Novel hybrids of natural β-elemene bearing isopropanolamine moieties: synthesis, enhanced anticancer profile, and improved aqueous solubility

A series of novel β-elemene isopropanolamine derivatives were synthesized and evaluated for their antitumor activity. The results indicated that all of the compounds showed stronger antiproliferative activities than β-elemene as well as improved aqueous solubility. In particular dimer 6q showed the strongest cytotoxicity against four tumor cell lines (SGC-7901, HeLa, U87 and A549) with IC50 values ranging from 4.37 to 10.20 μM. Moreover, combination of 6q with cisplatin exhibited a synergistic effect on these cell lines with IC50 values ranging from 1.21 to 2.94 μM, and reversed the resistance of A549/DPP cells with an IC50 value of 2.52 μM. The mechanism study revealed that 6q caused cell cycle arrest at the G2 phase and induced apoptosis of SGC-7901 cells through a mitochondrial-dependent apoptotic pathway. Further in vivo study in H22 liver cancer xenograft mouse model validated the antitumor activity of 6q with a tumor inhibitory ratio (TIR) of 60.3%, which was higher than that of β-elemene (TIR, 49.1%) at a dose of 60 mg/kg. Altogether, the potent antitumor activity of 6qin vitro and in vivo warranted further preclinical investigation for potential anticancer chemotherapy

Discovery of novel antitumor nitric oxide-donating b-elemene hybrids through inhibiting the PI3K/Akt pathway

A series of novel furoxan-based NO-donating b-elemene hybrids were designed and synthesized to improve the anticancer efficacy of natural b-elemene. The bioassay results indicated that all of the target compounds exhibited significantly improved antiproliferative activities against three cancer cell lines (SGC-7901, HeLa and U87) compared to parent compound b-elemene. Interestingly, these compounds displayed excellent sensitivity to U87 cells with IC50 values ranging from 173 to 2 nM. Moreover, most compounds produced high levels of NO in vitro, and the antitumor activity of 11a in U87 cells was markedly attenuated by an NO scavenger (hemoglobin or carboxy-PTIO). Further mechanism studies revealed that 11a caused the G2 phase arrest of the cell cycle and induced apoptosis of U87 cells by preventing the activation of the PI3K/Akt pathway. Moreover, 11a significantly suppressed the tumor growth in H22 liver cancer xenograft mouse model with a tumor inhibitory ratio (TIR) of 64.8%, which was superior to that of b-elemene (TIR, 49.6%) at the same dose of 60 mg/kg. Together, the remarkable biological profiles of these novel NO-donating b-elemene derivatives may make them promising candidates for the intervention of human cancers

BlyS is up-regulated by hypoxia and promotes migration of human breast cancer cells

<p>Abstract</p> <p>Background</p> <p>The role of B Lymphocyte Stimulator (BLyS) in the survival of malignant B cells and the maintenance of normal B cell development and homeostasis has been intensively studied in the literature. However, the influence of BLyS on breast cancer progression remains unclear. The study aimed to investigate the effect of hypoxia on BLyS regulation, cell migratory response to BLyS and the possible molecular mechanisms.</p> <p>Methods</p> <p>In this study, we examined the role of BLyS in the migration of human breast cancer cells by transwell assay. We also explored whether BLyS and its receptors expressed in human breast cancer cell lines by immunofluorescence and Western Blotting. Then we detected the expression level of BLyS in both normoxic and hypoxic conditions by real time-PCR and Western Blotting. Pathways involved were confirmed by Western Blotting, immunofluorescence, transwell assay and luciferase assay.</p> <p>Results</p> <p>According to our study, the expression level of BlyS was increased in human breast cancer cell lines in hypoxic conditions. Up-regulation of this protein led to activation and nuclear translocation of NF-kappa B p65. We also found that the number of migrated cells was increased in the presence of BLyS and inhibition of phosphorylation of Akt attenuated the enhanced migratory response.</p> <p>Conclusions</p> <p>It suggested that better understanding of BLyS, an immunopotentiator, may offer a potential therapeutic target for the treatment of human breast cancers. In addition, BLyS promoted breast cancer cells migration, underscoring the necessity of appropriate applications of immunopotentiators to cancer treatment.</p

Epigenetic repression of PDZ-LIM domain-containing protein 2 promotes ovarian cancer via NOS2-derived nitric oxide signaling.

