Human Colon Mucosal Epithelial Cells Research Articles

Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies

Considering the important increase in the incidence and mortality of colorectal cancer, it is necessary to develop new strategies in the search for new alternatives against this disease. Hence, we designed and synthesized a new series of monastrol/melatonin hybrids and evaluated them in vitro and in silico to determine the potential of these new chemical entities on this type of cancer. To achieve this goal, the different compounds were evaluated in human colorectal adenocarcinoma cells SW480, while establishing the selective potential of the hybrids through the nonmalignant human colon mucosal epithelial cell line (NCM460). According to the results, hybrids 6a, 6c, 6i, and 6j displayed the best response, with IC50 values in the range of 5.2 and 6.3 μM, inducing important changes depending on concentration and time. In addition, these compounds were extremely active in comparison to the single molecules, and they were slightly more selective than the reference drug (5 fluorouracil, 5-FU). Besides, an optimal pharmacokinetic and toxicological profile was also estimated for hybrids 6a, 6c, 6i, and 6j. Altogether, novel hybrids of monastrol-MLT, in particular, 6a (-H), 6c (3-OMe), 6i (3,4-OMe), and 6j (3,5-OMe) could be addressed as starting points for further pharmacological studies concerning to combat colorectal cancer.

Combination of Selenite and Butyrate Enhances Efficacy Against Colon Cancer by Targeting ASCT2-Mediated Amino Acid Metabolism.

Drug combination is considered to be an effective approach to improve the efficacy of cancer therapy and chemoprevention. Selenite, a representative of inorganic form of selenium, and butyrate, a major short-chain fatty acid, are two well-documented colon cancer dietary chemopreventive agents with distinct molecular mechanisms. We hypothesized that combination of selenite and butyrate might produce improved outcome against colon cancer. This hypothesis was tested using both HCT116 human colon cancer cells and its xenograft mouse model in the present study. The in vitro study showed a synergistically inhibitory effect on HCT116 colon cancer cells but not on NCM460 normal human colon mucosal epithelial cells. Consistent with the in vitro study, results of the xenograft mouse model further demonstrated that combination of selenite and butyrate led to improved efficacy in comparison with each agent alone. Mechanistically, the induction of alanine-serine-cysteine transporter 2 (ASCT2) by selenite repressed its inhibitory effect on colon cancer cells, which was reversed by its co-treatment with butyrate. The findings of the present study denote the likely potential for developing selenite/butyrate combination remedy to combat against colon cancer.

Jaceosidin inhibits NLRP3-mediated pyroptosis by activating SIRT1/NRF2 and ameliorating intestinal epithelial cell injury

Purpose: To investigate the effect of Jaceosidin in ulcerative colitis (UC).Methods: An ulcerative colitis cell model was established by stimulating normal human colon mucosal epithelial cell lines (NCM460 cells) with lipopolysaccharide (LPS). The cells were treated with 5, 10, 20 or 40 μM Jaceosidin. Cell viability was performed using cell counting kit 8 (CCK8) assay. Oxidative stress was measured with superoxide dismutase (SOD), lipid peroxidation MDA, reduced glutathione (GSH), oxidized glutathione (GSSG), and human myeloperoxidase enzyme-linked immunoassay (ELISA) kits. The mRNA levels were determined by quantitative polymerase chain reaction (qPCR) assay, while protein levels of SIRT1, NRF2, NLRP3, caspase-1, TNF-α, IL-1β, and IL-6 were determined by western blotting.Results: Jaceosidin significantly inhibited oxidative stress and accumulation of inflammatory cytokines in LPS-induced NCM460 cells, as well as NLRP3-mediated cell pyroptosis (p < 0.05). Jaceosidin also inhibited activation of NLRP3 inflammasome by activating SIRT1/NRF2 pathway, thereby preventing NCM460 cell pyroptosis.Conclusion: Jaceosidin inhibits NLRP3-mediated pyroptosis, thus suggesting that jaceosidin is a potential lead for UC secondary to NLRP3 inflammasome.

