TPX2 enhances the transcription factor activation of PXR and enhances the resistance of hepatocellular carcinoma cells to antitumor drugs.

The pregnane X receptor (PXR) is an important regulator of hepatocellular carcinoma cellular resistance to antitumor drugs. Activation of PXR was modulated by the co-regulators. The target protein for the Xenopus plus end-directed kinesin-like protein (Xklp2) known as TPX2 that was previously considered as a tubulin regulator, also functions as the regulator of some transcription factors and pro-oncogenes in human malignances. However, the actions of TPX2 on PXR and HCC cells are still unclear. In the present study, our results demonstrate that the high expression of endogenous mRNA level of TPX2 not only correlated with the poor prognosis of advanced HCC patients who received sorafenib treatment but also with expression of PXR's downstream genes, cyp3a4 and/or mdr-1. Results from luciferase and real-time polymerase chain reaction (qPCR) showed that TPX2 leads to enhancement of the transcription factor activation of PXR. Protein-protein interactions between PXR and TPX2 were identified using co-immunoprecipitation. Mechanically, overexpression of TPX2 led to enhancement of PXR recruitment to its downstream gene cyp3a4's promoter region (the PXRE region) or enhancer region (the XREM region). Treatment of HCC cells with paclitaxel, a microtubule promoter, led to enhancement of the effects of TPX2, whereas vincristine, a microtubule depolymerizing agent caused a decrease in TPX2-associated effects. TPX2 was found to cause acceleration of the metabolism or clearance of sorafenib, a typical tyrosine kinase inhibitor (TKI) in HCC cells and in turn led to the resistance to sorafenib by HCC cells. By establishing novel actions of TXP2 on PXR in HCC cells, the results indicate that TPX2 could be considered a promising therapeutic target to enhance HCC cells sensitivity to antitumor drugs.

The Combination of AFP and "Up-To-Seven" Criteria May Be a Better Strategy for Liver Transplantation in Chinese Cirrhotic HCC Patients.

Background: Orthotopic liver transplantation (OLT) is a life-saving option for patients with hepatocellular carcinoma (HCC), but the expanded OLT criteria remain controversial. Objective: The study aimed to explore whether expanded OLT criteria can be applied to Chinese cirrhotic patients with HCC. Methods: This retrospective study analyzed risk factors for HCC recurrence and death and compared patients' tumor characteristics and outcomes in groups of Milan, "Up-to-seven," and Hangzhou criteria, and groups between met and unmet the combinative criteria of "Up-to-seven" and AFP of < 1000 ng/mL. Results: Among 153 patients who underwent OLT for HCC from January 2015 to February 2019 in 4 years of follow-up, 20 (13.1%) patients had HCC recurrence, and 11 (7.2%) had HCC-related death. Multivariate Cox regression analysis showed that preoperative alpha-fetoprotein (AFP) of > 1000 ng/mL (hazard ratio [HR]: 10.05, 95% confidence interval [CI]: 2.45-41.13, P = 0.001) was an independent risk factor for HCC recurrence and HCC-related death (HR: 6.63, 95%CI: 1.31-33.52, P = 0.022). Patients who did not meet Milan criteria but satisfied the "Up-to-seven" criteria had no differences in overall survival (OS) (P = 0.69) and disease-free survival (DFS) (P = 0.35) than patients who met the Milan criteria. The combination of "Up-to-seven" criteria and AFP of < 1000 ng/mL differed significantly (HR: 18.9; 95% CI: 4.0-89.2; P < 0.001). Patients with HCC who met the "Up-to-seven" criteria and AFP of < 1000 ng/mL (n = 121) had excellent survival with 4-year OS of 91.6% (P < 0.001) and DFS of 90.8% (P < 0.001), which is significantly better compared to the other group (n = 32) (OS of 67.5% and DFS of 46.5%) and patients who met the Milan criteria (n = 108, OS of 89.8%, DFS of 89.6%), allowing 28.9% (13/45) of patients who did not meet the Milan criteria to benefit from OLT. Conclusion: Chinese cirrhotic patients with HCC who met the combinative criteria of "Up-to-seven" and AFP of < 1000 ng/mL had better survival than those who met the Milan criteria, and these combinative criteria benefited more patients and may become a better option for OLT.

