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"Jin-Man, Kim"
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GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections
Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain; however, the roles of GABA in antimicrobial host defenses are largely unknown. Here we demonstrate that GABAergic activation enhances antimicrobial responses against intracellular bacterial infection. Intracellular bacterial infection decreases GABA levels in vitro in macrophages and in vivo in sera. Treatment of macrophages with GABA or GABAergic drugs promotes autophagy activation, enhances phagosomal maturation and antimicrobial responses against mycobacterial infection. In macrophages, the GABAergic defense is mediated via macrophage type A GABA receptor (GABA
A
R), intracellular calcium release, and the GABA type A receptor-associated protein-like 1 (GABARAPL1; an Atg8 homolog). Finally, GABAergic inhibition increases bacterial loads in mice and zebrafish in vivo, suggesting that the GABAergic defense plays an essential function in metazoan host defenses. Our study identified a previously unappreciated role for GABAergic signaling in linking antibacterial autophagy to enhance host innate defense against intracellular bacterial infection.
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in neuronal systems, but the potential role for such neurotransmitters on the immune system are emerging. Here the authors show GABA signaling is linked to autophagy, enhancing the host response against intracellular bacteria.
Journal Article
GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation
Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial–mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.
Journal Article
Diagnosis of Crohn’s disease and ulcerative colitis using the microbiome
Background
Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disease resulting from dysregulation of the mucosal immune response and gut microbiota. Crohn's disease (CD) and ulcerative colitis (UC) are difficult to distinguish, and differential diagnosis is essential for establishing a long-term treatment plan for patients. Furthermore, the abundance of mucosal bacteria is associated with the severity of the disease. This study aimed to differentiate and diagnose these two diseases using the microbiome and identify specific biomarkers associated with disease activity.
Results
Differences in the abundance and composition of the microbiome between IBD patients and healthy controls (HC) were observed. Compared to HC, the diversity of the gut microbiome in patients with IBD decreased; the diversity of the gut microbiome in patients with CD was significantly lower. Sixty-eight microbiota members (28 for CD and 40 for UC) associated with these diseases were identified. Additionally, as the disease progressed through different stages, the diversity of the bacteria decreased. The abundances of
Alistipes shahii
and
Pseudodesulfovibrio aespoeensis
were negatively correlated with the severity of CD, whereas the abundance of
Polynucleobacter wianus
was positively correlated. The severity of UC was negatively correlated with the abundance of
A. shahii
,
Porphyromonas asaccharolytica and Akkermansia muciniphilla,
while it was positively correlated with the abundance of
Pantoea candidatus pantoea carbekii
. A regularized logistic regression model was used for the differential diagnosis of the two diseases. The area under the curve (AUC) was used to examine the performance of the model. The model discriminated UC and CD at an AUC of 0.873 (train set), 0.778 (test set), and 0.633 (validation set) and an area under the precision-recall curve (PRAUC) of 0.888 (train set), 0.806 (test set), and 0.474 (validation set).
Conclusions
Based on fecal whole-metagenome shotgun (WMS) sequencing, CD and UC were diagnosed using a machine-learning predictive model. Microbiome biomarkers associated with disease activity (UC and CD) are also proposed.
Journal Article
Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin
Parkin penalty
The
PINK1
gene was recently implicated in autosomal recessive juvenile Parkinson's disease. Two groups have studied the equivalent gene in the fruitfly
Drosophila
, and find that it localizes to mitochondria
in vivo
and is essential to mitochondrial function. It also interacts genetically with
parkin
, another familial Parkinson's disease-related gene that encodes Parkin, an E3 ubiquitin ligase. The
pink1-parkin
pathway in
Drosophila
should provide a powerful tool for the study of the molecular mechanisms of neurodegeneration and for screening agents of possible therapeutic interest.
Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset form of Parkinson's disease characterized by motor disturbances and dopaminergic neurodegeneration
1
,
2
. To address its underlying molecular pathogenesis, we generated and characterized loss-of-function mutants of
Drosophila PTEN-induced putative kinase 1
(
PINK1
)
3
, a novel AR-JP-linked gene
4
. Here, we show that
PINK1
mutants exhibit indirect flight muscle and dopaminergic neuronal degeneration accompanied by locomotive defects. Furthermore, transmission electron microscopy analysis and a rescue experiment with
Drosophila
Bcl-2
demonstrated that mitochondrial dysfunction accounts for the degenerative changes in all phenotypes of
PINK1
mutants. Notably, we also found that
PINK1
mutants share marked phenotypic similarities with
parkin
mutants. Transgenic expression of Parkin markedly ameliorated all
PINK1
loss-of-function phenotypes, but not vice versa, suggesting that Parkin functions downstream of PINK1. Taken together, our genetic evidence clearly establishes that Parkin and PINK1 act in a common pathway in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons.
