Application value of contrast-enhanced ultrasonography in the treatment of uterine fibroids by high-intensity focused ultrasound ablation: A retrospective study.

PURPOSE: To determine efficacy and safety of contrast-enhanced ultrasonography (CEUS) in high-intensity focused ultrasound (HIFU) ablation of uterine fibroids (UFs). METHODS: We retrospectively reviewed women undergoing HIFU ablation for UFs between June 2018 and January 2020. Before and after HIFU, patients underwent CEUS and magnetic resonance imaging (MRI) examinations. The relationship between CEUS features and ablation rate was analyzed. The time-intensity curves on CEUS were measured before and after HIFU ablation, and compared with those obtained using MRI. Adverse reactions were recorded. RESULTS: A total of 64 patients were included. The immediate HIFU ablation rate significantly differed between low-, iso-, and high-enhancement UFs (87.2% ± 1.6%, 83.3% ± 2.1%, and 72.9% ± 3.1%, respectively; p < 0.05). On CEUS, the peak time of the time-intensity curve was significantly longer after treatment than before treatment (32.2 ± 9.7 and 26.7 ± 9.4 s, respectively; p < 0.05). Peak intensity was significantly lower after treatment than before treatment (13.7 ± 7.5 and 30.9 ± 11.2 dB, respectively; p < 0.05). All measurements were comparable between CEUS and MRI. The most common peri- and post-procedure adverse reaction was pain, which was temporary. CONCLUSION: CEUS could dynamically and safely evaluate the immediate effects of the HIFU ablation of UFs.

Comparison of outcomes of hysteroscopic myomectomy of type 2 submucous fibroids greater than 4 cm in diameter via pretreatment with HIFU or GnRH-a.

OBJECTIVE: To compare the efficacy and safety of high-intensity focused ultrasound (HIFU) and gonadotropin-releasing analogues (GnRH-a) as pretreatments for the hysteroscopic transcervical resection of myoma (TCRM) for type 2 submucosal fibroids greater than 4 centimeters in diameter. MATERIALS AND METHODS: Seventy-nine patients were assigned into two groups according patient preference: 42 in HIFU and 37 in GnRHa. TCRM was performed after 3 months of pretreatment with HIFU or GnRHa. RESULTS: Following pretreatment with HIFU or GnRHa, uterine-fibroid symptom (UFS) scores and hemoglobin levels (HGB) showed improvement. The fibroid maximum diameter, size of fibroids, and volume of the uterus were decreased. Following HIFU pretreatment, one case reported complete vaginal fibroid expulsion, and four reported partial fibroid expulsion. No similar cases were found in the GnRHa group. Eighteen patients were lost to follow-up prior to TCRM. Among the 31 patients in HIFU, the fibroids were downgraded to type 0 in 10 cases and type 1 in 5 cases. Of the 30 patients in GnRHa, the treated fibroids were downgraded to type 1 in 9 cases. The mean operation time and intraoperative blood loss of the HIFU group were significantly lower than those in the GnRHa group. No significant differences were observed in the incidence of intraoperative complications and the one-time resection rate of fibroids between the two groups (p>.05). CONCLUSIONS: HIFU seems to be superior to GnRHa as a pretreatment method prior to TCRM for type 2 submucosal fibroids greater than 4 centimeters in diameter.

[The Effect of miR-503-5p on the Proliferation, Invasion, Migration and Epithelial Interstitium of Cervical Cancer HeLa Cells via Targeting E2 F3].

