Efficacy and safety of total neoadjuvant therapy in locally advanced rectal cancer: a meta-analysis.

PURPOSE: The standard of care for locally advanced rectal cancer (LARC) has changed from a single radical surgical treatment to the current multimodality treatment (standard chemoradiotherapy (CRT) and total neoadjuvant therapy (TNT)). The efficacy and safety of both TNT and standard CRT are evaluated in randomized controlled trials (RCTs). METHODS: RCTs were comprehensively searched in Chinese and English electronic databases. The experimental and control groups were TNT and the standard CRT, respectively, included in this meta-analysis. The outcomes were assessed through a fixed-effect or random-effect model of pooled odds (OR) or hazard ratios (HR). RESULTS: Eleven RCTs, involving 3,101 patients were included in the final analysis. TNT showed increase in the pathological complete response (pCR) (OR = 1.95, 95% confidence interval (CI): 1.57-2.41; P < 0.05) and the R0 resection (OR = 1.19, 95% CI: 0.99-1.43; P = 0.062). There was no significant difference in local recurrence-free survival (LRFS) (HR = 0.97, P = 0.803), but TNT had better 3-year disease-free survival (DFS) (HR = 0.82, 95% CI: 0.72-0.93, P < 0.05), overall survival (OS) (HR = 0.87, 95% CI: 0.74-1.02, P = 0.08) and distant metastasis-free survival (DMFS) (HR = 0.79, 95% CI: 0.67-0.93, P < 0.05) than standard CRT. CONCLUSIONS: TNT was safe and feasible as it improved pCR and survival outcomes, and reduced the risk of distant metastasis compared with standard CRT. TNT may be a superior strategy for LARC, but more RCTs are needed to prove it. REGISTRATION AND PROTOCOL: PROSPERO CRD42022327697. We added the Chinese database after registration because of the inclusion of fewer RCTs www.crd.york.ac.uk/PROSPERO/ .

ß-Sitosterol blocks the LEF-1-mediated Wnt/ß-catenin pathway to inhibit proliferation of human colon cancer cells.

OBJECTIVES: This study aimed to investigate the LEF-1-mediated Wnt/ß-catenin pathway for its biological functions and prognostic value in colon cancer (CC). Furthermore, the potential molecular mechanism of ß-sitosterol in CC was investigated in vitro. METHODS: Clinical information and gene expression profiles from CC patients were obtained based on Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In addition, we applied R software "Limma" package for the differential analysis of LEF-1 between cancer and para-carcinoma tissue samples. Kaplan-Meier (KM) survival analysis was adopted for analyzing whether LEF-1 was of prognostic significance. Moreover, gene set enrichment analysis (GSEA) was adopted for pathway enrichment analysis and visualization. In addition, CCK8, plate cloning, scratch and high-content screening (HCS) imaging assays were performed to examine the therapeutic efficacy of ß-sitosterol in human CC HCT116 cells. siRNA technology was employed to knock down LEF1 expression in HCT116 cells. qRT-PCR and Western-blot (WB) analysis were carried out to analyze the HCT-116 mRNA and protein expression levels, respectively. RESULTS: LEF-1 was up-regulated within CC and acted as an oncogenic gene. LEF-1 up-regulation predicted the dismal prognostic outcome and activated the Wnt/ß-catenin pathway. ß-sitosterol effectively suppressed HCT116 cells proliferation and invasion. For the mechanism underlying ß-sitosterol, ß-sitosterol was found to significantly down-regulate LEF-1 gene and protein expression and disrupt Wnt/ß-catenin pathway transmission in HCT116 cells. After suppressing LEF-1 expression, its downstream targets including C-myc, Survivin and CCND1 were also down-regulated. CONCLUSION: According to our results, LEF-1 down-regulation can effectively block Wnt/ß-catenin pathway, inhibit CC cell growth and migration. Collectively, ß-sitosterol can be used to treat CC, which can provide anti-tumor activity by targeting LEF-1.

Berberine promotes M2 macrophage polarisation through the IL-4-STAT6 signalling pathway in ulcerative colitis treatment.