Two new dinor-eudesmane sesquiterpenoids from the roots of Chloranthus multistachys.

Two new dinor-eudesmane sesquiterpenoids, named multistalin A (1), and multistalin B (2), together with three sesquiterpene glycosides (3-5), and a norlabdane-type diterpene (6) were isolated from the root extract of Chloranthus multistachys Pei. Their structures were elucidated on the basis of spectroscopic analysis including 1D, 2D NMR techniques and HR-ESI-MS. In addition, the cytotoxicity activities of the isolated compounds against selected cancer cells (Hela and A-549) were evaluated by MTT assay.

A structural signature of the breakdown of the Stokes-Einstein relation in metallic liquids.

The breakdown of the Stokes-Einstein relation (SER) in three model metallic liquids is investigated via molecular dynamics simulations. It is found that the breakdown of SER is closely correlated with the clustering behavior of well-packed atoms. When the SER breaks down, many cluster properties have almost the same value in these metallic liquids. At the breakdown temperature of SER, the temperature dependence of the number of clusters begins to deviate from a linear increase and the average number of well-packed atoms in the clusters reaches about 2, which indicates an increase in structure heterogeneity. Moreover, the size of the largest cluster shows a direct correlation with the SER. Therefore, our study provides a possible structural origin for the breakdown of SER in metallic liquids.

Structural disorder in metallic glass-forming liquids.

We investigated structural disorder by a new structural parameter, quasi-nearest atom (QNA), in atomistic configurations of eight metallic glass-forming systems generated through molecular dynamics simulations at various temperatures. Structural analysis reveals that the scaled distribution of the number of QNA appears to be an universal property of metallic liquids and the spatial distribution of the number of QNA displays to be clearly heterogeneous. Furthermore, the new parameter can be directly correlated with potential energy and structural relaxation at the atomic level. Some straightforward relationships between QNA and other properties (per-atom potential energy and α-relaxation time) are introduced to reflect structure-property relationship in metallic liquids. We believe that the new structural parameter can well reflect structure disorder in metallic liquids and play an important role in understanding various properties in metallic liquids.

Chronic radial head dislocation caused by a rare solitary osteochondroma of the proximal radius in a child: a case report and review of the literature.

BACKGROUND: Osteochondroma is the most common benign bone tumor of the upper limbs that occurs during the developmental phase of children. Solitary epiphyseal enchondromas can be usually found in the humeral capitellum, and the proximal ulna of the elbow. CASE PRESENTATION: Herein, we report the case of a 12-year-old boy of Han ethnicity with a developmental radial head dislocation with a progressive radius deformities, caused by a solitary osteochondroma which originated from the proximal metaphysis of the radius. Obvious complaints and limitations were present. After tumor excision was performed, radial head reduction and deformity correction were achieved through a biplanar shortening osteotomy of the radius. CONCLUSIONS: After a follow-up of 18 months, the child remained asymptomatic and regained a full range of motion. Radiographic study revealed satisfactory reduction of the radial head with no recurrence of the osteochondroma.

C-reactive protein as a prognostic factor for human osteosarcoma: a meta-analysis and literature review.

BACKGROUND: Osteosarcoma is the most common primary bone cancer in growing adolescents and young adults. The prognostic role of C-reactive protein (CRP) in patients with osteosarcoma is not fully investigated. The purpose of this study is to perform a meta-analysis and literature review on the role of CRP in osteosarcoma and to assess the potential role of serum CRP as a prognostic factor for patients with osteosarcoma. METHODS: A detailed literature search was made in Medline for related research publications written in English. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, risk ratio (RR) and corresponding confidence intervals (CIs) were calculated and summarized respectively. RESULTS: Final analysis of 397 patients from 2 eligible studies was performed. Combined RR of CRP expression suggested that the raised serum CRP level had an adverse prognostic effect on overall survival of patients with osteosarcoma (n = 397 in 2 studies; RR = 0.35; 95% CI: 0.18-0.68; p = 0.002). In the uni- and multivariate survival analysis, response rate and CRP levels were the only independent prognostic variables. CONCLUSIONS: The results of this meta-analysis suggest that CRP expression confers a worse prognosis in patients with osteosarcoma. Large prospective studies are necessary to provide solid data to confirm the prognostic significance of CRP.

Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice.

The quaternary benzo[c]phenanthridine alkaloid, chelerythrine (CHE), is of great practical and research interest because of its pronounced, widespread physiological effects, primarily antimicrobial and anti-inflammatory, arising from its ability to interact with proteins and DNA. Although CHE was originally shown to possess anti-inflammatory properties, its effects on acute gastric ulcer have not been previously explored. The aim of the present study is to evaluate the protective effect of CHE on ethanol induced gastric ulcer in mice. Administration of CHE at doses of 1, 5 and 10mg/kg bodyweight prior to ethanol ingestion dose-dependently inhibited gastric ulcer. The gastric mucosal lesion was assessed by ulcer area, gastric juice acidity, myeloperoxidase (MPO) activities, macroscopic and histopathological examinations. CHE significantly reduced the gastric ulcer index, myeloperoxidase activities, macroscopic and histological score in a dose-dependent manner. In addition, CHE also significantly inhibited nitric oxide (NO) concentration, pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level in serum and gastric mucosal in the mice exposed to ethanol induced ulceration in a dose-dependent manner. In addition, immunohistochemical analysis revealed that CHE markedly attenuated the overexpression of nuclear factor-κB in gastric mucosa of mice. It was concluded that CHE represents a potential therapeutic option to reduce the risk of gastric ulceration. In addition, acute toxicity study revealed no abnormal sign to the mice treated with CHE (15mg/kg). These findings suggest that the gastroprotective activity of CHE might contribute in adjusting the inflammatory cytokine by regulating the NF-κB signalling pathway.

Steroidal saponins from Smilacina japonica.

Three new steroidal saponins, japonicoside A (1), japonicoside B (2) and japonicoside C (3) were isolated from the dried rhizomes and roots of Smilacina japonica A. Gray. Their structures were elucidated as (25S)-5α-spirostan-9(11)-en-3ß-ol 3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-xylopyranosyl-(1→3)]-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (1), (25S)-5α-spirostan-9(11)-en-3ß,17α-diol 3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-xylopyranosyl-(1→3)]-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (2) and (25S)-5α-spirostan-9(11)-en-3ß,17α,24α-triol 3-O-ß-D-glucopyranosyl-(1→2)-[ß-D-xylopyranosyl-(1→3)]-ß-D-glucopyranosyl-(1→4)-ß-D-galactopyranoside (3) on the basis of chemical methods and detailed spectroscopic analysis, including 1D, 2D NMR and HR-ESI-MS. The cytotoxicity of isolated compounds was evaluated in vitro for cytotoxic properties against human hepatocellular carcinoma cells (SMMC-7221) and human colorectal adenocarcinoma cells (DLD-1), respectively.

[Study on the chemical constituents of Chloranthus multistachys].

OBJECTIVE: To isolate and identify the chemical constituents of the root of Chloranthus multistachys Pei. METHODS: The compounds were isolated by column chromatography, semi-preparative thin layer chromatography and related techniques, their structures were elucidated through spectroscopic analyses. RESULTS: Nine compounds were isolated and identified as: lupeol (I), cycloeucalenol (II), isofragidin (III), daphnin (IV), umbelliferone (V), palmitic acid (VI), stigmasterol (VII), beta-sitosterol (VIII), beta-daucosterol (IX). CONCLUSION: Except VI, all compounds are isolated from this plant for the first time.

Oleanene triterpenes from Sedum lineare Thunb.