OBJECTIVE: To investigate the effect of miR-503-5p on the proliferation, invasion, migration and epithelialization of cervical cancer HeLa cells via targeting E2 F3. METHODS: Four ccervical cancer HeLa cells groups were set up including control group, mimic-NC group, miR-503-5p mimic group, E2 F3 group, miR-503-5p mimic+ E2 F3 group (mimic+ E2 F3 group). The plasmids were separately or jointly transinfected into cervical cancer Hela cells of each group by Lipofectamine 2000, After transinfection, the target gene was predicted by gene prediction software, the targeting relationship was verified by fluorescein experiment, the expression of miR-503-5p and E2 F3 was detected by RT-PCR, cell proliferation was detected by MTT assay, expression of Ki67, proliferating cell nuclear antigen (PCNA), E-cadherin and N-cadherin were detected by Western blot, cell invasion was detected by Transwell, and cell migration was detected by scratch test. Nude mice were divided into control group and miR-503-5p mimic group, and 0.2 mL of cervical cancer HeLa cell suspension transfected with mimic-NC or miR-503-5p mimic was injected subcutaneously into the ventral side of the right hind limb of nude mice. Thirty days post injection, the nude mice were sacrificed by cervical dislocation. The tumor weight was weighed by an electronic balance, and the expression of KI67 and Vimentin in the tumor tissue was detected by immunohistochemistry. RESULTS: The expression level of miR-503-5p in cervical cancer HeLa cells was down-regulated, miR-503-5p directly targeted E2 F3 by binding with E2 F3 at binding sites in the 3'UTR region. Over-expressing of miR-503-5p inhibited the expression of E2 F3, significantly decreased cell growth rate and the expression level of Ki67 and PCNA, decreased the number of invasive cells, widened the scratches, reduced the healing rate, up-regulated the expression of E-cadherin and also down-regulated the expression of N-cadherin ( P<0.01). Over-expressing of miR-503-5p significantly reduced the volume and weight of transplanted tumors, and decreased the proportion of positive Ki67 and Vimentin ( P<0.01). CONCLUSION: miR-503-5p inhibits the proliferation, invasion, migration and epithelialization of cervical cancer HeLa cells by targeting E2 F3.

Effects of a microbubble ultrasound contrast agent on high-intensity focused ultrasound for uterine fibroids: a randomised controlled trial.

OBJECTIVE: To investigate the effects of a microbubble ultrasound contrast agent on high-intensity focused ultrasound (HIFU) treatment of uterine fibroids. METHODS: A total of 120 patients with solitary uterine fibroid were randomly assigned into Groups A, B, C and D. Patients in Groups A and B received 1.5 ml of SonoVue, Groups C and D received 1.5 ml of saline before HIFU ablation. HIFU sonication started at 6 min after administration of SonoVue or saline in Groups A and C, whereas it started at 10 min in Groups B and D. On day 1 after HIFU, magnetic resonance imaging was performed. Patients were followed up via phone or clinic visit during the first week after HIFU. RESULTS: No significant difference was observed in terms of age, fibroid location, diameter of fibroids, signal intensity on T2-weighted imaging, or tumour volume among the four groups (p > 0.05). The use of SonoVue significantly shortened the treatment time and sonication time. The sonication start time of 6 min, relative to 10 min, had significant effects on the treatment time and sonication time. The use of intravenous SonoVue followed by HIFU ablation 6 min later significantly increased the rate of significant grey-scale changes (55.9%) and the non-perfused volume ratio (94.2% ± 10.6%). No significant differences were observed in the incidence of intra-procedure and post-HIFU adverse effects among the four groups (p > 0.05). CONCLUSIONS: SonoVue could be safely used to enhance the ablation effects of HIFU treatment of uterine fibroids.

Follicle-Stimulating Hormone ß-Subunit Potentiates Bone Morphogenetic Protein 9-Induced Osteogenic Differentiation in Mouse Embryonic Fibroblasts.

