Spatiotemporal heterogeneity of LMOD1 expression summarizes two modes of cell communication in colorectal cancer.

Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity.

Early administration of Wumei Wan inhibit myeloid-derived suppressor cells via PI3K/Akt pathway and amino acids metabolism to prevent colitis-associated colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Wumei Wan (WMW), a traditional Chinese medicine prescription, has been proved to be effective in treating Colitis-associated colorectal cancer (CAC), but it has not been proven to be effective in different stages of CAC. AIM OF THE STUDY: The purpose of our study is to investigate the therapeutic effect and mechanism of WMW on the progression of CAC. MATERIALS AND METHODS: Azioximethane (AOM) and dextran sulfate sodium (DSS) were used to treat mice for the purpose of establishing CAC models. WMW was administered in different stages of CAC. The presentative chemical components in WMW were confirmed by LC-MS/MS under the optimized conditions. The detection of inflammatory cytokines in the serum and colon of mice were estimated by qRT-PCR and ELISA. The changes of T cells and myeloid-derived suppressor cells (MDSCs) in each group were detected by flow cytometry. The metabolic components in serum of mice were detected by UPLC-MS/MS. Expression of genes and proteins were detected by eukaryotic transcriptomics and Western blot to explore the key pathway of WMW in preventing CAC. RESULTS: WMW had significant effect on inhibiting inflammatory responses and tumors during the early development stage of CAC when compared to other times. WMW increased the length of mice's colons, reduced the level of IL-1ß, IL-6, TNF-α in colon tissues, and effectively alleviated colonic inflammation, and improved the pathological damage of colon tissues. WMW could significantly reduce the infiltration of MDSCs in the spleen, increase CD4+ T cells and CD8+ T cells in the spleen of CAC mice, and effectively reform the immune microenvironment in CAC mice. Transcriptomics analysis revealed that 2204 genes had different patterns of overlap in the colon tissues of mice between control group, AOM + DSS group, and early administration of WMW group. And KEGG enrichment analysis showed that PI3K/Akt signaling pathway, ECM-receptor interaction, IL-17 signaling pathway, MAPK signaling pathway, pancreatic secretion, thermogenesis, and Rap1 signaling pathway were all involved. The serum metabolomics results of WMW showed that the metabolic compositions of the control group, AOM + DSS group and the early stage of WMW were different, and 42 differential metabolites with the opposite trends of changes were screened. The metabolic pathways mainly included pyrimidine metabolism, glycine, serine and threonine metabolism, tryptophan metabolism, and purine metabolism. And amino acids and related metabolites may play an important role in WMW prevention of CAC. CONCLUSION: WMW can effectively prevent the occurrence and development of CAC, especially in the initial stage. WMW can reduce the immune infiltration of MDSCs in the early stage. Early intervention of WMW can improve the metabolic disorder caused by AOM + DSS, especially correct the amino acid metabolism. PI3K/Akt signaling pathway was inhabited in early administration of WMW, which can regulate the amplification and function of MDSCs.

Predicting colorectal cancer prognosis based on long noncoding RNAs of disulfidptosis genes.