Journal Article
Age‐related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high‐risk cases
As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the β‐catenin pathway. This study aimed to investigate the mechanism by which age‐related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning‐based digital image analysis with fluorescence‐immunohistochemistry, we assessed SQLE, GSK3βpS9 (GSK3β activity inhibition through serine 9 phosphorylation at GSK3β), p53 wild‐type (p53WT), and p53 mutant (p53MT) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53WT, and p53MT and increase in GSK3βpS9 levels, all associated with the substantial accumulation of intra‐tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression‐free survival in grade 2–3 CRC patients aged over 50. SQLE and GSK3βpS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53WT, p53MT, and GSK3βpS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging‐linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3βpS9, for older patients at elevated risk of CRC. As people age, the incidence and mortality of colorectal cancer, as well as high cholesterol levels, increases. Age‐related accumulation of cholesterol accelerates CRC progression in humans by reducing SQLE, inhibiting GSK3β, and suppressing the p53 pathway, thereby providing valuable biomarkers for populations at high risk of CRC.
Journal Article
Rg6, a rare ginsenoside, inhibits systemic inflammation through the induction of interleukin-10 and microRNA-146a
The immunobiological functions of Rg6, a rare ginsenoside from ginseng, have been largely unreported. In this paper, we demonstrate that Rg6 has a significant immunosuppressive function on Toll-like receptor (TLR) 4-induced systemic inflammatory responses. Rg6 was found to negatively regulate pro-inflammatory responses and severity
in vivo
, and thus induced recovery in mice with lipopolysaccharide (LPS)-induced septic shock and cecal ligation and puncture (CLP)-induced sepsis. Rg6 treatment also facilitated recovery in mice with LPS-induced lung damage via reduced neutrophil infiltration and tumor necrosis factor-α expression in lung tissues. Rg6 injection also downregulated pro-inflammatory cytokines and increased the levels of interleukin (IL)-10 in the serum of septic mice. Mechanistically, Rg6 did not induce TLR negative regulators, such as A20 and IRAK-M, in bone marrow-derived macrophages (BMDMs). Instead, addition of Rg6 to LPS-activated BMDMs augmented IL-10 expression, whereas it inhibited inflammatory signaling, such as by nuclear factor κB activation and mitogen-activated protein kinases. Furthermore, Rg6 significantly induced miR-146a, an operator miRNA for anti-inflammation, in BMDMs. Collectively, these data indicate that Rg6 inhibits inflammatory responses through the induction of IL-10 and miR-146a.
Journal Article
2D transition metal dichalcogenides with glucan multivalency for antibody-free pathogen recognition
The ability to control the dimensions and properties of nanomaterials is fundamental to the creation of new functions and improvement of their performances in the applications of interest. Herein, we report a strategy based on glucan multivalent interactions for the simultaneous exfoliation and functionalization of two-dimensional transition metal dichalcogenides (TMDs) in an aqueous solution. The multivalent hydrogen bonding of dextran with bulk TMDs (WS
2
, WSe
2
, and MoSe
2
) in liquid exfoliation effectively produces TMD monolayers with binding multivalency for pathogenic bacteria. Density functional theory simulation reveals that the multivalent hydrogen bonding between dextran and TMD monolayers is very strong and thermodynamically favored (Δ
E
b
= −0.52 eV). The resulting dextran/TMD hybrids (dex-TMDs) exhibit a stronger affinity (
K
d
= 11 nM) to
Escherichia coli
O157:H7 (
E. coli
) than
E. coli
-specific antibodies and aptamers. The dex-TMDs can effectively detect a single copy of
E. coli
based on their Raman signal.
The detection of pathogenic microorganisms is key consideration for safety across a wide range of fields. Here, the authors report on the simultaneous exfoliation and functionalisation of transition metal dichalcogenides with dextran for antibody-free detection of pathogenic
Escherichia coli
.
Journal Article
Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis
Loss of Hippo signaling in Drosophila leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45 deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell-derived tumors.
Journal Article