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.

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.

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.

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.

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.

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.