Search Results (928)

Mounting evidence from large-scale association studies has identified transmembrane BAX inhibitor motif-containing 1 (TMBIM1) as a promising candidate gene in colorectal cancer (CRC) pathogenesis. Our clinical analysis confirmed this association, demonstrating significantly reduced TMBIM1 expression in human colon cancer tissues. To elucidate its functional role, we employed complementary experimental approaches across different cellular contexts. In normal colonic epithelial cells (NCM460), TMBIM1 deficiency triggered distinct morphological changes and suppressed cellular growth. Conversely, in malignant HCT-116 cells, TMBIM1 knockdown paradoxically enhanced proliferation and other pro-tumorigenic characteristics, suggesting context-dependent functions. Transcriptomic profiling via RNA-seq revealed that TMBIM1 suppression enhances cell viability, and the specific mutational background of HCT-116 cells appears to exploit the consequent loss of E-cadherin to further drive progression. Mechanistic investigations further identified E-cadherin (CDH1) as a key downstream effector, showing significant down-regulation following TMBIM1 knockdown. We therefore define a context-dependent tumor-suppressive mechanism for TMBIM1, wherein its loss in MSI-H cells promotes tumorigenesis via E-cadherin suppression and the consequent loss of epithelial integrity. Full article

Background/Objectives: Ulcerative colitis (UC) is an inflammatory bowel disease and a major cause of ulcers and chronic inflammation in the colon and rectum. Recurring symptoms include abdominal pain, rectal bleeding, and diarrhoea, and patients with UC are at a higher risk of developing comorbidities such as colorectal cancer and poor mental health. In UC, the decreased diversity and changed metabolic profile of gut microbiota, along with a diminished mucus layer, leads to disruption of the underlying epithelial barrier, with an ensuing excessive and detrimental inflammatory response. Treatment options currently rely on drugs that reduce the inflammation, but less emphasis has been placed on improving the resilience of the epithelial barrier. Macrolide antibiotics exhibit epithelial barrier-enhancing capacities unrelated to their antibacterial properties. Methods: We investigated two novel barriolides, macrolides with reduced antibacterial effects in common bacterial strains. Gut epithelial cell barrier resistance in the Caco-2 cell line, with and without co-culture with mucus-producing HT-29 cells, was increased when treated with barriolides. Using ^AXGut-on-Chip technology with inflammatory cytokine-stimulated Caco-2/HT-29 co-cultures, the effectiveness of the barriolides was confirmed. Lastly, we reveal the barrier-enhancing and inflammation-reducing effects of the barriolides in a dextran-sulphate sodium (DSS)-induced colitis mouse model. Results: We show the predictive power of the novel ^AXGut-on-Chip system and the effectiveness of the novel barriolides. Indications include reduced inflammatory response, increased epithelial barrier and decreased overall clinical score. Conclusions: The results of this study indicate the notion that barriolides could be used as a treatment option for UC. Full article

Helicobacter pylori (H. pylori) is recognized as one of the most widespread and persistent bacterial infections globally, with a remarkable ability to colonize the human stomach. This pathogen is a major contributor to the development of gastric diseases, including gastric lymphoma and adenocarcinoma. The H. pylori infection triggers a complex pathogenic cascade within the gastric environment, characterized by prolonged inflammation and heightened oxidative stress, which fosters a milieu of immune dysregulation, where both innate and adaptive immune cells become activated inappropriately, thereby leading to epithelial injury and subsequent remodeling of the gastric tissue. As the infection persists, repeated cycles of inflammation and epithelial damage contribute to the development of epigenetic alterations, including changes in DNA methylation, histone modifications, and non-coding RNA expression, all of which render the gastric epithelium more susceptible to further aberrations, including dysplasia and cancer. In this article, we review the latest advances in understanding the molecular mechanisms of H. pylori-induced gastritis and its role in the progression of gastric cancer, offering new perspectives on the complex biology of this infection and its potential therapeutic implications for preventing the development of gastric malignancies. Full article