Optimization of parameters for stir-frying of Kansui Radix with vinegar based on conversion of toxic components

This study aims to optimize the parameters for stir-frying of Kansui Radix with vinegar based on the conversion of representative toxic diterpenes, which is expected to serve as a reference for the standardized production of Kansui Radix stir-fried with vinegar. To be specific, the toxic components [3-O-(2'E,4'Z-decadienoyl)-20-O-acetylingenol(3-O-EZ), kansuiphorin C(KPC)] in Kansui Radix and the products(ingenol, 20-deoxyingenol) after the stir-frying with vinegar were selected. The toxicity to intestine and water-draining activity were evaluated with NCM460(normal human colon mucosal epithelial cell line) and HT-29(a human colorectal adenocarcinoma cell line). An HPLC method was then developed to assess the conversion of toxic components. On this basis, temperature, time, and amount of vinegar for the processing of Kansui Radix were optimized with the Box-Behnken design and the content of ingenol and 20-deoxyingenol as evaluation index. The results showed that after the stir-frying of Kansui Radix with vinegar, 3-O-EZ and KPC were first converted to monoester 3-O-(2'E,4'Z-decadienoyl)ingenol(3-EZ) and 5-O-benzoyl-20-deoxyingenol(5-O-Ben) and finally to almost non-toxic ingenol and 20-deoxyingenol, respectively. Meanwhile, the water-draining activity was retained. Six compounds had a good linear relationship with the peak area in the corresponding concentration ranges(R~2≥0.999 8), and the average recovery fell in the range of 98.20%-102.3%(RSD≤2.4%). The content of representative diterpenes and intermediate products was 14.78%-24.67% lower in the Kansui Radix stir-fried with vinegar than in the Kansui Radix, while the content of the conversed products was 14.37%-71.37% higher. Among the process parameters, temperature had significant influence on the total content of products, followed by time. The optimal parameters were 210 ℃, 15 min, and 30% vinegar. The relative error between the experimental results and the predicted values was 1.68%, indicating that the process was stable and reproducible. The strategy of screening optimal parameters for stir-frying of Kansui Radix with vinegar based on the transformation of toxic components can help improve the production stability, reduce the toxicity, and ensure the efficacy of Kansui Radix stir-fried with vinegar, which can serve as a reference for the process optimization of similar toxic Chinese medicinals.

Preparation of Stereo-Divergent Compounds from the Natural Product Drupacine Based on Complexity-to-Diversity Strategy.

The Complexity-to-Diversity (CtD) strategy was applied to synthesize a 23-member compound collection from the natural product drupacine, including 21 novel compounds. An unusual benzo [d] cyclopenta [b] azepin skeleton was constructed by Von Braun reaction to cleave C-N bond of drupacine. Moreover, compound 10 has potential cytotoxicity to human colon cancer cells with low toxicity to the normal human colon mucosal epithelial cell lines.

A novel senescence-associated LncRNA signature predicts the prognosis and tumor microenvironment of patients with colorectal cancer: a bioinformatics analysis

BackgroundAccumulating evidence suggests that cellular senescence promotes tumor formation and that long non-coding RNAs (lncRNAs) expression predicts tumor prognosis. However, senescence-related variables, particularly lncRNAs, are still largely unknown. Therefore, the present study developed a novel senescence-associated lncRNA signature to predict colorectal cancer (CRC) prognosis.MethodsA co-expression network of senescence-associated mRNAs and lncRNAs was built using RNA-sequence data from The Cancer Genome Atlas (TCGA). By using the prognosis outcomes data of overall survival (OS) and disease-free survival (DFS) from TCGA, we constructed a prognostic senescence-associated lncRNA signature (SenALSig). The OS and DFS were compared between the low- and high- risk groups defined by SenALSig. A single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithm were used to investigate the relationship between the predictive signature and immune status. Finally, the relationship between SenALSig and drug treatment options was investigated. An independent CRC cohort and three CRC cell lines were recruited to perform real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis to validate the results discovered in silico.ResultsA prognostic risk model consisting of six senescence-associated lncRNAs was constructed, including SNHG16, AL590483.1, ZEB1-AS1, AC107375.1, AC068580.3, and AC147067.1. High-risk scores according to the SenALSig were significantly associated with poor OS (hazard ratio =1.218, 95% confidence interval: 1.140–1.301; P<0.001). The model’s accuracy was further supported by receiver operating characteristic (ROC) curves (the area under the curve is 0.714) and a principal component analysis (PCA). In univariate and multivariate Cox regression analyses, SenALSig was further found to be a prognostic factor independent of other clinical factors. Furthermore, we discovered that immune checkpoint expression and response to chemotherapy and targeted therapy differed significantly between the SenALSig-stratified high- and low-risk groups. Finally, the qPCR results revealed that the expression levels of the six senescence-associated lncRNAs differed significantly between tumor and normal tissues and between the CRC cell lines and a normal human colon mucosal epithelial cell line.ConclusionsSenALSig can better predict survival and risk in CRC patients, as well as help develop new anti-cancer treatment strategies for CRC.