BACKGROUND: A recently hypothesized cause of cell death called disulfidptosis has been linked to the expansion, emigration, and vascular rebuilding of cancer cells. Cancer can be treated by targeting the pathways that trigger cell death. AIM: To discover the long non-coding RNA of the disulfidaptosis-related lncRNAs (DRLs), prognosis clinical survival, and treat patients with colorectal cancer with medications. METHODS: Initially, we queried the Cancer Genome Atlas database to collect transcriptome, clinical, and genetic mutation data for colorectal cancer (CRC). Training and testing sets for CRC patient transcriptome data were generated randomly. Key long non-coding RNAs (lncRNAs) related to DRLs were then identified and evaluated using a least absolute shrinkage and selection operator procedure, as well as univariate and multivariate Cox regression models. A prognostic model was then created after risk scoring. Also, Immune infiltration analysis, immune checkpoint analysis, and medication susceptibility analysis were used to investigate the causes of the different prognoses between high and low risk groups. Finally, we validated the differential expression and biomarker potential of risk-predictive lncRNAs through induction using both NCM460 and HT-29 cell lines, as well as a disulfidptosis model. RESULTS: In this work, eight significant lncRNAs linked to disulfidptosis were found. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of differentially expressed genes between high- and low-risk groups from the prognostic model showed a close relationship with the immune response as well as significant enrichment in neutrophil extracellular trap formation and the IL-17 signaling pathway. Furthermore, significant immune cell variations between the high-risk and low-risk groups were seen, as well as a higher incidence of immunological escape risk in the high-risk group. Finally, Epirubicin, bortezomib, teniposide, and BMS-754807 were shown to have the lowest sensitivity among the four immunotherapy drugs. CONCLUSION: Our findings emphasizes the role of disulfidptosis in regulating tumor development, therapeutic response, and patient survival in CRC patients. For the clinical treatment of CRC, these important LncRNAs could serve as viable therapeutic targets.

Robotic posterior retroperitoneal adrenalectomy versus laparoscopic posterior retroperitoneal adrenalectomy: outcomes from a pooled analysis.

Background: The comparative advantages of robotic posterior retroperitoneal adrenalectomy (RPRA) over laparoscopic posterior retroperitoneal adrenalectomy (LPRA) remain a topic of ongoing debate within the medical community. This systematic literature review and meta-analysis aim to assess the safety and efficacy of RPRA compared to LPRA, with the ultimate goal of determining which procedure yields superior clinical outcomes. Methods: A systematic search was conducted on databases including PubMed, Embase, Web of Science, and the Cochrane Library database to identify relevant studies, encompassing both randomized controlled trials (RCTs) and non-RCTs, that compare the outcomes of RPRA and LPRA. The primary focus of this study was to evaluate perioperative surgical outcomes and complications. Review Manager 5.4 was used for this analysis. The study was registered with PROSPERO (ID: CRD42023453816). Results: A total of seven non-RCTs were identified and included in this study, encompassing a cohort of 675 patients. The findings indicate that RPRA exhibited superior performance compared to LPRA in terms of hospital stay (weighted mean difference [WMD] -0.78 days, 95% confidence interval [CI] -1.46 to -0.10; p = 0.02). However, there were no statistically significant differences observed between the two techniques in terms of operative time, blood loss, transfusion rates, conversion rates, major complications, and overall complications. Conclusion: RPRA is associated with a significantly shorter hospital stay compared to LPRA, while demonstrating comparable operative time, blood loss, conversion rate, and complication rate. However, it is important to note that further research of a more comprehensive and rigorous nature is necessary to validate these findings. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=453816, identifier CRD42023453816.

Perioperative, oncologic, and functional outcomes of robot-assisted partial nephrectomy for special types of renal tumors (hilar, endophytic, or cystic): an evidence-based analysis of comparative outcomes.

Purpose: This study aims to perform a pooled analysis to compare the outcomes of robot-assisted partial nephrectomy (RAPN) between complex tumors (hilar, endophytic, or cystic) and non-complex tumors (nonhilar, exophytic, or solid) and evaluate the effects of renal tumor complexity on outcomes in patients undergoing RAPN. Methods: Four databases were systematically searched, including Science, PubMed, Web of Science, and Cochrane Library, to identify relevant studies published in English up to December 2022. Review Manager 5.4 was used for statistical analyses and calculations. The study was registered with PROSPERO (Registration number: CRD42023394792). Results: In total, 14 comparative trials, including 3758 patients were enrolled. Compared to non-complex tumors, complex tumors were associated with a significantly longer warm ischemia time (WMD 3.67 min, 95% CI 1.78, 5.57; p = 0.0001), more blood loss (WMD 22.84 mL, 95% CI 2.31, 43.37; p = 0.03), and a higher rate of major complications (OR 2.35, 95% CI 1.50, 3.67; p = 0.0002). However, no statistically significant differences were found between the two groups in operative time, length of stay, transfusion rates, conversion to open nephrectomy and radical nephrectomy rates, estimated glomerular filtration rate (eGFR) decline, intraoperative complication, overall complication, positive surgical margins (PSM), local recurrence, and trifecta achievement. Conclusions: RAPN can be a safe and effective procedure for complex tumors (hilar, endophytic, or cystic) and provides comparable functional and oncologic outcomes to non-complex tumors. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=394792, identifier CRD42023394792.

