Cigarette smoke compromises macrophage innate sensing in response to pneumococcal infection.

BACKGROUND: Cigarette smoking remains a leading cause of mortality worldwide. Streptococcus pneumoniae, also known as pneumococcus, is one of the most common pathogens that colonizes the human respiratory tract, causing life-threatening infections. Several studies have reported that cigarette smoke (CS) exposure promotes pneumococcal infectivity; however, the underlying mechanisms remain to be illustrated. METHODS: In this study, we prepared cigarette smoke extract (CSE) from tobacco containing nicotine (0.8 mg/cigarette) and tar (10 mg/cigarette) to investigate the effects of CSE on innate immune response using murine macrophage models. RESULTS: The results from the cytokine array showed that the production of C-C Motif Chemokine Ligand 2 (CCL2), CCL4, CCL3, C-X-C Motif Chemokine Ligand 2 (CXCL2), and CXCL-10, in pneumococcus-infected cells was reduced upon 5 % CSE treatment. Our results further demonstrated that 5 % CSE exposure, followed by pneumococcal challenge, significantly decreased CCL2 and type I interferon (IFN) production in macrophages by inhibiting nuclear factor (NF)-κB and IFN regulatory factor 3 (IRF3) signaling pathways. Moreover, CSE disrupts macrophage polarization and impedes innate immune signaling to suppress pneumococcal phagocytosis by macrophages. CONCLUSION: Our results provide evidence that CS manipulates the signaling molecules to subvert macrophage functions, thereby hindering the innate response against pneumococcal infection.

RAGE participates in the intracellular transport of Campylobacter jejuni cytolethal distending toxin.

BACKGROUND: Cytolethal distending toxin (CDT) belongs to the genotoxin family and is closely related to Campylobacter jejuni-associated gastroenteritis. We recently reported that CDT triggers the danger-associated molecular pattern (DAMP) signaling to exert deleterious effects on host cells. However, how CDT traffics in cells and the mechanism of CDT intoxication remain to be elucidated. METHODS: Recombinant CDT subunits (CdtA, CdtB, and CdtC) were purified, and their activity was characterized in gastrointestinal cells. Molecular approaches and image tracking were employed to analyze the delivery of CDT in host cells. RESULTS: In this study, we found that CDT interacts with the receptor of advanced glycation end products (RAGE) and high mobility group box 1 (HMGB1) to enter the cells. Our results further showed that CdtB transport in cells through the dynamin-dependent endocytic pathway and lysosome is involved in this process. Conversely, blockage of RAGE signaling resulted in a reduction in CDT-arrested cell cycles, indicating that RAGE is involved in CDT intracellular transport and its subsequent pathogenesis. CONCLUSION: Our results demonstrate that RAGE is important for CDT trafficking in the cells. These findings expand our understanding of important issues related to host cell intoxication by C. jejuni CDT.

Probiotic Lactobacillus spp. improves Drosophila memory by increasing lactate dehydrogenase levels in the brain mushroom body neurons.

Probiotics are live microorganisms that offer potential benefits to their hosts and can occasionally influence behavioral responses. However, the detailed mechanisms by which probiotics affect the behavior of their hosts and the underlying biogenic effects remain unclear. Lactic acid bacteria, specifically Lactobacillus spp. are known probiotics. Drosophila melanogaster, commonly known as the fruit fly, is a well-established model organism for investigating the interaction between the host and gut microbiota in translational research. Herein, we showed that 5-day administration of Lactobacillus acidophilus (termed GMNL-185) or Lacticaseibacillus rhamnosus (termed GMNL-680) enhances olfactory-associative memory in Drosophila. Moreover, a combined diet of GMNL-185 and GMNL-680 demonstrated synergistic effects on memory functions. Live brain imaging revealed a significant increase in calcium responses to the training odor in the mushroom body ß and γ lobes of flies that underwent mixed feeding with GMNL-185 and GMNL-680. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and whole-mount brain immunohistochemistry revealed significant upregulation of lactate dehydrogenase (LDH) expression in the fly brain following the mixed feeding. Notably, the genetic knockdown of Ldh in neurons, specifically in mushroom body, ameliorated the beneficial effects of mixed feeding with GMNL-185 and GMNL-680 on memory improvement. Altogether, our results demonstrate that supplementation with L. acidophilus and L. rhamnosus enhances memory functions in flies by increasing brain LDH levels.