Development of Strigolactones as Novel Autophagy/Mitophagy Inhibitors against Colorectal Cancer Cells by Blocking the Autophagosome-Lysosome Fusion.

Inhibition of autophagy has been widely viewed as a promising strategy for anticancer therapy. However, few effective and specific autophagy inhibitors have been reported. Herein, we described the design, synthesis, and biological characteristics of new analogues of strigolactones (SLs), an emerging class of plant hormones, against colorectal cancers. Among them, an enantiopure analogue 6 exerted potent and selective cytotoxicity against colorectal cancer cells, but not normal human colon mucosal epithelial cells, which were further confirmed by the plate colony formation assay. Moreover, it significantly inhibited tumor growth in an HCT116 xenograft mouse model with low toxicity. Mechanistically, it is associated with selective induction of cell apoptosis and cell cycle arrest. Remarkably, 6 acted as a potent autophagy/mitophagy inhibitor by selectively increasing the autophagic flux while blocking the autophagosome-lysosome fusion in HCT116 cells. This study features stereo-defined SLs as novel autophagy inhibitors with high cancer cell specificity, which paves a new path for anticolorectal cancer therapy.

COL11A1 is Downregulated by miR-339-5p and Promotes Colon Carcinoma Progression.

The roles of COL11A1 in cancer have been increasingly considered, but the understandings of the effects of COL11A1 on colon carcinoma progress are much limited yet. qRT-PCR and Western blot were utilized to evaluate COL11A1 expression at mRNA and protein levels, respectively, in colon carcinoma cell lines. Afterward, the tumorigenesis biological effects of COL11A1 were examined by CCK-8, colony formation, Transwell, and wound healing methods. Moreover, upstream miRNAs containing the binding sites with COL11A1 were predicted by the bioinformatics methods. The interplay between COL11A1 and miR-339-5p was identified by a dual-luciferase assay. COL11A1 expression was prominently upregulated in colon carcinoma cell lines relative to that in normal human colon mucosal epithelial cell lines, and it was related to tumor stages. The outcomes of in-vitro experiments suggested that interfering with COL11A1 remarkably repressed the malignant behaviors of SW480 and SW620 cells. MiR-339-5p was markedly lowly expressed in colon carcinoma cell lines. Furthermore, miR-339-5p directly targeted and negatively regulated COL11A1 expression. COL11A1 upregulation promoted colon carcinoma cell functions, while overexpressing miR-339-5p evidently attenuated the promotion. These results proved the modulation of the miR-339-5p/COL11A1 axis in colon carcinoma cells, and miR-339-5p repressed colon carcinoma progression via COL11A1 downregulation. These results offer new underlying targets for the accurate therapy of colon carcinoma patients.

MiR-19a targeting CLCA4 to regulate the proliferation, migration, and invasion of colorectal cancer cells.

The role of miR-19a in colorectal cancer (CRC), a devastating disease with high mortality and morbidity, remains controversial. In the present study, we show that the level of miR-19a is significantly higher in clinical CRC tissue samples than in paracancerous tissue samples, and significantly higher in CRC cells lines HT29, SW480, and CaCO2 than in the normal human colon mucosal epithelial cell line NCM460. miR-19a mimics and inhibitors were synthesized and validated. Overexpression of miR-19a mimics significantly promoted, while miR-19a inhibitors inhibited, the proliferation, survival, migration, and invasion of SW480 and CaCO2 CRC cells. Furthermore, mRNA and protein levels of chloride channel accessory 4 (CLCA4) were lower in CRC cells and tissues. Bioinformatics and a luciferase reporter assay confirmed that CLCA4 was a miR-19a target. Further, miR-19a inhibition increased CLCA4 expression. The inhibitory effect of miR-19a on cell growth, survival, migration, and invasion was reversed by knockdown of CLCA4 expression. The data demonstrated that the miR-19a/CLCA4 axis modulates phospho-activation of the PI3K/AKT pathway in CRC cells. In conclusion, our results revealed that miR-19a overexpression decreases CLCA4 levels to promote CRC oncogenesis, suggesting that miR-19a inhibitors have potential applications for future therapeutic of CRC.

