Biology subjects

Kim, H.-Y.

Publications and source records attributed to Kim, H.-Y..

10 recordsLinked to original sources

bioRxiv2026

Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury

Although acute kidney injury (AKI) has been implicated as a potential adverse effect of statin therapy, experimental evidence supporting this association remains limited. Here, we investigated whether elevated levels of 25-hydroxycholesterol (25-HC), an oxysterol produced by activated macrophages and monocytes, increase susceptibility to statin-induced AKI. We found that atorvastatin and fluvastatin induced cell death in proximal tubular cells when combined with 25-HC. Consistently, administration of low-dose lipopolysaccharide triggered AKI in statin-treated mice. Mechanistically, impaired protein prenylation disrupted the autophagosome-lysosome pathway in proximal tubular cells. AKI was attenuated by mevalonate supplementation, which restored protein prenylation, and by macrophage/monocyte depletion, which reduced the cellular sources of 25-HC. Furthermore, combined exposure to fluvastatin and 25-HC increased kidney injury molecule-1 (KIM-1) expression in human induced pluripotent stem cell-derived kidney organoids. Together, these findings suggest that elevated macrophage-derived 25-HC under conditions of infection, inflammation, or major surgery may increase susceptibility to statin-induced AKI. Our study identifies a previously unrecognized interaction between statins and 25-HC and suggests potential strategies to mitigate kidney injury while preserving the therapeutic benefits of statins.

pharmacology and toxicology↗

bioRxiv2024

Inhibiting EZH2 complements steroid effects in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by mutations in the dystrophin gene. Despite recent advances in understanding the disease etiology and applying emerging treatment methodologies, glucocorticoid derivatives remain the only general therapeutic option that can slow disease development. However, the precise molecular mechanism of glucocorticoid action remains unclear, and there is still need for additional remedies to complement the treatment. Here, using single-nucleus RNA-sequencing and spatial transcriptome analyses of human and mouse muscles, we investigated pathogenic features in DMD patients and palliative effects of glucocorticoids. Our approach further illuminated the importance of proliferating satellite cells, and revealed increased activity of a signal transduction pathway involving EZH2 in the patient cells. Subsequent administration of EZH2 inhibitors to Dmd mutant mice resulted in improved muscle phenotype through maintaining the immune-suppressing effect but overriding the muscle weakness and fibrogenic effects exerted by glucocorticoids. Our analysis reveals pathogenic mechanisms that can be readily targeted by extant therapeutic options for DMD. TeaserA survey of DMD tissues in human and mouse suggests EZH2 as a critical factor in DMD satellite cells; its inhibition resulted in better prognosis.

genetics↗

bioRxiv2024

GPR43 in Eosinophils Prevents the Emergence of Pathogenic Siglec-Fhi Neutrophils in Allergic Airway Inflammation

Eosinophils are major effector cells in type 2 immune responses, contributing to host defense and allergic diseases. They also play critical roles in maintaining tissue homeostasis by regulating various immune cell types. However, evidence of the crosstalk between eosinophils and neutrophils is limited. Here, we show that eosinophils directly associate with neutrophils in the lungs of asthma-induced mice. Eosinophil-specific deficiency of the short-chain fatty acid receptor GPR43 results in hyperactivation of eosinophils and increases the expression of neutrophil chemoattractants and PECAM-1, thus enhancing the interaction between eosinophils and neutrophils. This binding event exposes the neutrophils to eosinophil-derived IL-4 and GM-CSF, which induces the conversion of conventional neutrophils into more pathogenic Siglec-Fhi neutrophils that strongly enhance Th17 cell differentiation and aggravate asthma symptoms. These results reveal GPR43 as a critical regulator of eosinophils and highlight that eosinophils have a hitherto little-known ability to directly modulate neutrophil differentiation and function. One Sentence SummaryEosinophils directly recruit neutrophils and induce their differentiation into a pathogenic Siglec-Fhi subset in allergic airway inflammation.

immunology↗

bioRxiv2022

Physics of sliding on water predicts morphological and behavioral allometry across a wide range of body sizes in water striders (Gerridae)

Laws of physics shape morphological and behavioral adaptations to locomotion at different body sizes. Water striders serve as a model taxon to study how simple physical constraints of water-surface habitats affect their behavior and morphology, and hydrodynamics of rowing by midlegs on the surface is well understood. However, the physics of the subsequent passive sliding has been less explored. We created a model of sliding on the water surface to simulate the effect of body mass, striding type, and wetted leg lengths on an insects ability to float on the surface and on the sliding resistance. The model predicts that to support their weight on the surface during sliding, the heavy species should either develop long forelegs that support the frontal part of its body during symmetrical striding (when two midlegs thrust) or use asymmetrical striding (when one forward-extended midleg supports the body while the other midleg and contra-lateral hindleg thrust). These predictions are confirmed by the behavior and morphology of various Gerridae species. Hence, the results illustrate how simple physical processes specific to a certain habitat type have far-reaching consequences for the evolution of morphological and behavioral diversification associated with body size among biological organisms in these habitats.

biophysics↗

bioRxiv2022

Design of a highly specific glutamine sensor by splitting the glutamine-binding protein

Studies on glutamine (Gln) metabolism have illuminated the vital role of Gln in cellular functions and its potential as a biomarker for disease detection. Despite the increasing interest in Gln metabolism, in-depth evaluations are challenging owing to limitations of conventional Gln-measuring methods. Thus, we developed a ligand-induced dimerization-based sensor for Gln, termed Q-SHINE, by splitting a glutamine binding protein into two separate domains. Q-SHINE enables highly accurate and convenient measurement of Gln concentration in bio-fluid samples, and the detection range is optimal for physiological Gln levels. Genetically encoded Q-SHINE sensors could also visualize intracellular Gln levels and quantify cytoplasmic and mitochondrial Gln change in living cells, which enabled detection of various cell responses to extracellular Gln supplement.