Molecular characterization of rifabutin-resistance in refractory Helicobacter pylori infection in Taiwan.

OBJECTIVES: To explore the molecular characteristics of rpoB, encoding ß-subunit of DNA-directed RNA polymerase, and unravel the link to rifabutin-resistance in patients with refractory Helicobacter pylori infection. METHODS: From January 2018-March 2021, a total of 1590 patients were screened for eligibility to participate in the study. Patients with refractory H. pylori infection were confirmed by using the (13C)-urea breath assay. All enrolled patients underwent esophagogastroduodenoscopy, and biopsies were taken for H. pylori culture and antibacterial susceptibility testing. Sequence analysis of rpoB was conducted for all rifabutin-resistant isolates. RESULTS: In total, 70 patients were diagnosed with refractory H. pylori infection, and 39 isolates were successfully cultured. Amongst, 10 isolates were identified as rifabutin-resistance and nine isolates exhibited at least one amino acid substitution in RpoB. Isolates with a minimal inhibitory concentration >32 mg/l displayed a higher number of mutational changes in RpoB than the others. Additionally, more amino acid substitutions in RpoB correlated with developing a higher minimal inhibitory concentration for H. pylori rifabutin-resistance. CONCLUSION: Our findings highlight the relationship between rifabutin-resistance in refractory H. pylori infection and specific mutations in RpoB, which will aid the clinical selection of appropriate antibacterial agents with better therapeutic effects.

Clostridium innocuum, an emerging pathogen that induces lipid raft-mediated cytotoxicity.

Clostridium innocuum is an emerging spore-forming anaerobe that is often observed in Clostridioides difficile-associated inflammatory bowel disease (IBD) exacerbations. Unlike C. difficile, C. innocuum neither produces toxins nor possesses toxin-encoding genetic loci, but is commonly found in both intestinal and extra-intestinal infections. Membrane lipid rafts are composed of dynamic assemblies of cholesterol and sphingolipids, allowing bacteria to gain access to cells. However, the direct interaction between C. innocuum and lipid rafts that confers bacteria the ability to disrupt the intestinal barrier and induce pathogenesis remains unclear. In this study, we investigated the associations among nucleotide-binding oligomerization domain containing 2 (NOD2), lipid rafts, and cytotoxicity in C. innocuum-infected gut epithelial cells. Our results revealed that lipid rafts were involved in C. innocuum-induced NOD2 expression and nuclear factor (NF)-κB activation, triggering an inflammatory response. Reducing cholesterol by simvastatin significantly dampened C. innocuum-induced cell death, indicating that the C. innocuum-induced pathogenicity of cells was lipid raft-dependent. These results demonstrate that NOD2 mobilization into membrane rafts in response to C. innocuum-induced cytotoxicity results in aggravated pathogenicity.

Total solution of a smart shade matching.

Background/purpose: The simulated color of restorations plays an important role in improving patient satisfaction. The aim of this study was to test a new intelligent colorimetric solution using the Advanced Reflectionless Technology (ART) monitor and compare them using commercially available shade systems. Materials and methods: Six participants' right maxillary central incisors were tested with three devices, including the AUO Display Plus (Group A), a Canon single-lens reflex camera with eLAB's polar eyes filter (Group E), and the VITA Easyshade V (Group V). Each porcelain tooth was divided into three areas, and was assigned a CIELAB L∗a∗b∗ value by using the VITA Easyshade V. The original data were compared with the CIELAB L∗a∗b∗ obtained using the VITA Easyshade V. A prosthodontist compared the color of the porcelain veneers by eyes and gave the scores from 1 to 3. Results: For the ΔE, the three areas of Group A had the smallest differences between the color of the fabricated teeth and that of the original teeth. Colorimetric analysis indicated that Groups A and V did not differ much in the color of the three areas of the tooth. Groups E and A exhibited significant differences between the cervical third and middle third of the tooth, and Groups E and V exhibited significant differences between the middle third and incisal third of the tooth. Conclusion: Compared with traditional monitors, ART is closer to real images in terms of color, contrast, and detail grayscale. Technicians are able to produce realistic and pleasing colors.

