Matrine: A Promising Treatment for Ulcerative Colitis by Targeting the HMGB1/NLRP3/Caspase-1 Pathway.

BACKGROUND: Previous studies have found that matrine (MAT) effectively treated Ulcerative Colitis (UC). The purpose of this study is to explore its mechanism based on the HMGB1/NLRP3/Caspase-1 signaling pathway. METHODS: MAT was administered intragastrically to DSS-induced UC mice for 14 days. The Disease Activity Index (DAI) and histological staining were measured to detect histopathological changes in colon. The levels of IL-1ß, IL-6, and TNF-α in serum were measured by ELISA. The protein and mRNA expression of HMGB1/NLRP3/Caspase-1 in the colon were detected by immunohistochemistry, western Blotting or qRT-PCR. RESULTS: MAT improved the histological pathological changes of UC mice, as assessed by DAI, colonic length, and colonic mucosal injury. MAT also reduced colonic inflammatory damage by reducing the serum IL-1ß, IL-6, and TNF-α content and decreasing the expression of HMGB1, NLRP3, Caspase-1, and IL-1ß and proteins and mRNA in the colon. CONCLUSION: MAT could significantly alleviate DSS-induced UC symptoms by reducing the expressions of pro-inflammatory cytokines, such as IL-1ß, TNF-α, and IL-6, the mechanism of which is related to the inhibition of HMGB1/NLRP3/Caspase-1 signaling pathway.

Upregulated NLGN1 predicts poor survival in colorectal cancer.

BACKGROUND: Neuroligin1 (NLGN1) is a main component of excitatory glutamatergic synapses complex and is important for synapse assembly and function. The clinical value of NLGN1 in colorectal cancer (CRC) is not clear. METHODS: We obtained the expression data of 1143 CRC patients from 3 independent Gene Expression Omnibus (GEO) datasets (GSE32323, GSE24551, GSE39582) and The Cancer Genome Atlas (TCGA) to make the comparison of the NLGN1 expression level between CRC tissues and matched noncancerous tissues, and to evaluate its value in predicting survival of CRC patients. At the protein level, these results were further confirmed by immunohistochemical staining of 52 CRC samples in our own centre. Finally, the function of NLGN1 was explored by gene set enrichment analysis (GSEA). RESULTS: Increased mRNA and protein levels of NLGN1 expression were associated with worse overall survival or recurrence-free survival in CRC patients from 2 GEO datasets, the TCGA database, and our cohort. In addition, multivariate regression analysis showed that NLGN1 was an independent poor prognostic factor of survival in patients with CRC in TCGA database (OR = 2.524, P = 0.010). Functional analysis revealed that NLGN1 was correlated with function involving the Hedgehog signaling pathway, mismatch repair process, and some material metabolism processes. CONCLUSIONS: This study is the first to implicate and verify NLGN1 as a new poor prognostic marker for CRC.

Increased CD44 Expression and MEK Activity Predict Worse Prognosis in Gastric Adenocarcinoma Patients Undergoing Gastrectomy.