Ovarian cancer constitutes one of the most lethal gynaecological malignancies worldwide and currently no satisfactory therapeutic approaches have been established. Therefore, elucidation of molecular mechanisms to develop targeted therapy of ovarian cancer is crucial. PDLIM2 is critical to promote ubiquitination of nuclear p65 and thus its role in inflammation has been highlighted recently. We demonstrate that PDLIM2 is decreased in both ovarian high-grade serous carcinoma and in various human ovarian cancer cell lines compared with normal ovary tissues and human ovarian surface epithelial cells (HOSE). Further functional analysis revealed that PDLIM2 is epigenetically repressed in ovarian cancer development and inhibition of PDLIM2 promoted ovarian cancer growth both in vivo and in vitro via NOS2-derived nitric oxide signaling, leading to recruitment of M2 type macrophages. These results suggest that PDLIM2 might be involved in ovarian cancer pathogenesis, which could serve as a promising therapeutic target for ovarian cancer patients

Intraoperative and postoperative short-term outcomes of intracorporeal anastomosis versus extracorporeal anastomosis in laparoscopic right hemicolectomy

BackgroundIntracorporeal anastomosis (IA) is a difficult but popular anastomotic approach for reconstruction of digestive tract after laparoscopic right hemicolectomy, which may reduce some limitations faced during extracorporeal anastomosis (EA).MethodsA retrospective review of 78 patients who underwent laparoscopic right hemicolectomy by a veteran surgeon in a high-volume public tertiary hospital, including 50 patients with IA and 28 patients with EA. The intraoperative-related factors and short-term results of the two anastomotic approaches were compared.ResultsThere was no significant difference in demographics and clinical characteristics between the two groups (P&gt;0.05). The intraoperative blood loss was less (P=0.010) and the incision length was shorter (P&lt;0.001) in the intracorporeal group. Postoperative farting time was faster (P=0.005) and postoperative pain score (VAS) was lower (P&lt;0.001) in IA group. Although the anastomotic time of IA was shorter (P&lt;0.001), the operative time of the two groups were similar. And number of lymph nodes harvested, NLR from POD1 to POD3, postoperative hospital stay and overall hospital stay between the two groups were comparable. Except for significant difference in abdominal infection rate, the Clavien-Dindo classification and the incidence of other postoperative complications were not statistically different. Moreover, the morbidity of abdominal infection decreased with time in the IA group (P=0.040).ConclusionIA is a reliable and feasible procedure, which has faster anastomotic time, earlier return of bowel function and superior postoperative comfort of patient, compared to EA. The postoperative complication rate of IA is similar to that of EA, and may be improved with the IA technical maturity of surgeons, which potentially contributes to the development of ERAS

Design, synthesis and biological evaluation of novel nitric oxidedonating protoberberine derivatives as antitumor agents

A novel class of NO-donating protoberberine derivatives were synthesized and initially evaluated for their anti-hepatocellular carcinoma activities. Most of the compounds exhibited more potent activity against HepG2 cells than parent compounds berberine and palmatine. In particular, compound 15a exerted the strongest activity with an IC50 value of 1.36 μM. Moreover, most compounds released moderate levels of NO in vitro, and the antitumor activity of 15a in HepG2 cells was remarkably diminished by an NO scavenger. Interestingly, compound 15a displayed a broad-spectrum antitumor efficacy and possessed good selectivity between tumor cells (HepG2, SMMC-7721, HCT-116, HL-60) and normal liver LO-2 cells. The mechanism studies revealed that 15a blocked the G2 phase of the cell cycle and induced apoptosis of HepG2 cells by mitochondrial depolarization. Furthermore, 15a inhibited tumor growth in H22 liver cancer xenograft mouse model by 62.5% (w/w), which was significantly superior to parent compound palmatine (41.6%, w/w). Overall, the current study may provide a new approach for the discovery of novel antitumor agents

