[Protective Effect of S-isopentenyl-L-cysteine against DNA Damage in Irradiated Mice].

OBJECTIVE: To evaluate the protective effect of S-isopentenyl-L-cysteine,a new cysteine derivative,on DNA damage induced by radiation by using acute radiation injury animal models. METHODS: Forty ICR mice were randomly divided into five groups:the control group,1.0Gy gamma irradiation group,1.0Gy gamma irradiation combined with S-isopentenyl-L-cysteine group,7.2Gy gamma irradiation group,and 7.2Gy gamma irradiation combined with S-isopentenyl-L-cysteine group,with 8 mice in each group.The comet assay and bone marrow polychromatic micronucleus experiments were performed to evaluate the double-strand DNA breaks in ICR mice exposed to 1.0 and 7.2Gy gamma-ray, respectively. RESULTS: The tail DNA percentage,tail length,tail moment,and olive tail moment of peripheral blood lymphocytes in 7.2Gy gamma irradiation group were significantly higher than that of the control group (P<0.01).And it was also observed that above experimental indexes of 7.2Gy gamma irradiation combined with S-isopentenyl-L-cysteine group was significantly less than that of 7.2Gy gamma irradiation group (P<0.05). In addition,the micronucleus rate of 1.0Gy gamma irradiation group and 7.2Gy gamma irradiation group were both significantly higher than in the control group (P<0.01). In addition,in mice given S-isopentenyl-L-cysteine before irradiation,the micronucleus rate of ICR mice exposed to 1.0 and 7.2Gy gamma-ray decreased from (39.5000 ± 3.3141)‰ to (28.1667±4.1345)‰ (P=0.033) and from (76.5000 ± 4.6242)‰ to (22.8333 ± 3.6553)‰(P=0.000),respectively. The bone marrow polychromatic micronucleus experiment indicated that the value of polychromatic erythrocyte (PCE)/normochromatic erythrocyte(NCE) of ICR mice exposed to 1.0 and 7.2Gy gamma-ray was less than the control group(P<0.05). Meanwhile,after irradiating by certain dose,the value of PCE/NCE in mice given S-isopentenyl-L-cysteine before irradiation was significantly higher than the corresponding groups (P<0.05). CONCLUSION: S-isopentenyl-L-cysteine has a good protective effect against DNA damage induced by radiation.

Passing through the renal clearance barrier: toward ultrasmall sizes with stable ligands for potential clinical applications.

The use of nanoparticles holds promise for medical applications, such as X-ray imaging, photothermal therapy and radiotherapy. However, the in vivo toxicity of inorganic nanoparticles raises some concern regarding undesirable side effects which prevent their further medical application. Ultrasmall sub-5.5 nm particles can pass through the barrier for renal clearance, minimizing their toxicity. In this letter we address some recent interesting work regarding in vivo toxicity and renal clearance, and discuss the possible strategy of utilizing ultrasmall nanomaterials. We propose that small hydrodynamic sized nanoclusters can achieve both nontoxic and therapeutic clinical features.

Enhanced tumor accumulation of sub-2 nm gold nanoclusters for cancer radiation therapy.

A new type of metabolizable and efficient radiosensitizers for cancer radiotherapy is presented by combining ultrasmall Au nanoclusters (NCs, <2 nm) with biocompatible coating ligands (glutathione, GSH). The new nanoconstruct (GSH-coated Au25 NCs) inherits attractive features of both the Au core (strong radiosensitizing effect) and GSH shell (good biocompatibility). It can preferentially accumulate in tumor via the improved EPR effect, which leads to strong enhancement for cancer radiotherapy. After the treatment, the small-sized GSH-Au25 NCs can be efficiently cleared by the kidney, minimizing any potential side effects due to the accumulation of Au25 NCs in the body.

Size-dependent radiosensitization of PEG-coated gold nanoparticles for cancer radiation therapy.

