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Heliyon Sep 2023Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive...
Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde derived from lipid peroxidation of ω-6 polyunsaturated fatty acids that contributes to colorectal carcinogenesis. Glutathione -transferase alpha 4 (Gsta4) specifically conjugates glutathione to 4-HNE and thereby detoxifies 4-HNE. The correlation of these oxidative biomarkers with the pathological changes in CAC is, however, unclear. In this study, we investigated the expression of Gsta4 and 4-HNE adducts in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced murine CAC, and analyzed the correlations of 4-HNE and Gsta4 with inflammatory cytokines and the pathological scores in the colon biopsies. Real-time quantitative PCR showed that expression of IL6, TNFα, and Gsta4 sequentially increased in colon tissues for mice treated with DSS for 1, 2, and 3 cycles, respectively. Moreover, immunohistochemical staining showed remarkably increased expression of 4-HNE adducts, Gsta4, TNFα, and IL6 in the colon biopsies after 3 cycles of DSS treatment. Correlation analysis demonstrated that 4-HNE adducts in the colon biopsies were positively correlated with Gsta4 expression. Additionally, the expression of Gsta4 and 4-HNE adducts were strongly correlated with the pathological changes of colon, as well as the expression of TNFα and IL6 in colon tissues. These results provide evidence for the association of oxidative biomarkers Gsta4 and 4-HNE with the pathological changes of CAC and may help developing novel histopathological biomarkers and prevention targets for CAC.
PubMed: 37810110
DOI: 10.1016/j.heliyon.2023.e19815 -
International Journal of Biological... 2023(), a gram-negative anaerobic bacterium, is selectively decreased in the fecal microbiota of patients with colorectal cancer (CRC), but its molecular mechanism in CRC...
(), a gram-negative anaerobic bacterium, is selectively decreased in the fecal microbiota of patients with colorectal cancer (CRC), but its molecular mechanism in CRC development remains inconclusive. In this study, we first confirmed the inhibitory effect of on CRC formation and analyzed the metabolic role of intestinal flora in human Polyps, A-CRA (advanced colorectal adenoma) and CRC samples. To better clarify the role of in CRC development, a pseudo-germ-free (GF) azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established, followed by infection with or without . Metabolomic analysis and RNA-seq analysis showed tryptophan-mediated aryl hydrocarbon receptor (AhR) was significantly down-regulated in -infected CRC mice. Then, mice with intestinal specific AhR deficiency (AhR Cre) were generated and were used in 2 murine models: AOM/DSS treatment as a model of carcinogen-induced colon cancer and a genetically induced model using mice. Notably, AhR deficiency inhibited CRC growth in the AOM/DSS and mouse model. Moreover, AhR deficiency inhibited, rather than enhanced, tumor formation and tumor-derived organoids in Apc-deficient cells both and by activating Wnt/β-catenin signaling and TCF4/LEF1-dependent transcription. Furthermore, the antitumor effectiveness of was abolished either in a human colon cancer tumor model induced by subcutaneous transplantation of AhR-silenced CRC cells, or AhR-deficienty spontaneous colorectal cancer model. In conclusion, supplementation with . protected mice from CRC development by specifically inhibiting tryptophan-mediated AhR/β-catenin signaling.
Topics: Humans; Mice; Animals; beta Catenin; Tryptophan; Receptors, Aryl Hydrocarbon; Base Composition; Phylogeny; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Colorectal Neoplasms; Colonic Neoplasms; Wnt Signaling Pathway; Mice, Inbred C57BL
PubMed: 37781044
DOI: 10.7150/ijbs.85712 -
Gut Nov 2023Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic and its role in improving...
OBJECTIVE
Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC).
DESIGN
The effects of in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites.
RESULTS
significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. synergised with anti-PD1 therapy by reducing Foxp3 CD25 regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8 T cells. -derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4 T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation.
CONCLUSION
-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. is a potential adjuvant to augment anti-PD1 efficacy against CRC.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Kynurenine; Receptors, Aryl Hydrocarbon; T-Lymphocytes, Regulatory; Lactobacillus; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Bacterial Lysates
PubMed: 37770127
DOI: 10.1136/gutjnl-2023-329543 -
Pharmaceutics Sep 2023Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease, is known to increase the risk of colitis-associated cancer (CAC). CAC has...
Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease, is known to increase the risk of colitis-associated cancer (CAC). CAC has been found to be unresponsive to standard chemotherapy regimens, and the current treatments do not utilize effective small-molecule drugs and colon-targeted delivery systems. Previous studies indicated that the M13-nano-liposome (NL) formulation can effectively target the colon and reshape the gut microbiota in ex vivo cultures, generating altered microbial metabolites that can efficiently prevent chronic UC. In this study, we tested the cancer cell uptake ability of the NL formulation and investigated the potential of the M13-NL formulation to prevent CAC in the azoxymethane (AOM)-exposed IL10 mouse model. Our findings demonstrate that oral administration of M13-NL prevents tumor development in AOM-exposed IL10 mice, suggesting that M13-NL is a promising oral drug formulation for preventing CAC.
PubMed: 37765299
DOI: 10.3390/pharmaceutics15092331 -
Cell Communication and Signaling : CCS Sep 2023Several studies show that natural foods are a source of compounds with anticancer properties that affect the gut microbiota and its metabolites. In the present study, we...
BACKGROUND
Several studies show that natural foods are a source of compounds with anticancer properties that affect the gut microbiota and its metabolites. In the present study, we investigate the effect of a delactosed buffalo milk whey by-product (DMW) on colorectal carcinogenesis.
METHODS
The effect of DMW on colorectal carcinoma (CRC) was investigated in the established mouse model of azoxymethane (AOM)-induced colon carcinoma, which closely resembles the human clinical condition of CRC. The effect of DMW on CRC immortalized cell lines was also evaluated to further identify the antineoplastic mechanism of action.
RESULTS
Pretreatment of AOM-treated mice with DMW significantly (P < 0.05) reduced the percentage of mice bearing both aberrant crypt foci with more than four crypts (which are early precancerous lesions that progress to CRC) and tumors. In addition, DMW completely counteracted the effect of AOM on protein expression of caspase-9, cleaved caspase-3 and poly ADP-ribose polymerase in colonic tissue. Administration of DMW alone (i.e. without AOM) resulted in changes in the composition of the gut microbiota, leading to enrichment or depletion of genera associated with health and disease, respectively. DMW was also able to restore AOM-induced changes in specific genera of the gut microbiota. Specifically, DMW reduced the genera Atopobiaceae, Ruminococcus 1 and Lachnospiraceae XPB1014 and increased the genera Parabacteroides and Candidatus Saccharimonas, which were increased and reduced, respectively, by AOM. Blood levels of butyric acid and cancer diagnostic markers (5-methylcytidine and glycerophosphocholine), which were increased by AOM treatment, were reduced by DMW. Furthermore, DMW exerted cytotoxic effects on two human CRC cell lines (HCT116 and HT29) and these effects were associated with the induction of apoptotic signaling.
CONCLUSIONS
Our results suggest that DMW exerts chemopreventive effects and restores the gut microbiota in AOM-induced CRC, and induces cytotoxic effect on CRC cells. DMW could be an important dietary supplement to support a healthy gut microbiota and reduce the prevalence of CRC in humans. Video Abstract.
Topics: Humans; Animals; Mice; Whey; Buffaloes; Milk; Carcinogenesis; Colorectal Neoplasms; Azoxymethane; Butyric Acid
PubMed: 37730576
DOI: 10.1186/s12964-023-01271-5 -
Autophagy Feb 2024A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1,... (Review)
Review
A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1, autophagy related; CAC: colitis-associated colon cancer; CCDC50: coiled-coil domain containing 50; CLDN2: claudin 2; CoPEC: colibactin-producing Escherichia coli; CRC: colorectal cancer; DAMPs: danger/damage-associated molecular patterns; DC: dendritic cell; DSS: dextran sulfate sodium; DTP: drug-resistant persistent; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IKK: IkappaB kinase; IL: interleukin; IRGM1: immunity-related GTPase family M member 1; ISC: intestinal stem cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; MELK: maternal embryonic leucine zipper kinase; MHC: major histocompatibility complex; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NRBF2: nuclear receptor binding factor 2; PAMPs: pathogen-associated molecular patterns; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PYCARD/ASC: PYD and CARD domain containing; RALGAPA2/RalGAPα2: Ral GTPase activating protein protein, alpha subunit 2 (catalytic); RIPK2/CARD3: receptor (TNFRSF)-interacting serine-threonine kinase 2; RIPK3: receptor-interacting serine-threonine kinase 3; ROS: reactive oxygen species; sCRC: sporadic colorectal cancer; SMARCA4/BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TNF/TNFA: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; WT: wild-type.
Topics: Humans; Autophagy; Phosphatidylinositol 3-Kinases; Endoribonucleases; Colitis-Associated Neoplasms; Protein Serine-Threonine Kinases; Inflammatory Bowel Diseases; Escherichia coli; DNA Helicases; Nuclear Proteins; Transcription Factors; GTPase-Activating Proteins
PubMed: 37723664
DOI: 10.1080/15548627.2023.2259214 -
Gastroenterology Dec 2023Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect...