Antioxidant properties of novel dimers derived from natural β‑elemene through inhibiting H2O2‑induced apoptosis

A series of novel β-elemene dimer derivatives were synthesized and evaluated for their antioxidant activities. The results indicated that most of the target compounds showed more potent cytoprotective effects than positive control vitamin E. In particular, dimer D5 exhibited the strongest antioxidant activity, which was significantly superior to the active compound D1 obtained in our previous study. Besides, D5 did not produce obvious cytotoxicity in normal human umbilical vein endothelial cells (HUVECs) and increased the viability of HUVECs injured by H2O2 in a concentration-dependent manner. Further studies suggested that the cytoprotective action of D5 might be mediated, at least in part, by increasing the intracellular superoxide dismutase activity and nitric oxide secretion as well as decreasing the intracellular malonyldialdehyde content and lactate dehydrogenase release. Furthermore, D5 observably inhibited ROS generation and prevented H2O2-induced apoptosis in HUVECs possibly via inhibiting the activation of the MAPK signaling pathway

Influence of IL-18 and IL-10 Polymorphisms on Tacrolimus Elimination in Chinese Lung Transplant Patients

Aims. The influence of interleukin-10 (IL-10) and interleukin-18 (IL-18) polymorphisms on tacrolimus pharmacokinetics had been described in liver and kidney transplantation. The expression of cytokines varied in different kinds of transplantation. The influence of IL-10 and IL-18 genetic polymorphisms on the pharmacokinetic parameters of tacrolimus remains unclear in lung transplantation. Methods. 51 lung transplant patients at Shanghai Pulmonary Hospital were included. IL-18 polymorphisms (rs5744247 and rs1946518), IL-10 polymorphisms (rs1800896, rs1800872, and rs3021097), and CYP3A5 rs776746 were genotyped. Dose-adjusted trough blood concentrations (C/D ratio, mg/kg body weight) in lung transplant patients during the first 4 postoperative weeks were calculated. Results. IL-18 rs5744247 allele C and rs1946518 allele A were associated with fast tacrolimus metabolism. Combined analysis showed that the numbers of low IL-18 mRNA expression alleles had positive correlation with tacrolimus C/D ratios in lung transplant recipients. The influence of IL-18 polymorphisms on tacrolimus C/D ratios was observed in CYP3A5 expresser recipients, but not in CYP3A5 nonexpresser recipients. No clinical significance of tacrolimus C/D ratios difference of IL-10 polymorphisms was found in our data. Conclusions. IL-18 polymorphisms may influence tacrolimus elimination in lung transplantation patients

High-Frame-Rate Contrast Echocardiography using diverging waves: initial in-vitro and in-vivo evaluation

Contrast Echocardiography (CE) ultrasound with microbubble contrast agents (UCA) has significantly advanced our capability for assessment of cardiac function, including myocardium perfusion quantification. However in standard CE techniques obtained with line by line scanning, the frame rate and image quality are limited. Recent research has shown significant frame rate improvement in non-contrast cardiac imaging. In this work we present and initially evaluate, both in-vitro and in-vivo, a high frame rate (HFR) CE imaging system using diverging waves and pulse inversion sequence. An imaging frame rate of 5500 frames per second before and 250 frames per second after compounding is achieved. A destruction-replenishment sequence has also been developed. The developed HFR CE is compared with standard CE in-vitro on a phantom and then in-vivo on a sheep heart. The image signal to noise ratio, contrast between the myocardium and the chamber are evaluated. Results show up to 13.4 dB improvement in contrast for HFR CE over standard CE when compared at the same display frame-rate even when the average spatial acoustic pressure in HFR CE is 36% lower than the standard CE. It is also found that when coherent compounding is used the HFR CE image intensity can be significantly modulated by the flow motion in the chamber