Postmenopausal osteoporosis (PMOP)-related fractures usually result in morbidity and mortality in aging women, so it remains a global public health concern, and new effective safe treatments are urgently needed recently. Efficient osteogenesis from mesenchymal stem cells (MSCs) would have the clinical application potential in treating multiple osteal disorders. Follicle-stimulating hormone (FSH), a pituitary glycoprotein hormone highly associated with menopausal bone turnover, whose peculiar part of receptor binding is follicle-stimulating hormone ß-subunit (FSHß). Bone morphogenetic protein 9 (BMP9), a potent osteogenic factor, can up-regulate FSHß in mouse embryonic fibroblasts (MEFs). However, it is unclear, whether extrapituitary FSHß affects BMP9-induced osteogenesis in MEFs. In this study, we investigated the role of FSHß in BMP9-induced osteogenesis in MEFs. We found that exogenous expression of FSHß significantly increased BMP9-induced alkaline phosphatase activity (ALP), the expression of osteogenic transcriptional factors, Runx2 and Osx, and the established late osteogenic markers, osteopontin (OPN) and osteocalcin (OCN), so does the ectopic bone formation. Mechanistically, FSHß dramatically enhanced BMP9-induced BMP/Smad signal transduction, presenting the augment phosphorylation of Smad1/5/8, whereas treatment with anti-FSHß antibodies suppressed these effects. An adenylate cyclase inhibitor obviously suppressed ALP and BMP/Smad signal transduction induced by BMP9 or the combination of BMP9 and FSHß in MEFs. Collectively, our findings suggested that FSHß may promote BMP9-induced activation of BMP/Smad signaling through a FSH/FSH receptor (FSHR)/cAMP dependent pathway in MEFs partly. J. Cell. Biochem. 118: 1792-1802, 2017. © 2016 Wiley Periodicals, Inc.

Hypertension and non-alcoholic fatty liver disease proven by transient elastography.

AIM: The relationship between non-alcoholic fatty liver disease (NAFLD) and hypertension is poorly understood. In the present study, we aimed to assess the relationship between essential hypertension and NAFLD, by using a new diagnostic tool, transient elastography (TE). METHODS: We enrolled 836 subjects in this study. All subjects underwent a comprehensive questionnaire survey and blood test. Each patient had undergone TE to detect the controlled attenuation parameter, which was used to and quantify liver steatosis with the help of TE. RESULTS: Participants with hypertension showed a higher prevalence of NAFLD defined by TE (P < 0.05). After adjusting for body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase, triglycerides, total cholesterol, and high-density lipoprotein cholesterol, the odds ratio for NAFLD, comparing the grade 3 group (systolic blood pressure level ≥ 180 mmHg and/or diastolic blood pressure level ≥ 110 mmHg) with the normal group, was 1.476 (95% confidence interval, 1.166-2.551). A stepwise multivariate linear regression analysis (R2 = 0.084, P = 0.043) retained NAFLD, BMI, and AST as significant predictors of the systolic blood pressure levels. Additionally, stepwise multivariate linear regression analysis (R2 = 0.199, P = 0.037) retained NAFLD, controlled attenuation parameter, BMI, triglycerides, and high-density lipoprotein cholesterol as significant predictors of diastolic blood pressure levels. In addition, BMI, AST, and alanine aminotransferase were associated with systolic blood pressure levels among individuals with NAFLD; BMI, AST, and total cholesterol were associated with diastolic blood pressure levels among individuals with NAFLD. CONCLUSION: The main finding of our study is that hypertensive patients have a higher prevalence of NAFLD defined by TE, and NAFLD is independently associated with hypertension and blood pressure category.

Patient-reported symptom burden and circulating cytokines undergoing chemotherapy: a pilot study in patients with ovarian cancer.

