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Acta Neuropathologica Communications Feb 2024
Topics: Humans; Mutagens; Guam; Methylazoxymethanol Acetate; Mutagenesis; Amyotrophic Lateral Sclerosis
PubMed: 38383591
DOI: 10.1186/s40478-024-01725-y -
Journal of Ethnopharmacology Jun 2024Colitis is an important risk factor for the occurrence of colorectal cancer (CRC), and the colonization of Fusobacterium nucleatum (Fn) in the intestines accelerates...
ETHNOPHARMACOLOGICAL RELEVANCE
Colitis is an important risk factor for the occurrence of colorectal cancer (CRC), and the colonization of Fusobacterium nucleatum (Fn) in the intestines accelerates this transformation process. Banxia Xiexin Decoction (BXD), originating from Shanghanlun, is a classic prescription for treating gastrointestinal diseases. Current researches indicate that BXD can effectively delay the colitis-to-cancer transition, but it is still unclear whether it can inhibit Fn colonization to achieve this delaying effect.
AIM OF STUDY
This study explored the effect and mechanism of BXD in inhibiting Fn intestinal colonization to delay colitis-to-cancer transition.
MATERIALS AND METHODS
We constructed a mouse model of colitis-to-cancer transition by regularly gavaging Fn combined with azoxymethane (AOM)/dextran sodium sulfate (DSS), and administered BXD by gavage. We monitored the body weight of mice, measured the length and weight of their colons, and calculated the disease activity index (DAI) score. The growth status of colon tumors was observed by hematoxylin and eosin (H&E) staining, and the changes in gut microbiota in each group of mice were detected by 16S rDNA analysis. Immunohistochemistry was used to detect the expression of E-cadherin and β-catenin in colon tissues, and immunofluorescence was used to observe the infiltration of M2 macrophages in colon tissues. In cell experiments, we established a co-culture model of Fn and colon cancer cells and intervened with BXD-containing serum. Malignant behaviors such as cell proliferation, invasion, and migration were detected, as well as changes in their cell cycle. We examined the protein levels of E-cadherin, β-catenin, Axin2, and Cyclin D1 in each group were detected by Western blot. We used US1 strain (fadA-) as a control and observed the effects of BXD-containing serum on Fn attachment and invasion of colon cancer cells through attachment and invasion experiments.
RESULTS
BXD can inhibit the colitis-to-cancer transition in mice infected with Fn, reduce crypt structure damage, improve gut microbiota dysbiosis, upregulate E-cadherin and decrease β-catenin expression, and reduce infiltration of M2 macrophages, thus inhibiting the process of colitis-to-cancer transition. Cell experiments revealed that BXD-containing serum can inhibit the proliferation, migration, and invasion of colon cancer cells infected with Fn and regulate their cell cycle. More importantly, we found that BXD-containing serum can inhibit the binding of Fn's FadA adhesin to E-cadherin, reduce Fn's attachment and invasion of colon cancer cells, thereby downregulating the E-cadherin/β-catenin signaling pathway.
CONCLUSIONS
These findings show that BXD can inhibit Fn colonization by interfering with the binding of FadA to E-cadherin, reducing the activation of the E-cadherin/β-catenin signaling pathway, and ultimately delaying colitis-to-cancer transition.
Topics: Animals; Mice; beta Catenin; Fusobacterium nucleatum; Signal Transduction; Colitis; Cadherins; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Colon; Drugs, Chinese Herbal
PubMed: 38382652
DOI: 10.1016/j.jep.2024.117932 -
Heliyon Feb 2024Natural killer (NK) cells constitute an active and potent anti-tumor effector population against multiple malignancies. NK cells exploit tumoricidal machinery to...
Natural killer (NK) cells constitute an active and potent anti-tumor effector population against multiple malignancies. NK cells exploit tumoricidal machinery to restrain colorectal carcinoma (CRC) expansion and invasion. Nonetheless, it is becoming increasingly evident that functional exhaustion considerably compromises the potency of NK cells in patients with CRC. To elucidate the factors that impair NK cell function in the context of CRC, we determined the role of zinc finger protein 335 (ZFP335) in modulating NK cell activity in mouse CRC induced by azoxymethane and dextran sulfate sodium. ZFP335 was profoundly decreased in NK cells in mesenteric lymph nodes of CRC-bearing mice. ZFP335 was especially diminished in NK cells that were both phenotypically and functionally exhausted. Besides, effective ZFP335 knockdown markedly undermined NK cell proliferation, tumoricidal protein production, degranulation, and cytotoxic efficacy on malignant cells, strongly suggesting that ZFP335 reinforces NK cell function. Importantly, ZFP335 knockdown lowered the expression of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), both of which play crucial roles in NK cell homeostasis and activation. Collectively, ZFP335 down-regulation is essential for NK cell exhaustion in mesenteric lymph nodes of mice with CRC. We discovered a new ZFP335-JAK1/3 signaling pathway that modulates NK cell exhaustion.