Aim: This study focusses on the anti-inflammatory and immune-modulatory roles of berberine (BBR) in ulcerative colitis (UC) treatment. Additionally, the underlying mechanisms of BBR were systematically explored. Methods: A 3% (w/v) dextran sodium sulphate (DSS) solution was used for establishing the mice UC model. M2 macrophage polarisation was induced in RAW 264.7 cells using interleukin 4 (IL-4), whereas M1 macrophage polarisation was induced using lipopolysaccharide. Colon length, colon mucosa damage index (CMDI), and haematoxylin-eosin (HE) staining were used to evaluate colon damage induced by DSS. M1/M2 macrophages in the colon tissue were identified using immunofluorescence (IF) staining with CD86+ or CD163+. M1/M2 macrophages in the abdomen were examined using flow cytometry. An enzyme-linked immunosorbent assay was conducted to identify M1/M2 macrophage supernatant biomarkers in RAW 264.7 cells. Western blotting, immunohistochemical staining, and real-time PCR were performed to investigate the potential mechanisms of BBR for treating UC in vivo and in vitro. Results: BBR was found to prolong colon length, ameliorate CMDI and alleviate the colon's pathological changes in UC mice. In DSS-induced UC mice, M1 macrophages predominated. BBR promoted M2 macrophages and suppressed M1 macrophages in the colon and abdomen of DSS-induced UC mice. Additionally, BBR significantly decreased M1-specific markers (IFN-γ and IL-1ß) while increasing M2-specific markers (IL-10 and TGF-ß) in the supernatants of RAW 264.7 cells. BBR upregulated the mRNA expression of IL-4, STAT6, and Chil3 while downregulating TNF-α, IFN-γ, and NOS2 expression in vivo. Moreover, BBR activated the downstream targets of the IL-4-STAT6 signalling pathway and enhanced the phosphorylation of STAT6 in vivo and in vitro to polarise M2 macrophage. Conclusion: In UC mice, BBR suppressed M1 macrophages while promoting M2 macrophages. M1 macrophage suppression and M2 macrophage activation were strongly correlated with the anti-inflammatory and immune-modulating activities of BBR. BBR induced the polarisation of M2 macrophages by activating the IL-4-STAT6 signalling pathway, which contributed to its therapeutic efficacy against UC.

Cinnamic acid regulates the intestinal microbiome and short-chain fatty acids to treat slow transit constipation.

BACKGROUND: Slow transit constipation (STC) is a disorder with delayed colonic transit. Cinnamic acid (CA) is an organic acid in natural plants, such as Radix Scrophulariae (Xuan Shen), with low toxicity and biological activities to modulate the intestinal microbiome. AIM: To explore the potential effects of CA on the intestinal microbiome and the primary endogenous metabolites-short-chain fatty acids (SCFAs) and evaluate the therapeutic effects of CA in STC. METHODS: Loperamide was applied to induce STC in mice. The treatment effects of CA on STC mice were assessed from the 24 h defecations, fecal moisture and intestinal transit rate. The enteric neurotransmitters: 5-hydroxytryptamine (5-HT) and vasoactive intestinal peptide (VIP) were determined by the enzyme-linked immunosorbent assay. Hematoxylin-eosin and Alcian blue and Periodic acid Schiff staining were used to evaluate intestinal mucosa's histopathological performance and secretory function. 16S rDNA was employed to analyze the composition and abundance of the intestinal microbiome. The SCFAs in stool samples were quantitatively detected by gas chromatography-mass spectrometry. RESULTS: CA ameliorated the symptoms of STC and treated STC effectively. CA ameliorated the infiltration of neutrophils and lymphocytes, increased the number of goblet cells and acidic mucus secretion of the mucosa. In addition, CA significantly increased the concentration of 5-HT and reduced VIP. CA significantly improved the diversity and abundance of the beneficial microbiome. Furthermore, the production of SCFAs [including acetic acid (AA), butyric acid (BA), propionic acid (PA) and valeric acid (VA)] was significantly promoted by CA. The changed abundance of Firmicutes, Akkermansia, Lachnoclostridium, Monoglobus, UCG.005, Paenalcaligenes, Psychrobacter and Acinetobacter were involved in the production of AA, BA, PA and VA. CONCLUSION: CA could treat STC effectively by ameliorating the composition and abundance of the intestinal microbiome to regulate the production of SCFAs.

Efficacy and safety of nab-paclitaxel plus platinum in non-small cell lung cancer: a meta-analysis.

