Colonization Of Sites Research Articles

Vibrio cholerae CsrA controls ToxR levels by increasing the stability and translation of toxR mRNA.

Intestinal colonization and virulence factor production in response to environmental cues is mediated through several regulatory factors in Vibrio cholerae, including the highly conserved RNA-binding global regulatory protein CsrA. We have shown previously that CsrA increases synthesis of the virulence-associated transcription factor ToxR in response to specific amino acids (NRES) and is required for the virulence of V. cholerae in the infant mouse model of cholera. In this study, we mapped the 5' untranslated region (5' UTR) of toxR and showed that CsrA can bind directly to an RNA sequence encompassing the 5' UTR, indicating that the regulation of ToxR levels by CsrA is direct. Consistent with this observation, the 5' UTR of toxR contains multiple putative CsrA binding sequences (GGA motifs), and mutating these motifs disrupted the CsrA-mediated increase in ToxR. Optimal binding of CsrA to a defined RNA oligonucleotide required the bridging of two GGA motifs within a single RNA strand. To determine the mechanism of regulation by CsrA, we assayed toxR transcript levels, stability, and efficiency of translation. Both the amount of toxR mRNA in NRES and the stability of the toxR transcript were increased by CsrA. Using an in vitro translation assay, we further showed that synthesis of ToxR was greatly enhanced in the presence of purified CsrA, suggesting a direct role for CsrA in the translation of toxR mRNA. We propose a model in which CsrA binding to the 5' UTR of the toxR transcript promotes ribosomal access while precluding interactions with RNA-degrading enzymes.IMPORTANCEVibrio cholerae is uniquely adapted to marine environments as well as the human intestinal tract. Global regulators, such as CsrA, which help translate environmental cues into an appropriate cellular response, are critical for switching between these distinct environments. Understanding the pathways involved in relaying environmental signals is essential for understanding both the environmental persistence and the intestinal pathogenesis of this devastating human pathogen. In this study, we demonstrate that CsrA directly regulates the synthesis of ToxR, a key virulence factor of V. cholerae. Under conditions favoring high levels of active CsrA in the cell, such as in the presence of particular amino acids, CsrA increases ToxR protein levels by binding to the toxR transcript and enhancing both its stability and translation. By responding to nutrient availability, CsrA is perfectly poised to activate the virulence gene regulatory cascade at the preferred site of colonization in the human host, the nutrient-rich small intestinal mucosa.

A Novel Colon-Targeting Ratiometric Probe with Large Emission Shift for Imaging Peroxynitrite in Ulcerative Colitis.

Ulcerative colitis (UC) is an inflammatory disease that leads to the overexpression of peroxynitrite (ONOO-). Up to now, it has been a challenge to design a colon-targeted fluorescent probe with a large emission shift that can detect and image ONOO- in UC mice. Here, a fluorophore (pyran-coumarin) is linked with cholic acid to develop a colon-targeted fluorescent probe (CPC) for the detection of ONOO-. The fluorescent probe showed strong near-infrared emission at 725 nm. After reacting with ONOO-, it can be observed that the fluorescence intensity at 725 nm decreases obviously, and the signal at 490 nm increases clearly with an obvious emission shift (235 nm). This response mechanism causes the probe to have good sensitivity and selectivity. Additionally, the probe CPC shows good targeting ability for the cells with overexpressingTGR5 receptors and displays good results for detecting exogenous and endogenous ONOO- in the cells. More importantly, the probe CPC can be especially assembled in the colon site to distinguish normal and UC mice and provide significant information for the diagnosis of UC.

Oncologic outcomes and trends in each colon cancer location and stages over the last two decades: insights from the SEER registry.