PubMed: 38375265
DOI: 10.1016/j.heliyon.2024.e25721 -
Frontiers in Oncology 2023The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R)...
INTRODUCTION
The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC.
METHODS
In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, ), and mice harboring a Treg cell-specific deletion of IL-23 ( ). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings.
RESULTS
In CAC, mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model, mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4 T cells. The decreased tumor size in mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4 T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.
CONCLUSION
Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells.
PubMed: 38375204
DOI: 10.3389/fonc.2023.1276743 -
Journal of Translational Medicine Feb 2024Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression...
BACKGROUND
Adenomatous polyps (APs) with inflammation are risk factors for colorectal cancer. However, the role of inflammation-related gut microbiota in promoting the progression of APs is unknown.
METHODS
Sequencing of the 16S rRNA gene was conducted to identify characteristic bacteria in AP tissues and normal mucosa. Then, the roles of inflammation-related bacteria were clarified by Spearman correlation analysis. Furthermore, colorectal HT-29 cells, normal colon NCM460 cells, and azoxymethane-treated mice were used to investigate the effects of the characteristic bacteria on progression of APs.
RESULTS
The expression levels of inflammation-related markers (diamine oxidase, D-lactate, C-reactive protein, tumor necrosis factor-α, interleukin-6 and interleukin-1β) were increased, whereas the expression levels of anti-inflammatory factors (interleukin-4 and interleukin-10) were significantly decreased in AP patients as compared to healthy controls. Solobacterium moorei (S. moorei) was enriched in AP tissues and fecal samples, and significantly positively correlated with serum inflammation-related markers. In vitro, S. moorei preferentially attached to HT-29 cells and stimulated cell proliferation and production of pro-inflammatory factors. In vivo, the incidence of intestinal dysplasia was significantly increased in the S. moorei group. Gavage of mice with S. moorei upregulated production of pro-inflammatory factors, suppressed proliferation of CD4 and CD8cells, and disrupted the integrity of the intestinal barrier, thereby accelerating progression of APs.
CONCLUSIONS
S. moorei accelerated the progression of AP in mice via activation of the NF-κB signaling pathway, chronic low-grade inflammation, and intestinal barrier disruption. Targeted reduction of S. moorei presents a potential strategy to prevent the progression of APs.
Topics: Humans; Animals; Mice; RNA, Ribosomal, 16S; Firmicutes; Inflammation; Adenomatous Polyps
PubMed: 38368407
DOI: 10.1186/s12967-024-04977-3 -
Scientific Reports Feb 2024This study investigated the sex-specific correlation between obesity and colorectal cancer emphasizing a more pronounced association in males. Estrogen, chromosomal...
This study investigated the sex-specific correlation between obesity and colorectal cancer emphasizing a more pronounced association in males. Estrogen, chromosomal genes, and gut bacteria were assessed in C57BL6/J male, female and ovariectomized (OVX) female mice, subjected to either a low-fat diet (LFD) or high-fat diet (HFD) for 14 weeks. Induction of colon tumor involved azoxymethane (10 mg/kg) administration, followed by three cycles of dextran sulfate sodium. Male mice on HFD exhibited higher final body weight and increased colon tumors compared to females. Colonic mucin 2 expression was significantly higher in females. HFD-modulated differentially expressed genes numbered 290 for males, 64 for females, and 137 for OVX females. Only one up-regulated gene (Gfra3) overlapped between females and OVX females, while two down-regulated genes (Thrsp and Gbp11) overlapped between males and OVX females. Genes up-regulated by HFD in males were linked to cytokine-cytokine interaction, HIF-1 signaling pathway, central carbon metabolism in cancer. Sex-specific changes in gut microbial composition in response to HFD were observed. These findings suggest a male-specific vulnerability to HFD-induced colon tumor formation, implicating key genes and colonic bacteria in colon tumorigenesis.