Preliminary comparison of the remineralization and desensitization effects of a novel mineralized ion-releasing toothpaste and commercially available competitive products.

Background/purpose: Toothpaste plays an important role in brushing teeth to maintain oral hygiene and health. The purpose of this study was to develop a new toothpaste containing surface nanocrystal-rich dicalcium phosphate anhydrous (DCPA) powder and to investigate its effect on tooth samples. Materials and methods: The innovative toothpaste (REALCaP®/Group R) was compared with two commercial toothpastes (BioRepair®/Group B and Sensodyne®/Group S). Brushing cycle tests were performed on bovine tooth slices coated with individual toothpaste and a control group without toothpaste (Group C). Microhardness, roughness, surface structure observation, and X-ray diffraction (XRD) were performed on cycle days 4, 7, and 14 to analyze the impact of the toothpastes on tooth samples. Reults: Microhardness in the Group R was higher than that of the other groups regardless of the cycle days. Roughness in the Group R increased on days 4 and 7 but decreased on day 14. Roughness in the groups S and B increased with days. Microstructural observation revealed that most exposed dentinal tubules had been sealed in the Group R on day 14. Overlay thickness in the Group R was significantly higher than that in the groups S and B on days 4, 7, and 14. XRD analysis showed no hydroxyapatite (HA) peak in the Group S. The HA peak in the Group R was higher than that in the Group B on day 14. Conclusion: The innovative toothpaste has better properties than the commercially available products in terms of microhardness, roughness, and effectiveness in sealing dentinal tubules.

Multiple amino acid substitutions in penicillin-binding protein-1A confer amoxicillin resistance in refractory Helicobacter pylori infection.

BACKGROUND: Amoxicillin resistance in Helicobacter pylori is mainly associated with mutations in penicillin-binding protein-1A (PBP-1A). However, the specific amino acid substitutions in PBP-1A that confer amoxicillin resistance in H. pylori remain to be investigated. OBJECTIVE: This study aimed to investigate the molecular mechanism underlying amoxicillin resistance in patients with refractory H. pylori infection. METHODS: Esophagogastroduodenoscopy (EGD) was performed in patients with persistent H. pylori infection after at least two courses of H. pylori eradication therapy between January-2018 to March-2021. Refractory H. pylori was cultured from the gastric biopsy specimens. Antibiotic susceptibility testing was conducted to determine the minimum inhibitory concentrations (MICs). Sequence analysis of pbp-1A was performed for amoxicillin-resistant strains. RESULTS: Thirty-nine successfully cultured isolates were classified as refractory H. pylori isolates, and seventeen isolates were resistant to amoxicillin (MIC > 0.125 mg/L). Sequence analysis of resistant strains showed multiple mutations in the C-terminal region of PBP-1A that conferred amoxicillin resistance in H. pylori. However, the number of PBP-1A mutations did not correlate with the high MICs of amoxicillin-resistant isolates. Notably, some amino acid substitutions were identified in all Taiwanese isolates with history of eradication failure but not in published amoxicillin-susceptible strains, suggesting that the mutations may play a role in conferring antibiotic resistance to these strains. CONCLUSIONS: Our results show that amoxicillin resistance in refractory H. pylori is highly correlated with numerous PBP-1A mutations that are strain specific. Continuous improvements in diagnostic tools, particularly molecular analysis approaches, can help to optimize current antimicrobial regimens.

Gastroprotective Effect of Anisomeles indica on Aspirin-Induced Gastric Ulcer in Mice.

