertin or Cerezyme in a predetermined sequence. Results Abcertin reached peak plasma concentrations at a median tmax of 61 min (range: 40–121 min). The mean Cmax, AUC0–last, and AUC0–inf were 115.4 mU/mL, 12,190 min·mU/mL, and 12,210 min mU/mL, respectively, indicating bioequivalence to Cerezyme. The mean t½, CL, and Vz were 6.88 min, 376.7 mL/min, and 3.62 L, respectively, and were comparable between the two treatments. One participant in the Cerezyme group developed anti‐drug antibodies, which were non‐neutralizing A total of 24 subjects experienced treatment‐emergent adverse event (TEAE). The most common TEAE was headache (3 in the Abcertin group and 5 in the Cerezyme group), followed by general disorders and administration site condition (3 in Abcertin group and 5 in Cerezyme group). Two participants in the Cerezyme sequence experienced severe TEAEs: one had a urinary tract infection, and the other developed urticaria, which leading to study withdrawal. Conclusion Abcertin demonstrated pharmacokinetic equivalence to Cerezyme, with a comparable safety, immunogenicity, and tolerability profile. These findings support its potential as an affordable biosimilar for GD treatment. This study evaluates the pharmacokinetic equivalence, immunogenicity, and safety profiles of Abcertin and Cerezyme in healthy volunteers. It demonstrated the pharmacokinetic bioequivalence of Abcertin to Cerezyme, highlighted favorable safety and tolerability profiles with no clinically significant adverse events for Abcertin, and confirmed its low immunogenic potential.
Journal Article
Low-dose ionizing radiation alleviates Aβ42-induced cell death via regulating AKT and p38 pathways in Drosophila Alzheimer's disease models
Ionizing radiation is widely used in medicine and is valuable in both the diagnosis and treatment of many diseases. However, its health effects are ambiguous. Here, we report that low-dose ionizing radiation has beneficial effects in human amyloid-β42 (Aβ42)-expressing
Alzheimer's disease (AD) models. Ionizing radiation at a dose of 0.05 Gy suppressed AD-like phenotypes, including developmental defects and locomotive dysfunction, but did not alter the decreased survival rates and longevity of Aβ42-expressing flies. The same dose of γ-irradiation reduced Aβ42-induced cell death in
AD models through downregulation of
(
), which encodes a protein that activates caspases. However, 4 Gy of γ-irradiation increased Aβ42-induced cell death without modulating pro-apoptotic genes
,
and
The AKT signaling pathway, which was suppressed in
AD models, was activated by either 0.05 or 4 Gy γ-irradiation. Interestingly, p38 mitogen-activated protein-kinase (MAPK) activity was inhibited by exposure to 0.05 Gy γ-irradiation but enhanced by exposure to 4 Gy in Aβ42-expressing flies. In addition, overexpression of phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, or a null mutant of AKT strongly suppressed the beneficial effects of low-dose ionizing radiation in Aβ42-expressing flies. These results indicate that low-dose ionizing radiation suppresses Aβ42-induced cell death through regulation of the AKT and p38 MAPK signaling pathways, suggesting that low-dose ionizing radiation has hormetic effects on the pathogenesis of Aβ42-associated AD.
Journal Article
KBG syndrome: Clinical features and molecular findings in seven unrelated Korean families with a review of the literature
Background KBG syndrome is a rare genetic disorder involving macrodontia of the upper central incisors, craniofacial, skeletal, and neurologic symptoms, caused either by a heterozygous variant in ANKRD11 or deletion of 16q24.3, including ANKRD11. Diagnostic criteria were proposed in 2007 based on 50 cases, but KBG syndrome remains underdiagnosed. Methods Whole exome sequencing (WES) and array comparative genomic hybridization (array CGH) were conducted for genetic analysis and patient phenotypes were characterized based on medical records. Results Eight patients from seven unrelated families were confirmed with KBG syndrome. All patients (8/8, 100%) had some degree of craniofacial dysmorphism and developmental delay or intellectual disabilities. Triangular face, synophrys, anteverted nostril, prominent ears, long philtrum, and tented upper lip, which are typical facial dysmorphism findings in patients with KBG syndrome, were uniformly identified in the eight patients participating in this study, with co‐occurrence rates of 4/8 (50%), 4/8 (50%), 4/8 (50%), 4/8 (50%), 5/8 (62.5%), and 5/8 (62.5%), respectively. Various clinical manifestations not included in the diagnostic criteria were observed. Six patients had point mutations in ANKRD11, one had an exonic deletion of ANKRD11, and one had a 16q24.3 microdeletion. According to the ACMG guidelines, all mutations were classified as pathogenic. The c.2454dup (p.Asn819fs*1) mutation in Pt 4 was reported previously. The remaining variants (c.397 + 1G>A, c.226 + 1G>A, c.2647del (p.Glu883Argfs*94), and c.4093C>T (p.Arg1365Ter)) were novel. Conclusion The clinical and molecular features of eight patients from seven unrelated Korean families with KBG syndrome described here will assist physicians in understanding this rare genetic condition. KBG syndrome (OMIM #148050) is a rare genetic disease caused by ANKRD11 gene mutation or deletion of 16q24.3, including ANKRD11, and is characterized by neurodevelopmental disorders, macrodontia, and craniofacial dysmorphism. In addition to its rarity, the spectrum of phenotypes in KBG syndrome is broad, often underdiagnosed, or overlooked. The clinical and molecular features of eight patients from seven unrelated Korean families with KBG syndrome described here will assist in the understanding of this rare genetic condition and contribute to the identification of underdiagnosed patients.
Journal Article