Topics: Female; Male; Animals; Mice; Sex Characteristics; Obesity; Colonic Neoplasms; Diet, High-Fat; Cytokines; Microbiota; Gene Expression; Mice, Inbred C57BL
PubMed: 38347027
DOI: 10.1038/s41598-024-53861-z -
Cancers Jan 2024Colorectal cancer (CRC) is the third most common neoplasia in the world. Its mortality rate is high due to the lack of specific and effective treatments, metastasis, and...
Colorectal cancer (CRC) is the third most common neoplasia in the world. Its mortality rate is high due to the lack of specific and effective treatments, metastasis, and resistance to chemotherapy, among other factors. The natural products in cancer are a primary source of bioactive molecules. In this research, we evaluated the antitumor activity of an acetogenin (ACG), laherradurin (LH), isolated from the Mexican medicinal plant Donn.Sm. in a CRC murine model. The CRC was induced by azoxymethane-dextran sulfate sodium (AOM/DSS) in Balb/c mice and treated for 21 days with LH or cisplatin. This study shows for the first time the antitumor activity of LH in an AOM/DSS CRC model. The acetogenin diminished the number and size of tumors compared with cisplatin; the histologic studies revealed a recovery of the colon tissue, and the blood toxicity data pointed to less damage in animals treated with LH. The TUNEL assay indicated cell death by apoptosis, and the in vitro studies exhibited that LH inhibited cell migration in HCT116 cells. Our study provides strong evidence of a possible anticancer agent for CRC.
PubMed: 38339324
DOI: 10.3390/cancers16030573 -
Probiotics and Antimicrobial Proteins Feb 2024Colorectal cancer is the third most common cancer in the world today, and studies have shown that the ratio of Candida to Saccharomyces cerevisiae increased, and the...
Colorectal cancer is the third most common cancer in the world today, and studies have shown that the ratio of Candida to Saccharomyces cerevisiae increased, and the abundance of S. cerevisiae in the intestines of patients with colorectal cancer decreased, which suggests that there is an imbalance in the proportion of fungi in the intestines of patients with colorectal cancer. The objective of this study was to screen S. cerevisiae isolate from traditional Chinese fermentation starters and assess its ability to ameliorate dysbiosis and to alleviate the carcinogenic process of azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice model. S. cerevisiae strain SC-2201 was isolated and exhibited probiotic properties, including the ability to survive in an acidic pH environment and in the presence of bile salts in the gastrointestinal tract, as well as antioxidant activities. Oral administration of S. cerevisiae SC-2201 not only alleviated weight loss but also reduced colonic shortening and histological damage in azoxymethane/dextran sodium sulfate-induced colorectal cancer in mice. Furthermore, the administration of S. cerevisiae SC-2201 suppressed the expression of proinflammatory mediators, such as interleukin-1β, interleukin-6, cyclooxygenase-2, vascular endothelial growth factor, nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3. Specifically, the analysis of gut bacteriome showed a significant decrease in Bacteroidota and Campylobacterota levels, as well as an increase in Proteobacteria level in the colorectal cancer group, which was alleviated by supplementation with S. cerevisiae SC-2201. The analysis of the mycobiome revealed a significant increase in the levels of Basidiomycota, Apiosordaria, Naganishia, and Taphrina genera in the colorectal cancer group, which were alleviated after supplementation with S. cerevisiae SC-2201. However, the levels of Xenoramularia, Entoloma, and Keissleriella were significantly increased after administration with S. cerevisiae SC-2201. Overall, the findings of this study demonstrate that S. cerevisiae SC-2201 possesses potential probiotic properties and can effectively attenuate the development of colorectal cancer, highlighting its cancer-preventive potential. This is the first report of a S. cerevisiae strain isolated from traditional Chinese fermentation starters which showed good probiotic properties, and mitigated azoxymethane/dextran sodium sulfate-induced colorectal cancer by modulating the gut microbiome and blocking proinflammatory mediators in mice.
PubMed: 38329696
DOI: 10.1007/s12602-024-10228-0 -
Heliyon Jan 2024Metastasis is the major problem of colorectal cancer (CRC) and is correlated with the high mortality. Tumor necrosis factor-like cytokine 1A (TL1A) is a novel regulatory...