The main purpose of the study is to comprehensively evaluate population-level survival disparities stage-by-stage, according to specific anatomical colon segments, and based on prognosis as defined by lymph nodes among patients who have undergone curative resection for non-metastatic colon cancer. The study was conducted from the Surveillance Epidemiology and End Result (SEER) program from the USA. Patients who underwent surgery for colon adenocarcinoma between 2000 and 2019 were identified. Demographics and clinical and pathologic factors were compared amongst each other according to different colon segments, stages, and time periods. A total of 482,672 patients were identified and 195,105 of them met the inclusion criteria. Patients with proximal cancers were significantly older, more likely to be female, had a higher number of lymph nodes, and node positivity (p < 0.001). During the study period, an almost 10% improvement in overall survival rate was observed at 3 and 5years for each colon site and stage (p < 0.05). The study's findings revealed a notable improvement in overall and cancer-specific survival rates across all colon segments and stages in patients who underwent curative treatment for non-metastatic primary colon cancer from a nationwide database.

Mucus-Penetrable Biomimetic Nanoantibiotics for Pathogen-Induced Pneumonia Treatment.

Bacterial pneumonia has garnered significant attention in the realm of infectious diseases owing to a surge in the incidence of severe infections coupled with the growing scarcity of efficacious therapeutic modalities. Antibiotic treatment is still an irreplaceable method for bacterial pneumonia because of its strong bactericidal activity and good clinical efficacy. However, the mucus layer forming after a bacterial infection in the lungs has been considered as the "Achilles' heels" facing the clinical application of such treatment. Herein, traceable biomimetic nanoantibiotics (BioNanoCFPs) were developed by loading indacenodithieno[3,2-b]thiophene (ITIC) and cefoperazone (CFP) in nanoplatforms coated with natural killer (NK) cell membranes. The BioNanoCFP exhibited excellent demonstrated mucus-penetrating abilities, facilitating their arrival at the infection site. The presence of Toll-like receptors in the NK cell membrane rendered the BioNanoCFP with the capability to recognize pathogen-associated molecular patterns within bacteria, allowing precise targeting of bacterial colonization sites and achieving substantial therapeutic efficacy. Overall, our findings demonstrate the viability and desirability of using NK cell membrane-mediated drug delivery as a promising strategy for precision treatment.

Discovery of Mycobacterium avium subsp. paratuberculosis Lytic Phages with Extensive Host Range Across Rapid- and Slow-Growing Pathogenic Mycobacterial Species.

Developing interventions for Johne's disease, which focuses on controlling Mycobacterium avium subsp. paratuberculosis (MAP) in contaminated environments by treating infected cows and preventing transmission from diseased animals, is a critical priority. Bacteriophage (phage) therapy, an emerging biological intervention, offers a promising alternative for the treatment and management of MAP infections. In this study, we generated an MAP-specific lytic phage library aimed at characterizing the therapeutic potential of phages under environmental and biological conditions that mimic those encountered in infected cattle such as ruminal fluid, milk, colostrum, and the bovine intestinal epithelium, a key site of MAP colonization and, later, transmission. Our library contains a diverse collection of phages that have demonstrated robust lytic activity against MAP. The host range of these phages was thoroughly assessed, revealing that several isolates produce clear plaques on a range of MAP strains, as well as other pathogenic non-tuberculous mycobacterial (NTM) species and M. tuberculosis strains. This broad host range expands the therapeutic potential of the phage collection, positioning it as a potential cross-species antimicrobial tool. In vitro tests under conditions replicating the rumen, milk, and colostrum environments show that selected phages maintain stability and lytic efficacy, even in the presence of complex biological fluids. Furthermore, a subset of these phages was capable of preventing MAP colonization and invasion in cultured bovine epithelial cells, suggesting their potential for direct prophylactic application in cattle. Our collection of MAP phages represents a valuable source that can be developed into probiotic-like preparations, offering a cost-effective solution for prophylaxis and control of Johne's disease.

Giardia spp.-induced microbiota dysbiosis disrupts intestinal mucin glycosylation

