Biology subjects

Ko, H. S.

Publications and source records attributed to Ko, H. S..

5 recordsLinked to original sources

bioRxiv2025

G1899, an American ginseng extract, alleviates neuroinflammation and cognitive impairment in models of Alzheimer's disease

BackgroundAlzheimers disease (AD) is characterized by amyloid {beta} (A{beta}) accumulation, tau pathology, and chronic neuroinflammation, yet current therapeutic strategies provide only limited efficacy. Natural compounds with pleiotropic actions have emerged as potential adjunctive interventions. This study evaluated G1899, a standardized American ginseng (Panax quinquefolius) extract, for its effects on neuroinflammation, A{beta} clearance, and cognitive function. MethodsNeuronal cultures were exposed to glutamate or A{beta} oligomers (A{beta}o) and pre-treated with G1899 to assess cell viability and excitotoxicity. Primary murine microglia were analyzed for validating expression levels of TMEM119, CD68, NLRP3 inflammasome, IL-1{beta}, Caspase-1, and STAT3 phosphorylation. Behavioral testing was performed in scopolamine-injected mice with short term G1899 treatment and in 5xFAD transgenic mice following long-term G1899 administration at multiple doses. Amyloid burden, microglial recruitment, and plaque morphology were quantified by immunohistochemistry and high-resolution imaging. Human induced microglia (iMG) were examined for neuroinflammatory responses following A{beta}o exposure with or without G1899 treatment. ResultsG1899 significantly improved neuronal viability and reduced glutamate- and A{beta}o-induced toxicity. In microglia, G1899 upregulated TMEM119 and CD68, while suppressing NLRP3 inflammasome formation, proinflammatory cytokine expression, and STAT3 phosphorylation. G1899 rescued scopolamine-induced memory deficits and, in 5xFAD mice, reduced hippocampal and cortical A{beta} burden, alleviated neuroinflammatory markers, and improved both spatial/fear learning and memory, with the most consistent efficacy observed at 300 mg/kg. Imaging revealed enhanced microglial recruitment to plaques and facilitated fragmentation of A{beta} deposits. In iMG, G1899 elevated homeostatic and phagocytic markers while attenuating A{beta}o-induced NLRP3/STAT3-mediated neuroinflammatory signaling pathway. ConclusionsG1899 confers multimodal neuroprotection by preserving neuronal survival, modulating microglial activity, and facilitating A{beta} clearance. These findings highlight its potential as a safe and clinically translatable botanical intervention for AD.

neuroscience↗

bioRxiv2023

Linking Gba1 E326K mutation to microglia activation and mild age-dependent dopaminergic Neurodegeneration

Mutations in the GBA1 gene have been identified as a prevalent genetic risk factor for Parkinsons disease (PD). GBA1 mutations impair enzymatic activity, leading to lysosomal dysfunction and elevated levels of -synuclein (-syn). While most research has primarily focused on GBA1s role in promoting synucleinopathy, emerging evidence suggests that neuroinflammation may be a key pathogenic alteration caused by GBA1 deficiency. To examine the molecular mechanism underlying GBA1 deficiency-mediated neuroinflammation, we generated Gba1 E326K knock-in (KI) mice using the CRISPR/Cas9 technology, which is linked to an increased risk of PD and dementia with Lewy bodies (DLB). In the ventral midbrain and hippocampus of 24-month-old Gba1 E326K KI mice, we found a moderate decline in GBA1 enzymatic activity, a buildup of glucosylceramide, and an increase in microglia density. Furthermore, we observed increased levels of pro-inflammatory cytokines and formation of reactive astrocytes in primary microglia and astrocytes, respectively, cultured from Gba1 E326K KI mice following treatment with pathologic -syn preformed fibrils (PFF). Additionally, the gut inoculation of -syn PFF in Gba1 E326K KI mice significantly enhanced the accumulation of Lewy bodies in the dentate gyrus of the hippocampus, accompanied by aggravated neuroinflammation and exacerbated non-motor symptoms. This research significantly enhances our understanding of the Gba1 E326K mutations involvement in neuroinflammation and the cell-to-cell transmission of pathogenic -syn in the brain, thereby opening new therapeutic avenues.