PURPOSE: We have shown that activation of the receptor tyrosine kinase (RTK)-RAS pathway in gastric adenocarcinoma (GA) promotes acquisition of cancer stem-like cell (CSC) phenotypes including metastasis and chemotherapy resistance. Here, we evaluated the prognostic value of the CSC marker CD44 and the RTK-RAS activation marker phosphorylated MEK (p-MEK) in patients with resectable GA. METHODS: CD44 and p-MEK were measured in tumors from GA patients who underwent curative-intent gastrectomy at Fujian Medical University Union Hospital (FMUUH, n = 134) and Memorial Sloan Kettering Cancer Center (MSKCC, n = 56). Overall survival (OS) was estimated by the Kaplan-Meier method, and multivariate analysis was performed by Cox proportional hazards regression modeling. RESULTS: Despite multiple significant differences in clinicopathologic characteristics between the FMUUH and MSKCC cohorts, high CD44 and high p-MEK expression were both independent negative prognostic factors for OS on univariate analysis in both cohorts (p < 0.05). Both factors were also significant on multivariate analysis when the cohorts were combined (p ≤ 0.003). On subgroup analysis, the 5-year OS of patients with both high CD44 and high p-MEK was 39.5-41.6% compared with 55.4-66.4% for patients with low CD44. High CD44 expression was associated with more advanced TNM stage in the FMUUH cohort and larger tumor size and undifferentiated histology in the MSKCC cohort. High p-MEK was associated with undifferentiated histology in the FMUUH cohort and larger tumor size in the MSKCC cohort. CONCLUSIONS: Increased CD44 and p-MEK expression are predictive of worse OS in GA patients. Thus, targeting the RTK-RAS pathway may benefit patients with CD44-positive, RAS-activated GA by inhibiting metastasis and reversing chemotherapy resistance.

Therapies for cognitive impairment in breast cancer survivors treated with chemotherapy: A protocol for systematic review.

OBJECTIVE: The aim of this systematic review was to evaluate the effect of therapies for cognitive impairment on patients' perceived cognitive function in breast cancer survivors with chemotherapy-related cognitive impairment. METHOD: A literature search of PubMed, Embase, and the Cochrane Library was conducted up to April 2019. Search terms included breast cancer, chemotherapy, and cognitive impairment. RESULT: Six randomized controlled trials with a total of 305 patients were included in this review. A total of 6 randomized controlled trials using various treatments (Tibetan sound meditation, donepezil, memory and attention adaptation training, aerobic exercise, acupuncture, Qigong) for chemotherapy-related cognitive impairment met the eligibility criteria and were included. This review showed that meditative interventions (Tibetan sound meditation, Qigong) and cognitive therapy (memory and attention adaptation training) may partially improve some aspects of patients' perceived (self-reported) cognitive functioning, particularly patients' perceived cognitive impairment and ability. CONCLUSION: In this systematic review, the results showed that meditative interventions (Tibetan sound meditation, Qigong) and cognitive therapy (memory and attention adaptation training) may be optional therapies. We hope to have more randomized controlled trials to support this result in the future.

Clinical characteristics of moderate-severe obsessive-compulsive disorder in children and adolescents in China.

OBJECTIVE: This study reports clinical characteristic of moderate-severe obsessive-compulsive disorder (OCD) among school students in China. METHODS: We examined 153 patients for the distribution of OCD symptoms using the Yale-Brown Obsessive Compulsive Scale Symptoms Checklist, the severity of anxiety and depression symptoms using the Hamilton Anxiety Scale and the Hamilton Depression Scale-24, respectively, and impairment in learning, family and social functions using the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: The number of total OCD, obsession and compulsion symptoms was 6.71 (standard deviation [SD] = 2.25), 3.77 (SD = 1.32) and 2.94 (SD = 1.59), respectively. The incidence of moderate and severe depressive symptoms for junior high school students was significantly higher than for primary and high school students. The number of children and adolescents with OCD increased with age, reaching a peak in the senior high school stage. CONCLUSION: The most common symptoms in children and adolescent OCD patients are miscellaneous obsessions, aggressiveness, religiousness, checking, miscellaneous compulsions, cleaning-washing and repeating. These patients show a relatively high co-occurrence rate of anxiety symptoms and depressive symptoms, which impairs their learning, as well as their family and social functions.

Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis.

Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to identify randomised controlled trials (RCTs) in Pubmed, Embase, Cochrane, and major conferences. Studies meeting predefined selection criteria were selected, and two independent investigators performed data extraction; overall survival (OS), progression-free survival (PFS), and overall response rate were compared between anti-PD-1/PD-L1 inhibitors and control therapies. We calculated the pooled response rate and 95% CIs of all-grade and high-grade (≥3) adverse effects and evaluated the within-study heterogeneity using subgroup, sensitivity, and meta-regression analyses. In final, we included eligible 35 RCTs (21047 patients). The main estimated hazard ratios (HRs) for OS and PFS were 0.76 (0.71-0.82) and 0.81 (0.73-0.89) in a random-effects model. The anti-PD-1/PD-L1 inhibitor group had a significantly high risk for all-grade immune-related adverse events. Anti-PD-1/PD-L1 inhibitors were identified as a preferable treatment option for advanced or metastatic cancer patients who are male, aged < 65 years, current or former smokers, had no CNS or liver metastasis, had not EGFR mutation, and had high PD-L1 expression.

Identification of biomarkers in colon cancer based on bioinformatic analysis.

BACKGROUND: Colon cancer is one of the most common cancers in the world. Targeting biomarkers is helpful for the diagnosis and treatment of colon cancer. This study aimed to identify biomarkers in colon cancer, in addition to those that have already been reported, using microarray datasets and bioinformatics analysis. METHODS: We downloaded two mRNA microarray datasets (GSE44076 and GSE47074) for colon cancer from the Gene Expression Omnibus (GEO) database and the most recent colon cancer data (COAD) from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) between colon cancer and adjacent normal tissues were determined based on these three datasets. Additionally, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network analysis. The hub genes in the PPI network were then selected and analysed. RESULTS: We identified 150 DEGs and the GO enrichment analysis revealed that these DEGs were enriched in functions related to accelerating the cell cycle, promoting tumour cell accumulation, promoting cell division, positively regulating cell division, and negatively regulating apoptosis. The KEGG pathway analysis indicated that the DEGs were also involved in the cell cycle pathway. In the PPI network, 34 hub genes were found to be enriched in cell division. Prognostic analysis of the 34 hub genes revealed that eight genes (CCNB1, CHEK1, DEPDC1, ECT2, GINS2, HMMR, KIF14, and KIF18A) were associated with the prognosis of colon cancer. And our qRT-PCR results confirmed that DEPDC1, ECT2, GINS2, HMMR and KIF18A were highly expressed in colon cancer cells. CONCLUSIONS: The genes DEPDC1, ECT2, GINS2, HMMR, and KIF18A could serve as novel diagnostic biomarkers of colon cancer.

CDK5RAP3 inhibits angiogenesis in gastric neuroendocrine carcinoma by modulating AKT/HIF-1α/VEGFA signaling.

BACKGROUND: Angiogenesis plays critical roles in the progression and metastasis of malignant tumors. Gastric neuroendocrine carcinoma is an uncommon stomach cancer that is rich in blood vessels and exhibits highly malignant biological behavior with a poor prognosis. The role of CDK5RAP3 in GNEC has not been reported to date. METHODS: Immunohistochemistry was used to assess the expression of CDK5RAP3 in GNEC tissues and adjacent non-tumor tissues. Cell lines with stable overexpression or knockdown of CDK5RAP3 were constructed using lentiviral transfection. Wound-healing assays, invasion and metastasis assays, tube formation assays, and tumor xenograft transplantation assays were performed to evaluate the effect of CDK5RAP3 on GNEC angiogenesis in vitro and in vivo. Real-time PCR, ELISA, western blot analysis, and confocal-immunofluorescence staining were used to explore the molecular mechanism of CDK5RAP3's effect on angiogenesis. RESULTS: Compared with their respective adjacent non-tumor tissues, protein levels of CDK5RAP3 were significantly decreased in GNEC tissues. Furthermore, low expression of CDK5RAP3 was correlated with more advanced TNM stage, increased tumor microvessel density, and poor prognosis. Functionally, we found that GNEC cells with CDK5RAP3 knockdown promoted human umbilical vein endothelial cells migration and tube formation via activation of AKT/HIF-1α/VEGFA signaling, resulting in increased levels of VEGFA in GNEC cell supernatant. In addition, CDK5RAP3 overexpression in GNEC cells caused the opposing effect. Consistent with these results, nude mouse tumorigenicity assays showed that CDK5RAP3 expression downregulated angiogenesis in vivo. Lastly, patients with low CDK5RAP3 expression and high VEGFA expression exhibited the worst prognosis. CONCLUSIONS: This study demonstrated that CDK5RAP3 inhibits angiogenesis by downregulating AKT/HIF-1α/VEGFA signaling in GNEC and improves patient prognosis, suggesting that CDK5RAP3 could be a potential therapeutic target for GNEC.