Adherent-invasive E. coli (AIEC) is closely related to inflammatory bowel disease (IBD). However, its pathogenic mechanism has not yet been fully elucidated. Using a BLASTP search, we discovered that the amino acid sequence of a putative protein (UFP37798.1) in the AIEC LF82 strain is highly homologous to some regulators in the SlyA family. We named it EruA. We displayed the secondary structures of EruA using bioinformatics, overexpressed the His₆-tagged EruA protein using SDS-PAGE, and dissected the genetic organization of the eruA chromosomal region using 5′RACE. We constructed an eruA deletion mutant (ΔeruA) and a complementary strain (CΔeruA) of the LF82 strain. The transcriptomes of wild-type (WT) and ΔeruA bacteria were compared using RNA sequencing and qRT-PCR, thereby identifying 32 differentially expressed genes (DEGs). Based on YASARA software and EMSA analysis, EruA directly binds to the consensus sequences (P_fimA and P_tnaB) in the promoter region of the fimA and tnaB genes from these DEGs. By using a super-resolution confocal microscope (SCM), counting CFUs of colonies on plates, indole quantification, and crystal violet staining of biofilms adhered to tubes or 96-well plates, we found that EruA activates the fimA to promote bacterial adhesion to intestinal epithelial cells and activates the tnaB to enhance bacterial indole production and biofilm formation. Moreover, EruA helps AIEC resist environmental stress and enhances bacterial survival within macrophages as well as loading in mouse tissues. Notably, EruA promotes AIEC colonization in the colons of mice and exacerbates intestinal inflammation caused by bacterial infection in mice with DSS-induced inflammatory colitis, manifested by weight loss, colon length shortening, and pathological changes in colon tissues. Therefore, EruA plays a key role in the pathogenicity of AIEC. Full article

Colorectal cancer is one of the leading causes of cancer-associated mortality, and multifactorial resistance remains one of the main challenges in its treatment. Essential oils and their main compounds show interesting anticancer properties, but their mechanism of action is yet to be defined. This study aims to assess the cytotoxic effects of eugenol (EU) and cinnamaldehyde (CN) on colorectal cancer (CRC) cells, highlighting possible mechanisms of action. These compounds were tested on normal immortalized colonocytes (NCM-460) and two CRC cell lines: Caco-2, a human colon epithelial adenocarcinoma cell line, and SW-620, colon cancer cells derived from a lymph node metastatic site. The efficacy of EU and CN was evaluated through CellTiter-Glo^® and clonogenic assays and by determining proinflammatory cytokine secretion. Transcriptome analysis was used to identify possible pathways affected by EU and CN treatments. The results confirmed that EU and CN were selectively cytotoxic and pro-apoptotic against CRC cells, with different putative mechanisms. While EU drove cytotoxicity through robust transcriptional remodeling, CN yielded a stronger anti-inflammatory action. We confirmed that EU and CN are promising natural candidates in CRC prevention and treatment, even in association with chemotherapeutic drugs. Full article

This article describes the microbiome of the outer ear and the earwax in the ear canal, which performs various protective functions against bacterial infections. This article is based on an analysis of literature gathered from databases including PubMed, Google Scholar, Web of Science, and Scopus, primarily from the last 15 years. The search strategy included MeSH terms: ear canal, microbiome, earwax, cerumen, antibacterial peptides, ear infections, biofilm. Only peer-reviewed articles were included. The natural ear canal microbiota provides so-called colonization resistance, which protects against invasion by pathogenic microorganisms. Earwax is composed primarily of keratin secreted by epithelial cells and substances secreted by sweat and apocrine glands. It plays a key role in the physiology of the ear canal, maintaining a low pH, limiting moisture, and exhibiting antimicrobial properties. Both an excess and a deficiency of earwax can lead to dysbiosis of the outer ear, and consequently to the development of various infections. In an era of increasing antibiotic resistance and the search for new solutions in the fight against pathogenic microorganisms, understanding the natural properties of earwax is becoming increasingly important. Full article

