Radiomics and machine learning analysis of liver magnetic resonance imaging for prediction and early detection of tumor response in colorectal liver metastases.

PURPOSE: The aim of this study was to demonstrate the effectiveness of a machine learning-based radiomics model for distinguishing tumor response and overall survival in patients with unresectable colorectal liver metastases (CRLM) treated with targeted biological therapy. METHODS: We prospectively recruited 17 patients with unresectable liver metastases of colorectal cancer, who had been given targeted biological therapy as the first line of treatment. All patients underwent liver magnetic resonance imaging (MRI) three times up until 8 weeks after chemotherapy. We evaluated the diagnostic performance of machine learning-based radiomics model in tumor response of liver MRI compared with the guidelines for the Response Evaluation Criteria in Solid Tumors. Overall survival was evaluated using the Kaplan-Meier analysis and compared to the Cox proportional hazard ratios following univariate and multivariate analyses. RESULTS: Performance measurement of the trained model through metrics showed the accuracy of the machine learning model to be 76.5%, and the area under the receiver operating characteristic curve was 0.857 (95% confidence interval [CI], 0.605-0.976; P < 0.001). For the patients classified as non-progressing or progressing by the radiomics model, the median overall survival was 17.5 months (95% CI, 12.8-22.2), and 14.8 months (95% CI, 14.2-15.4), respectively (P = 0.431, log-rank test). CONCLUSION: Machine learning-based radiomics models could have the potential to predict tumor response in patients with unresectable CRLM treated with biologic therapy.

Advanced MRI techniques in abdominal imaging.

Magnetic resonance imaging (MRI) is a crucial modality for abdominal imaging evaluation of focal lesions and tissue properties. However, several obstacles, such as prolonged scan times, limitations in patients' breath-hold capacity, and contrast agent-associated artifacts, remain in abdominal MR images. Recent techniques, including parallel imaging, three-dimensional acquisition, compressed sensing, and deep learning, have been developed to reduce the scan time while ensuring acceptable image quality or to achieve higher resolution without extending the scan duration. Quantitative measurements using MRI techniques enable the noninvasive evaluation of specific materials. A comprehensive understanding of these advanced techniques is essential for accurate interpretation of MRI sequences. Herein, we therefore review advanced abdominal MRI techniques.

Advanced Abdominal MRI Techniques and Problem-Solving Strategies.

MRI plays an important role in abdominal imaging because of its ability to detect and characterize focal lesions. However, MRI examinations have several challenges, such as comparatively long scan times and motion management through breath-holding maneuvers. Techniques for reducing scan time with acceptable image quality, such as parallel imaging, compressed sensing, and cutting-edge deep learning techniques, have been developed to enable problem-solving strategies. Additionally, free-breathing techniques for dynamic contrast-enhanced imaging, such as extra-dimensional-volumetric interpolated breath-hold examination, golden-angle radial sparse parallel, and liver acceleration volume acquisition Star, can help patients with severe dyspnea or those under sedation to undergo abdominal MRI. We aimed to present various advanced abdominal MRI techniques for reducing the scan time while maintaining image quality and free-breathing techniques for dynamic imaging and illustrate cases using the techniques mentioned above. A review of these advanced techniques can assist in the appropriate interpretation of sequences.

A Composite Blood Biomarker Including AKR1B10 and Cytokeratin 18 for Progressive Types of Nonalcoholic Fatty Liver Disease.

Background: We aimed to evaluate whether composite blood biomarkers including aldo-keto reductase family 1 member B10 (AKR1B10) and cytokeratin 18 (CK-18; a nonalcoholic steatohepatitis [NASH] marker) have clinically applicable performance for the diagnosis of NASH, advanced liver fibrosis, and high-risk NASH (NASH+significant fibrosis). Methods: A total of 116 subjects including healthy control subjects and patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were analyzed to assess composite blood-based and imaging-based biomarkers either singly or in combination. Results: A composite blood biomarker comprised of AKR1B10, CK-18, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) showed excellent performance for the diagnosis of, NASH, advanced fibrosis, and high-risk NASH, with area under the receiver operating characteristic curve values of 0.934 (95% confidence interval [CI], 0.888 to 0.981), 0.902 (95% CI, 0.832 to 0.971), and 0.918 (95% CI, 0.862 to 0.974), respectively. However, the performance of this blood composite biomarker was inferior to that various magnetic resonance (MR)-based composite biomarkers, such as proton density fat fraction/MR elastography- liver stiffness measurement (MRE-LSM)/ALT/AST for NASH, MRE-LSM+fibrosis-4 index for advanced fibrosis, and the known MR imaging-AST (MAST) score for high-risk NASH. Conclusion: Our blood composite biomarker can be useful to distinguish progressive forms of NAFLD as an initial noninvasive test when MR-based tools are not available.