BACKGROUND
Metastasis is the major problem of colorectal cancer (CRC) and is correlated with the high mortality. Tumor necrosis factor-like cytokine 1A (TL1A) is a novel regulatory factor for inflammatory diseases. This work aimed to investigate the role of TL1A in CRC metastasis.
METHOD
AOM/DSS-induced mouse model, xenograft tumor model and metastasis murine model were established to mimic the colitis-associated CRC and investigate CRC growth and metastasis . Colon tissues were assessed by hematoxylin/eosin (HE) staining and immunohistochemistry (IHC). CRC cell metastasis was observed using imaging system (IVIS). Cell viability and proliferation were examined using cell counting kit 8 (CCK-8) and EdU experiments. The expression of tumor growth factor β (TGFβ) and metastatic biomarkers were detected using western blotting experiment. The cell metastasis was measured by Transwell.
RESULTS
Knockdown of TL1A notably suppressed the generation of colonic tumors in azoxymethane/dextran sodium sulfate (AOM/DSS) model, suppressed CRC cell growth, as well as lung and liver metastasis. The inflammation response and inflammatory cell infiltration in tumor sites were decreased by TL1A depletion. The CRC cell growth and metastasis was also suppressed by shTL1A, along with altered expression of epithelial mesenchymal transition (EMT) biomarkers. TL1A depletion suppressed the level of the TGF-β1 receptor (TβRI) and phosphorylation of Smad3 in CRC cells. Stimulation with TGF-β recovered the CRC cell migration and invasion that suppressed by shTL1A.
CONCLUSION
Our work implicated TL1A as a promoter of CRC generation and metastasis and defines TGF-β/Smad3 signaling as mediator of TL1A-regualated CRC cell metastasis.
PubMed: 38312710
DOI: 10.1016/j.heliyon.2024.e24392 -
Phytomedicine : International Journal... Mar 2024Osthole is active constituent of Cnidium monnieri (L.) Cuss. with various physiological functions including anti-inflammation and anti-lipedemic effects. However, the...
BACKGROUND
Osthole is active constituent of Cnidium monnieri (L.) Cuss. with various physiological functions including anti-inflammation and anti-lipedemic effects. However, the regulatory activity of osthole in colorectal cancer development, focusing on mitochondrial metabolism, is not well known.
HYPOTHESIS/PURPOSE
We hypothesized that osthole may suppress progression of colorectal cancer and aimed to determine the underlying mitochondrial metabolism and the autophagic flux.
STUDY DESIGN
In this study, we elucidated the mechanism of action of osthole in colorectal cancer using an in vivo azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model and an in vitro cell culture system.
METHODS
AOM/DSS mouse model was established and analyzed the effects of osthole on survival rate, diseases activity index, number of tumor and histopathology. Then, cell based assays including viability, cell cycle, reactive oxygen species (ROS), apoptosis, calcium efflux, and mitochondrial function were analyzed. Moreover, osthole-mediated signaling was demonstrated by western blot analyses.
RESULTS
Osthole effectively suppressed the growth of colorectal tumors and alleviated AOM/DSS-induced intestinal injury. Osthole restored the function of goblet cells and impaired the expression of Claudin1 and Axin1 impaired by AOM/DSS. In addition, osthole specifically showed cytotoxicity in colorectal carcinoma cells, but not in normal colon cells. Osthole decreased the ASC/caspase-1/IL-1β inflammasome pathway and induced mitochondrial dysfunction in redox homeostasis, calcium homeostasis. Furthermore, osthole inhibited both oxidative phosphorylation (OXPHOS) and glycolysis, leading to the suppression of ATP production. Moreover, via combination treatment with chloroquine (CQ), we demonstrated that osthole impaired autophagic flux, leading to apoptosis of HCT116 and HT29 cells. Finally, we elucidated that the functional role of tiRNA regulated by osthole directly affects the cellular fate of colon cancer cells.
CONCLUSION
These results suggest that osthole has the potential to manage progression of colorectal cancer by regulating autophagy- and mitochondria-mediated signal transduction.
Topics: Mice; Animals; Calcium; Mitochondria; Colorectal Neoplasms; Azoxymethane; Autophagy; Dextran Sulfate; Coumarins
PubMed: 38295666
DOI: 10.1016/j.phymed.2024.155383