ABSTRACT Infection with the protozoan parasite Giardia duodenalis (syn. intestinalis, lamblia) has been associated with intestinal mucus disruptions and microbiota dysbiosis. The mechanisms remain incompletely understood. Mucus consists primarily of densely glycosylated mucin glycoproteins. Mucin O-glycans influence mucus barrier properties and mucin–microbe interactions and are frequently altered during disease. In this study, we observed time-dependent and regiospecific alterations to intestinal mucin glycosylation patterns and the expression of mucin-associated glycosyltransferase genes during Giardia infection. Glycosylation alterations were observed in Giardia-infected mice in the upper small intestine, the site of parasite colonization, and in the distal colon, where active trophozoites were absent. Alterations occurred as early as day 2 post-infection and persisted in mice after parasite clearance. We also observed small intestinal goblet cell hyperplasia and thinning of the distal colon mucus barrier during early infection, and microbiota alterations and altered production of cecal SCFAs. Giardia-induced alterations to mucin glycosylation were at least in part dependent on microbiota dysbiosis, as transplantation of a dysbiotic mucosal microbiota collected from Giardia-infected mice recapitulated some alterations. This study describes a novel mechanism by which Giardia alters intestinal mucin glycosylation, and implicates the small intestinal microbiota in regulation of mucin glycosylation patterns throughout the gastrointestinal tract.

Plant-based milk substitutes as probiotic vehicles: Health effect and survival, a review

The use of plant extracts or nondairy milk alternatives as a substitute for Cow's milk in the formulation of foods that function as vehicles for the consumption of probiotics has become popular. This substitution aims to formulate food products without lactose, low in fat, and, therefore, low in calories. Additionally, they can enter vegan or vegetarian markets. The use of these vegetable extracts has been explored for the development of probiotic foods that confer health benefits without cow milk allergy. However, few studies support that replacing Cow's milk in these foods allows probiotics to remain viable during storage, survive the digestive tract sufficiently, and reach their colonization site. Additionally, even fewer clinical studies in human or animal model assays have analyzed the impact of probiotic foods formulated with plant extracts.

Vibrio cholerae CsrA controls ToxR levels by increasing the stability and translation of toxR mRNA.

Vibrio cholerae is uniquely adapted to life in marine environments as well as in the human intestinal tract. Global regulators such as CsrA, which help translate environmental cues into an appropriate cellular response, are critical for switching between these distinct environments. Understanding the pathways involved in relaying environmental signals is essential for understanding both the environmental persistence and the intestinal pathogenesis of this devastating human pathogen. In this study, we demonstrate that CsrA directly regulates synthesis of ToxR, a key virulence factor of V. cholerae . Under conditions favoring high levels of active CsrA in the cell, such as in the presence of particular amino acids, CsrA increases ToxR protein levels by binding to the toxR transcript and enhancing both its stability and translation. By responding to nutrient availability, CsrA is perfectly poised to activate the virulence gene regulatory cascade at the preferred site of colonization, the nutrient-rich small intestinal mucosa.

Carbapenem-Resistant Enterobacter hormaechei Uses Mucus Metabolism to Facilitate Gastrointestinal Colonization.

Bloodstream infections caused by Enterobacter species pose a significant clinical threat. The intestine acts as the primary site for colonization and serves as a reservoir for infection. To combat this pathogen, it is crucial to understand how carbapenem-resistant Enterobacter species colonize the gut, as such knowledge can pave the way for alternative therapeutic targets. In this study, we developed a novel neonatal mouse model for gastrointestinal colonization by Enterobacter species and discovered that mucus plays a key role as a carbon source during colonization. Additionally, we identified two mucus catabolism pathways that contribute to intestinal colonization by carbapenem-resistant E. hormaechei. This new mouse model offers valuable insights into host-pathogen interactions and helps identify critical gastrointestinal fitness factors of Enterobacter, potentially guiding the development of vaccines and alternative therapeutic strategies to minimize intestinal carriage in patient populations at risk for infection with Enterobacter species.

Insights into the Two Most Common Cancers of Primitive Gut-Derived Structures and Their Microbial Connections.

