Targeting myeloperoxidase to stabilize unruptured aneurysm: an imaging-guided approach.

Inflammation plays a key role in pathogenesis and rupture of aneurysms. Non-invasively and dynamically monitoring aneurysm inflammation is critical. This study evaluated myeloperoxidase (MPO) as an imaging biomarker and therapeutic target for aneurysm inflammation using an elastase-induced rabbit model treated with or without 4-aminobenzoic acid hydrazide (ABAH), an irreversible inhibitor of MPO. Myeloperoxidase-sensitive magnetic resonance imaging (MRI) using Mn-TyrEDTA, a peroxidase activity-dependent contrast agent, revealed weak contrast enhancement in contralateral arteries and decreased contrast enhancement in aneurysm walls with ABAH treatment, indicating MPO activity decreased and inflammation mitigated. This was supported by reduced immune cell infiltration, matrix metalloproteinases (MMP-2 and - 9) activity, ROS production and arterial wall destruction on histology. Finally, the aneurysm expansion rate remained < 50% throughout the study in the ABAH(+) group, but increased gradually in the ABAH(-) group. Our results suggest that inhibition of MPO attenuated inflammation and expansion of experimental aneurysm and MPO-sensitive MRI showed promise as a noninvasive tool for monitoring aneurysm inflammation.

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.

Molecular and Functional Analysis of the Type IV Pilus Gene Cluster in Streptococcus sanguinis SK36.

Streptococcus sanguinis, dominant in the oral microbiome, is the only known streptococcal species possessing a pil gene cluster for the biosynthesis of type IV pili (Tfp). Although this cluster is commonly present in the genome of S. sanguinis, most of the strains do not express Tfp-mediated twitching motility. Thus, this study was designed to investigate the biological functions encoded by the cluster in the twitching-negative strain S. sanguinis SK36. We found that the cluster was transcribed as an operon, with three promoters located 5' to the cluster and one in the intergenic region between SSA_2307 and SSA_2305. Studies using promoter-cat fusion strains revealed that the transcription of the cluster was mainly driven by the distal 5' promoter, which is located more than 800 bases 5' to the first gene of the cluster, SSA_2318. Optimal expression of the cluster occurred at the early stationary growth phase in a CcpA-dependent manner, although a CcpA-binding consensus is absent in the promoter region. Expression of the cluster resulted in a short hairlike surface structure under transmission electron microscopy. Deletion of the putative pilin genes (SSA_2313 to SSA_2315) abolished the biosynthesis of this structure and significantly reduced the adherence of SK36 to HeLa and SCC-4 cells. Mutations in the pil genes downregulated biofilm formation by S. sanguinis SK36. Taken together, the results demonstrate that Tfp of SK36 are important for host cell adherence, but not for motility, and that expression of the pil cluster is subject to complex regulation.IMPORTANCE The proteins and assembly machinery of the type IV pili (Tfp) are conserved throughout bacteria and archaea, and yet the function of this surface structure differs from species to species and even from strain to strain. As seen in Streptococcus sanguinis SK36, the expression of the Tfp gene cluster results in a hairlike surface structure that is much shorter than the typical Tfp. This pilus is essential for the adherence of SK36 but is not involved in motility. Being a member of the highly diverse dental biofilm, perhaps S. sanguinis could more effectively utilize this structure to adhere to host cells and to interact with other microbes within the same niche.

Candidate Genes for Yellow Leaf Color in Common Wheat (Triticum aestivum L.) and Major Related Metabolic Pathways according to Transcriptome Profiling.

The photosynthetic capacity and efficiency of a crop depends on the biosynthesis of photosynthetic pigments and chloroplast development. However, little is known about the molecular mechanisms of chloroplast development and chlorophyll (Chl) biosynthesis in common wheat because of its huge and complex genome. Ygm, a spontaneous yellow-green leaf color mutant of winter wheat, exhibits reduced Chl contents and abnormal chloroplast development. Thus, we searched for candidate genes associated with this phenotype. Comparative transcriptome profiling was performed using leaves from the yellow leaf color type (Y) and normal green color type (G) of the Ygm mutant progeny. We identified 1227 differentially expressed genes (DEGs) in Y compared with G (i.e., 689 upregulated genes and 538 downregulated genes). Gene ontology and pathway enrichment analyses indicated that the DEGs were involved in Chl biosynthesis (i.e., magnesium chelatase subunit H (CHLH) and protochlorophyllide oxidoreductase (POR) genes), carotenoid biosynthesis (i.e., ß-carotene hydroxylase (BCH) genes), photosynthesis, and carbon fixation in photosynthetic organisms. We also identified heat shock protein (HSP) genes (sHSP, HSP70, HSP90, and DnaJ) and heat shock transcription factor genes that might have vital roles in chloroplast development. Quantitative RT-PCR analysis of the relevant DEGs confirmed the RNA-Seq results. Moreover, measurements of seven intermediate products involved in Chl biosynthesis and five carotenoid compounds involved in carotenoid-xanthophyll biosynthesis confirmed that CHLH and BCH are vital enzymes for the unusual leaf color phenotype in Y type. These results provide insights into leaf color variation in wheat at the transcriptional level.