Anticancer Properties of Selenium-Enriched Oyster Culinary-Medicinal Mushroom, Pleurotus ostreatus (Agaricomycetes), in Colon Cancer In Vitro.

Mushrooms have become an important way to safely supply the body with the daily needs of organic selenium and they also possess remarkable medicinal properties. In this study, we examined the ability of the Pleurotus ostreatus mushroom to grow in selenium (Se) and its ability to accumulate and convert Se from inorganic form to organic form during growth. Additionally, we achieved the potential anticancer properties of mushroom extract in colon cancer cells using the CaCo-2 cell and the normal human colon mucosal epithelial cell line, NCM-460 cell line. Interestingly, Se-enriched mushroom extract (SME) showed a competitive regulation in colon cancer cell line; CaCo-2 cell line indicated by cell morphology, the number of survived cells, lactate dehydrogenase (LDH) production, and cell viability rate. Moreover, SME treatment regulates the expression profile of the cancer cell proliferation factor Raf-1 and pro-apoptotic related factors P53 and Caspase-3 Furthermore, the production of inflammatory-regulated cytokines, including interleukin 6 (IL-6) and IL-10, increased. At the same time, the level of produced tumor necrosis factor-alpha (TNF-α) markedly decreased in a dose and time-dependent of colon cancer-treated cells. Notably, the purified selenomethionine (SeMe) showed sufficient inhibition of colon cancer proliferation compared with the inorganic form of selenium (sodium selenite) via blocking the Raf/MEK/ERK signaling pathway. In addition, SeMe treatment also stimulated the production of IL-6 and IL-10 while decreasing the production of TNF-α, which plays a crucial role in the necrotic event. Meanwhile, the SeMe treatment showed a neglected cytotoxic effect in the normal colon epithelial cells. Collectively, these findings indicate that the fruiting bodies of Se-enriched mushrooms revealed anti-colon cancer activity via targeting Raf-1 signaling pathway and increasing the production of IL-6 and IL-10.

Bisphenol S exposure induces intestinal inflammation: An integrated metabolomic and transcriptomic study

As a typical substitute for bisphenol A (BPA), bisphenol S (BPS) is raising concerns due to the potential adverse effects on human health. Limit evidence is available to understand the toxicity of BPS to the digestive system, especially for intestine. In this study, we aimed to investigate the potential effects and underlying mechanisms of BPS exposure on human colon mucosal epithelial cells (NCM460). Our results showed that BPS exposure significantly increased the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-17A (IL-17A). The tight junctions of the cells has been destroyed by BPS exposure, which was characterized by a down-regulation of the tight junction proteins (Claudin1 and zonula occluden 1 (ZO1)). A multi-omics study explored the underlying mechanisms based on the metabolomic and transcriptomic responses. A variety of neurotransmitters increased significantly after exposure to BPS. The top enriched pathway was “glutamatergic synapse”, which was activated by BPS exposure, resulting in the up-regulation of l-glutamine. Links were observed among the altered metabolites, genes and cytokines. Our results indicate that exposure to BPS may disturb the balance of gut-brain axis, leading to the production of inflammatory cytokines and the destruction of tight junction in NCM460 cells. It provides new clue for the development of intestinal inflammation in terms of the environmental pollutants.

Systematic Analysis of the Clinical Significance of Hyaluronan-Mediated Motility Receptor in Colorectal Cancer.

Background: The role of hyaluronan-mediated motility receptor (HMMR) in colorectal cancer (CRC) remains unclear. The present study aimed to explore the association of HMMR with the development and prognosis of CRC using sequence datasets, clinical tissues, blood samples, and cell lines. Methods: CRC datasets were downloaded from TCGA and GEO databases. Forty CRC tissue samples, 120 CRC blood samples, and 100 healthy controls were collected. Four CRC cell lines (HCT116, HT-29, LoVo, and SW480) and one normal human colon mucosal epithelial cell line (NCM460) were cultured. RT-qPCR was used to determine the expression of HMMR in the tissues and cell lines. ELISA was used to measure HMMR levels in the blood samples. Results: The expression of HMMR was significantly increased in CRC tissues than in corresponding adjacent tissues based on TCGA and GEO datasets, and clinical CRC tissues. No associations were found between the expression of HMMR and the TNM stage or other clinical parameters. The expression of HMMR varied in different CRC cell lines. The blood levels of HMMR tended to be higher in patients with CRC than in healthy controls. TCGA and GEO datasets showed inconsistent results regarding the association of HMMR expression with the survival of patients with CRC. Conclusion: The expression of HMMR is increased in CRC tissues but not in the blood. The expression of HMMR is independent of CRC development and has no prognostic significance in patients with CRC.