The gastrointestinal and respiratory systems are closely linked in different ways, including from the embryological, anatomical, cellular, and physiological angles. The highest number (and various types) of microorganisms live in the large intestine/colon, and constitute the normal microbiota in healthy people. Adverse alterations of the microbiota or dysbiosis can lead to chronic inflammation. If this detrimental condition persists, a sequence of pathological events can occur, such as inflammatory bowel disease, dysplasia or premalignant changes, and finally, cancer. One of the most commonly identified bacteria in both inflammatory bowel disease and colon cancer is Escherichia coli. On the other hand, patients with inflammatory bowel disease are at risk of several other diseases-both intestinal (such as malnutrition and intestinal obstruction, besides cancer) and extraintestinal (such as arthritis, bronchiectasis, and cancer risk). Cancers of the lung and colon are the two most common malignancies occurring worldwide (except for female breast cancer). Like the bacterial role in colon cancer, many studies have shown a link between chronic Chlamydia pneumoniae infection and lung cancer. However, in colon cancer, genotoxic colibactin-producing E. coli belonging to the B2 phylogroup may promote tumorigenesis. Furthermore, E. coli is believed to play an important role in the dissemination of cancer cells from the primary colonic site. Currently, seven enteric pathogenic E. coli subtypes have been described. Conversely, three Chlamydiae can cause infections in humans (C. trachomatis may increase the risk of cervical and ovarian cancers). Nonetheless, striking genomic plasticity and genetic modifications allow E. coli to constantly adjust to the surrounding environment. Consequently, E. coli becomes resistant to antibiotics and difficult to manage. To solve this problem, scientists are thinking of utilizing suitable lytic bacteriophages (viruses that infect and kill bacteria). Several bacteriophages of E. coli and Chlamydia species are being evaluated for this purpose.

Spatio-temporally controlled all-in-one hydrogel microspheres for ulcerative colitis treatment based on cocktail strategy

Due to the complex pathogenesis of ulcerative colitis (UC), particularly excessive reactive oxygen species (ROS), gut microbiota dysbiosis, and hyperpolarization of M1 macrophages, the cocktail strategy is urgently needed to obtain a sufficient therapeutic outcome. Meanwhile, the accurate lesion location targeting of these combined therapeutic agents is still crucial. Herein, based on NPs-in-MPs approach, a novel integrated “all-in-one” oral delivery system (BMM/MPs), containing the natural gut microbiota regulator berberine, MnO2 nanoenzymes, and cell penetrating peptides-decorated magnolol liposomes to regulate macrophage polarization, was constructed to address these above issues in sequence. BMM/MPs could non-destructively cross the gastrointestinal tract, enduringly detain, and dissociate in the colon site due to the pH-sensitive properties. Conceivably, the released MnO2 nanoenzymes depleted the excess ROS at the colitis location into O2, sequentially promoting the acceleration of hydrogel microspheres rupture and oxidative damage remission. Accordingly, the oral administration of BMM/MPs exhibited remarkably satisfactory therapeutic effects against DSS-induced UC mice, by ameliorating the representative symptoms, scavenging ROS, relieving inflammation, and inhibiting M1 macrophage polarization at colon sites. Meanwhile, the dysbiosis of microbes was effectively regulated by facilitating SCFAs production. This study provides a feasible strategy for administration in the treatment of UC.

A phase I/II study of nanoliposomal irinotecan and carboplatin in patients with advanced or metastatic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma characterized by tissue and liquid next-generation sequencing.

52 Background: For locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), standard chemotherapy typically incorporates etoposide or irinotecan plus platinum agents. Herein, we initiate a phase I/II trial to apply Nal-IRI in combination with carboplatin as the 1st line treatment in patients with GEP-NECs to define the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). Methods: In the phase I part, traditional 3+3 design was applied. Enrolled patients would receive escalating dose of 60 (level -1), 80 (starting dose, level 0) or 100 (level 1) mg/m2 salt-form nal-IRI plus carboplatin AUC=4 with maximum total dose of 600 mg on D1, every 21 days as a cycle. DLTs were evaluated during the first one cycle of treatment with tumor assessment every 6 weeks. Prophylaxis G-CSF was not allowed in the first cycle Paired testing of tissue (TBx) and liquid biopsy (LBx) was done by Illumina TSO500 platform before treatment. The second LBx would be repeated for confirmed partial responders when progression. Results: Totally 6 GEP-NEC patients with primary sites of colon in three, and each one in esophagus, ampulla of Vater and pancreas were enrolled to level 0. One patient had DLT of grade 4 neutropenia lasting for 3 days even under salvage G-CSF. Treatment-related adverse events showed grade 3/4 neutropenia (33.4%), grade 2 anemia (16.7%), grade 3 fatigue (16.7%), and grade 2 skin rash (16.7%). Four patients achieved confirmed partial response and 2 patients got stable disease, with the objective response rate of 66.7% (95% confidence interval: 22%-96%). After the data and safety monitoring board meeting, level 0 was decided as RP2D but not escalation to level 1 because of acceptable toxicity profiles and promising efficacies. Comprehensive genomic profiling showed that driver mutations were identified in three cases including two harboring BRAFV600E mutation and one with KRASG12D mutation. The other three cases lacking driver mutation showed frequent copy number alteration including 1 with MDM2 amplification (copy number 27) and a wild-type TP53. Homologous recombination deficiency (HRD), as determined by GIS score, was identified in a colon GEP-NEC who remained to be HRD-positive at progression but a higher TMB (from 4.7 to 10.2 Muts/Mb) and a higher BRAFV600E mutation allele frequency (from 24.1% to 43.6%) in tumor tissue, compared to the baseline profiling. Conclusions: Based on current data, the RP2D is 80 mg/m2 of nal-IRI (salt-form) and carboplatin of AUC=4, every 3 weeks. The extension phase II study in GEP-NEC is ongoing. Clinical trial information: NCT05385861 .