Gastric ulcers are commonly seen in the upper gastrointestinal tract and may be related to the Helicobacter pylori infection and the use of aspirin, a nonsteroidal anti-inflammatory drug (NSAID). Typically, proton-pump inhibitors (PPIs) are used to treat gastric ulcers; however, adverse effects have emerged following long-term treatment. Natural medicines are used as alternative therapeutic agents in the treatment of gastric ulcers, with few side effects. Despite various reports on the anti-H. pylori and anti-gastric cancer activities of Anisomeles indica, its gastroprotective effect on ulcers remains undetermined. This study investigated the protective effect of A. indica on aspirin-induced gastric ulcers in murine models. Our results show that three fractions of ethanol-extracted A. indica inhibited aspirin-induced gastric injury. Among these, A. indica Fraction 1 was observed to enrich ovatodiolide, which effectively diminished gastric acidity and alleviated aspirin-induced inflammation in the stomach. Our results provide evidence that A. indica could be developed as an effective therapeutic agent for gastroprotective purposes.

Gut Commensal Parabacteroides goldsteinii MTS01 Alters Gut Microbiota Composition and Reduces Cholesterol to Mitigate Helicobacter pylori-Induced Pathogenesis.

Helicobacter pylori infection is closely associated with various gastrointestinal diseases and poses a serious threat to human health owing to its increasing antimicrobial resistance. H. pylori possesses two major virulence factors, vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), which are involved in its pathogenesis. Probiotics have recently been used to eradicate H. pylori infection and reduce the adverse effects of antibiotic-based therapies. Parabacteroides goldsteinii MTS01 is a novel next-generation probiotic (NGP) with activities that can alleviate specific diseases by altering the gut microbiota. However, the mechanism by which P. goldsteinii MTS01 exerts its probiotic effects against H. pylori infection remains unclear. Our results showed that administration of P. goldsteinii MTS01 to H. pylori-infected model mice altered the composition of the gut microbiota and significantly reduced serum cholesterol levels, which mitigated H. pylori-induced gastric inflammation. In addition, the pathogenic effects of H. pylori VacA and CagA on gastric epithelial cells were markedly abrogated by treatment with P. goldsteinii MTS01. These results indicate that P. goldsteinii MTS01 can modulate gut microbiota composition and has anti-virulence factor functions, and thus could be developed as a novel functional probiotic for reducing H. pylori-induced pathogenesis.

Drosophila Model for Studying Gut Microbiota in Behaviors and Neurodegenerative Diseases.

Mounting evidence indicates that the gut microbiota is linked to several physiological processes and disease development in mammals; however, the underlying mechanisms remained unexplored mostly due to the complexity of the mammalian gut microbiome. The fruit fly, Drosophila melanogaster, is a valuable animal model for studying host-gut microbiota interactions in translational aspects. The availability of powerful genetic tools and resources in Drosophila allowed the scientists to unravel the mechanisms by which the gut microbes affect fitness, health, and behavior of their hosts. Drosophila models have been extensively used not only to study animal behaviors (i.e., courtship, aggression, sleep, and learning & memory), but also some human related neurodegenerative diseases (i.e., Alzheimer's disease and Parkinson's disease) in the past. This review comprehensively summarizes the current understanding of the gut microbiota of Drosophila and its impact on fly behavior, physiology, and neurodegenerative diseases.

Helicobacter pylori cholesterol-α-glucosyltransferase manipulates cholesterol for bacterial adherence to gastric epithelial cells.

Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcers, and gastric cancer. Infection of cells with H. pylori is dependent on lipid rafts, which are cholesterol-rich microdomains located in the cell membrane. H. pylori cholesterol-α-glucosyltransferase (CGT) catalyzes the conversion of membrane cholesterol to cholesteryl glucosides, which can be incorporated into the bacterial cell wall, facilitating evasion from immune defense and colonization in the host. However, the detailed mechanisms underlying this process remain to be explored. In this study, we discovered for the first time that H. pylori CGT could promote adherence to gastric epithelial cells in a cholesterol-dependent manner. Externalization of cell membrane phosphatidylserine (PS) is crucial for enhancement of binding of H. pylori to cells by CGT and for cytotoxin-associated gene A (CagA)-induced pathogenesis. Furthermore, exogenous cholesterol interferes with the actions of H. pylori CGT to catalyze cellular cholesterol, which impedes bacterial binding to cells and attenuates subsequent inflammation, indicating that the initial attachment of H. pylori to cells is closely dependent on host cholesterol. These results provide evidence that CGT contributes to H. pylori infectivity and it may serve as a key target for the treatment of H. pylori-associated diseases.