Purpose: This meta-analysis was exerted in assessing the anticancer efficacy and safety of nab-paclitaxel (nab-P) when combined with platinum compound agents for therapy in patients with non-small cell lung cancer (NSCLC). Method: We systematically searched the following seven electronic databases: PubMed, Cochrane Library, Web of Science, Embase, CNKI, Wan Fang, and China Science and Technology Journal Data. Randomized comparative clinical [randomized controlled clinical trial (RCT)] studies on nab-P plus platinum and carboplatin or cisplatin in combination with conventional chemotherapy agents or traditional paclitaxel were searched. Results: A total of 19 RCT studies involving 6,011 patients were analyzed. The primary outcome includes the overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). The secondary outcome includes adverse events (AEs). Nab-P combined with platinum (carboplatin/cisplatin) had a better ORR [odds ratio (OR) = 1.66, 95% confidence interval (CI) (1.34, 2.05), p < 0.001] and improved PFS [hazard ratio (HR) = 0.84, 95% CI: (0.74, 0.94), p = 0.01] and OS [HR = 0.86, 95% CI: (0.78, 0.96), p = 0.008] in NSCLC patients. ORR [OR = 2.18, 95% CI: (1.07, 4.43)], PFS [HR = 0.62, 95% CI: (0.40, 0.97)], and OS [HR = 0.63, 95% CI: (0.49, 0.81)] were significantly improved among patients aged >70 years, and ORR [OR = 1.80, 95% CI: (1.20, 2.70)] and PFS [HR = 0.74, 95% CI: (0.56, 0.97)] were significantly elevated with SCC rate ≥65% in NSCLC patients (all p > 0.05). Among the adverse effects, the prevalence of neutropenia, neuralgia, and arthralgia/myalgia (≥ grade 3) compared to that of the control group. On the other hand, the prevalence of anemia and thrombocytopenia was higher in the nab-P plus platinum (carboplatin/cisplatin) compared to that of controls. It is worth noting that fatigue did not show statistical significance. Conclusion: Nab-P in combination with carboplatin/cisplatin regimen improves efficacy and tolerability in patients with NSCLC. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022288499.

Meta-analysis of omega-3 polyunsaturated fatty acids on immune functions and nutritional status of patients with colorectal cancer.

This meta-analysis assessed the clinical significance of omega-3 polyunsaturated fatty acids (PUFAs) in the management of patients with colorectal cancer (CRC) after radical resection. We comprehensively searched electronic databases, such as EMBASE, PubMed, MEDLINE and Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Database (CBM), Wanfang Electronic Database, and VIP Medical Information System (VIP) from inception to 10 April 2022. Randomized controlled trials (RCTs) of omega-3 PUFAs and conventional nutrition or blank treatments were selected. The following were evaluated in the pooled analysis: immune function-related indices (IgA, IgG, IgM, CD3+, CD4+, CD8+, and ratio of CD4+/CD8+), nutritional status-related indices [total protein (TP), albumin (ALB), and prealbumin (PA)], and their corresponding 95% confidence intervals (CIs). Next, we conducted heterogeneity detection, sensitivity analysis, contour-enhanced funnel plot to detect possible publication bias, and meta-regression analysis. In all, 20 studies, including 1,613 patients (809 in the omega-3 PUFAs group and 804 in the control group), were selected in the final analysis. The results of the pooled analysis showed that omega-3 PUFAs significantly increased the humoral immune function indices, including IgA [standardized mean difference (SMD) = 0.54, 95% CI 0.10-0.99], IgM (SMD = 0.52, 95% CI 0.05-0.99), IgG (SMD = 0.65, 95% CI 0.47-0.84); T cell immune function indices, including CD3+ (SMD = 0.73, 95% CI 0.54-0.92), CD4+ (SMD = 0.76, 95% CI 0.53-0.98), and ratio of CD4+/CD8+ (SMD = 0.66, 95% CI 0.39-0.92). However, CD8+ was markedly reduced after intervention of omega-3 PUFAs (SMD = -0.28, 95% CI -0.66-0.09). In addition, pooled analysis indicated that omega-3 PUFAs markedly improved the nutritional status indicators, including TP (SMD = 0.53, 95% CI 0.17-0.88), ALB (SMD = 0.43, 95% CI 0.15-0.70), and PA (SMD = 0.46, 95% CI 0.01-0.90). The meta-regression analysis revealed that the covariates of the small sample affected the robustness and credibility of the CD4+ results. Conclusively, this study suggested that omega-3 PUFAs have the potential to be used as a valid immunonutritional therapy/support for treating patients with CRC postoperatively. This meta-analysis protocol was registered in PROSPERO (no. CRD42021288487). Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021288487], identifier [CRD42021288487].

Meta analysis of indocyanine green fluorescence in patients undergoing laparoscopic colorectal cancer surgery.