Probiotic spore-derived multifunctional nanoparticles for enhanced ulcerative colitis treatment by activating metabolic pathways and repairing epithelial barrier

Ulcerative colitis is an agnogenic and refractory intestinal disease. Probiotic therapy has gained prevalence in medical research. Particularly, the probiotic spore coat has shown effectiveness in delivering oral drugs or probiotics for colitis treatment. Nevertheless, challenges persist in understanding the exact mechanism of the spore coat for optimal anti-inflammatory efficacy. Consequently, we develop a type of multifunctional spore coat nanoparticles (CN) derived from probiotic spore coat to comprehensively investigate its mechanisms of action in alleviating inflammation. Surprisingly, our research findings demonstrate that CN exhibits remarkable resistance to the harsh gastric acid environment and possesses the ability to selectively target inflammatory colonic sites characterized by an accumulation of positive charges. Additionally, CN effectively maintains the normal expression levels of zonula-1, occludin, and claudin-1 while simultaneously enhancing the small intestinal mucin 2 to ensure the integrity of intestinal barriers. Furthermore, the metabolomics analysis identifies 88 potential biomarkers that are enriched in three metabolic pathways, including tyrosine metabolism, tryptophan metabolism, and biosynthesis of valine, leucine, and isoleucine. These pathways are associated with Nrf2 signaling pathway activation, NF-κB and Nrf2 signaling pathways regulation, and metabolic disorders regulation. Collectively, our work provides a multifunctional nanomaterial CN and elucidates its anti-inflammatory mechanisms for ulcerative colitis treatment.

Clinical characteristics and genome epidemiology of Stenotrophomonas maltophilia in Japan.

Stenotrophomonas maltophilia is a carbapenem-resistant Gram-negative pathogen increasingly responsible for difficult-to-treat nosocomial infections. To describe the contemporary clinical characteristics and genome epidemiology of patients colonized or infected by S. maltophilia in a multicentre, prospective cohort. All patients with a clinical culture growing S. maltophilia were enrolled at six tertiary hospitals across Japan between April 2019 and March 2022. The clinical characteristics, outcomes, antimicrobial susceptibility and genomic epidemiology of cases with S. maltophilia were investigated. In total, 78 patients were included representing 34 infection and 44 colonization cases. The median age was 72.5 years (IQR, 61-78), and males accounted for 53 cases (68%). The most common comorbidity was localized solid malignancy (39%). Nearly half of the patients (44%) were immunosuppressed, with antineoplastic chemotherapy accounting for 31%. The respiratory tract was the most common site of colonization (86%), whereas bacteraemia accounted for most infection cases (56%). The 30 day all-cause mortality rate was 21%, which was significantly higher in infection cases than colonization cases (35% versus 9%; adjusted HR, 3.81; 95% CI, 1.22-11.96). Susceptibility rates to ceftazidime, levofloxacin, minocycline and sulfamethoxazole/trimethoprim were 14%, 65%, 87% and 100%, respectively. The percentage of infection ranged from 13% in the unclassified group to 86% in genomic group 6A. The percentage of non-susceptibility to ceftazidime ranged from 33% in genomic group C to 100% in genomic groups 6 and 7 and genomic group geniculate. In this contemporary multicentre cohort, S. maltophilia primarily colonized the respiratory tract, whereas patients with bacteraemia had the highest the mortality from this pathogen. Sulfamethoxazole/trimethoprim remained consistently active, but susceptibility to levofloxacin was relatively low. The proportions of cases representing infection and susceptibility to ceftazidime differed significantly based on genomic groups.