Bacterial Genotoxin-Coated Nanoparticles for Radiotherapy Sensitization in Prostate Cancer.

Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men and usually becomes refractory because of recurrence and metastasis. CD44, a transmembrane glycoprotein, serves as a receptor for hyaluronic acid (HA). It has been found to be abundantly expressed in cancer stem cells (CSCs) that often exhibit a radioresistant phenotype. Cytolethal distending toxin (CDT), produced by Campylobacter jejuni, is a tripartite genotoxin composed of CdtA, CdtB, and CdtC subunits. Among the three, CdtB acts as a type I deoxyribonuclease (DNase I), which creates DNA double-strand breaks (DSBs). Nanoparticles loaded with antitumor drugs and specific ligands that recognize cancerous cell receptors are promising methods to overcome the therapeutic challenges. In this study, HA-decorated nanoparticle-encapsulated CdtB (HA-CdtB-NPs) were prepared and their targeted therapeutic activity in radioresistant PCa cells was evaluated. Our results showed that HA-CdtB-NPs sensitized radioresistant PCa cells by enhancing DSB and causing G2/M cell-cycle arrest, without affecting the normal prostate epithelial cells. HA-CdtB-NPs possess maximum target specificity and delivery efficiency of CdtB into the nucleus and enhance the effect of radiation in radioresistant PCa cells. These findings demonstrate that HA-CdtB-NPs exert target specificity accompanied with radiomimetic activity and can be developed as an effective strategy against radioresistant PCa.

IL13RA2 is overexpressed in malignant gliomas and related to clinical outcome of patients.

OBJECTIVE: To study the expression of IL13RA2 in gliomas and to analyze its correlation with clinicopathological/molecular features, immune cell infiltration and prognostic significance. METHODS: mRNA expression data for IL13RA2 were downloaded and analyzed from two open access datasets (TCGA & CGGA). IL13RA2 protein expression was examined by immunohistochemistry. The association between IL13RA2 and important clinicopathological/molecular markers was examined using χ2 and Spearman correlation tests. The TIMER tool was used to evaluate the correlation of IL13RA2 with multiple intra-tumoral immune cell types in glioma. Kaplan-Meier test and multivariate Cox analyses were applied to evaluate the prognosis. RESULTS: Out of the 297 glioma tissues and 20 normal brain tissues in our cohort, IL13RA2 protein was highly expressed in 115 glioma tissues (115/297, 38.7%), but no expression was detected in normal brain tissues (0/20, 0%). The expression of IL13RA2 was significantly higher in GBMs (P<0.001). More than half of GBMs (68/132, 51.5%) were high expression of IL13RA2 protein, especially GBM patients with IDH wild-type and TERT promoter mutated (60/78, 76.9%). Moreover, 11/13 (84.6%) diffuse midline gliomas and 31/51 (64.7%) IDH wild-type LGGs also highly expressed IL13RA2 in our cohorts. Chi-square test showed that the expression of IL13RA2 was correlated with patient age, WHO grade, Ki67 index, IDH status, TERT promoter status and immune cell infiltration. Additionally, IL13RA2 was strongly associated with patients' OS and served as a negative prognostic marker in infiltrating gliomas. CONCLUSION: IL13RA2 was high expression in some glioma subtypes, and significantly correlated with poor prognosis. Based on its role in CAR-T therapy, it might act as an extremely important and specific therapeutic target for human malignant gliomas, especially in IDH wild-type LGG, "IDH wild-type and TERT promoter mutated" GBM and H3K27M-mutated diffuse midline glioma, and improve the clinical outcomes of these patients.