Anti-silencing function 1B knockdown suppresses the malignant phenotype of colorectal cancer by inactivating the phosphatidylinositol 3-kinase/AKT pathway.

BACKGROUND: Mounting studies have highlighted the pivotal influence of anti-silencing function 1B (ASF1B) on the malignancy of cancers. AIM: To explore the influence and mechanism of ASF1B in colorectal cancer (CRC). METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA expression of ASF1B. Immunohistochemical staining was performed to detect protein expression of ASF1B and Ki67 in tumor tissues. Western blot analysis was used to determine levels of ASF1B and proliferation/epithelial mesenchymal transition (EMT)/stemness-related proteins. In addition, the proliferation of CRC cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2'-Deoxyuridine assays. The migration and invasion of CRC cells were evaluated using transwell assays. Stemness of CRC cells was tested using the sphere formation assay. To construct a xenograft tumor model, HCT116 cells were introduced into mouse flanks via subcutaneous injection. RESULTS: ASF1B expression was markedly increased in CRC tissues and cells, and it was inversely correlated with overall survival of CRC patients and was positively associated with the tumor node metastasis (TNM) stage of CRC patients. Silencing of ASF1B suppressed proliferation, migration, invasion, stemness and EMT of CRC cells as well as tumorigenesis of xenograft mice. Furthermore, protein levels of P-phosphatidylinositol 3-kinase (p-PI3K) and p-AKT were decreased after silencing of ASF1B in CRC cells. The inhibitory effects of ASF1B knockdown on cell proliferation, stemness and EMT were partly abolished by PI3K activator in CRC cells. CONCLUSION: Silencing of ASF1B inactivated the PI3K/AKT pathway to suppress CRC malignancy in vitro.

The nomograms for predicting overall and cancer-specific survival in elderly patients with early-stage lung cancer: A population-based study using SEER database.

Purpose: Lung cancer is the leading cause of death from cancer and the number of operable elderly lung cancer patients is increasing, with advanced age being associated with a poorer prognosis. However, there is no easy and comprehensive prognostic assessment method for these patients. Methods: Clinicopathological data of patients aged 65 years or older with TNM stage I-II lung cancer from 2004 to 2018 were downloaded from the SEER database. Patients from 2004 to 2015 were randomized into a training group (n = 16,457) and a validation group (n = 7,048). Data from 2016 to 2018 (n = 6,231) were used for external validation. Two nomogram prognostic models were created after independent prognostic factors connected to both overall survival (OS) and cancer-specific survival (CSS) in the training set by using univariate and multivariate Cox proportional hazards regression analysis. In turn, overall survival (OS) and cancer-specific survival (CSS) were predicted for patients at 1, 3, and 5 years. Based on the concordance index (C-index), calibration curves, area under the receiver operating characteristics (ROC) curve (AUC), the time-dependent area under the ROC curve, the validity, accuracy, discrimination, predictive ability, and clinical utility of the models were evaluated. Decision curve analysis (DCA) was used to assess the clinical value of the models. Results: A total of 29,736 patients were included. Univariate and multivariate analyses suggested that age, race, gender, marriage, disease grade, AJCC stage, T-stage, surgery, radiotherapy, chemotherapy, and tumor size were independent risk factors for patient prognosis. These 11 variables were included in nomogram to predict OS and CSS of patients. C-indexes of OS for the training, validation and external validation sets were 0.730 (95% CI, 0.709-0.751), 0.734 (95% CI, 0.722-0.746), and 0.750 (95% CI, 0.734-0.766), respectively. The AUC results for the training and validation sets indicated good accuracy for this nomogram. The calibration curves demonstrated a high degree of concordance between actual and anticipated values, and the DCA demonstrated that the nomograms had better clinical application than the traditional TNM staging approach. Conclusion: This study identified risk factors for survival in operable elderly lung cancer patients and established a new column line graph for predicting OS and CSS in these patients. The model has good clinical application and can be a good clinical decision-making tool for physicians and patients.

Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC.

BACKGROUND: Current evidence suggests that the hypoxic tumor microenvironment further aggravates tumor progression, leading to poor therapeutic outcomes. There is as yet no biomarker capable of evaluating the hypoxic state of the tumor. The cytochrome c oxidase (COX) subunit is crucial to the mitochondrial respiratory chain. METHODS: We investigated the potential oncogenic role of COX subunit 4 isoform 2 gene (COX4I2) in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and COX regression analysis to examine whether COX4I2 overexpression can predict colorectal cancer (CRC) prognosis. The association of COX4I2 levels with clinical features and its biological actions were evaluated both in vitro and in vivo. RESULTS: Our analysis showed that elevated COX4I2 levels were correlated with poor clinical outcomes. We also observed that that COX4I2 may be involved in epithelial-mesenchymal transition, activation of cancer-related fibroblasts and angiogenesis in relation to fibroblast growth factor 1. CONCLUSIONS: The COX4I2 level may be a predictor of outcome in CRC and may represent a novel target for treatment development.

An analysis of the significance of the Tre2/Bub2/CDC 16 (TBC) domain protein family 8 in colorectal cancer.

The TBC (Tre-2/Bub2/Cdc16, TBC) structural domain is now considered as one of the factors potentially regulating tumor progression. However, to date, studies on the relationship between TBC structural domains and tumors are limited. In this study, we identified the role of TBC1 domain family member 8 (TBC1D8) as an oncogene in colorectal cancer (CRC) by least absolute shrinkage and selection operator (LASSO) and Cox regression analysis, showing that TBC1D8 may independently predict CRC outcome. Functional enrichment and single-cell analysis showed that TBC1D8 levels were associated with hypoxia. TBC1D8 levels were also positively correlated with M2 macrophage infiltration, which may have a complex association with hypoxia. Taken together, these results show that the TBC1D8 gene is involved in colorectal carcinogenesis, and the underlying molecular mechanisms may include hypoxia and immune cell infiltration.

Biochemical Characterization of a Novel Bacterial Laccase and Improvement of Its Efficiency by Directed Evolution on Dye Degradation.

Laccase is a copper-containing polyphenol oxidase with a wide range of substrates, possessing a good application prospect in wastewater treatment and dye degradation. The purpose of this research is to study the degradation of various industrial dyes by recombinant laccase rlac1338 and the mutant enzyme lac2-9 with the highest enzyme activity after modification by error-prone PCR. Four enzyme activities improved mutant enzymes were obtained through preliminary screening and rescreening, of which lac2-9 has the highest enzyme activity. There are four mutation sites, including V281A, V281A, P309L, S318G, and D232V. The results showed that the expression of the optimized mutant enzyme also increased by 22 ± 2% compared to the unoptimized enzyme and the optimal reaction temperature of the mutant enzyme lac2-9 was 5°C higher than that of the rlac1338, and the optimal pH increased by 0.5 units. The thermal stability and pH stability of mutant enzyme lac2-9 were also improved. With ABTS as the substrate, the kcat/Km of rlac1338 and mutant strain lac2-9 are the largest than other substrates, 0.1638 and 0.618 s-1M-1, respectively, indicating that ABTS is the most suitable substrate for the recombinant enzyme and mutant enzyme. In addition, the Km of the mutant strain lac2-9 (76 µM) was significantly lower, but the kcat/Km (0.618 s-1M-1) was significantly higher, and the specific enzyme activity (79.8 U/mg) increased by 3.5 times compared with the recombinant laccase (22.8 U/mg). The dye degradation results showed that the use of rlac1338 and lac2-9 alone had no degradation effect on the industrial dyes [indigo, amaranth, bromophenol blue, acid violet 7, Congo red, coomassie brilliant blue (G250)], however, adding small molecular mediators Ca2+ and ABTS at the same time can significantly improve the degradation ability. Compared to the rlac1338, the degradation rates with the simultaneous addition of Ca2+ and ABTS of mutant enzyme lac2-9 for acid violet 7, bromophenol blue and coomassie brilliant blue significantly improved by 8.3; 3.4 and 3.4 times. Therefore, the results indicated that the error-prone PCR was a feasible method to improve the degradation activity of laccase for environmental pollutants, which provided a basis for the application of laccase on dye degradation and other environmental pollutants.

Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort.

Colorectal cancers (CRC) with microsatellite instability (MSI) or mismatch repair-deficiency (dMMR), but without detectable MMR germline mutations are termed Lynch-like syndrome (LLS). We assess the clinicopathologic and molecular characteristics of LLS tumors and the proportion in LLS, which remain poorly investigated in China. We enrolled 404 CRC patients with surgery in our institution from 2014 to 2018. LLS tumors were detected by a molecular stratification based on MMR protein expression, MLH1 methylation and MMR gene mutation. LLS tumors were profiled for germline mutations in 425 cancer-relevant genes. Among 42 MMR-deficient tumors, 7 (16.7%) were attributable to MLH1 methylation and 7 (16.7%) to germline mutations, leaving 28 LLS cases (66.6%). LLS tumors were diagnosed at a mean age of 60.7 years, had an almost equivalent ratio among rectum, left colon and right colon, and had high rates of lymph node metastases (50%, 4/28 N2). Most MMR gene mutations (88.2%, 15/17) in LLS tumors were variants of unknown significance (VUS). Two novel frameshift mutations were detected in ATM and ARID1A, which are emerging as candidate responsible genes for LLS. In this study, 28 (66.6%) MMRd tumors were classified as LLS, which were significantly higher than reports of western countries. LLS tumors were more likely to carry lymph node metastases. However, it's hard to differentiated LLS tumors from LS through family history, tumor location, histological type of tumors, immunohistochemistry (IHC) for MMR proteins and MSI analysis.

Investigating the loco-regional control of simultaneous integrated boost intensity-modulated radiotherapy with different radiation fraction sizes for locally advanced non-small-cell lung cancer: clinical outcomes and the application of an extended LQ/TCP model.

BACKGROUND: To investigate the loco-regional progression-free survival (LPFS) of intensity-modulated radiotherapy (IMRT) with different fraction sizes for locally advanced non-small-cell lung cancer (LANSCLC), and to apply a new radiobiological model for tumor control probability (TCP). METHODS: One hundred and three LANSCLC patients treated with concurrent radiochemotherapy were retrospectively analyzed. Factors potentially predictive of LPFS were assessed in the univariate and multivariate analysis. Patients were divided into group A (2.0 ≤ fraction size<2.2Gy), B (2.2 ≤ fraction size<2.5Gy), and C (2.5 ≤ fraction size≤3.1Gy) according to the tertiles of fraction size. A novel LQRG/TCP model, incorporating four "R"s of radiobiology and Gompertzian tumor growth, was developed to predict LPFS and compared with the classical LQ/TCP model. RESULTS: With a median follow-up of 22.1 months, the median LPFS was 23.8 months. Fraction size was independently prognostic of LPFS. The median LPFS of group A, B and C was 13.8, 35.7 months and not reached, respectively. Using the new LQRG/TCP model, the average absolute and relative fitting errors for LPFS were 6.9 and 19.6% for group A, 5.5 and 8.8% for group B, 6.6 and 9.5% for group C, compared with 9.5 and 29.4% for group A, 16.6 and 36.7% for group B, 24.8 and 39.1% for group C using the conventional LQ/TCP model. CONCLUSIONS: Hypo-fractionated IMRT could be an effective approach for dose intensification in LANSCLC. Compared with conventional LQ model, the LQRG model showed a better performance in predicting follow-up time dependent LPFS.