UFM1 suppresses invasive activities of gastric cancer cells by attenuating the expres7sion of PDK1 through PI3K/AKT signaling.

BACKGROUND: UFM1 has been found to be involved in the regulation of tumor development. This study aims to clarify the role and potential molecular mechanisms of UFM1 in the invasion and metastasis of gastric cancer. METHODS: Expression of UFM1 in gastric tumor and paired adjacent noncancerous tissues from 437 patients was analyzed by Western blotting, immunohistochemistry, and realtime PCR. Its correlation with the clinicopathological characteristics and prognosis of gastric cancer patients was analyzed. The effects of UFM1 on the invasion and migration of gastric cancer cells were determined by the wound and trans-well assays, and the effect of UFM1 on subcutaneous tumor formation was verified in nude mice. The potential downstream targets of UFM1 and related molecular mechanisms were clarified by the human protein kinase assay and co-immunoprecipitation technique. RESULTS: Compared with the corresponding adjacent tissues, the transcription level and protein expression level of UFM1 in gastric cancer tissues were significantly downregulated (P < 0.05). The 5-year survival rate of gastric cancer patients with low UFM1 expression was significantly lower than the patients with high UFM1 expression (42.1% vs 63.0%, P < 0.05). The invasion and migration abilities of gastric cancer cells with stable UFM1 overexpression were significantly decreased, and the gastric cancer cells with UFM1 stable knockdown showed the opposite results; similar results were also obtained in the nude mouse model. Further studies have revealed that UFM1 could increase the ubiquitination level of PDK1 and decrease the expression of PDK1 at protein level, thereby inhibiting the phosphorylation level of AKT at Ser473. Additionally, the effect of UFM1 on gastric cancer cell function is dependent on the expression of PDK1. The expression level of UFM1 can improve the poor prognosis of PDK1 in patients with gastric cancer. CONCLUSION: UFM1 suppresses the invasion and metastasis of gastric cancer by increasing the ubiquitination of PDK1 through negatively regulating PI3K/AKT signaling.

Expression of Protein 4.1 Family in Breast Cancer: Database Mining for 4.1 Family Members in Malignancies.

BACKGROUND The protein 4.1 family is a family of cytoskeletal proteins that play an important role in maintaining normal cell morphology and cell adhesion, migration, division, and intercellular signaling. The main aim of this study was to explore the prognostic significance of the protein 4.1 family in breast cancer (BC) patients and to provide new biomarkers and therapeutic targets for the diagnosis and treatment of BC. MATERIAL AND METHODS The expression of 4.1 family members in various tumor types was compared to normal controls using the ONCOMINE and GOBO databases. The prognostic significance of the 4.1 family in BC patients was determined by Kaplan-Meier Plotter. RESULTS EPB41L2 (4.1G) was expressed at higher levels in normal tissues compared with BC patients for all 4.1 family members. In survival analysis, 4.1G and EPB41 (4.1R) mRNA high expressions were associated with better survival in BC patients. Moreover, 4.1G high expression was significantly associated with longer overall survival (OS) in luminal A and protracted relapse-free survival (RFS) in luminal B subtype BC patients who received Tamoxifen treatment. In addition, high expression of each 4.1 family member also showed better prognostic value in different molecular subtypes of BC. CONCLUSIONS These results indicate that the protein 4.1 family can be regarded as novel biomarkers and potential therapeutic targets for BC. Further research is needed to explore the detailed biological functions.