Membrane Cholesterol Is Crucial for Clostridium difficile Surface Layer Protein Binding and Triggering Inflammasome Activation.

Clostridium difficile, an obligate anaerobic gram-positive bacillus, generates spores and is commonly found colonizing the human gut. Patients with C. difficile infection (CDI) often exhibit clinical manifestations of pseudomembranous colitis or antibiotic-associated diarrhea. Surface layer proteins (SLPs) are the most abundant proteins in the C. difficile cell wall, suggesting that they might involve in immune recognition. Our previous results demonstrated that C. difficile triggers inflammasome activation. Here, we found SLPs as well as C. difficile induced inflammasome activation, and in a dose-dependent manner. In addition, the cholesterol-rich microdomains on the cell membrane (also referred to as lipid rafts) are thought to be crucial for bacterial adhesion and signal transduction. We demonstrated that lipid rafts participated in C. difficile SLPs binding to the cell membrane. Fluorescence microscopy showed that membrane cholesterol depletion by methyl-ß-cyclodextrin (MßCD) reduced the association of SLPs with the cell surface. The coalescence of SLPs in the cholesterol-rich microdomains was confirmed in C. difficile-infected cells. Furthermore, the inflammasome activations induced by SLPs or C. difficile were abrogated by MßCD. Our results demonstrate that SLPs recruit the lipid rafts, which may be a key step for C. difficile colonization and inducing inflammasome activation.

PM2.5 impairs macrophage functions to exacerbate pneumococcus-induced pulmonary pathogenesis.

BACKGROUND: Pneumococcus is one of the most common human airway pathogens that causes life-threatening infections. Ambient fine particulate matter (PM) with aerodynamic diameter ≤ 2.5 µm (PM2.5) is known to significantly contribute to respiratory diseases. PM2.5-induced airway inflammation may decrease innate immune defenses against bacterial infection. However, there is currently limited information available regarding the effect of PM2.5 exposure on molecular interactions between pneumococcus and macrophages. RESULTS: PM2.5 exposure hampered macrophage functions, including phagocytosis and proinflammatory cytokine production, in response to pneumococcal infection. In a PM2.5-exposed pneumococcus-infected mouse model, PM2.5 subverted the pulmonary immune response and caused leukocyte infiltration. Further, PM2.5 exposure suppressed the levels of CXCL10 and its receptor, CXCR3, by inhibiting the PI3K/Akt and MAPK pathways. CONCLUSIONS: The effect of PM2.5 exposure on macrophage activity enhances pneumococcal infectivity and aggravates pulmonary pathogenesis.

Helium/Argon-Generated Cold Atmospheric Plasma Facilitates Cutaneous Wound Healing.

Cold atmospheric plasma jet (CAPJ) or non-thermal plasma jet has been employed in various biomedical applications based on their functions in bactericidal activity and wound healing. However, the effect of CAPJ generated by a particular composition of gases on wound closure and the underlying mechanisms that regulate wound healing signals remain elusive. In the present study, we investigated the impact of helium (He)- or a gas mixture of He and argon (He/Ar)-generated CAPJ on cell proliferation, which is a pivotal step during the wound healing process. With careful treatment duration control, He/Ar-CAPJ effectively induced keratinocyte proliferation and migration mediated through the activation of epithelial-to-mesenchymal transition (EMT) and cell cycle progression, which was evidenced by a decrease in E-cadherin levels and increases in N-cadherin, cyclin D1, Ki-67, Cdk2, and p-ERK levels. Rat wound healing studies showed that He/Ar-CAPJ treatment facilitated granulation tissue formation and mitigated inflammation in cutaneous tissue, resulting in accelerated wound closure. These findings highlight the possibility that He/Ar-CAPJ can be developed as a therapeutic agent for enhancing wound healing.

Practice of the New Integrated Molecular Diagnostics in Gliomas: Experiences and New Findings in a Single Chinese Center.