Hepatobiliary phase imaging in cirrhotic patients using compressed sensing and controlled aliasing in parallel imaging results in higher acceleration.

OBJECTIVE: We aimed to compare the image quality and focal lesion detection ability of hepatobiliary phase (HBP) images obtained using compressed sensing (CS) and controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) in patients with liver cirrhosis. MATERIALS AND METHODS: We retrospectively included 244 gadoxetic acid-enhanced liver MRI from 244 patients with cirrhosis obtained by two HBP images using CS and CAIPIRINHA from July 2020 to December 2020. The optimized resolution and scan time for CS-HBP and CAIPIRINHA-HBP were 0.9 × 0.9 × 1.5 mm3 and 15 s and 1.3 × 1.3 × 3 mm3 and 16 s, respectively. We compared the image quality between the two sets of images in 244 patients and focal lesion (n = 294) analyses for 112 patients. RESULTS: CS-HBP showed comparable overall image quality (3.7 ± 0.9 vs. 3.6 ± 0.8, p = 0.680), superior liver edge sharpness (3.9 ± 0.6 vs. 3.6 ± 0.5, p < 0.001), and fewer respiratory motion artifacts (4.0 ± 0.7 vs. 3.8 ± 0.5, p < 0.001), but higher non-respiratory artifacts (3.4 ± 0.7 vs. 3.6 ± 0.6, p < 0.001) and subjective image noise (3.5 ± 0.8 vs. 3.6 ± 0.7, p = 0.014) than CAIPIRINHA-HBP. CS-HBP showed a higher signal-to-noise ratio in the liver than CAIPIRINHA-HBP (20.9 ± 9.0 vs. 18.9 ± 7.1, p = 0.008). The pooled sensitivity, specificity, and AUC were 90.0%, 77.5%, and 0.84 for CS-HBP and 73.5%, 82.4%, and 0.78 for CAIPIRINHA-HBP, respectively. CONCLUSIONS: CS-HBP showed better focal lesion detection ability, comparable overall image quality, and fewer respiratory motion artifacts, but higher non-respiratory artifacts and noise compared to CAIPIRINHA-HBP. Thus, CS-HBP could be recommended for liver MRI in patients with cirrhosis to improve diagnostic performance. CLINICAL RELEVANCE STATEMENT: Thin-slice CS-HBP may be useful for detecting sub-centimeter hepatocellular carcinoma in cirrhotic patients with Child-Pugh classification A while maintaining comparable subjective image quality. KEY POINTS: • Compared with controlled aliasing in parallel imaging results in higher acceleration, compressed sensing hepatobiliary phase yielded thinner slices and shorter scan time at a higher accelerating factor. • Compressed sensing hepatobiliary phase showed comparable overall image quality, superior liver edge sharpness, and fewer respiratory motion artifacts, but higher non-respiratory artifacts and subjective image noise than controlled aliasing in parallel imaging results in higher acceleration-hepatobiliary phase. • Compressed sensing hepatobiliary phase can detect sub-centimeter hepatocellular carcinoma in cirrhotic patients with Child-Pugh classification A.

Typical and Atypical Imaging Features of Malignant Lymphoma in the Abdomen and Mimicking Diseases.

Malignant lymphoma typically presents with homogeneous enhancement of enlarged lymph nodes without internal necrotic or cystic changes on multiphasic CT, which can be suspected without invasive diagnostic methods. However, some subtypes of malignant lymphoma show atypical imaging features, which makes diagnosis challenging for radiologists. Moreover, there are several lymphoma-mimicking diseases in current clinical practice, including leukemia, viral infections in immunocompromised patients, and primary or metastatic cancer. The ability of diagnostic processes to distinguish malignant lymphoma from mimicking diseases is necessary to establish effective management strategies for initial radiological examinations. Therefore, this study aimed to discuss the typical and atypical imaging features of malignant lymphoma as well as mimicking diseases and discuss important diagnostic clues that can help narrow down the differential diagnosis.

TGF-ß and SHH Regulate Pluripotent Stem Cell Differentiation into Brain Microvascular Endothelial Cells in Generating an In Vitro Blood-Brain Barrier Model.