Comparison and preparation of multilayered polylactic acid fabric strengthen calcium phosphate-based bone substitutes for orthopedic applications.

An attempt to maintain the three-dimensional space into restorative sites through the conveniently pack porous fillers are general used strategy. Advancement in the manufacturing protective shells in the scaffolds, which would be filled with brittle ceramic grafts for the development of highly connective pores provides the approach to solve crack problem for generating the tissues. Therefore, multilayered braided and alkalized poly(lactic acid) (PLA) composites with calcium phosphate bone cement (CPC) were synthesized and compared. The PLA/CPC composites were divided into various groups according to a series of heat-treatment temperatures (100-190 °C) and periods (1-3 h) and then characterized. The effects of 24-h immersion on the strength decay resistance of the samples were compared. Results showed that the residual oil capped on the surfaces of alkalized PLA braid was removed, and the structure was unaltered. However, the reduced tensile stress of alkalized PLA braids was due to ester-group formation by hydrolysis. Mechanical test results of PLA/CPC composites showed that the strength significantly increased after heat treatment, except when the heating temperature was higher than the PLA melting point at approximately 160-170 °C. The degree of PLA after recrystallization became higher than that of unheated composites, thereby leading to reduced strength and toughness of the specimen. Braiding fibers of biodegradable PLA reinforced and toughened the structure particularly of the extra-brittle material of thin-sheet CPC after implantation.

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.

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.

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.

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.

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.

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.

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.

Triple-Negative Breast Cancer Analysis Based on Metabolic Gene Classification and Immunotherapy.

Triple negative breast cancer (TNBC) has negative expression of ER, PR and HER-2. TNBC shows high histological grade and positive rate of lymph node metastasis, easy recurrence and distant metastasis. Molecular typing based on metabolic genes can reflect deeper characteristics of breast cancer and provide support for prognostic evaluation and individualized treatment. Metabolic subtypes of TNBC samples based on metabolic genes were determined by consensus clustering. CIBERSORT method was applied to evaluate the score distribution and differential expression of 22 immune cells in the TNBC samples. Linear discriminant analysis (LDA) established a subtype classification feature index. Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were generated to validate the performance of prognostic metabolic subtypes in different datasets. Finally, we used weighted correlation network analysis (WGCNA) to cluster the TCGA expression profile dataset and screen the co-expression modules of metabolic genes. Consensus clustering of the TCGA cohort/dataset obtained three metabolic subtypes (MC1, MC2, and MC3). The ROC analysis showed a high prognostic performance of the three clusters in different datasets. Specifically, MC1 had the optimal prognosis, MC3 had a poor prognosis, and the three metabolic subtypes had different prognosis. Consistently, the immune characteristic index established based on metabolic subtypes demonstrated that compared with the other two subtypes, MC1 had a higher IFNγ score, T cell lytic activity and lower angiogenesis score, T cell dysfunction and rejection score. TIDE analysis showed that MC1 patients were more likely to benefit from immunotherapy. MC1 patients were more sensitive to immune checkpoint inhibitors and traditional chemotherapy drugs Cisplatin, Paclitaxel, Embelin, and Sorafenib. Multiclass AUC based on RNASeq and GSE datasets were 0.85 and 0.85, respectively. Finally, based on co-expression network analysis, we screened 7 potential gene markers related to metabolic characteristic index, of which CLCA2, REEP6, SPDEF, and CRAT can be used to indicate breast cancer prognosis. Molecular classification related to TNBC metabolism was of great significance for comprehensive understanding of the molecular pathological characteristics of TNBC, contributing to the exploration of reliable markers for early diagnosis of TNBC and predicting metastasis and recurrence, improvement of the TNBC staging system, guiding individualized treatment.

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.

Primary Ewing's sarcoma of sphenoid sinus: A case report and literature review.

Background: Primary Ewing's sarcoma of sphenoid sinus, observed in children and adolescents, is an extremely rare malignancy. Such rarity makes the imaging features and treatment strategies for Ewing's sarcoma of sphenoid sinus unclear. This study aimed to offer guidance for treating this very disease by describing a patient with a rare primary Ewing's sarcoma of sphenoid sinus and reviewing the available data in the literature. Case description: A case of Ewing's sarcoma in sphenoid sinus treated with multidisciplinary treatment approaches, including tumor resection, radiotherapy, chemotherapy, and antiangiogenic therapy, was presented in this study. Moreover, literature for Ewing's sarcoma in the head was systematically searched, and two cases in the sphenoid sinus and five cases in the sphenoid bone were identified. Furthermore, the clinical features, imaging findings, pathological characteristics, treatment, and prognosis were summarized. Conclusion: Tumor resection combined with radiotherapy and chemotherapy may provide favorable results for patients with Ewing's sarcoma of sphenoid sinus and bone. However, more reports are still necessary to further clarify optimal management.

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.

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.

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.