This meta-analysis intended to systematically evaluate the clinical implications of indocyanine green fluorescence (ICG) in patients undergoing laparoscopic colorectal surgery. PubMed, MEDLINE, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Medical Information System and China Biomedical Database were synthetically searched for studies published from inception to April 14, 2022. The randomized controlled trials comparing ICG-use with controls were selected. The incidence of anastomotic leakage (AL), lymph node detection, operation duration, intraoperative bleeding, postoperative morbidity, and hospitalization time were evaluated in summary analysis, and calculated the corresponding 95% confidence intervals (CI). Subsequently, in addition to subgroup analyses, studies for heterogeneity, sensitivity, and publication bias were carried out. Consequently, 3453 patients in the enrolled 15 studies were included; 1616 patients were allocated to the experimental group, and 1837 patients were assigned to the control group. The ICG group had a significantly decreased risk of AL (RR: 0.50, 95% CI: 0.37-0.67) and shorter hospitalization time (SMD: -0.31, 95% CI: -0.54-0.08) compared to the control group. Meanwhile, the ICG showed clearly better lymph node detection (SMD: 0.19, 95% CI: 0.02-0.36). However, when the content of operation duration (SMD: -0.07, 95% CI: -0.30-0.15) and intraoperative bleeding (SMD: -0.16, 95% CI: -0.35-0.04) were compared, no statistical significance was found. Furthermore, the pooled analysis of postoperative morbidity was not statistically significant (RR:0.79, 95% CI: 0.58-1.08). The results of the subgroup analysis of AL indicated that there may be regional variations in AL (RR: 0.50, 95% CI: 0.37-0.67) but not in postoperative morbidity (RR: 0.79, 95% CI: 0.58-1.08). In conclusion, the application of ICG in laparoscopic colorectal surgery can effectively reduce the AL, lymph node detection, and hospitalization time. However, more multicenter large-sample randomized controlled trials are required to further confirm its advantages. The meta-analysis was registered in PROSPERO (no. CRD42022288054).

Meta-Analysis of Hepatic Arterial Infusion for Liver Metastases From Colorectal Cancer.

The aim of the present study was to evaluate the potential benefits of hepatic arterial infusion chemotherapy (HAIC) in the management of colorectal liver metastases (CRLM). Electronic databases, including PubMed, EMBASE, Medline, Web of Science, and Cochrane Library, were comprehensively searched from inception to November 2020. Prospective randomized trials with HAIC vs. systemic chemotherapy (SC) were selected. The overall survival (OS), tumor response rates (RRs), progression-free survival (PFS), and corresponding 95% confidence intervals (CIs) were assessed in the meta-analysis. Subsequently, the heterogeneity between studies, sensitivity, publication bias, and meta-regression analyses were performed. Finally, 18 studies, which contained 1,766 participants (922 in the HAIC group and 844 in the SC group) were included. There was a significantly higher OS rate in the HAIC as palliative treatment group (HR, 0.17; 95% CI, 0.08-0.26; P = 0.000) and HAIC as adjuvant treatment group compared with SC group (HR, 0.63; 95% CI, 0.38-0.87; P = 0.000). The complete and partial tumor RRs were also increased significantly in the HAIC as palliative treatment group (RR = 2.09; 95% CI, 1.36-3.22; P = 0.001) and as adjuvant treatment group compared with SC group (RR = 2.14; 95% CI, 1.40-3.26; P = 0.000). However, PFS did not differ significantly between the HAIC and SC groups (P > 0.05). Meta-regression analysis showed potential covariates did not influence on the association between HAIC and OS outcomes (P > 0.05). The results of the present study suggested that HAIC may be a potential therapeutic regimen that may improve the outcomes of patients with CRLM. The present meta-analysis has been registered in PROSPERO (no. CRD 42019145719).

Protective Effects and Network Analysis of Ginsenoside Rb1 Against Cerebral Ischemia Injury: A Pharmacological Review.

