The Natural Alkaloid (-)-N-Hydroxyapiosporamide Suppresses Colorectal Tumor Progression as an NF-κB Pathway Inhibitor by Targeting the TAK1-TRAF6 Complex.

Colorectal cancer (CRC) is an exceptionally deadly disease, whereas effective therapeutic drugs for CRC have declined over the past few decades. Natural products have become a reliable source of anticancer drugs. Previously we isolated an alkaloid named (-)-N-hydroxyapiosporamide (NHAP), which exerts potent antitumor effects, but its effect and mechanism in CRC remain unclear. This study aimed to reveal the antitumor target of NHAP and identify NHAP as a promising lead compound for CRC. Various biochemical methods and animal models were used to investigate the antitumor effect and molecular mechanism for NHAP. These results showed that NHAP exhibited potent cytotoxicity, induced both apoptosis and autophagic cell death of CRC cells, and inhibited the NF-κB signaling pathway by blocking the interaction of the TAK1-TRAF6 complex. NHAP also markedly inhibited CRC tumor growth in vivo without obvious toxicities and possessed good pharmacokinetic characteristics. These findings identify, for the first time, that NHAP is an NF-κB inhibitor with potent antitumor activity in vitro and in vivo. This study clarifies the antitumor target of NHAP against CRC, which will contribute to the future development of NHAP as a novel therapeutic lead compound for CRC.

Identification of meroterpenoids from Bipolaris victoriae S27 and their potential activity against tumor metastasis and inhibition of the NF-κB signaling pathway.

Three undescribed meroterpenoids, named bipolacochlioquinones A-C, together with seven known compounds, were isolated from the plant endophytic fungus Bipolaris victoriae S27 derived from the fresh stems of Rubia podantha Diels. Their structures were mainly determined by extensive spectroscopic analysis. The relative configurations of bipolacochlioquinones A-C were assigned using the ROESY spectrum, comparison of their spectral data with that reported in the literatures, and NMR calculations. Moreover, their complete absolute configurations were further established by electronic circular dichroism calculations using density functional theory. Among them, bipolacochlioquinone A is found to represent the first example of previously undescribed 6/6/6/6/6 pentacyclic dioxane-containing cochlioquinones, and bipolacochlioquinone B possesses a rare 6/6/6/6/5 pentacyclic system bearing a tetrahydrofuran ring fused to a polyketide and a sesquiterpenoid subunit. All compounds were evaluated for their inhibitory effects on tumor growth, metastasis, and the NF-κB signaling pathway. Among them, bipolacochlioquinone C and cochlioquinone A show the most potent cytotoxicities and NF-κB inhibitory activities. The effects of bipolacochlioquinone C and cochlioquinone A on the expression of NF-κB-associated proteins were also evaluated using western blotting. These results indicate that bipolacochlioquinone C and cochlioquinone A can inhibit the growth and metastasis of HCT116 and MDA-MB-231 cells by suppressing the NF-κB signaling pathway.

Personalized Three-Dimensional Printed Anterior Titanium Plate to Treat Double-Column Acetabular Fractures: A Retrospective Case-Control Study.

OBJECTIVE: To compare the clinical efficacy and safety of a personalized three-dimensional (3D) printed dynamic anterior plate-screw system for the quadrilateral area (DAPSQ) titanium plate and a traditional DAPSQ reconstruction plate in the treatment of double-column acetabular fractures. METHODS: This was a retrospective case-control study. From May 2014 to January 2018, 43 patients with double-column acetabular fractures underwent open reduction and internal fixation. Among these, 20 cases were fixed with a 3D printed DAPSQ plate (3D printed group) and 23 cases were fixed with a DAPSQ reconstruction plate (control group). The 3D printed group comprised 15 men and 5 women, with an average age of 50.1 ± 8.2 years. The control group comprised 16 men and 7 women, with an average age of 51.0 ± 8.6 years. The evaluation index included the surgical data (i.e. blood loss, operating time, duration of hospital stay, and intraoperative and postoperative complications), position and length of implants, reduction quality, hip function, and related complications. The reduction quality was evaluated using the Matta scoring standard and hip function was evaluated using the modified Merle d'Aubigné score. RESULTS: A total of 43 patients met the inclusion criteria. The mean postoperative follow up was 35.2 months in the 3D printed group and 36.9 months in the control group. There were no significant group differences in demographic data between the two groups. The position and length of the 3D printed implants were generally in accord with preoperative planning using a 3D pelvic model. Patients in the 3D printed group had significantly shorter operation time (223.2 vs 260.5 min, P < 0.05) and less intraoperative blood loss (930.4 vs 1426.1 mL, P < 0.05) compared to the control group. Anatomic, imperfect, and poor reduction was obtained in 13, 5, and 2 cases in the 3D printed group, respectively, and was obtained in 12, 8, and 3 cases in the control group. The modified Merle d'Aubigné scores were excellent in 11 cases, good in seven cases, and fair in two cases in the 3D printed group. They were excellent in 11 cases, good in eight cases, fair in three cases, and poor in one case in the control group. The reduction quality and hip function did not differ within the groups (P > 0.05). The general complication rate in the 3D printed group and the control group was 15% and 26.1%, respectively, but the difference between the two groups was not statistically significant. CONCLUSION: Use of a personalized 3D printed DAPSQ plate has potential advantages in reducing the operation time and blood loss during the treatment of double-column acetabular fractures.