Comparing the Microbiome of the Adenoids in Children with Secretory Otitis Media and Children without Middle Ear Effusion.

The adenoids, primary sites of microbial colonization in the upper airways, can influence the development of various conditions, including otitis media with effusion (OME). Alterations in the adenoid microbiota have been implicated in the pathogenesis of such conditions. This study aims to utilize 16S rRNA genetic sequencing to identify and compare the bacterial communities on the adenoid surfaces of children with OME and children with healthy middle ears. Additionally, we seek to assess the differences in bacterial diversity between these two groups. We collected adenoid surface swabs from forty children, divided into two groups: twenty samples from children with healthy middle ears and twenty samples from children with OME. The V3-V4 hypervariable region of the bacterial 16S rRNA gene was amplified and sequenced using the Illumina MiSeq platform. Alpha and beta diversity indices were calculated, and statistical analyses were performed to identify significant differences in bacterial composition. Alpha diversity analysis, using Pielou's index, revealed significantly greater evenness in the bacterial communities on the adenoid surfaces of the healthy ear group compared with the OME group. Beta diversity analysis indicated greater variability in the microbial composition of the OME group. The most common bacterial genera in both groups were Haemophilus, Fusobacterium, Streptococcus, Moraxella, and Peptostreptococcus. The healthy ear group was primarily dominated by Haemophilus and Streptococcus, whereas the OME group showed higher abundance of Fusobacterium and Peptostreptococcus. Additionally, the OME group exhibited statistically significant higher levels of Alloprevotella, Peptostreptococcus, Porphyromonas, Johnsonella, Parvimonas, and Bordetella compared with the healthy ear group. Our study identified significant differences in the bacterial composition and diversity on the adenoid surfaces of children with healthy middle ears and those with OME. The OME group exhibited greater microbial variability and higher abundances of specific bacterial genera. These findings suggest that the adenoid surface microbiota may play a role in the pathogenesis of OME. Further research with larger sample sizes and control groups is needed to validate these results and explore potential clinical applications.

Association of Staphylococcus aureus Bacterial Load and Colonization Sites With the Risk of Postoperative S. aureus Infection.

The independent effects of extranasal-only carriage, carriage at multiple bodily sites, or the bacterial load of colonizing Staphylococcus aureus (SA) on the risk of developing SA surgical site infections and postoperative bloodstream infections (SA SSI/BSIs) are unclear. We aimed to quantify these effects in this large prospective cohort study. Surgical patients aged 18 years or older were screened for SA carriage in the nose, throat, or perineum within 30 days before surgery. SA carriers and noncarriers were enrolled in a prospective cohort study in a 2:1 ratio. Weighted multivariable Cox proportional hazard models were used to assess the independent associations between different measures of SA carriage and occurrence of SA SSI/BSI within 90 days after surgery. We enrolled 5004 patients in the study cohort; 3369 (67.3%) were SA carriers. 100 SA SSI/BSI events occurred during follow-up, and 86 (86%) of these events occurred in SA carriers. The number of colonized bodily sites (adjusted hazard ratio [aHR], 3.5-8.5) and an increasing SA bacterial load in the nose (aHR, 1.8-3.4) were associated with increased SA SSI/BSI risk. However, extranasal-only carriage was not independently associated with SA SSI/BSI (aHR, 1.5; 95% CI, 0.9-2.5). Nasal SA carriage was associated with an increased risk of SA SSI/BSI and accounted for the majority of SA infections. Higher bacterial load, as well as SA colonization at multiple bodily sites, further increased this risk.