BACKGROUND & AIMS
Pien Tze Huang (PZH) is a well-established traditional medicine with beneficial effects against inflammation and cancer. We aimed to explore the chemopreventive effect of PZH in colorectal cancer (CRC) through modulating gut microbiota.
METHODS
CRC mouse models were established by azoxymethane plus dextran sulfate sodium treatment or in Apc mice treated with or without PZH (270 mg/kg and 540 mg/kg). Gut barrier function was determined by means of intestinal permeability assays and transmission electron microscopy. Fecal microbiota and metabolites were analyzed by means of metagenomic sequencing and liquid chromatography mass spectrometry, respectively. Germ-free mice or antibiotic-treated mice were used as models of microbiota depletion.
RESULTS
PZH inhibited colorectal tumorigenesis in azoxymethane plus dextran sulfate sodium-treated mice and in Apc mice in a dose-dependent manner. PZH treatment altered the gut microbiota profile, with an increased abundance of probiotics Pseudobutyrivibrio xylanivorans and Eubacterium limosum, while pathogenic bacteria Aeromonas veronii, Campylobacter jejuni, Collinsella aerofaciens, and Peptoniphilus harei were depleted. In addition, PZH increased beneficial metabolites taurine and hypotaurine, bile acids, and unsaturated fatty acids, and significantly restored gut barrier function. Transcriptomic profiling revealed that PZH inhibited PI3K-Akt, interleukin-17, tumor necrosis factor, and cytokine-chemokine signaling. Notably, the chemopreventive effect of PZH involved both microbiota-dependent and -independent mechanisms. Fecal microbiota transplantation from PZH-treated mice to germ-free mice partly recapitulated the chemopreventive effects of PZH. PZH components ginsenoside-F2 and ginsenoside-Re demonstrated inhibitory effects on CRC cells and primary organoids, and PZH also inhibited tumorigenesis in azoxymethane plus dextran sulfate sodium-treated germ-free mice.
CONCLUSIONS
PZH manipulated gut microbiota and metabolites toward a more favorable profile, improved gut barrier function, and suppressed oncogenic and pro-inflammatory pathways, thereby suppressing colorectal carcinogenesis.
Topics: Mice; Animals; Signal Transduction; Gastrointestinal Microbiome; Dextran Sulfate; Phosphatidylinositol 3-Kinases; Apoptosis; Medicine, Traditional; Colorectal Neoplasms; Carcinogenesis; Azoxymethane
PubMed: 37704113
DOI: 10.1053/j.gastro.2023.08.052 -
Ga-FAPI-04 Positron Emission Tomography Distinguishes Malignancy From F-FDG-Avid Colorectal Lesions.International Journal of Radiation... Jan 2024Lesions with a high uptake of F-fluorodeoxyglucose (F-FDG) on positron emission tomography-computed tomography (PET-CT) can be benign and malignant. New radiotracers,...
PURPOSE
Lesions with a high uptake of F-fluorodeoxyglucose (F-FDG) on positron emission tomography-computed tomography (PET-CT) can be benign and malignant. New radiotracers, such as the gallium 68 (Ga)-labeled fibroblast activation protein inhibitor 4 (FAPI-04), could be used to diagnose colorectal carcinoma. This study aimed to evaluate the efficacy of Ga-FAPI-04 PET in differentiating benign from malignant F-FDG-avid colorectal lesions.
METHODS AND MATERIALS
An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced rat colorectal tumor model was developed. Double-tracer Ga-FAPI-04 and F-FDG PET-CT were applied in the rat model and 22 patients. The PET-CT data were analyzed with enteroscopy, histopathologic observations, immunohistochemistry (IHC) staining, and radioautography results. One hundred seventy-two patients with pathologically confirmed colorectal lesions were enrolled in FAP IHC staining.
RESULTS
We found that Ga-FAPI-04 PET-CT imaging accurately distinguished the malignant from benign inflammatory lesions in an AOM/DSS-induced rat colorectal tumor model. Of 22 patients with gastric cancer but without colorectal carcinoma, 8 had F-FDG uptake in the colorectum, but Ga-FAPI-04 PET was negative in these sites. An inflammatory lesion or adenoma did not interfere with Ga-FAPI-04 PET imaging. Among the F-FDG-avid colorectal lesions, 80 of 94 pathologically malignant lesions (85.1%) were FAP-positive, and only 16 of the 78 premalignant or benign lesions (20.5%) had a weak Ga-FAPI-04 uptake.