neuroscience↗

bioRxiv2021

Analysis of the blood microbiome in a porcine model of fecal-induced peritonitis

BackgroundRecent studies have proposed the existence of a blood microbiome, even in the healthy host. However, we do not know how the blood microbiome changes when a bloodstream infection (BSI) occurs. Here, we analyzed the dynamics of the blood microbiome in a porcine model of polymicrobial bacteremia induced by fecal peritonitis. Serial blood samples were taken over 12 hours post-induction of fecal peritonitis, and BSI was validated by conventional blood culture and assessment of clinical symptoms. ResultsThe bacterial populations in the blood microbiome were retained throughout the experimental period. However, there were significant taxonomic differences between the profile in the fecal and blood microbiomes, reflecting tropism for the blood environment. We also confirmed that the microbiota we detected was not contaminated by low mass bacteria in the bloodstream. However, at the same time, we noted a slight increase in Bacteroidetes, which is a major component of the gut microbiome, as sepsis developed. Comparison of the functional pathways in the blood and fecal microbiomes revealed upregulation of pathways involved in environmental interactions, and downregulation of those related to cell proliferation, in the former. Based on the enriched biological pathways, we concluded that communication and stress management pathways are essential for the survival of the blood microbiome under harsh conditions. ConclusionThis study suggests that the microbiota can be stably retained in the bloodstream over time. Although further investigation in humans is required, we suggest that the blood microbiome may be another factor to be considered in the context of BSI and subsequent sepsis.

microbiology↗

bioRxiv2020

SLC7A11 is a superior determinant of APR-246 (Eprenetapopt) response than TP53 mutation status

PurposeAPR-246 (Eprenetapopt) is in clinical development with a focus on haematological malignancies and is marketed as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with combination chemotherapy (cisplatin and 5-Fluorouracil) in metastatic oesophageal cancer, together with previous pre-clinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for response to APR-246. This study aimed to identify a robust biomarker for response to APR-246. MethodsCorrelation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression and metabolite abundance across over 800 cancer cell lines was performed. Functional validation and a boutique siRNA screen of over 750 redox-related genes were also conducted. ResultsTP53 mutation status was not predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53 and c-Myc were confirmed to also regulate cancer cell sensitivity to APR-246. ConclusionsSLC7A11 expression is the major determinant of sensitivity to APR-246 and should be utilised as a predictive biomarker in future clinical investigation of APR-246.

cancer biology↗

bioRxiv2020

Complement and coagulation cascades are potentially involved in dopaminergic neurodegeneration in alpha-synuclein-based mouse models of Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and eventually, cognitive impairment. -Synuclein protein has been known to be the most culprit protein, but the underlying pathological mechanism still remains to be elucidated. As an effort to clarify the pathogenesis mechanism by -synuclein, various PD mouse models with -synuclein overexpression have been developed. However, the systemic analysis of protein abundance change by the overexpressed -synuclein in the whole proteome level has been still lacking. To address this issue, we established two sophisticated mouse models of PD by injecting -synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T -synuclein to discover overlapping pathways, which could be altered in the two different types of PD mouse model. For more accurate quantification of mouse brain proteome, stable isotope labeling with amino acid in mammal-based quantification was implemented. As a result, we have successfully identified a total of 8,355 proteins from both of the mouse models; [~]6,800 and [~]7,200 proteins from -synuclein PFF injected mice and human A53T -synuclein transgenic mice, respectively. From the pathway analysis of the differentially expressed proteins in common, the complement and coagulation cascade pathway were determined as the most enriched ones. This is the first study that highlights the significance of the complement and coagulation pathway in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

neuroscience↗