Gold nanoparticles have been conceived as a radiosensitizer in cancer radiation therapy, but one of the important questions for primary drug screening is what size of gold nanoparticles can optimally enhance radiation effects. Herein, we perform in vitro and in vivo radiosensitization studies of 4.8, 12.1, 27.3, and 46.6 nm PEG-coated gold nanoparticles. In vitro results show that all sizes of the PEG-coated gold nanoparticles can cause a significant decrease in cancer cell survival after gamma radiation. 12.1 and 27.3 nm PEG-coated gold nanoparticles have dispersive distributions in the cells and stronger sensitization effects than 4.8 and 46.6 nm particles by both cell apoptosis and necrosis. Further, in vivo results also show all sizes of the PEG-coated gold nanoparticles can significantly decrease tumor volume and weight after 5 Gy radiations, and 12.1 and 27.3 nm PEG-coated gold nanoparticles have greater sensitization effects than 4.8 and 46.6 nm particles, which can lead to almost complete disappearance of the tumor. In vivo biodistribution confirms that 12.1 and 27.3 nm PEG-coated gold nanoparticles are accumulated in the tumor with high concentrations. The pathology, immune response, and blood biochemistry indicate that the PEG-coated gold nanoparticles have not caused spleen and kidney damages, but give rise to liver damage and gold accumulation. It can be concluded that 12.1 and 27.3 nm PEG-coated gold nanoparticles show high radiosensitivity, and these results have an important indication for possible radiotherapy and drug delivery.

Oxysophoridine suppresses the growth of hepatocellular carcinoma in mice: in vivo and cDNA microarray studies.

OBJECTIVE: To observe the in vivo effects of oxysophoridine on hepatocellular carcinoma in mice and to study the related mechanisms. METHODS: C57BL mice were inoculated with mouse hepatoma H22 cells subcutaneously, then divided into 5 groups (14 per group), and treated with oxysophoridine (50, 100, or 150 mg/kg) or cisplatin (4 mg/kg) for 10 days. Inhibitory rate of tumor, body weight gain, and influence indices on internal organs (liver, spleen and thymus) were evaluated. The differentially expressed genes between the oxysophoridine-treated group, and the control group were analyzed using cDNA microarray and quantitative real-time PCR (qRT-PCR) experiments. RESULTS: Compared with the tumor weight of the control group (2.75±0.66 g), oxysophoridine significantly suppressed hepatocellular carcinoma growth in mice (P <0.01), with 0.82±0.36 g, 0.57±0.22 g, and 1.22±0.67 g for the tumor weight in the low, moderate, and high dose treatment group, respectively. The moderate dose led to the highest inhibitory rate, 79.3%. Observation of body weight gain and influence on three organs showed that compared with cisplatin, oxysophoridine produced fewer side effects in vivo. cDNA microarray and qRT-PCR showed that the most significant differentially expressed genes in the tumor samples of oxysophoridine-treated mice were mostly involved in regulating apoptosis, with the Tnfrsf11b (osteoprotegerin) gene being the most significantly affected. CONCLUSION: Oxysophoridine was a promising compound for developing drugs against hepatocellular carcinoma, and its anti-hepatoma effect was probably related to osteoprotegerin activation.

In vivo renal clearance, biodistribution, toxicity of gold nanoclusters.

Gold nanoparticles have shown great prospective in cancer diagnosis and therapy, but they can not be metabolized and prefer to accumulate in liver and spleen due to their large size. The gold nanoclusters with small size can penetrate kidney tissue and have promise to decrease in vivo toxicity by renal clearance. In this work, we explore the in vivo renal clearance, biodistribution, and toxicity responses of the BSA- and GSH-protected gold nanoclusters for 24 h and 28 days. The BSA-protected gold nanoclusters have low-efficient renal clearance and only 1% of gold can be cleared, but the GSH-protected gold nanoclusters have high-efficient renal clearance and 36% of gold can be cleared after 24 h. The biodistribution further reveals that 94% of gold can be metabolized for the GSH-protected nanoclusters, but only less than 5% of gold can be metabolized for the BSA-protected nanoclusters after 28 days. Both of the GSH- and BSA-protected gold nanoclusters cause acute infection, inflammation, and kidney function damage after 24 h, but these toxicity responses for the GSH-protected gold nanoclusters can be eliminated after 28 days. Immune system can also be affected by the two kinds of gold nanoclusters, but the immune response for the GSH-protected gold nanoclusters can also be recovered after 28 days. These findings show that the GSH-protected gold nanoclusters have small size and can be metabolized by renal clearance and thus the toxicity can be significantly decreased. The BSA-protected gold nanoclusters, however, can form large compounds and further accumulate in liver and spleen which can cause irreparable toxicity response. Therefore, the GSH-protected gold nanoclusters have great potential for in vivo imaging and therapy, and the BSA-protected gold nanoclusters can be used as the agent of liver cancer therapy.