OBJECTIVE: To analyze the fluctuations of patient-reported outcomes (PROs) and their relationships with cytokines in the peripheral blood of patients undergoing chemotherapy for ovarian cancer (OC). METHODS: PROs burden was prospectively measured by the M.D. Anderson Symptom Inventory-Ovarian Cancer (MDASI-OC) at baseline before chemotherapy, on a daily basis during and post-chemotherapy days (PCD) 7, 14, and 20. Cytokines were collected at baseline, days prior to hospital discharge and PCD 20. Pearson correlation was used to explore the associations between PROs and cytokines levels in peripheral blood. RESULTS: The top 8 rated symptoms were compared between the neoadjuvant chemotherapy (NACT) group (n=20) and the postoperative adjuvant chemotherapy (PAC) group (n=7). Before chemotherapy, the mean scores of fatigue and lack of appetite in the NACT group were higher than those in the PAC group. After chemotherapy, pain, nausea, vomiting, disturbed sleep, lack of appetite, and constipation increased to peak during PCD 2-6; while, fatigue and numbness or tingling remained at high levels over PCD 2-13. By PCD 20, disturbed sleep and fatigue showed a significant increase in mean scores, particularly in the NACT group; while, other symptom scores decreased and returned to baseline levels. Additionally, the longitudinal fluctuations in pain, fatigue, and lack of appetite were positively associated with circulating levels of interleukin-6 and interferon gamma (p<0.05). CONCLUSION: MDASI-OC was feasible and adaptable for demonstrating the fluctuations of symptom burden throughout chemotherapy course. Moreover, symptoms changing along with cytokines levels could provide clues for exploring mechanism underlying biochemical etiology.

Causal effects and functional mechanisms of the Internet on residents' physical fitness-An empirical analysis based on China family panel survey.

Introduction: Physical fitness is an essential part of a healthy lifestyle that concerns the overall health of the nation. Research on the relationship between the Internet and physical fitness has long been caught in the dilemma of "media mobilization" and "media suppression," and previous studies have rarely examined the causal relationship and functional mechanism. Methods: This study selected the data of 23,989 samples successfully followed in all three surveys of the China Family Panel Survey (CFPS) from 2014 to 2018 to explore the correlation and causal inference between the Internet and physical fitness by using the Time Fixed Effects Model and cross-lagged models, respectively; meanwhile, the data of 24,687 samples in CFPS 2020 to examine the functional mechanism of the Internet's effect on residents' physical fitness behavior by the KHB method. Results: We obtained three valuable conclusions as follows: First, there is a significant correlation between the Internet and physical fitness behavior. Second, the Internet use is the cause for the increase in fitness frequency, and there is a rival relationship between Internet duration and fitness time. Third, under regular prevention and control of the COVID-19 epidemic, social capital and health risk perceptions are the functional mechanisms of the Internet influencing fitness behavior, and the mediating effect of psychological health risk perceptions is higher than that of social capital. Discussion: It's necessary to create an intelligent, informative, and digital sports public service system by enriching and optimizing sports media and facilitating the Internet to serve residents' physical fitness better. The new concept of "Internet plus Fitness" will be of great significance in the implementation of the "Healthy China Initiative."

Development and Validation of a Hypoxia-related Prognostic Model for Ovarian Cancer.

BACKGROUND: The high heterogeneity of ovarian cancer (OC) brings great difficulties to its early diagnosis and prognostic forecast. There is an urgent need to establish a prognostic model of OC based on clinicopathological features and genomics. METHODS: We identified hypoxia-related differentially expressed genes (DEGs) between OC tissues from The Cancer Genome Atlas (TCGA) and normal tissues from the Genotype-Tissue Expression (GTEx). LASSO Cox regression analysis was applied for building a prognostic model in the TCGA-GTEx cohorts, and its predictive value was validated in the GEO-OC cohort. Functional enrichment analysis was performed to investigate the underlying mechanisms. By constructing a hypoxia model of the SKOV3 cell line and applying qRT-PCR, we investigated the relationship between hypoxia with two novel genes in the prognostic model (ISG20 and ANGPTL4). RESULTS: Twelve prognostic hypoxia-related DEGs were identified, and nine of them were selected to establish a prognostic model. OC patients were stratified into two risk groups, and the high-risk group showed reduced survival time compared to the low-risk group upon survival analysis. Univariate and multivariate Cox regression analysis demonstrated that the risk score was an independent risk factor for overall survival. The biological function of the identified prognostic hypoxia-related gene signature was involved in immune cell infiltration. Low expression of ISG20 was observed in the CoCl2-mimicked hypoxic SKOV3 cell line and negatively correlated with HIF-1α. CONCLUSION: Our findings showed that this hypoxia-related gene signature could serve as a satisfactory prognostic classifier for OC and will be beneficial to the research and development of targeted therapeutic strategies.