Blood-brain barrier (BBB) models are important tools for studying CNS drug delivery, brain development, and brain disease. In vitro BBB models have been obtained from animals and immortalized cell lines; however, brain microvascular endothelial cells (BMECs) derived from them have several limitations. Furthermore, obtaining mature brain microvascular endothelial-like cells (BME-like cells) from human pluripotent stem cells (hPSCs) with desirable properties for establishing BBB models has been challenging. Here, we developed an efficient method for differentiating hPSCs into BMECs that are amenable to the development and application of human BBB models. The established conditions provided an environment similar to that occurring during BBB differentiation in the presence of the co-differentiating neural cell population by the modulation of TGF-ß and SHH signaling. The developed BME-like cells showed well-organized tight junctions, appropriate expression of nutrient transporters, and polarized efflux transporter activity. In addition, BME-like cells responded to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance. Moreover, the BME-like cells exhibited an immune quiescent property of BBB endothelial cells by decreasing the expression of adhesion molecules. Therefore, our novel cellular platform could be useful for drug screening and the development of brain-permeable pharmaceuticals.

Three-dimensional label-free visualization of the interactions of PM2.5 with macrophages and epithelial cells using optical diffraction tomography.

Particulate matter ≤ 2.5 µm (PM2.5) poses health risks related to various diseases and infections. However, the interactions between PM2.5 and cells such as uptake and cell responses have not been fully investigated despite advances in bioimaging techniques, because the heterogeneous morphology and composition of PM2.5 make it challenging to employ labeling techniques, such as fluorescence. In this work, we visualized the interaction between PM2.5 and cells using optical diffraction tomography (ODT), which provides quantitative phase images by refractive index distribution. Through ODT analysis, the interactions of PM2.5 with macrophages and epithelial cells, such as intracellular dynamics, uptake, and cellular behavior, were successfully visualized without labeling techniques. ODT analysis clearly shows the behavior of phagocytic macrophages and nonphagocytic epithelial cells for PM2.5. Moreover, ODT analysis could quantitatively compare the accumulation of PM2.5 inside the cells. PM2.5 uptake by macrophages increased substantially over time, but uptake by epithelial cells increased only marginally. Our findings indicate that ODT analysis is a promising alternative approach to visually and quantitatively understanding the interaction of PM2.5 with cells. Therefore, we expect ODT analysis to be employed to investigate the interactions of materials and cells that are difficult to label.

Antioxidants prevent particulate matter-induced senescence of lung fibroblasts.

Particulate matter (PM) contributes to human diseases, particularly lung disease; however, the molecular mechanism of its action is yet to be determined. Herein, we found that prolonged PM exposure induced the cellular senescence of normal lung fibroblasts via a DNA damage-mediated response. This PM-induced senescence (PM-IS) was only observed in lung fibroblasts but not in A549 lung adenocarcinoma cells. Mechanistic analysis revealed that reactive oxygen species (ROS) activate the DNA damage response signaling axis, increasing p53 phosphorylation, ultimately leading to cellular senescence via an increase in p21 expression without affecting the p16-pRB pathway. A549 cells, instead, were resistant to PM-IS due to the PM-induced ROS production suppression. Water-soluble antioxidants, such as vitamin C and N-Acetyl Cysteine, were found to alleviate PM-IS by suppressing ROS production, implying that antioxidants are a promising therapeutic intervention for PM-mediated lung pathogenesis.

Endothelial PTP4A1 mitigates vascular inflammation via USF1/A20 axis-mediated NF-κB inactivation.

AIMS: The nuclear factor-κB (NF-κB) signalling pathway plays a critical role in the pathogenesis of multiple vascular diseases. However, in endothelial cells (ECs), the molecular mechanisms responsible for the negative regulation of the NF-κB pathway are poorly understood. In this study, we investigated a novel role for protein tyrosine phosphatase type IVA1 (PTP4A1) in NF-κB signalling in ECs. METHODS AND RESULTS: In human tissues, human umbilical artery ECs, and mouse models for loss of function and gain of function of PTP4A1, we conducted histological analysis, immunostaining, laser-captured microdissection assay, lentiviral infection, small interfering RNA transfection, quantitative real-time PCR and reverse transcription-PCR, as well as luciferase reporter gene and chromatin immunoprecipitation assays. Short hairpin RNA-mediated knockdown of PTP4A1 and overexpression of PTP4A1 in ECs indicated that PTP4A1 is critical for inhibiting the expression of cell adhesion molecules (CAMs). PTP4A1 increased the transcriptional activity of upstream stimulatory factor 1 (USF1) by dephosphorylating its S309 residue and subsequently inducing the transcription of tumour necrosis factor-alpha-induced protein 3 (TNFAIP3/A20) and the inhibition of NF-κB activity. Studies on Ptp4a1 knockout or transgenic mice demonstrated that PTP4A1 potently regulates the interleukin 1ß-induced expression of CAMs in vivo. In addition, we verified that PTP4A1 deficiency in apolipoprotein E knockout mice exacerbated high-fat high-cholesterol diet-induced atherogenesis with upregulated expression of CAMs. CONCLUSION: Our data indicate that PTP4A1 is a novel negative regulator of vascular inflammation by inducing USF1/A20 axis-mediated NF-κB inactivation. Therefore, the expression and/or activation of PTP4A1 in ECs might be useful for the treatment of vascular inflammatory diseases.