Risk of Colorectal Cancer in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Ulcerative colitis (UC) patients have an increased risk for the development of colorectal cancer (CRC). Our aim was to assess the risk of CRC in UC patients compared with disease extent, disease duration, and geographic variation. METHODS: In this systematic review and meta-analysis, we searched PubMed, scientific meetings, and the bibliographies of identified articles, with English language restrictions for studies published from 1988 to 2018, and assessed the risk of CRC in UC patients. Patients with Crohn's disease, family history of CRC, and colorectal adenomatous polyp (CAP) were excluded from this research. The study was registered with PROSPERO, number CRD42018102213. FINDINGS: We included 58 studies that included 267566 UC patients. Extensive UC and left-sided UC had a higher risk of CRC than proctitis UC. Geography also played a role in UC-associated CRC development. The time of malignant transformation in Asian UC patients started after 10-20 years of this disease duration. North American UC-associated CRC patients significantly increased in more than 30 years of this disease duration. CONCLUSION: In a systematic review of the literature, we found that disease extent, disease duration, and geography were strong, independent risk factors in UC-associated CRC development.

Traditional Chinese medicine (Xiaoai Jiedu Decoction) as an adjuvant treatment for prevention new colorectal adenomatous polyp occurrence in post-polypectomy: Study protocol for a randomized controlled trial.

BACKGROUND: Colorectal Adenomatous Polyp (CAP) was one precursor of colorectal cancer (CRC) and having a high chance of developing into CRC. There was a lack of conclusive chemoprevention evidences to prevention new CAP occurrence in post-polypectomy. Xiaoai Jiedu Decoction, Chinese National Medical Professor (Zhou Zhongying)'s experience formula, has been used to treat new CAP occurrence in post-polypectomy from the 20th century in China. However, clinical research of Xiaoai Jiedu Decoction in the treatment of CAP recurrence was lack. We design this study to evaluate the efficacy and safety of Xiaoai Jiedu Decoction in the treatment of new CAP occurrence in post-polypectomy on colonoscopy. METHODS/DESIGN: A randomized, controlled, blind and multicenter trial to evaluate the efficacy and safety of Xiaoai Jiedu Decoction is proposed. CAP patients (after complete polypectomy under colonoscopy) will be randomly assigned into Xiaoai Jiedu Decoction group and Xiaoai Jiedu Decoction mimetic agent group. Patients will receive 6-course treatments and a 2-year follow-up. Follow-up colonoscopy will be anticipated to perform in 1 and 2 years after the baseline examinations. The primary outcome measure is the new CAP occurrence in 1 and 2 years. The secondary outcome measure is the occurrence of advanced adenoma in 1 and 2 years. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Xiaoai Jiedu Decoction as an adjuvant treatment for new CAP occurrence in post-polypectomy. TRIAL REGISTRATION: NCT03616444.

Total flavone of Abelmoschus manihot ameliorates Crohn's disease by regulating the NF­κB and MAPK signaling pathways.

Crohn's disease (CD) is a chronic relapsing form of inflammatory bowel disease, and its pathogenesis remains unknown. Total flavone of Abelmoschus manihot L. Medic (TFA), has been used as anti­inflammatory and myocardial ischemia protective drug. The present study aimed to explore the effects of TFA on CD and its underlying mechanism. We reported that TFA comprises eight flavone glycosides, including quercetin­3­O­robinobioside, gossypetin­3­O­glucoside, quercetin­3'­O­glucoside, isoquercetin, hyperoside, myricetin, gossypetin and quercetin. In vivo, TFA promoted the survival of 2,4,6­trinitrobenzene sulfonic acid (TNBS)­induced colitis in mice, decreased weight loss and increased colon length in a dose­dependent manner. Additionally, TFA notably ameliorated the inflammatory response in mice with TNBS­induced colitis as determined by histopathological analysis. In addition, the administration of TFA in mice with TNBS­induced colitis led to a significant decrease in the levels of cytokines in the sera and colon tissues; a significant decrease myeloperoxidase activity in the colon tissues was also observed. These findings may be associated with the suppression of the nuclear factor­κB (NF­κB) and mitogen­activated protein kinase (MAPK) signaling pathways. In vitro, TFA significantly downregulated the expression of cytokines in lipopolysaccharide (LPS)­induced RAW264.7 cells. In addition, TFA suppressed LPS­induced activation of the NF­κB and MAPK signaling pathways in RAW264.7 cells. Our findings indicated that TFA could suppress the inflammatory response in mice with TNBS­induced colitis via inhibition of the NF­κB and MAPK signaling pathways. The results of the present study may improve understanding of the function of TFA and provide a novel theoretical basis for the treatment of CD.