Efficacy and safety of auto-cross-linked hyaluronic gel to prevent intrauterine adhesion after hysteroscopic electrosurgical resection: a multi-center randomized controlled trial.

Background: The electrothermal effect of hysteroscopic bipolar electrosurgical resection may cause damage to the endometrium, leading to intrauterine adhesion (IUA). Although some studies have demonstrated the efficacy and feasibility of auto-cross-linked hyaluronic (ACP) gel in preventing IUAs, controversy over its use continues. In this randomized controlled multi-center 2-arm parallel trial, we aimed to examine the efficacy and safety of ACP gel in preventing IUA after hysteroscopic electrosurgical resection and facilitate pregnancy in patients. Methods: Patients from 4 centers in China were randomly assigned (1:1) to receive an intrauterine infusion of ACP gel or nothing after hysteroscopic electrosurgical resection. The randomization assignment was generated by computer and kept in a sealed envelope. A second-look hysteroscopy was performed within 3 months of the surgery. Results: From June 2018 to May 2021, 200 patients were recruited. Ultimately, 82 patients in both groups were included in the result analysis. The baseline characteristics were comparable. The outcomes were assessed by using per-protocol analysis. The incidence of IUA in the ACP gel group was lower than that in the control group [3.66% vs. 10.98%, risk ratio (RR) =0.333, 95% confidence interval (CI): 0.094-1.187, P=0.072], and the planned pregnancy rate was higher than that of the control group (60.98% vs. 40.54%, RR =1.504, 95% CI: 0.949-2.384, P=0.071), but the difference was not statistically significant. There was no significant difference in menstruation change. Menstrual volume remained unchanged in most cases (86.59% in ACP gel group vs. 89.02% in the control group, RR =0.877, 95% CI: 0.877-1.109, P=0.815). Menstrual volume decreased in 10 women in the ACP gel group and 8 in the control group (12.20% vs. 9.76%, RR =1.250, 95% CI: 0.520-3.007, P=0.617). No adverse effects were observed after the ACP administration. Conclusions: The present study showed that the use of ACP gel appeared to reduce both the tendency of IUA and American Fertility Society (AFS) scores and improve the subsequent pregnancy rate during hysteroscopic electrosurgical resection when treating polyps, fibroids, and uterine septum. ACP might be recommended to prevent IUA after such surgery. Further studies should be conducted with larger numbers of participants. Trial Registration: Chinese Clinical Trial Registry ChiCTR2100047165.

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells.

Colon cancer is common worldwide and accounts for the significant cancer related morbidity and mortality in patients. Although extensive advancement has been made in colon cancer treatment and diagnosis in the last decades, there is still a giant gap between the clinical expectation. It has been reported that resveratrol (Res) may be a potential candidate for cancer treatment. However, the specific mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Res in human colon cancer cells, and unveiled the possible mechanism for this effect. With cell viability, flow cytometry, PCR and western blot analysis, we demonstrated the efficacious anticancer activity of Res in HCT116 cells. Mechanically, we found that Res greatly upregulates BMP7 in HCT116 cells. Exogenous BMP7 enhances the anticancer effect of Res in HCT116 cells, which was almost reversed by the BMP7 specific antibody. Res does not activate the BMPs/Smads signaling, but decreases the phosphorylation of Akt1/2/3 substantially in HCT116 cells. Exogenous BMP7 enhances the inhibitory effect of Res on the phosphorylation of Akt1/2/3, while BMP7 immunodepletion reverses this effect notably. Res markedly decreases the phosphorylation of PTEN, which can be enhanced by exogenous BMP7 but partly reversed by the BMP7 antibody. Our findings suggested that Res may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating BMP7 to decrease, at least, the phosphorylation of PTEN.