One new olean-13(18)-ene-3,12,19-trione (1), and two known oleanene triterpenes δ-amyrone (2), and δ-amyrine acetate (3) were isolated from the petroleum ether fraction from an alcoholic extract of the whole plant of Sedum linear Thunb. The new compound was characterized by means of spectroscopic methods including 1D, 2D NMR and HR-ESI-MS, and was further confirmed by X-ray diffraction analysis. The known ones were established on the basis of comparing their NMR data with those of the corresponding compounds in the literature. In addition, the inhibitory effects of the compounds isolated on the TNF-α and NO production were examined in vitro.

Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis.

The Slit family of guidance cues binds to Roundabout (Robo) receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robo1 or recombinant Slit2 treatment of Robo1-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin (E-cad) ubiquitination and lysosomal degradation, epithelial-mesenchymal transition (EMT), and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robo1 or specific blockade of Slit2 binding to Robo1 prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robo1 also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robo1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robo1 by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis.

Effects of chelerythrine, a specific inhibitor of cyclooxygenase-2, on acute inflammation in mice.

Chelerythrine (CHE), a quaternary benzo[c]phenanthridine alkaloid, which is an agent in traditional Chinese medicine exhibits a wide spectrum of pharmacological effects. In this study, we examined the anti-inflammatory activities and mechanism of CHE in vivo and in vitro, respectively. Further, in the analgesic test, CHE also showed pronounced inhibition of the acetic acid-induced writhing response. These results clearly suggested that CHE is a bioactive agent which has a significant anti-inflammatory action, which may be relevant to the inhibition of the release/production of exudates and prostaglandin E(2) mediated through cyclooxygenase-2 regulation.

[High-performance liquid chromatography-based determination of plasma and renal tissue cisplatin levels after subcutaneous cisplatin implantation in mice].

OBJECTIVE: To develop a method for determining plasma and renal tissue concentrations of cisplatin (DDP) after subcutaneous DDP implantation in mice. METHODS: DDP was extracted from the plasma and tissue of mice receiving subcutaneous DDP implantation and reacted with sodium diethyldithiocarbamate (DDTC). The product Pt (DDTC)(2) extracted by diethyl ether was determined using high-performance liquid chromatography (HPLC) with the mobile phase of water and methanol at the ratio of 25:75 and the flow rate of 1.0 ml/min. The derivatives of DDP and nickel chloride were detected at the wavelength of 254 nm. RESULTS: The linear range of DDP was 0.1-10 microg/ml (r=0.9998 for plasma and 0.9993 for kidney). The intra-day and inter-day RSD was below 10%, and the minimum concentration detectable was 50 ng. CONCLUSION: The method is accurate and effective for determining plasma and tissue DDP levels after subcutaneous DDP administration and can be used in pharmacokinetic study of DDP.

[Protecting effect of brevifolin and 8,9-single-epoxy brevifolin of Phyllanthus simplex on rat liver injury].

OBJECTIVE: To investigate the effect of protecting liver of brevifolin and 8,9-single-epoxy brevifolin of Phyllanthus simplex. METHOD: Rats were administered with CCl4 (ip) or alcohol (ig) to establish acute or chronic liver injured model, respectively. ALT, AST and TBIL in serum were measured using colorimetric analysis to evaluate liver function. MDA content or SOD activity in serum and liver tissue was measured by thiobarbituric acid chromatometry and xanthine oxidase methods, respectively. The hemorheological parameters were observed. RESULT: Brevifolin and 8,9-single-epoxy brevifolin reduced the increase of ALT induced by CCl4, but they did not influence the increase of AST. And it could inhibit the pathologic increase of serum TBIL induced by alcohol. They could ameliorate the MDA increase or SOD decrease in serum and liver tissue in rats with liver injury, and decrease abnormal changed hemorheological parameters. CONCLUSION: Brevifolin and 8,9-single-epoxy brevifolin show protective effective against acute and chronic liver injuries, and the mechanism is relevant to antagonizing the lipid peroxidation of free radical and improving the blood circulation.