The modified Si-Jun-Zi Decoction attenuates colon cancer liver metastasis by increasing macrophage cells.

BACKGROUND: The modified Si-Jun-Zi Decoction (SJZ), a Chinese medicine formula, is clinically used against multiple malignancies including colorectal cancer (CRC). This study aims to evaluate the effect of modified SJZ on CRC liver metastasis and identify the therapeutic mechanisms. METHODS: Human CRC cells with GFP fluorescence were transplanted into Balb/c nude mice spleens. Modified SJZ, 5-fluorouracil or the combined treatment was given for 3 weeks. CRC liver metastasis was measured by fluorescence imaging and plasma cytokines were analyzed. Furthermore, the effects of administration time and doses for the modified SJZ were investigated in nude mice. RESULTS: Modified SJZ could increase the survival rate and reduce CRC liver metastasis in the nude mice model. Plasma GM-CSF level was elevated. Three weeks of treatment with the modified SJZ at the full dose (45 g/kg) could significantly increase the number of macrophages but not neutrophils in the spleen. CONCLUSIONS: These results indicate that modified SJZ can inhibit CRC liver metastasis by activating the innate immune system, providing a complementary and alternative therapy for CRC.

Artesunate induces apoptosis and autophagy in HCT116 colon cancer cells, and autophagy inhibition enhances the artesunate­induced apoptosis.

The present study assessed the antitumor effect of artesunate (ART) in vitro and in vivo, as well as its underlying mechanism of action in HCT116 colon cancer cells. An MTT assay, DAPI staining, flow cytometry, western blotting, immunohistochemistry, transmission electron microscopy and TUNEL assay were performed to study the molecular mechanism underlying the antitumor effects of ART in HCT116 colon cancer cells. ART was observed to inhibit proliferation by inducing the apoptosis of HCT116 cells both in vitro and in vivo. Flow cytometry analysis demonstrated that treatment with 2 and 4 µg/ml ART for 48 h induced early apoptosis in 22.7 and 33.8% of cells, respectively. In the xenograft tumors of BALB/c nude mice, TUNEL­positive cells increased in the ART group compared with that in the normal saline group. Furthermore,the associated mitochondrial cleaved­caspase 3, poly­ADP ribose polymerase (PARP), caspase 9 and Bcl­2­associated X protein levels increased while B­cell lymphoma­2 (Bcl­2) decreased both in the cell and animal ART­treated group. ART­treated cells also exhibited autophagy induction, as evidenced by increased protein expression levels of light chain 3 (LC3) and beclin­1, and the presence of autophagosomes. Notably, pharmacological blockade of autophagy activation using hydroxychloroquine markedly enhanced ART­induced apoptosis and increased the protein levels of cleaved caspase 3 and PARP, while decreasing the levels of LC3 and beclin­1. These findings suggested that the ART­induced autophagy may have a cytoprotective effect by suppressing apoptosis. In conclusion, ART may be a potentially clinically useful anticancer drug for human colon cancer. In addition, co­treatment with ART and an autophagy inhibitor may be an effective anticancer therapy.