Anticancer activity of total flavonoids isolated from Xianhe Yanling Recipe (仙鹤延龄方).

OBJECTIVE: To investigate the anticancer activity of the total flavonoids isolated from a herbal formula, Xianhe Yanling Recipe (仙鹤延龄方), a recipe commonly used in cancer patients in China. METHODS: The in vitro anticancer activity of the total flavonoids was determined using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay on three cancer cell lines: MCF-7 (a human breast adenocarcinoma cell line), HepG-2 (a human hepatocellular carcinoma cell line) and ES-2 (a human ovarian cancer cell line). The in vivo anticancer effect of the total flavonoids was assessed in a mouse tumor model bearing H22-induced hepatocellular carcinoma, and cisplatin was used as a positive control. RESULTS: The total flavonoids exerted a powerful inhibitory effect on the three cell lines, with 50% inhibiting concentrations (IC(50)) of 24.948, 31.569 and 6.923 µg/mL, respectively. In vivo studies showed that the total flavonoids had dose-dependent inhibitory effects on hepatocellular carcinoma in mice. CONCLUSION: The total flavonoids from Xianhe Yanling Recipe have potential anticancer activity, and further researches and development are warranted.

First-principles investigation of Ag-doped gold nanoclusters.

Gold nanoclusters have the tunable optical absorption property, and are promising for cancer cell imaging, photothermal therapy and radiotherapy. First-principle is a very powerful tool for design of novel materials. In the present work, structural properties, band gap engineering and tunable optical properties of Ag-doped gold clusters have been calculated using density functional theory. The electronic structure of a stable Au(20) cluster can be modulated by incorporating Ag, and the HOMO-LUMO gap of Au(20-) (n)Ag(n) clusters is modulated due to the incorporation of Ag electronic states in the HOMO and LUMO. Furthermore, the results of the imaginary part of the dielectric function indicate that the optical transition of gold clusters is concentration-dependent and the optical transition between HOMO and LUMO shifts to the low energy range as the Ag atom increases. These calculated results are helpful for the design of gold cluster-based biomaterials, and will be of interest in the fields of radiation medicine, biophysics and nanoscience.

Toxicologic effects of gold nanoparticles in vivo by different administration routes.

Gold nanoparticles have potential applications in biomedicine, but one of the important concerns is about their safety. Most toxicology data are derived from in vitro studies and may not reflect in vivo responses. Here, an animal toxicity study of 13.5 nm gold nanoparticles in mice is presented. Animal survival, weight, hematology, morphology, and organ index are characterized at different concentrations (137.5-2200 µg/kg) over 14-28 days. The results show that low concentrations of gold nanoparticles do not cause an obvious decrease in body weight or appreciable toxicity, even after their breakdown in vivo. High concentrations of gold nanoparticles induced decreases in body weight, red blood cells, and hematocrit. It was also found that gold nanoparticles administered orally caused significant decreases in body weight, spleen index, and red blood cells. Of the three administration routes, the oral and intraperitoneal routes showed the highest toxicity, and the tail vein injection showed the lowest toxicity. Combining the results of all of these studies, we suggest that targeted gold nanopartices by tail vein injection may be suitable for enhancement of radiotherapy, photothermal therapy, and related medical diagnostic procedures.

[Progress of study on action mechanisms of TCM in anti-tumor and preventing metastasis of tumor].

In this article, the literatures concerning the mechanism of TCM in anti-tumor and tumor metastasis prevention in recent years were reviewed and summarized into categories of effective components, effective portion, extraction of single drug, and TCM compound.

[Progress in study of chemical constituents and anti-tumor activities of Cnidium monnieri].

The main pharmacological constituents of Chinese traditional medicine herb Cnidium monnieri are coumarin compounds and volatile oil. In addition, it contains monoterpene polyols, glucides, as well as recently discovered sesquiterpene components. In recent years, rather active investigations of its anti-tumor were performed at home and abroad. C. monnieri possesses multi-aspect and comprehensive anti-tumor functions, involving directly tumor-inhibitory activity, anti-mutagenicity, reversing multi-drug tolerance of tumor, as well as improving immune functions and so on. In this review, chemical constituents, anti-tumor activities and relevant investigations of Fructus Cnidii were summarized recent decade.