Particulate matter induces ferroptosis by accumulating iron and dysregulating the antioxidant system.

Particulate matter is an air pollutant composed of various components, and has adverse effects on the human body. Particulate matter is known to induce cell death by generating an imbalance in the antioxidant system; however, the underlying mechanism has not been elucidated. In the present study, we demonstrated the cytotoxic effects of the size and composition of particulate matter on small intestine cells. We found that particulate matter 2.5 (PM2.5) with extraction ion (EI) components (PM2.5 EI), is more cytotoxic than PM containing only polycyclic aromatic hydrocarbons (PAHs). Additionally, PM-induced cell death is characteristic of ferroptosis, and includes iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) generation. Furthermore, ferroptosis inhibitor as liproxstatin-1 and iron-chelator as deferiprone attenuated cell mortality, lipid peroxidation, iron accumulation, and ROS production after PM2.5 EI treatment in human small intestinal cells. These results suggest that PM2.5 EI may increase ferroptotic-cell death by iron accumulation and ROS generation, and offer a potential therapeutic clue for inflammatory bowel diseases in human small intestinal cells. [BMB Reports 2023; 56(2): 96-101].

Particulate matter promotes cancer metastasis through increased HBEGF expression in macrophages.

Although many cohort studies have reported that long-term exposure to particulate matter (PM) can cause lung cancer, the molecular mechanisms underlying the PM-induced increase in cancer metastasis remain unclear. To determine whether PM contributes to cancer metastasis, cancer cells were cultured with conditioned medium from PM-treated THP1 cells, and the migration ability of the treated cancer cells was assessed. The key molecules involved were identified using RNA-seq analysis. In addition, metastatic ability was analyzed in vivo by injection of cancer cells into the tail vein and intratracheal injection of PM into the lungs of C57BL/6 mice. We found that PM enhances the expression of heparin-binding EGF-like growth factor (HBEGF) in macrophages, which induces epithelial-to-mesenchymal transition (EMT) in cancer cells, thereby increasing metastasis. Macrophage stimulation by PM results in activation and subsequent nuclear translocation of the aryl hydrocarbon receptor and upregulation of HBEGF. Secreted HBEGF activates EGFR on the cancer cell surface to induce EMT, resulting in increased migration and invasion in vitro and increased metastasis in vivo. Therefore, our study reveals a critical PM-macrophage-cancer cell signaling axis mediating EMT and metastasis and provides an effective therapeutic approach for PM-induced malignancy.

The role of immunomodulatory metabolites in shaping the inflammatory response of macrophages.

Macrophage activation has long been implicated in a myriad of human pathophysiology, particularly in the context of the dysregulated capacities of an unleashing intracellular or/and extracellular inflammatory response. A growing number of studies have functionally coupled the macrophages' inflammatory capacities with dynamic metabolic reprogramming which occurs during activation, albeit the results have been mostly interpreted through classic metabolism point of view; macrophages take advantage of the rewired metabolism as a source of energy and for biosynthetic precursors. However, a specific subset of metabolic products, namely immune-modulatory metabolites, has recently emerged as significant regulatory signals which control inflammatory responses in macrophages and the relevant extracellular milieu. In this review, we introduce recently highlighted immuno-modulatory metabolites, with the aim of understanding their physiological and pathological relevance in the macrophage inflammatory response. [BMB Reports 2022; 55(11): 519-527].

Low-dose abdominopelvic computed tomography in patients with lymphoma: An image quality and radiation dose reduction study.