Overexpression of IC53d promotes the proliferation of gastric cancer cells by activating the AKT/GSK3ß/cyclin D1 signaling pathway.

Cyclin­dependent kinase 5 regulatory subunit­â€‹associated protein 3 (CDK5RAP3 or C53) is involved in the development of various types of tumor, and alternative splicing of C53 results in numerous transcription variants that encode different isoforms. The present study aimed to clone human C53 isoform d (IC53d) and explore its role in the proliferation of gastric cancer cells. Reverse transcription­quantitative polymerase chain reaction was used to detect the expression levels of IC53d in 80 primary gastric adenocarcinoma tissues and adjacent normal tissues. In addition, the association between IC53d and clinicopathological parameters was determined. Gastric cancer cell lines stably overexpressing IC53d were established to observe its effects on cell proliferation, invasion and migration, and on in vivo tumorigenicity, and the mechanism of action was explored. The results of the presen study demonstrated that IC53d was upregulated in gastric cancer tissues and was associated with tumor T­stage. Furthermore, overexpression of IC53d promoted the proliferation, colony formation and G1/S phase transition of gastric cancer cells, leading to enhancement of tumorigenesis in vitro and in vivo. Overexpression of IC53d also promoted phosphorylation of protein kinase B (AKT) and glycogen synthase kinase 3ß (GSK3ß), which increased the expression of cyclin D1. In addition, high cyclin D1 expression was associated with a significantly worse prognosis for patients compared with in patients with low cyclin D1 expression. These results indicated that IC53d may promote the phosphorylation of AKT and GSK3ß, which in turn may increase cyclin D1 expression, enhancing G1/S phase transition, accelerating cell cycle progression, promoting the proliferation of gastric cancer cells, and inducing a poor prognosis in patients with gastric cancer.

Rhizoma Amorphophalli inhibits TNBC cell proliferation, migration, invasion and metastasis through the PI3K/Akt/mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Triple-negative breast cancer (TNBC) often presents with a high histological grade and high malignancy, which greatly contribute to patient morbidity and mortality. Rhizoma Amorphophalli exhibits many biological and pharmacological activities, but its potential as a therapeutic agent for the treatment of metastatic TNBC patients remains poorly understood. AIM OF THE STUDY: The aim of this study was to determine whether Rhizoma Amorphophalli inhibits metastasis in the human TNBC MDA-MB-231 cell line. MATERIALS AND METHODS: CCK-8 and colony formation assays were adopted for the analysis of cell activity and cell proliferation, respectively. Flow cytometry was used for cell cycle analysis. Wound healing and transwell assays were performed to assess cell migration and invasion, respectively. PI3K/Akt/mTOR signaling pathways were analyzed through western blotting. Breast cancer cell metastasis to the lung in a xenograft model was evaluated by in vivo fluorescence imaging. A GC-MS analysis was performed to determine the main components of the petroleum ether fraction from the ethanol extract of Rhizoma Amorphophalli (abbreviated RhA). RESULTS: RhA significantly reduced breast cancer cell viability and proliferation. The flow cytometry analysis indicated that RhA induced MDA-MB-231 cell arrest at the S phase. Additionally, RhA decreased MDA-MB-231 cell migration and invasion and inhibited the PI3K/Akt/mTOR signaling pathway. In addition, mice treated with RhA exhibited a significant reduction in tumor infiltration and a decrease in breast cancer cell metastasis to the lung. The GC-MS analysis results showed that RhA contained a large number of unsaturated fatty acids, such as octadecadienoic acid (linoleic acid), octadecatrienoic acid (linolenic acid), and oleate, which might represent the anticancer components of the extract. CONCLUSIONS: The results of this study suggest that RhA has potential as a therapeutic candidate for metastatic TNBC treatment.