Effect of Faecal Microbiota Transplantation for Treatment of Clostridium difficile Infection in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: Evidence concerning the effect of faecal microbiota transplantation [FMT] in Clostridium difficile infection [CDI] patients with inflammatory bowel disease [IBD] has not been firmly established. Therefore, we performed a systematic review and meta-analysis to evaluate FMT treatment outcomes in patients with IBD treated for CDI. METHODS: An electronic search of four databases was conducted until November 1, 2017. Cohort studies of FMT efficacy and safety in CDI patients with IBD were included. Pooled effect sizes were calculated with 95% confidence intervals [CI] using a random-effects model. RESULTS: Nine cohort studies comprising a total of 346 CDI patients with IBD were included. The initial cure rate was 81% [95% CI = 76%-85%] and the overall cure rate was up to 89% [95% CI = 83%-93%], both with no significant heterogeneity. The recurrence rate was 19% [95% CI = 13%-27%] with moderate heterogeneity [Cochran's Q, p = 0.19; I2 = 33%]. There was no significant difference in the CDI cure rate after FMT in patients with and without IBD (risk ratio [RR] = 0.92; 95% CI = 0.81-1.05; Cochran's Q, p = 0.06; I2 = 53%). Subgroup analysis revealed a similar CDI treatment effects after FMT in patients with Crohn's disease and in those with ulcerative colitis [p = 0.1804]. Four studies reported adverse events of IBD flares. CONCLUSIONS: FMT is an effective therapy for CDI in patients with IBD. Well-designed randomised controlled trials and well-conducted microbiological studies are needed to validate its efficacy and safety.

Amyloid and immune homeostasis.

Extracellular amyloid deposition defines a range of amyloidosis and amyloid-related disease. Addition to primary and secondary amyloidosis, amyloid-related disease can be observed in different tissue/organ that sharing the common pathogenesis based on the formation of amyloid deposition. Currently, both Alzheimer's disease and type 2 diabetes can be diagnosed with certainly only based on the autopsy results, by which amyloidosis of the associative tissue/organ is observed. Intriguingly, since it demonstrated that amyloid deposits trigger inflammatory reaction through the activation of cascaded immune response, wherein several lines of evidence implies a protective role of amyloid in preventing autoimmunity. Furthermore, attempts for preventing amyloid formation and/or removing amyloid deposits from the brain have caused meningoencephalitis and consequent deaths among the subjects. Hence, it is important to note that amyloid positively participates in maintaining immune homeostasis and contributes to irreversible inflammatory response. In this review, we will focus on the interactive relationship between amyloid and the immune system, discussing the potential functional roles of amyloid in immune tolerance and homeostasis.

Poly (I:C) alleviates obesity related pro-inflammatory status and promotes glucose homeostasis.

Obesity associated insulin resistance (IR) is implicated in chronic inflammation that mediated by the immune system. Imbalance between anti-inflammatory and pro-inflammatory response contributes to the origins and drivers of IR. However, cells of innate and adaptive immune system participate in the pathogenesis of IR, while glucose homeostasis related immune tolerance could be compromised high fat diet (HFD) reduced metabolic disorder. Although previous studies have demonstrated that anti-inflammatory therapy has a protective role in alleviating the pro-inflammatory status in HFD induced IR, the precise mechanism is still unclear. Ploy (I:C) is a synthetic double-stranded RNA that activates innate and/or adaptive immune response via retinoic acid-inducible gene-I (RIG-I), toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein 5 (MDA5). In the present study, we initially perform a novel research on the relationship between Poly (I:C) preconditioning and improved glucose metabolism in obesity related IR. Interestingly, Poly (I:C) treatment has alleviated the pro-inflammatory status and promoted glucose homeostasis during a HFD feeding. Improved insulin sensitivity is consistent with enhanced immune tolerance, which accompanied with increased Foxp3+ regulatory T cells (Tregs). Of note, Tregs have a pivotal role in orchestrating the self-balance between autoimmunity and inflammation reaction. Thus, our findings reveal that Ploy (I:C) preconditioning prevents HFD induced glucose intolerance, which may be recognized as vaccination by the host. Overall, selectively targeting precise immune regulators may lead to new classes of potentially meaningful therapies for IR in the clinical trials.