This study aimed to evaluate image quality, the detection rate of enlarged lymph nodes, and radiation dose exposure of ultralow-dose and low-dose abdominopelvic computed tomography (CT) in patients with lymphoma. Patients with lymphoma who underwent abdominopelvic CT using dual-source scanner were retrospectively recruited from a single center. CT images were obtained at 90 kVp dual-source mode reformatted in three data sets using the advanced modelled iterative reconstruction algorithm: 100% (standard-dose CT), 66.7% (low-dose CT), and 33.3% (ultralow-dose CT). Two radiologists analyzed subjective image quality and detection of abdominal enlarged lymph nodes on ultralow-dose, low-dose, and standard-dose CT blindly and independently. The results were compared with reference standards. Three readers (two radiologists and one hematologist) reviewed overall image quality and spleen size. In total, 128 consecutive CT scans (77 complete response, 44 partial response, 6 progressive disease, and 1 initial evaluation) from 86 patients (64 B-cell lymphoma, 14 T/NK-cell lymphoma, and 8 Hodgkin's lymphoma cases) were assessed. The enlarged lymph node-based detection rates for two readers were 97.0% (96/99) and 94.0% (93/99) on standard-dose CT, 97.0% (96/99) and 94.0% (93/99) on low-dose CT, and 94.0% (93/99) and 89.9% (89/99) on ultralow-dose CT. Overall image quality was 3.8 ± 0.5, 3.9 ± 0.5, and 4.1 ± 0.5 on ultralow-dose CT; 4.7 ± 0.4, 4.6 ± 0.5, and 4.8 ± 0.3 on low-dose CT; and 4.8 ± 0.4, 4.7 ± 0.4, and 4.9 ± 0.2 on standard-dose CT, according to two radiologists and one hematologist, respectively. Intraclass correlation coefficients of spleen size were 0.90 (95% confidence interval [CI], 0.87-0.93), 0.91 (95% CI, 0.88-0.93), and 0.91 (95% CI, 0.88-0.93) on ultralow-dose, low-dose, and standard-dose CT, respectively. Mean effective radiation doses of standard-dose, low-dose, and ultralow-dose CT were 5.7 ±1.8 mSv, 3.8 ± 1.2 mSv, and 1.9 ± 0.6 mSv, respectively. Our findings suggest that ultralow-dose and low-dose CT, even with radiation doses reduced by 66.7% and 33.3%, respectively, maintained adequate image quality. These imaging modalities may be employed for follow-up lymphoma evaluation in consideration of the long surveillance periods.

Ingestion and egestion of polystyrene microplastic fragments by the Pacific oyster, Crassostrea gigas.

Marine microplastics (MPs) pose a risk to human health through accumulation in maricultural organisms, particularly bivalves. Various studies have reported the presence of MP particles in Pacific oysters (Crasostrea gigas). In this study, we investigated the size-specific ingestion and egestion of polystyrene (PS) MPs by Pacific oysters. The cultivation density of C. gigas was maintained at 1 L of filtered seawater per oyster (n = 5) during the MP ingestion and egestion experiments. On exposure to 300 n/L of PS MP fragments for 7 d, 60.4% of the PS was ingested within 6 h (7.25 × 102 ± 1.36 × 102 n/indv.), and the ingestion was saturated at 12 h (1.2 × 103 ± 2.2 × 102 n/indv.) in C. gigas. The maximum MP ingestion capacity (Igmax) of a single Pacific oyster was 73.0 ± 16.3 n/g wet weight. Further, 62.9% of the PS MP particles were egested for 7 d from the saturated single C. gigas. Ingestion and egestion varied according to the PS MP size. In the case of <50 µm PS MP, ingestion rate was low but MP amount and net-ingestion efficiency was significantly higher than other PS MP sizes. In addition, egestion, egestion rate, and net-egestion efficiency for <50 µm PS MPs were significantly higher than other PS MP sizes. Therefore, smaller MPs (<50 µm) normally exhibit the highest ingestion and egestion rates; therefore, the 50-300 µm size fraction exhibited the highest residual possibility (particles >1000 µm were excluded). Additionally, considering the net-egestion efficiency, the most economical and efficient depuration period was 24 h. This study clarifies the size-specific MP accumulation in oysters, and the egestion results suggest that the potential risk of MPs to human health through the intake of maricultural products could be reduced by depuration.

Association of 25-hydroxyvitamin D status with brain volume changes.