Combined effects of berberine and evodiamine on colorectal cancer cells and cardiomyocytes in vitro

Chemotherapy induces inevitable adverse effects, while complementary and alternative medicine employs many chemical substances. Herb pairs normally contain two herbal medicines, and they have satisfactory effects on cancer therapy. Zuojinwan, a well-known herb pair, is composed of Coptidis Rhizoma and Euodiae Fructus. Berberine and evodiamine are considered the most important compounds in the Zuojinwan herb pair. Previous reports have shown that combined use of evodiamine and berberine displays synergistic anticancer activities in various types of cancers, but this combination has not been tested in colorectal cancer. Hence, this study aimed to explore the combined effects of evodiamine and berberine on colorectal cancer cell lines and cardiomyocytes. We found that the combination of berberine and evodiamine showed synergistic anticancer activity in P-glycoprotein (P-gp)-positive colorectal cancer cells through attenuating the overexpression of P-gp mRNA independent of cell cycle arrest and cell apoptosis. However, berberine did not increase the cytotoxicity of evodiamine in normal human colon mucosal epithelial cells. Furthermore, berberine attenuated evodiamine-induced cardiotoxicity by regulating extrinsic apoptosis via nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent and reactive oxygen species-independent pathways. Therefore, we suggest that the combination of berberine and evodiamine displays high anticancer activity while reducing the side effects in specific cell lines.

Long Non-Coding RNA STARD13-AS Suppresses Cell Proliferation And Metastasis In Colorectal Cancer.

BackgroundDysregulation of long non-coding RNAs (lncRNAs) is closely related with the progression of cancer in humans. The functional and regulatory roles of lncRNAs in colorectal cancer (CRC) are still largely unclear. The purpose of this study is to explore the function of lncRNA STARD13-AS in CRC.MethodsThe bioinformatics tool “GEPIA” was used to predict the potential expression of STARD13-AS in CRC. qRT-PCR was used to evaluate the relative expression level of STARD13-AS in CRC cells lines and tissues samples. The functional involvement of STARD13-AS in the CRC cells was assessed using MTT assay, flow cytometry, and Transwell assay. The expression levels of cyclin D, cyclin E, E-cadherin, N-cadherin, and vimentin were assessed using Western blot.ResultsBioinformatics prediction and qRT-PCR results showed that STARD13-AS expression was decreased in CRC tissues. Patients with low STARD13-AS expression exhibited distant and lymphatic metastasis as well as enhancement in tumor size. STARD13-AS expression was downregulated in CRC cell lines compared to normal human colon mucosal epithelial cell line NCM460 and STARD13-AS expression in SW620 and LoVo cell lines was lowest. Moreover, we observed that while STARD13-AS overexpression suppressed the cell cycle, proliferation, migration, and invasion, while promoted apoptosis both in LoVo and SW620 cells. In addition, STARD13-AS overexpression inhibited Cyclin E, Cyclin D, N-cadherin and vimentin expression, and promoted E-cadherin expression both in LoVo and SW620 cells.ConclusionExpression of STARD13-AS suppresses cell proliferation and metastasis in CRC, suggesting that STARD13-AS might act as a potential target for CRC treatment.

Regulatory effects of lncRNA ATB targeting miR-200c on proliferation and apoptosis of colorectal cancer cells.