Ischemic stroke is a leading cause of death and disability worldwide. Currently, only a limited number of drugs are available for treating ischemic stroke. Hence, studies aiming to explore and develop other potential strategies and agents for preventing and treating ischemic stroke are urgently needed. Ginseng Rb1 (GRb1), a saponin from natural active ingredients derived from traditional Chinese medicine (TCM), exerts neuroprotective effects on the central nervous system (CNS). We conducted this review to explore and summarize the protective effects and mechanisms of GRb1 on cerebral ischemic injury, providing a valuable reference and insights for developing new agents to treat ischemic stroke. Our summarized results indicate that GRb1 exerts significant neuroprotective effects on cerebral ischemic injury both in vivo and in vitro, and these network actions and underlying mechanisms are mediated by antioxidant, anti-inflammatory, and antiapoptotic activities and involve the inhibition of excitotoxicity and Ca2+ influx, preservation of blood-brain barrier (BBB) integrity, and maintenance of energy metabolism. These findings indicate the potential of GRb1 as a candidate drug for treating ischemic stroke. Further studies, in particular clinical trials, will be important to confirm its therapeutic value in a clinical setting.

Meta-analysis of Glutamine on Immune Function and Post-Operative Complications of Patients With Colorectal Cancer.

The aim of this meta-analysis was to evaluate the clinical significance of glutamine in the management of patients with colorectal cancer (CRC) after radical operation. Electronic databases, including PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), VIP medicine information system (VIP), and Wanfang electronic databases were comprehensively searched from inception to 30, July 2021. Prospective randomized trials with glutamine vs. routine nutrition or blank therapy were selected. The immune function related indicators (including IgA, IgG, IgM, CD4+, CD8+, and the ratio of CD4+/CD8+), post-operative complications [including surgical site infection (SSI), anastomotic leakage, and length of hospital stay (LOS)], and corresponding 95% confidence intervals (CIs) were assessed in the pooled analysis. Subsequently, the heterogeneity between studies, sensitivity, publication bias, and meta-regression analysis were performed. Consequently, 31 studies which contained 2,201 patients (1,108 in the glutamine group and 1,093 in the control group) were included. Results of pooled analysis indicated that glutamine significantly improved the humoral immune function indicators [including IgA (SMD = 1.15, 95% CI: 0.72-1.58), IgM (SMD = 0.68, 95% CI: 0.48-0.89), and IgG (SMD = 1.10, 95% CI: 0.70-1.50)], and the T cell immune function indicators [including CD4+ (SMD = 0.76, 95% CI: 0.53-0.99) and the ratio of CD4+/CD8+ (SMD = 0.92, 95% CI: 0.57-1.28)]. Meanwhile, the content of CD8+ was decreased significantly (SMD = -0.50, 95% CI: -0.91 to -0.10) followed by glutamine intervention. Pooled analysis of SSI (RR = 0.48, 95% CI: 0.30-0.75), anastomotic leakage (RR = 0.23, 95% CI: 0.09-0.61), and LOS (SMD = -1.13, 95% CI: -1.68 to -0.58) were decreased significantly in glutamine group compared with control group. Metaregression analysis revealed that the covariate of small-sample effects influenced the robustness and reliability of IgG outcome potentially. Findings of the present work demonstrated that glutamine ought to be applied as an effective immunenutrition therapy in the treatment of patients with CRC after radical surgery. The present meta-analysis has been registered in PROSPERO (no. CRD42021243327). Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, Identifier: CRD42021243327.

Oleanolic Acid Induces Autophagy and Apoptosis via the AMPK-mTOR Signaling Pathway in Colon Cancer.

AIMS: The purpose of this study was to explore the biological functions of the mTOR and AMPK signaling pathways in colon cancer (CC). The potential molecular mechanisms by which oleanolic acid (OA) induces autophagy and apoptosis were also investigated. METHODS: The biological functions of mTOR were analyzed by GeneCards, the Search Tool for the Retrieval of Interacting Genes (STRING), and the Database for Annotation, Visualization and Integrated Discovery (DAVID). Least absolute shrinkage and selection operator (LASSO) regression analysis was used to obtain prognostic and survival data of CC patients from the Gene Expression Omnibus (GEO) database. The effects of OA on the CC cell lines HCT-116 and SW-480 were analyzed by CCK-8, colony formation assay, and high-content system (HCS) array scan. The apoptosis rate of SW-480 and HCT-116 cells was detected by flow cytometry. The mRNA and protein expression levels in HCT-116 and SW-480 cells and NCM-460 normal colonic epithelial cells were detected by RT-PCR and Western blotting. RESULTS: mTOR was highly expressed in CC patients and acted as an oncogene. The AMPK signaling pathway mediated by mTOR predicted the poor prognosis of CC patients. OA effectively inhibited the proliferation and viability of CC cells. Furthermore, the apoptosis rate of CC cells was clearly increased following OA administration. Regarding the molecular mechanism of OA, the results indicated that mTOR and the antiapoptosis gene Bcl-2 were downregulated by OA. In addition, regulator genes of autophagy and apoptosis, including BAX, caspase-9, caspase-8, and caspase-3, were significantly upregulated by OA. Moreover, OA upregulated AMPK and its downstream proteins, including TSC2, BAX, Beclin 1, LC3B-II, and ULK1, to induce autophagy and apoptosis in CC cells. CONCLUSION: The findings from this study demonstrate that OA could effectively inhibit the proliferation and viability of CC cells. The anti-CC activity of OA is closely related to the activation of the AMPK-mTOR signaling pathway. Activation of AMPK and inhibition of mTOR are involved in the induction of autophagy and apoptosis by OA. OA induced autophagy and apoptosis mainly in an AMPK activation-dependent manner in CC cells.