TGF-ß1/PTEN/PI3K signaling plays a critical role in the anti-proliferation effect of tetrandrine in human colon cancer cells.

The diagnosis and treatment for colon cancer have been greatly developed, but the prognosis remains unsatisfactory. There is still a great clinical need to explore new efficacious drugs for colon cancer treatment. Tetrandrine (Tet) is a bis-benzylisoquinoline alkaloid. It has been shown that Tet may be a potential candidate for cancer treatment, but the explicit mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Tet in human colon cancer cells and dissected the possible mechanism. With cell viability assay and flow cytometry analysis, we confirmed that Tet can effectively inhibit the proliferation and induce apoptosis in HCT116 cells. Mechanically, we found that Tet greatly increases the mRNA and protein level of TGF-ß1 in HCT116 cells. Exogenous TGF-ß1 enhances the anti-proliferation and apoptosis inducing effect of Tet in HCT116 cells, which has been partly reversed by TGF-ß1 inhibitor. Tet decreases the phosphorylation of Akt1/2/3 in HCT116 cells. This effect can be enhanced by exogenous TGF-ß1, but partly reversed by TGF-ß1 inhibitor. Tet exhibits no effect on total level of PTEN, but decreases the phosphorylation of PTEN; exogenous TGF-ß1 enhances the effect of Tet on decreasing the phosphorylation of PTEN, which was partly reversed by TGF-ß1 inhibitor. Our findings suggested that Tet may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating TGF-ß1 to decrease the phosphorylation of PTEN.

Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK.

Oridonin (ORI), a diterpenoid purified from Rabdosia rubescens, has been reported as a promising chemotherapy drug for colon cancer treatment; yet, the precise mechanisms underlying this anticancer activity remain unclear. In the present study, we investigated the anticancer effect of ORI in HCT116 cells, and dissected the possible molecular mechanisms underlying this activity. With crystal violet staining, flow cytometry and western blot assay, we found that ORI effectively inhibited the proliferation and induced the apoptosis of HCT116 cells. Further analysis of the results indicated that BMP7 was greatly upregulated by ORI in the HCT116 cells, but its endogenous expression in FHC cells was apparently lower than that in the colon cancer cell lines. Exogenous expression of BMP7 inhibited the proliferation of the HCT116 cells, and substantially potentiated the anticancer effect of ORI. However, the specific antibody of BMP7 nearly abolished this anticancer activity of ORI in the HCT116 cells. Meanwhile, ORI exerted no significant effect on the level of phosphorylated Smad1/5/8 or total p38 MAPK, but greatly increased the level of phosphorylated p38 MAPK in the HCT116 cells. A p38 MAPK-specific inhibitor partly reversed the antiproliferative effect of BMP7 in the HCT116 cells, but prominently promoted the effect of the BMP7 antibody on proliferation. Exogenous expression of BMP7 increased the ORI-induced phosphorylation of p38 MAPK, while the BMP7 antibody almost abolished the ORI-elevated p38 MAPK phosphorylation. Our findings suggest that ORI may be an efficacious drug for colon cancer treatment. This anticancer activity of ORI may be mediated by upregulating BMP7 at least to increase the activation of p38 MAPK.

All-trans retinoic acid shifts rosiglitazone-induced adipogenic differentiation to osteogenic differentiation in mouse embryonic fibroblasts.