This investigation was intended to elucidate whether long noncoding RNA (lncRNA)-activated by transforming growth factor-β (ATB) interacting with miR-200c could mediate colorectal cancer (CRC) progression, offering potential strategies for diagnosing and treating CRC. Here totally 315 patients with CRC were recruited, and their CRC tissues and adjacent normal tissues were gathered. Concurrently, four colon cancer cell lines (ie, SW620, Lovo, HCT116, and SW480) and the human colon mucosal epithelial cell line (NCM460) were also purchased. Moreover, si-ATB, si-NC, miR-200c mimic, miR-200c inhibitor, and miR-NC were prepared for transfection into the CRC cells, and their effects on CRC cell lines were evaluated based on the conduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and flow cytometry assay. Eventually, the Luciferase reporter gene assay was carried out to judge if there existed a targeted relationship between ATB and miR-200c. The results of Cox regression analyses suggested that overexpressed lncRNA ATB, underexpressed miR-200c, poor tumor differentiation, lymph-vascular invasion, and perineural invasion were symbolic of shortened survival of the patients with CRC (all P < .05). Besides, transfection of pcDNA3.1-ATB and miR-200c inhibitor could boost the viability and proliferation of Lovo and SW620 cell lines (all P < .05). Meanwhile, the expressions of p53 and p21 were also reduced under treatments of pcDNA3.1-ATB and miR-200c inhibitor (P < .05). In addition, CDK2 seemed to reverse the contribution of miR-200c to intensifying viability and proliferation of Lovo and SW420 cell lines (P < .05). Furthermore, ATB might downregulate miR-200c expression by targeting it (P < .05), and CDK2 was subjected to dual regulation of both ATB and miR-200c (P < .05). In conclusion, the lncRNA ATB/miR-200c/CDK2 signaling was responsible for intensified proliferation and prohibited apoptosis of CRC cells, which might provide effective approaches for diagnosing and treating CRC.

Biogenic selenium nanoparticles synthesized by Lactobacillus casei ATCC 393 alleviate intestinal epithelial barrier dysfunction caused by oxidative stress via Nrf2 signaling-mediated mitochondrial pathway.

Background: Selenium (Se) can exert antioxidative activity and prevent the body from experiencing oxidative injury. Biogenic Se nanoparticles (SeNPs) synthesized by probiotics possess relatively strong chemical stability, high bioavailability, and low toxicity, this makes them potential Se supplements. Previously, we demonstrated that SeNPs synthesized by Lactobacillus casei ATCC 393 can alleviate hydrogen peroxide (H2O2)-induced human and porcine intestinal epithelial cells' oxidative damage. However, the antioxidant mechanism remains unclear.Methods: The possible antioxidant mechanism and protective effect of SeNPs on intestinal epithelial permeability and mitochondrial function were evaluated by establishing an H2O2-induced oxidative damage model of human colon mucosal epithelial cells (NCM460) and conducting Nrf2 inhibitor interference experiments. Mitochondrial membrane potential (MMP), mitochondrial DNA content, adenosine triphosphate (ATP), ROS, and protein expression levels of Nrf2-related genes were determined. Mitochondrial ultrastructure was visualized by transmission electron microscopy.Results: An amount of 4 μg Se/mL of SeNPs synthesized by L. casei ATCC 393 alleviated increase of ROS, reduced ATP and MMP, and maintained intestinal epithelial permeability in NCM460 cells challenged by H2O2. In addition, SeNPs improved the protein levels of Nrf2, HO-1, and NQO-1. Moreover, SeNPs attenuated the damage of mitochondrial ultrastructure caused by oxidative stress. Nrf2 inhibitor (ML385) abolished the regulatory effect of SeNPs on intracellular ROS production.Conclusion: Data suggest that biogenic SeNPs synthesized by L. casei ATCC 393 can protect the intestinal epithelial barrier function against oxidative damage by alleviating ROS-mediated mitochondrial dysfunction via Nrf2 signaling pathway. Biogenic SeNPs are an attractive candidate for potential Se supplement agent in preventing oxidative stress-related intestinal disease by targeting mitochondria.

Colonic Injuries Induced by Inhalational Exposure to Particulate-Matter Air Pollution.

Particulate matter (PM) exposure has been associated with intestinal disorders. Therefore, there is an urgent need to understand the precise molecular mechanism involved and explore potential prevention strategies. In this study, inhaled PM is shown to activate inflammatory pathways in murine colon. In a panel study, it is found that ambient PM levels are significantly associated with elevated number of fecal white blood cells in healthy subjects. Acting as a promoter, PM exposure accelerates chemical carcinogenesis‐induced colonic tumor formation in a murine model. Mechanistically, RNA‐seq assays suggest activation of phosphoinositide 3‐kinase (PI3K)/AKT cascades in chronically PM‐exposed human colon mucosal epithelial cells. Ablation of up‐stream driver fibroblast growth factor receptor 4 (FGFR4) effectively inhibits inflammation and neoplasia in PM‐exposed murine colons. Notably, dietary curcumin supplement is shown to protect against PM‐induced colonic injuries in mice. Collectively, these findings identify that PM exposure accelerates colonic tumorigenesis in a PI3K/AKT‐dependent manner and suggests potential nutrient supplement for prevention.