bioengineering↗

bioRxiv2022

Phenotypic and genotypic characterization of Listeria monocytogenes in clinical ruminant cases in Korea

Listeria monocytogenes is a foodborne human and veterinary pathogen. This study aimed to determine the phenotypic and genotypic characteristics of L. monocytogenes isolates from clinical cases of Korean ruminants. We collected 24 L. monocytogenes isolates from clinical cases with caprine neurological symptoms and bovine abortion. The most prevalent serotypes were 4b (IVb), 1/2a (IIa; IIc), and 1/2b (IIb). All isolates, including two found in humans, formed three genetically diverse pulsed-field gel electrophoresis clusters according to serotype, lineage, and sequence type. The most prevalent sequence type was ST1, followed by ST365 and ST91. L. monocytogenes isolates from ruminant listeriosis were resistant to oxacillin and ceftriaxone. These clinical ruminant isolates showed diverse lineage, serotype (serogroup), and sequence type characteristics. Considering that the atypical sequence types exhibited clinical manifestations and histopathological lesions, further study is needed to elucidate the pathogenicity of genetically diverse ruminant L. monocytogenes isolates. Furthermore, continuous monitoring of antimicrobial resistance is required to prevent the emergence of L. monocytogenes strains resistant to common antimicrobials.

microbiology↗

bioRxiv2021

Unraveling the roles of Mast4 in amelogenesis via regulating DLX3 and stem cell maintenance of mouse incisors

Asymmetric division of stem cells allows for maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows for examination of how the stem cell niche employs specific insights into essential phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with weak hardness as the apical bud was reduced and preameloblasts were shifted to the apical side, resulting in Amelogenesis Imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis accelerated. Distal-Less Homeobox 3 (DLX3), known to be a critical factor Tricho-Dento-Osseous (TDO) syndrome, is considered to be responsible for Amelogenesis Imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization sites (NLS) that promote the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role of MAST4 as a critical regulator of ameloblast maturation, which controls DLX3 transcriptional activity.

developmental biology↗

bioRxiv2021

PRMT5 in T cells drives Th17 responses, mixed granulocytic inflammation and severe allergic airway inflammation

Severe asthma is characterized by steroid insensitivity and poor symptom control, and is responsible for the majority of asthma-related hospital costs. Therapeutic options remain limited, in part due to limited understanding in mechanisms driving severe asthma. Increased arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is increased in asthmatic lungs. Here, we show that PRMT5 drives allergic airway inflammation in a mouse model reproducing multiple aspects of human severe asthma. We find that PRMT5 is required in CD4+ T cells for chronic steroid-insensitive severe lung inflammation, with selective T cell deletion of PRMT5 robustly suppressing eosinophilic and neutrophilic lung inflammation, pathology, airway remodeling and hyperresponsiveness. Mechanistically, we observed high pulmonary sterol metabolic activity, ROR-{gamma}t and Th17 responses, with PRMT5-dependent increases in ROR-{gamma}ts agonist desmosterol. Our work demonstrates that T cell PRMT5 drives severe allergic lung inflammation and has potential implications for the pathogenesis and therapeutic targeting of severe asthma.

immunology↗

bioRxiv2019

Homeodomain-interacting protein kinase (Hipk) is required for nervous system and muscle structure and function

Homeodomain-interacting protein kinases (Hipk) have been previously associated with cell proliferation and cancer, however, their effects in the nervous system are less well understood. We have used Drosophila melanogaster to evaluate the effects of altered Hipk expression on the nervous system and muscle. Using genetic manipulation of Hipk expression we demonstrate that knockdown and over-expression of Hipk produces early adult lethality, partially due to the effects on the nervous system and muscle involvement. We find that optimal levels of Hipk are critical for the function of dopaminergic neurons and glial cells in the nervous system, as well as muscle. Furthermore, manipulation of Hipk affects the structure of the larval neuromuscular junction (NMJ) and increases motor neuron axonal branching. Hipk regulates the phosphorylation of the synapse-associated cytoskeletal protein Hts (adducin) and modulates the expression of two important protein kinases, Calcium-calmodulin protein kinase II (CaMKII) and Partitioning-defective 1 (PAR-1), all of which may alter neuromuscular function and influence lethality. Hipk also modifies the distribution of an important nuclear protein, TBPH, the fly orthologue of TAR DNA-binding protein 43 (TDP-43), which may have relevance for understanding motor neuron diseases.

neuroscience↗

bioRxiv2018

Optimal diameter reduction ratio of acinar airways in human lungs

In the airway network of a human lung, the airway diameter gradually decreases through multiple branching. The diameter reduction ratio of the conducting airways that transport gases without gas exchange is 0.79, but this reduction ratio changes to 0.94 in acinar airways beyond transitional bronchioles. While the reduction in the conducting airways was previously rationalized on the basis of Murrays law, our understanding of the design principle behind the acinar airways has been far from clear. Here we elucidate that the change in gas transfer mode is responsible for the transition in the diameter reduction ratio. The oxygen transfer rate per unit surface area is maximized at the observed geometry of acinar airways, which suggests the minimum cost for the construction and maintenance of the acinar airways. The results revitalize and extend the framework of Murrays law over an entire human lung.

bioengineering↗