High-grade serous ovarian carcinoma (HGSC) is predominantly diagnosed at advanced stages with extensive peritoneal metastasis. A pivotal early event in HGSC development is the peritoneal seeding of tumor cells originating from the fallopian tube epithelial (FTE) precursor lesions. Ovulation releases follicular fluid (FF), which is known to contain oncogenic factors that promote FTE cell transformation. However, the specific mechanisms and factors within FF that drive the early metastatic seeding of precancerous FTE cells remain poorly defined. We investigated the role of FF in the peritoneal dissemination of FTE-derived cells, and the abundance of fibronectin (FN) as a potential key mediator. Functional assays were performed using FN-depleted FF to assess its impact on migration, invasion, anchorage-independent growth, and peritoneal attachment. The role of the fibronectin receptor, integrin β1 (ITGB1), and the signaling pathways were evaluated via knockdown studies. In vivo xenograft models were used to quantify peritoneal seeding, and mechanistic studies elucidated the involved signaling pathways. We identified FN as a critical component of FF, present at high concentrations (~210 µg/mL), that potently drives FTE cell migration, invasion, and peritoneal seeding. Depletion of FN from FF abrogated the majority of these pro-metastatic activities in vitro and led to a dramatic 82% reduction in peritoneal tumor seeding in vivo. Knockdown of ITGB1 similarly impaired seeding. Mechanistically, FF-derived FN activates the ITGB1/FAK-SRC signaling pathway to promote tumor cell motility and colonization. Our study establishes FF-fibronectin as an important regulator of the early peritoneal seeding of HGSC precursor cells. These findings reveal a direct link between ovulation and HGSC development, suggesting that targeting the FN-ITGB1 signaling axis may offer a novel preventive strategy for high-risk individuals. Full article

Introduction: The increasing global interest in plant-based diets has led to the development of innovative meat analogs that not only mimic the sensory properties of traditional products but may also offer potential health benefits. In this study, we investigated the nutritional characteristics and biological activity of potato protein-based vegan burgers (PBBs) enriched with plant-derived iron and fiber sources. Methods: The burgers were subjected to in vitro gastrointestinal digestion, followed by evaluation of their cytotoxic potential against human intestinal cancer cell lines (Caco-2 and HT-29) and normal colon epithelial cells (CCD 841 CoN). Additionally, their influence on the intestinal microbiota composition and enzymatic activity of β-glucosidase and β-glucuronidase was assessed. Results: PBBs demonstrated favorable nutritional profiles, high protein and fiber contents, and a balanced fatty acid ratio (n-6/n-3). After digestion, bioaccessible fractions showed selective cytotoxicity toward cancer cells, while maintaining safety for normal intestinal cells. Furthermore, PBBs modulated the gut microbiota by promoting the growth of beneficial genera (Lactobacillus, Bifidobacterium) and reducing potentially harmful Enterobacteriaceae, accompanied by decreased β-glucuronidase activity. Conclusions: These findings suggest that potato protein-based burgers could represent a functional plant-based alternative to conventional meat products, contributing to intestinal health and potentially reducing colorectal cancer risk. Full article

With growing emphasis on antibiotic-free poultry production, functional probiotics represent a promising strategy to improve gut health and reduce pathogen transmission. This study characterized three lactic acid bacteria (LAB) strains Lactobacillus delbrueckii subsp. bulgaricus NRRL-B-548 (LD), Lacticaseibacillus paracasei DUP-13076 (LP), and Lacticaseibacillus rhamnosus NRRL-B-442 (LR) for their probiotic potential and evaluated their efficacy against Salmonella enterica in poultry. The LAB strains were assessed for acid and bile tolerance, lysozyme resistance, cholesterol assimilation, antimicrobial activity, surface hydrophobicity, epithelial adherence, hemolysis, and antibiotic susceptibility. Genomic analysis was performed to identify genes associated with probiotic functionality. The protective potential of LR and LP was further validated in hatchlings using a hatchery spray model challenged with Salmonella Enteritidis. All strains survived simulated gastric and intestinal conditions, exhibited strong adhesion to epithelial cells, and demonstrated high hydrophobicity, indicating robust colonization capacity. The LAB significantly inhibited Salmonella Enteritidis, S. Typhimurium, and S. Heidelberg growth in vitro and remained sensitive to clinically relevant antibiotics. In vivo application of LR and LP to hatching eggs markedly reduced S. Enteritidis colonization in the liver, spleen, and ceca of hatchlings. Further, genomic profiling of the LAB strains revealed genes for bacteriocin production, exopolysaccharide synthesis, and carbohydrate metabolism supporting probiotic function. In summary, the evaluated LAB strains exhibit multiple probiotic attributes and strong anti-Salmonella activity, confirming their potential as safe, hatchery-applied probiotics for improving gut health and biosecurity in poultry production systems. Full article