Background: The latest WHO classification of CNS tumors using the integrated phenotypic and molecular parameters (IDH, ATRX, 1p19q, TERT etc.) have reestablished the CNS tumors classification in addition to traditional histology. The establishment of glioma molecular typing can more accurately predict prognosis, better guide individualized treatment to improve survival. Methods: The expression of IDH1, ATRX, PHH3, P53 and Ki67 was detected by IHC. Molecular status of IDH1/2 and TERT were analyzed using Sanger sequencing. MGMT was explored using methylation-specific PCR. 1p/19q codeletion status was firstly detected by FISH, then further confirmed by multiplex PCR-based next generation sequencing. Results: The mutation frequency of IDH1 was 68.7% (79/115) in WHO II astrocytoma, and 82 cases (82/344, 23.8%) were "triple-negative glioma" in our cohort. Multivariate COX analysis revealed that only IDH, 1p/19q, TERT and MGMT were independent prognostic factors. Noteworthily, we found 7 cases of the new molecular phenotype presented as "IDH wildtype and 1p/19q codeletion", not mentioned in the latest WHO guideline. Conclusion: We detected the newly recommended markers in a large cohort of Chinese glioma patients. Our data demonstrated a relatively lower frequency of IDH mutations and a higher prevalence of triple-negative glioma in Chinese compared with American and European, indicating ethnic and geographical difference in some markers. In addition, the new molecular phenotype "IDH wildtype and 1p/19q codeletion" glioma deserved special focus. These findings suggest that further stratification of infiltrating gliomas is needed for different treatment strategy and precision medicine.

Campylobacter jejuni Cytolethal Distending Toxin C Exploits Lipid Rafts to Mitigate Helicobacter pylori-Induced Pathogenesis.

Helicobacter pylori infection is associated with several gastrointestinal diseases, including gastritis, peptic ulcer, and gastrointestinal adenocarcinoma. Two major cytotoxins, vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA), interact closely with lipid rafts, contributing to H. pylori-associated disease progression. The Campylobacter jejuni cytolethal distending toxin consists of three subunits: CdtA, CdtB, and CdtC. Among them, CdtA and CdtC bind to membrane lipid rafts, which is crucial for CdtB entry into cells. In this study, we employed recombinant CdtC (rCdtC) to antagonize the functions of H. pylori cytotoxin in cells. Our results showed that rCdtC alleviates cell vacuolation induced by H. pylori VacA. Furthermore, rCdtC reduces H. pylori CagA translocation, which decreases nuclear factor kappa-B activation and interleukin-8 production, resulting in the mitigation of gastric epithelial cell inflammation. These results reveal that CdtC hijacks cholesterol to compete for H. pylori cytotoxin actions via lipid rafts, ameliorating H. pylori-induced pathogenesis.

Helicobacter pylori Induces IL-33 Production and Recruits ST-2 to Lipid Rafts to Exacerbate Inflammation.

Helicobacter pylori colonizes human gastric epithelial cells and contributes to the development of several gastrointestinal disorders. Interleukin (IL)-33 is involved in various immune responses, with reported proinflammatory and anti-inflammatory effects, which may be associated with colitis and colitis-associated cancer. IL-33 induces the inflammatory cascade through its receptor, suppression of tumorigenicity-2 (ST-2). Binding of IL-33 to membrane-bound ST-2 (mST-2) recruits the IL-1 receptor accessory protein (IL-1RAcP) and activates intracellular signaling pathways. However, whether IL-33/ST-2 is triggered by H. pylori infection and whether this interaction occurs in lipid rafts remain unclear. Our study showed that both IL-33 and ST-2 expression levels were significantly elevated in H. pylori-infected cells. Confocal microscopy showed that ST-2 mobilized into the membrane lipid rafts during infection. Depletion of membrane cholesterol dampened H. pylori-induced IL-33 and IL-8 production. Furthermore, in vivo studies revealed IL-33/ST-2 upregulation, and severe leukocyte infiltration was observed in gastric tissues infected with H. pylori. Together, these results demonstrate that ST-2 recruitment into the lipid rafts serves as a platform for IL-33-dependent H. pylori infection, which aggravates inflammation in the stomach.