Geraniin selectively promotes cytostasis and apoptosis in human colorectal cancer cells by inducing catastrophic chromosomal instability.

Homeostasis of chromosomal instability (CIN) facilitates the origin and evolution of abnormal karyotypes that are critical for the survival and proliferation of cancer cells, but excessive CIN can result in cellular toxicity. Geraniin is a multifunctional ellagitannin found in some species of Geranium and Phyllanthus. We employed the cytokinesis-block micronucleus cytome assay to evaluate the CIN, nuclear division index (NDI) and apoptosis induced by geraniin in human colorectal adenocarcinoma cells (Colo205 and Colo320) and human colon mucosal epithelial cells (NCM460). Cells were exposed to 25, 50 or 100 μg/ml geraniin for 24, 48 or 72 h. 0.05 μg/ml mitomycin C was used as a positive control and media as a negative control. The results showed that, compared to negative controls, geraniin significantly reduced NDI (P < 0.01) and increased CIN (P < 0.01) and apoptosis (P < 0.05) in Colo205 and Colo320 cells in a dose- and time-dependent manner. Conversely, geraniin significantly increased NDI (P < 0.05) and decreased CIN (P < 0.001) and apoptosis (P < 0.01) in NCM460 cells. Moreover, CIN was positively associated with apoptosis (r = 0.437, P < 0.001) and negatively associated with NDI (r = -0.744, P < 0.001) in these cells. Together, our results highlight that the induction of catastrophic CIN may underlie the antitumor potential of geraniin. Our data also suggest that geraniin can decrease the risk of oncogenic transformation via decreasing CIN in normal cells.

Supercritical carbon dioxide-developed silk fibroin nanoplatform for smart colon cancer therapy.

PurposeTo deliver insoluble natural compounds into colon cancer cells in a controlled fashion.Materials and methodsCurcumin (CM)–silk fibroin (SF) nanoparticles (NPs) were prepared by solution-enhanced dispersion by supercritical CO2 (SEDS) (20 MPa pressure, 1:2 CM:SF ratio, 1% concentration), and their physicochemical properties, intracellular uptake efficiency, in vitro anticancer effect, toxicity, and mechanisms were evaluated and analyzed.ResultsCM-SF NPs (<100 nm) with controllable particle size were prepared by SEDS. CM-SF NPs had a time-dependent intracellular uptake ability, which led to an improved inhibition effect on colon cancer cells. Interestingly, the anticancer effect of CM-SF NPs was improved, while the side effect on normal human colon mucosal epithelial cells was reduced by a concentration of ~10 μg/mL. The anticancer mechanism involves cell-cycle arrest in the G0/G1 and G2/M phases in association with inducing apoptotic cells.ConclusionThe natural compound-loaded SF nanoplatform prepared by SEDS indicates promising colon cancer-therapy potential.

DNA hypomethylation of CBS promoter induced by folate deficiency is a potential noninvasive circulating biomarker for colorectal adenocarcinomas.

Aberrant DNA methylation patterns, which induced by folate deficiency, play important roles in tumorigenesis of colorectal cancer (CRC). Some DNA methylation alterations can also be detected in cell-free DNA (cfDNA) of patients’ plasma, making cfDNA an ideal noninvasive circulating biomarker. However, exact DNA methylation alterations induced by folate deficiency in tumorigenesis of CRC and exact potential circulating cfDNA methylation biomarker are still unclear. Therefore, DNA methylation patterns of the normal human colon mucosal epithelial cell line (NCM460), cultured with normal or low folate content, were screened and the DNA hypomethylation of cystathionine-beta-synthase (CBS) promoter was further validated in vitro and vivo. Then, the correlation analysis between folate level, DNA methylation alteration in promoter and expression of CBS was carried out in vitro and vivo. Further, the methylation patterns of CBS promoter in plasma cfDNA were detected and statistically correlated with pathological parameters and clinical outcome. Our study showed that DNA hypomethylation in CBS promoter, induced by folate deficiency, would lead to up-regulation of CBS both in vitro and vivo. Patients with cfDNA hypomethylation of CBS promoter in plasma were correlated with high tumor stage and poor clinical outcome. In addition, cfDNA hypomethylation of CBS promoter in plasma was shown to be an independent prognostic factor for recurrence and cancer-related death in CRC. Our results indicated that DNA hypomethylation of CBS promoter induced by folate deficiency could serve as a potential noninvasive circulating biomarker and may be helpful in developing more effective prognostic markers for CRC.