Different doses of prucalopride in treating chronic idiopathic constipation: a meta-analysis and Bayesian analysis.

OBJECTIVE: This study aims to explore the incremental benefit of different doses of prucalopride in treating chronic idiopathic constipation (CIC). METHODS: PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese Biomedical Database, China National Knowledge Infrastructure, VIP medicine information and Wanfang databases were comprehensively searched up to March 2020. Prospective trials with different doses of prucalopride versus placebo were selected. The frequency of spontaneous bowel movements (SBMs) per week and the treatment-emergent adverse events (TEAEs), such as headache, arrhythmia, diarrhoea, dizziness, nausea and vomiting, were first synthesised in a meta-analysis. The probability of optimal dose of prucalopride was then ranked by random-effects within Bayesian analysis. RESULTS: 14 high-quality randomised controlled trials with 4328 patients were ultimately included. SBMs per week increased significantly after using 1 mg (OR: 2.40, 95% CI 1.32 to 4.37), 2 mg (OR: 2.55, 95% CI 1.93 to 3.36) and 4 mg (OR: 2.51, 95% CI 1.92 to 3.28) prucalopride. Bayesian analysis demonstrated 1 mg dose obtained the maximum SBMs per week (OR: 3.31, 95% credible interval 1.72 to 6.16, probability rank=0.70) indirectly compared with 2 mg and 4 mg doses. TEAEs were higher significantly in 2 mg (risk ratio (RR): 1.20, 95% CI 1.09 to 1.33) and 4 mg (RR: 1.14, 95% CI 1.07 to 1.22) prucalopride. The 1 mg dose did not reach statistical significance (RR: 1.17, 95% CI 0.94 to 1.44). CONCLUSIONS: The study concludes that 1 mg dose at commencement could be safer in treating CIC and that 2 mg prucalopride could be more efficacious in terms of SBMs per week outcome receiving. PROSPERO REGISTRATION NUMBER: CRD42019136679.

Ursolic Acid Regulates Cell Cycle and Proliferation in Colon Adenocarcinoma by Suppressing Cyclin B1.

Aims: The biological functions of cyclin B1 (CCNB1) in colon adenocarcinoma (COAD) will be explored in this study. Furthermore, the therapeutic effects and potential molecular mechanisms of ursolic acid (UA) in COAD cells will also be investigated in vitro. Methods: COAD data were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Differentially expressed genes (DEGs) were determined with differential analysis. The biological functions of CCNB1 were analyzed through the GeneCards, the Search Tool for the Retrieval of Interacting Genes (STRING), and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) databases. Therapeutic effects of UA on COAD cell lines HCT-116 and SW-480 were analyzed by CCK-8 and high-content screening (HCS) imaging assay. Flow cytometry was utilized to detect cell cycle changes of SW-480 and HCT-116 cells. Levels of mRNA and expression proteins of HCT-116, SW-480, and normal colon epithelial cells NCM-460 were determined by qRT-PCR and western blot. Results: CCNB1 was highly expressed and acted as an oncogene in COAD patients. CCNB1 and its interacting genes were significantly enriched in the cell cycle pathway. UA effectively inhibited the proliferation and injured COAD cells. In addition, UA arrested cell cycle of COAD cells in S phase. With regard to the molecular mechanisms of UA, we demonstrated that UA can significantly downregulate CCNB1 and its interacting genes and proteins, including CDK1, CDC20, CCND1, and CCNA2, which contributed to cell cycle blocking and COAD treatment. Conclusion: Results from this study revealed that UA possesses therapeutic effects on COAD. The anti-COAD activities of UA are tightly related to suppression of CCNB1 and its interacting targets, which is crucial in abnormal cell cycle process.