Vitamin D is critical to brain function and its deficiency accelerates cognitive impairment. There is limited understanding of the brain-specific areas that undergo volume change in relation to blood vitamin D levels. The objective of this study was to evaluate the association between blood 25-hydroxyvitamin D (25(OH)D) concentration and structural changes in the brain. We analyzed structural three-dimensional T1 MRI images of 201 elderly individuals (mean age = 74.91 ± 9.21 years; 68.1% female; mean 25(OH)D = 18.05 nmol/L), with 10 community-based normal healthy subjects, 33 with subjective cognitive decline, 97 with mild cognitive impairment, and 61 with Alzheimer's disease (AD). To analyze the structural changes in the brain respective to blood 25(OH)D, multiple regression analyses were performed using voxel-based morphometry with age and total intracranial volume as covariates. Lower 25(OH)D level were associated with reduced brain volume in right olfactory, rectus GM regions (FWE-corr, p < .05) for entire subjects. For AD subjects, left parahippocampal, fusiform, and hippocampal areas were positively associated with 25(OH)D (FWE-corr, p < .05). Low blood 25(OH)D was associated with reduced volumes in olfactory and hippocampal regions in elderly patients with cognitive decline. Our results may provide insight into the neurological pathophysiology of vitamin D.

Bacterial type III effector protein HopQ inhibits melanoma motility through autophagic degradation of vimentin.

Malignant melanoma is a fatal disease that rapidly spreads to the whole body. Treatments have limited efficiency owing to drug resistance and various side effects. Pseudomonas syringae pv. tomato (Pto) is a model bacterial pathogen capable of systemic infection in plants. Pto injects the effector protein HopQ into the plant cytosol via a type III secretion machinery and suppresses the host immunity. Intriguingly, host plant proteins regulated by HopQ are conserved even in humans and conferred in tumor metastasis. Nevertheless, the potential for HopQ to regulate human cancer metastasis was unknown. In this study, we addressed the suitability of HopQ as a possible drug against melanoma metastasis. In melanoma cells, overexpressed HopQ is phosphorylated and bound to 14-3-3 through its N-terminal domain, resulting in stronger interaction between HopQ and vimentin. The binding of HopQ to vimentin allowed for degradation of vimentin via p62-dependent selective autophagy. Attenuation of vimentin expression by HopQ inhibited melanoma motility and in vivo metastasis. These findings demonstrated that HopQ directly degraded vimentin in melanoma cells and could be applied to an inhibitor of melanoma metastasis.

Crossing the kingdom border: Human diseases caused by plant pathogens.

Interactions between pathogenic microorganisms and their hosts are varied and complex, encompassing open-field scale interactions to interactions at the molecular level. The capacity of plant pathogenic bacteria and fungi to cause diseases in human and animal systems was, until recently, considered of minor importance. However, recent evidence suggests that animal and human infections caused by plant pathogenic fungi, bacteria and viruses may have critical impacts on human and animal health and safety. This review analyses previous research on plant pathogens as causal factors of animal illness. In addition, a case study involving disruption of type III effector-mediated phagocytosis in a human cell line upon infection with an opportunistic phytopathogen, Pseudomonas syringae pv. tomato, is discussed. Further knowledge regarding the molecular interactions between plant pathogens and human and animal hosts is needed to understand the extent of disease incidence and determine mechanisms for disease prevention.

Thioredoxin-Interacting Protein Promotes Phagosomal Acidification Upon Exposure to Escherichia coli Through Inflammasome-Mediated Caspase-1 Activation in Macrophages.

In host defense, it is crucial to maintain the acidity of the macrophage phagosome for effective bacterial clearance. However, the mechanisms governing phagosomal acidification upon exposure to gram-negative bacteria have not been fully elucidated. In this study, we demonstrate that in macrophages exposed to Escherichia coli, the thioredoxin-interacting protein (TXNIP)-associated inflammasome plays a role in pH modulation through the activated caspase-1-mediated inhibition of NADPH oxidase. While there was no difference in early-phase bacterial engulfment between Txnip knockout (KO) macrophages and wild-type (WT) macrophages, Txnip KO macrophages were less efficient at destroying intracellular bacteria in the late phase, and their phagosomes failed to undergo appropriate acidification. These phenomena were associated with reactive oxygen species production and were reversed by treatment with an NADPH oxidase inhibitor or a caspase inhibitor. In line with these results, Txnip KO mice were more susceptible to both intraperitoneally administered E. coli and sepsis induced by cecum ligation and puncture than WT mice. Taken together, this study suggests that the TXNIP-associated inflammasome-caspase-1 axis regulates NADPH oxidase to modulate the pH of the phagosome, controlling bacterial clearance by macrophages.