CONCLUSIONS
Ga-FAPI-04 PET-CT could be used to distinguish between benign and malignant F-FDG-avid colorectal lesions.
Topics: Humans; Animals; Rats; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes; Positron-Emission Tomography; Quinolines; Colorectal Neoplasms; Azoxymethane
PubMed: 37634891
DOI: 10.1016/j.ijrobp.2023.08.019 -
Pharmacological Research Sep 2023Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated colorectal cancer (CAC) with poor prognosis. IBD etiology remains...
BACKGROUND
Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated colorectal cancer (CAC) with poor prognosis. IBD etiology remains undefined but involves environmental factors, genetic predisposition, microbiota imbalance (dysbiosis) and mucosal immune defects. Mesenchymal stromal cell (MSC) injections have shown good efficacy in reducing intestinal inflammation in animal and human studies. However, their effect on tumor growth in CAC and their capacity to restore gut dysbiosis are not clear.
METHODS
The outcome of systemic administrations of in vitro expanded human intestinal MSCs (iMSCs) on tumor growth in vivo was evaluated using the AOM/DSS model of CAC in C57BL/6J mice. Innate and adaptive immune responses in blood, mesenteric lymph nodes (MLNs) and colonic tissue were analyzed by flow cytometry. Intestinal microbiota composition was evaluated by 16S rRNA amplicon sequencing.
RESULTS
iMSCs significantly inhibited colitis and intestinal tumor development, reducing IL-6 and COX-2 expression, and IL-6/STAT3 and PI3K/Akt signaling. iMSCs decreased colonic immune cell infiltration, and partly restored intestinal monocyte homing and differentiation. iMSC administration increased the numbers of Tregs and IFN-γCD8 T cells in the MLNs while decreasing the IL-4Th2 response. It also ameliorated intestinal dysbiosis in CAC mice, increasing diversity and Bacillota/Bacteroidota ratio, as well as Akkermansia abundance, while reducing Alistipes and Turicibacter, genera associated with inflammation.
CONCLUSION
Administration of iMSCs protects against CAC, ameliorating colitis and partially reverting intestinal dysbiosis, supporting the use of MSCs for the treatment of IBD.
Topics: Humans; Mice; Animals; Colitis-Associated Neoplasms; Interleukin-6; Mice, Inbred C57BL; Dysbiosis; CD8-Positive T-Lymphocytes; RNA, Ribosomal, 16S; Phosphatidylinositol 3-Kinases; Colitis; Inflammation; Colon; Inflammatory Bowel Diseases; Immunity; Mesenchymal Stem Cells; Dextran Sulfate; Disease Models, Animal
PubMed: 37586618
DOI: 10.1016/j.phrs.2023.106891 -
Heliyon Aug 2023This research aims to identify the effects of the administration of a black rice bran diet on colorectal cancer in dextran sodium sulfate and azoxymethane-induced BALB/c...
This research aims to identify the effects of the administration of a black rice bran diet on colorectal cancer in dextran sodium sulfate and azoxymethane-induced BALB/c mice. The research was conducted on three groups consisting of eight Balb/c mice: two groups were fed with carcinogens, and the third group, referred to as the normal group, was supplied with Isotonic NaCl 0.9% intraperitoneally. One group fed with carcinogens was supplied a standard AIN 1993 M diet modified with black rice bran as a substitute of fibre source, while the other two mice groups were fed the standard diet (AIN-93M) containing cellulose fibre. At the 17th week, all mice were euthanized; their colonic sections were taken for histopathological evaluation, and cecum for short-chain fatty acids concentration, total lactic acid bacteria, pH and β-glucuronidase activity evaluations. The results show an increase in the total lactic acid bacteria and short-chain fatty acids in the mice group fed with rice bran. Consequently, pH value and β-glucuronidase activity had decreased. Histopathological evaluation of mucosal tissue exhibited inhibition of the tumor growth rate in the mice groups fed rice bran compared to the group supplied with the standard diet. Furthermore, the proliferating cell nuclear antigen expression had decreased significantly, while expression of caspase-8 and caspase-3 had increased notably, in the group fed with a rice bran diet. These results suggest that black rice bran can effectively inhibit colon carcinogenesis. The potential of black rice bran as a source of fibre has not been studied in detail regarding the inhibition mechanism of colorectal cancer cells; further investigation in this field could provide valuable information about new strategies to prevent colorectal cancer. This strand of research is very important to developing preventive methods against cancer and promoting the concept of healthy products, including functional foods.
PubMed: 37576300
DOI: 10.1016/j.heliyon.2023.e18528