Rosiglitazone (RSG) is a potent drug used in the treatment of insulin resistance; however, it is associated with marked skeletal toxicity. RSG-induced osteoporosis may contribute to the promotion of adipogenic differentiation at the expense of osteogenic differentiation in bone marrow stromal cells. The aim of this study was to investigate whether RSG-induced bone toxicity can be reversed by combined treatment with all-trans retinoic acid (ATRA). We examined different osteogenic markers in mouse embryonic fibroblasts (MEFs) following treatment with RSG, ATRA, or RSG and ATRA in combination. We examined the effects of RSG and/or ATRA on ectopic bone formation, and dissected the possible molecular mechanisms underlying this process. We found that ATRA or RSG both induced alkaline phosphatase (ALP) activity in the MEFs, and that the ATRA-induced ALP activity was enhanced by RSG and vice versa. However, only the combination of RSG and ATRA increased the expression of osteopontin and osteocalcin, promoted matrix mineralization, and induced ectopic ossification in MEFs. Mechanistically, we found that the osteogenic differentiation induced by the combination of RSG and ATRA may be mediated partly by suppressing RSG-induced adipogenic differentiation and activating bone morphogenetic protein (BMP)/Smad signaling. On the whole, our findings demonstrate that RSG in combination with ATRA promotes the commitment of MEFs to the osteoblast lineage. Thus, the combination of these two agents may prove to be a promising and novel therapeutic regimen for insulin resistance without skeletal toxicity. It may also be a better strategy with which to prevent RSG-induced osteoporosis.

BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer.

Colon cancer is one of the most common malignancies of the digestive system. Although more effective therapeutic strategies have been developed in the last decades, there is still a great clinical need to explore new treatment regimens for colon cancer due to the undesirable prognosis. In the present study, we investigated the anticancer activity of resveratrol (Res) in human colon cancer cells, and the possible mechanism underlying this effect. We employed crystal violet staining, flow cytometry and western blotting to test the antiproliferation- and apoptosis-inducing effects of Res in LoVo cells. A xenograft tumor model was also introduced to confirm the in vivo anticancer effect of Res. Using PCR, western blotting, a recombinant adenovirus and a specific inhibitor of p38 MAPK or bone morphogenetic protein receptor (BMPR) to explore the possible molecular mechanisms. We found that Res markedly inhibited the proliferation and promoted the apoptosis of LoVo cells, and suppressed the in vivo tumor growth of colon cancer. Res substantially upregulated the expression of bone morphogenetic protein 9 (BMP9). Exogenous expression of BMP9 enhanced the anticancer effect of Res in LoVo cells, while BMP9 knockdown partly reduced this activity. Res increased the activation of p38 MAPK, which was enhanced by the exogenous expression of BMP9. The anticancer activity of Res, or Res combined with BMP9, was reduced partly by the p38 MAPK inhibitor. The BMPR inhibitor almost abolished the Res-induced activation of p38 MAPK, and attenuated the antiproliferative effect of Res in the LoVo cells. Our findings strongly suggest that the anticancer effect of Res in human colon cancer cells may be partly mediated by upregulation of BMP9 to activate p38 MAPK in a BMPR-dependent manner.

Antiproliferation effect of evodiamine in human colon cancer cells is associated with IGF-1/HIF-1α downregulation.

Colon cancer is one of the most common malignancies. Although the current treatment regimes for colon cancer have been well-developed in the past decades, the prognosis remains still undesirable. It is still urgent to explore new treatment strategies for colon cancer. Natural products is one of the most useful sources for anticancer agents, although some of them have serious side-effects. Evodiamine (Evo) is an quinolone alkaloid from the traditional herb medicine Evodia rutaecarpa. In the present study, we investigated the anticancer effect of Evo in human colon cancer cells. We found that Evo exhibits prominent antiproliferation and apoptosis inducing effects in LoVo cells. Evo leads to apparent downregulation of HIF-1α either in vitro or in vivo; exogenous expression of HIF-1α can attenuate the antiproliferation effect of Evo in LoVo cells, while HIF-1α knockdown potentiates this effect greatly. Further analysis indicated that Evo can also inhibit the phosphorylation of Akt1/2/3 and decrease greatly the expression of IGF-1. Thus, our findings strongly suggested that the anticancer effect of Evo in human colon cancer may be partly mediated by downregulating HIF-1α expression, which is initiated by inactivating PI3K/Akt signaling transduction though decreasing the expression of IGF-1 in colon cancer cells. Therefore, Evo may be used alone or in combination as a potential anticancer agent for colon cancer treatment.