Beneficial effects of the microbiota-derived metabolite butyrate at the colonic level are well established, particularly through its relevance in colorectal cancer (CRC) and inflammatory bowel disease (IBD), two major intestinal pathologies. Therefore, the mechanisms involved in butyrate transport across colonic epithelial cell membranes (uptake transporters: monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter 1 (SMCT1); efflux transporters: breast cancer resistance protein (BCRP) and MCT1/monocarboxylate transporter 4 (MCT4)), which are determinant for its intracellular levels, are of primary importance for its beneficial effects at the colonic level. The available data suggest that all these butyrate transporters can be modulated by redox and inflammatory status, but the evidence is scarce and rather inconsistent. Nevertheless, a role of nuclear factor erythroid 2-related factor 2 (Nrf2) and of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in mediating the effect of oxidative stress and inflammation, respectively, on MCT1 and SMCT1 is suggested. So, more investigation on this subject is needed, given the fact that increased oxidative stress levels and inflammatory status are present in a series of intestinal conditions and pathologies, including CRC and IBD, which could help to establish these transporters as potential cellular targets in these diseases. Full article

Inflammatory bowel disease (IBD) involves chronic inflammation and disruption of the intestinal barrier, often accompanied by alterations in gut microbiota composition. This study examined the protective potential of a prebiotic mixture extract (PME) prepared from Vigna radiata (mung bean), Vigna angularis (red bean), and Foeniculum vulgare (fennel) using the HT-29 cell and colitis animal model. PME exhibited concentration-dependent antioxidant activity, with greater radical-scavenging capacity in the ABTS assay than in the DPPH assay. In LPS-stimulated HT-29 epithelial cells, PME reduced the mRNA expression of inflammation-associated genes (TNF-α, IL-1β, NF-κB) and upregulated tight junction markers (CLDN1 and OCLN), demonstrating its anti-inflammatory and supportive effects on the intestinal barrier. Vitexin, a C-glycosylated flavonoid, was detected in PME and is expected to mediate these protective effects. In a DSS-induced colitis mouse model, PME administration alleviated disease severity by increasing colon length, reducing serum levels of inflammatory cytokines and COX-2/PGE2, and restoring intestinal permeability. Furthermore, PME modulated the gut microbiota by enhancing beneficial bacteria such as Bifidobacterium and Faecalibaculum while suppressing inflammation-associated taxa, including Escherichia, Bacteroides, and Mucispirillum. These improvements collectively suggest that PME reinforces epithelial barrier integrity and promotes intestinal homeostasis through both anti-inflammatory and microbiota-regulating actions. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with its development closely linked to dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways. Background: Dual-specificity phosphatases (DUSPs), as key regulators of MAPKs, play a crucial role in maintaining the balance between proliferation and apoptosis. Methods: In this study, we investigated the effect of mesalazine (MES) on the expression and activity of selected DUSP family members in normal colon epithelial cells (CCD-841CoN) and colorectal cancer cells (DLD-1). Results: Microarray analysis identified 24 transcripts with altered expression upon mesalazine treatment. The number of significantly regulated genes decreased with increasing fold-change (FC) thresholds, from 20 genes (FC > 1.1) to 13 (FC > 1.5) and 5 (FC > 2.0), all with p < 0.001. Among the DUSP genes, DUSP4 and DUSP5 showed the most pronounced and cell-type-dependent modulation. Mesalazine upregulated DUSP4 and DUSP5 expression in DLD-1 cells (p < 0.001), while reducing their expression in normal CCD-841CoN cells. ELISA confirmed a 1.56-fold increase in DUSP5 protein concentration in mesalazine-treated cancer cells compared with controls (p < 0.001). Conclusions: These findings suggest that mesalazine differentially modulates DUSP gene expression in normal and malignant colon epithelial cells, potentially contributing to its antiproliferative and pro-apoptotic effects through the regulation of MAPK signaling. These results provide new insights into the molecular mechanisms underlying the anticancer effects of mesalazine in colorectal cancer. Full article