ROS-responsive thioketal nanoparticles delivering system for targeted ulcerative colitis therapy with potent HDAC6 inhibitor, tubastatin A

Ulcerative colitis (UC) is a common gastrointestinal problem characterized by the mucosal injury primarily affecting the large intestine. Currently available therapies are not satisfactory as evidenced by high relapse rate and adverse effects. In this study we aimed to develop an effective drug delivery system using reactive oxygen species (ROS)-responsive thioketal nanoparticles (TKNP), to deliver tubastatin A, a potent HDAC6 inhibitor, to the inflamed colon in mice with ulcerative colitis (UC). TKNPs were synthesized by step-growth polymerization from an acetal exchange reaction while TUBA-TKNP was prepared using the single emulsion solvent evaporation technique. Our developed nanoparticle showed release of tubastatin A only in presence of ROS which is found to be highly present at the site of inflamed colon. Oral administration of TUBA-TKNP resulted in the higher accumulation of tubastatin A at the inflamed colon site and decreased the inflammation as evidenced by reduced infiltration of immune cells and decreased level of pro-inflammatory cytokines in TUBA-TKNP treated mice. In summary, our results show the successful localization of tubastatin A at the site of colon inflammation through TUBA-TKNP delivery, as well as resolution of clinical features of UC in mice.

Clinical signature of exosomal tetraspanin proteins in cancer

AbstractExosomes are nano‐scale vesicles involved in intercellular communication and have a significant role in cancer progression. Tetraspanins, are transmembrane proteins enriched in exosomes. These proteins have significant role in exosome biogenesis, cargo sorting,and target‐cell interactions, influencing tumor development and therapeutic response. Exosomal tetraspanins, including CD9, CD63, CD81, and Tspan8, contribute to tumor cell proliferation, angiogenesis, extracellular matrix remodelling, immune evasion, and promote metastasis. Their ability to prepare distant organ sites for colonization highlights their role in establishing the premetastatic niche. Expression profiling of exosomal tetraspanin proteins in cancer become a promising diagnostic and prognostic biomarker. Exosomal tetraspanin proteins also be an effective therapeutic target in cancer.This article highlighted impactful role ofexosomal tetraspanin Proteins in Cancer.

Transcriptome Analysis of Human Dermal Cells Infected with Candida auris Identified Unique Pathogenesis/Defensive Mechanisms Particularly Ferroptosis.

Candida auris is an emerging multi-drug resistant yeast that can cause life-threatening infections. A recent report clarified the ability of C. auris to form a biofilm with enhanced drug resistance properties in the host skin's deep layers. The formed biofilm may initiate further bloodstream spread and immune escape. Therefore, we propose that secreted chemicals from the biofilm may facilitate fungal pathogenesis. In response to this interaction, the host skin may develop potential defensive mechanisms. Comparative transcriptomics was performed on the host dermal cells in response to indirect interaction with C. auris biofilm through Transwell inserts compared to planktonic cells. Furthermore, the effect of antifungals including caspofungin and fluconazole was studied. The obtained data showed that the dermal cells exhibited different transcriptional responses. Kyoto Encyclopedia of Genes and Genomes and Reactome analyses identified potential defensive responses employed by the dermal cells and potential toxicity induced by C. auris. Additionally, our data indicated that the dominating toxic effect was mediated by ferroptosis; which was validated by qRT-PCR, cytotoxicity assay, and flow cytometry. On the other hand, the viability of C. auris biofilm was enhanced and accompanied by upregulation of MDR1, and KRE6 upon interaction with dermal cells; both genes play significant roles in drug resistance and biofilm maturation, respectively. This study for the first-time shed light on the dominating defensive responses of human dermal cells, microbe colonization site, to C. auris biofilm and its toxic effects. Further, it demonstrates how C. auris biofilm responds to the defensive mechanisms developed by the human dermal cells.

Mesenteric lymph nodes: a critical site for the up-regulatory effect of hUC-MSCs on Treg cells by producing TGF-β1 in colitis treatment

BackgroundMesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects.MethodsFirst, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-β1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD.ResultsThe therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-β1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-β1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis.ConclusionsMLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-β1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.