With an aging population and the increase in life expectancy, colorectal cancer is becoming increasingly common. Currently, the mainstay of treatment is chemotherapy, which can cause a variety of side effects. However, herbalists in many cultures have long used herbs to promote health and treat various diseases, including colon cancer. This study investigated the chemical components of shell extracts from Plukenetia volubilis (sacha inchi) and their effects on colon cancer cells. First, cytotoxicity against both normal and cancer cells was assessed, followed by cell migration and invasion. Finally, transcriptomic and proteomic analyses were performed to investigate molecular mechanisms. Phytochemical analysis showed a total phenolic content of 134.61 ± 0.27 mgGAE/g extract and a total flavonoid content of 5.75 ± 0.01 mgQE/g extract; moreover, lidocaine (10.57%) and linolenic acid (10.39%) were identified as the most abundant compounds. In vitro, the extract inhibited cell migration, invasion, and colony formation and was associated with potential modulations of the Hippo pathways and epithelial–mesenchymal transition. Therefore, it can be concluded that these extracts are effective in inhibiting the progression of colon cancer cells, and thus, they can prospectively be developed as a dietary supplement or therapeutic agent for the treatment of colon cancer in the future. Full article

Antibiotic-resistant infections remain a major challenge in cystic fibrosis (CF), where chronic Pseudomonas aeruginosa colonization drives lung infection. The overexpression of adhesion-related proteins and extracellular matrix components, including fibronectin (Fn), facilitates bacterial colonization. Recent evidence identifies the RNA-binding protein Human Antigen R (HuR) as a key regulator of this process, as it stabilizes Vav3 mRNA, promoting Fn deposition and the formation of bacterial docking platforms. Here, we report the synthesis, optimization, and functional evaluation of the HuR-targeted small-molecule (2S,3S)-BOPC1. Functional assays in CF human airway epithelial cells demonstrated that (2S,3S)-BOPC1 significantly reduced P. aeruginosa adhesion in a dose-dependent manner without detectable cytotoxic effects. These findings provide the first evidence that targeting HuR can disrupt the HuR–Vav3–Fn axis, reducing bacterial attachment. This host-directed approach represents a promising strategy to prevent chronic infections in CF without promoting antibiotic resistance. Full article

Eurotium cristatum-Fermented White Tea (FWT) significantly alters white tea (WT) composition, increasing caffeine while decreasing polyphenols and amino acids. FWT effectively ameliorated dextran sulfate sodium (DSS)-induced murine colitis symptoms (reducing weight loss, colon shortening). Mechanistically, FWT suppressed TLR4/Myd88/NF-κB signaling and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) while upregulating tight junction proteins (ZO-1, occludin, claudin-1), MUC2, and E-cadherin. Single-cell/spatial transcriptomics revealed that FWT treatments augment enterocyte, goblet cell, and stem cell populations, optimize goblet function, restructure stem cell differentiation, and induce epithelial REG3B (antimicrobial) and LYPD8 (motility inhibitor), plus immunomodulator GM42418 lncRNA across cell types, repairing the barrier. FWT intervention was also associated with an increase in beneficial bacteria (Akkermansia, Lactobacillus, Bifidobacterium), restoration of microbiota balance, and elevated levels of short-chain fatty acids (SCFAs) and was associated with alterations in caffeine-related metabolite profiles. Collectively, these multi-scale changes correlate with the alleviation of UC, suggesting an integrated mechanism involving mucosal barrier repair, immune–stromal modulation, microbiota–metabolism regulation, and cellular reprogramming. Full article