Inhibitory effect of combination of tanshinone I,metformin and aspirin on malignant melanoma model mice北大核心CSCD

OBJECTIVE: To explore the antitumor effects of combined tanshinone I (Tan I), metformin (Met) and aspirin (Asp) on malignant melanoma in mice and the possible mechanisms. METHODS: C57BL/6 mice were injected with 0.1 mL B16F10 cells (2.8×109 L-1) to establish the subcutaneous transplantation tumor model at the right forelimbs axillary. Then, the mice were divided into 8 groups according to body mass, including model group, Tan I group (20 mg.kg-1 ip), Asp group (210 mg.kg-1, orally in drinking water), Met group (70 mg.kg-1, orally in drinking water), Asp+Met group, Tan I +Asp group, Tan I +Met group and Tan I +Asp+Met group, 10 mice in each group. Each mouse drank about 7 mL of water every day for a total of 18 d. The mouse body mass was measured every other day and the tumor diameter was calculated every day. The mice were sacrificed after treatment, the tumor mass was measured and the tumor inhibitory rates were counted. The histopathological changes of the liver and spleen were observed with HE staining. The percentage of lymphocytes in the tumor tissue such as CD8T, CD4+T and Treg cells was detected by flow cytometry. Inflammatory factors such as interleukin-6 (IL-6), IL-1β and tumor necrosis factor-α (TNF-α) were detected by ELISA. RESULTS: The body mass (including tumor mass) of mice in different groups increased during the experiment, but that of Tan I + Asp+Met group increased more slower than in model group (P<0.01). At the end of the experiment, no lesions were seen in any liver or spleen tissue by pathological observation, and the number of survivors was 8/10 (model group), 8/10 (Tan I group), 7/10 (Asp group), 7/10 (Met group), 8/10 (Tan I +Asp group), 8/10 (Tan I +Met group), 7/10 (Asp + Met group) and 5/10 (Tan I +Asp+ Met group), respectively. Compared with model group, there were no obvious changes in tumor volume or tumor mass in Tan I, Asp and Met groups and other two-two joint groups, but the tumor volume and tumor mass in Tan I + Asp+ Met group were significantly decreased (P<.01, P<0.05), and the tumor inhibitory rate in this group was 46.2%. Compared with the model group, the percentage of CD8+T cells increased (P<0.05) in Tan I + Asp+ Met group, but there were no significant changes in other groups. The contents of IL-6, IL-1β and TNF-α in tumor tissue of Tan I +Met group were much higher than in model group (P<0.01, P<.05, P<0.05) and the content of IL-6 increased in Tan I +Asp+Met group (P<0.01). CONCLUSION: Combination of Tan I, Asp and Met can effectively inhibit the growth of melanoma in mice, which may be related to the increasing percentage of CD8+T lymphocytes and IL-6 in tumor tissue. However there are possibly some side effects. © 2017 Chinese Journal of Pharmacology and Toxicology. All rights reserved.     

Inhibitory effects of tanshinone Ⅱ-A on invasion and metastasis of human colon carcinoma cells

Aim:

To investigate the effects and possible mechanisms of tanshinone II-A, an alcohol extract of the root of Salvia miltiorrhiza Bunge, on tumor invasion and metastasis of human colon carcinoma (CRC) cells.

Methods:

The effects of tanshinone II-A on invasion and metastasis of CRC cell lines HT29 and SW480 were evaluated by in vitro and in vivo assays. Western blotting was used to investigate possible molecular mechanisms of tanshinone II-A anti-cancer actions.

Results:

Tanshinone II-A inhibited migration and invasion of CRC cells in a dose-dependent manner. The inhibitory effect also depended on time, with the most significant effects observed at 72 h. Tanshinone II-A also significantly inhibited in vivo metastasis of colon carcinoma SW480 cells. It inhibited in vitro and in vivo invasion and metastasis of CRC cells by reducing levels of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMP)-2 and MMP-9, and by increasing levels of tissue inhibitor of matrix metalloproteinase protein (TIMP)-1 and TIMP-2. Tanshinone II-A was also shown to suppress the nuclear factor-kappaB (NF-κB) signal.

Conclusion:

Tanshinone II-A inhibited in vitro and in vivo invasion and metastasis of CRC cells. The effect resulted from changes in the levels of uPA, MMP-2, MMP-9, TIMP-1 and TIMP-2, and apparent inhibition of the NF-κB signal transduction pathway.     

Investigation of the improved effects of 2-hydroxypropyl-β-cyclodextrin on solubility,dissolution rate,and intestinal absorptive profile of tanshinone IIA in rats

In this paper, the effect of the chemically modified cyclodextrin [namely, 2-hydroxypropyl-beta-cyclodextrin, (HP-beta-CD)] on the aqueous solubility, dissolution rate, and intestinal permeability of the tanshinone IIA (TS) was investigated. The corresponding inclusion complex of TS-HP-beta-CD at the molar ratio of 1:1 was obtained by coevaporation. The solubility of complexed TS in water at 37+/-0.1 centi-degree was 17 times greater than that for the uncomplexed drug. The dissolution rate of TS was significantly increased by the complexation with HP-beta-CD, due to its solubilizing activity. The everted intestinal sac technique in rats was used to study the absorption behavior studies of TS and this complexation through the intestinal tissues. The permeability rates of TS across the intestinal epithelial membrane were enhanced by the formation of inclusion complex with HP-beta-CD about 89, 97 and 82 times of the uncomplexed TS in duodenum, jejunum and ileum, respectively. It was revealed that the absorption rate-limiting step of TS might be the dissolution process. The present results indicated the potential use of HP-beta-CD to improve the gastrointestinal tract absorption of TS.     

Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn’s disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration

1.?Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn’s disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug.

2.?Although the systemic TSA exposures were low (AUC_0–t approximately 330?ng*h/ml) in both the normal and colitis models after oral administration TSA 20?mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies.

3.?Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2?h after TSA administration.

4.?Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.     

Effects of tanshinone Ⅱ-A sullfonate on adhesion molecule expression of endothelial cells and platelets in vitro

探讨丹参酮ⅡＡ磺酸钠（Ｔａｎ）对培养人脐静脉内皮细胞（ＨＵＶＥＣ）和人血小板表达粘附分子的影响．方法：用流动血细胞计数仪测定肿瘤坏死因子（ＴＮＦα）诱导人脐静脉内皮细胞ＩＣＡＭ１和凝血酶诱导人血小板Ｐ选择素的表达．结果：ＨＵＶＥＣ经ＴＮＦα处理后，明显增加细胞表面ＩＣＡＭ１的表达，增加ＨＬ６０细胞粘附到内皮细胞表面达加入细胞总数的３０％±６％（对照组为４６％±０７％）．在ＴＮＦα处理前，用Ｔａｎ（２５－２００μｍｏｌ·Ｌ－１）与ＨＵＶＥＣ共孵育，则Ｔａｎ剂量依赖性地抑制ＴＮＦα的作用．Ｔａｎ（２５－２００μｍｏｌ·Ｌ－１）与人血小板孵育后，可剂量依赖性地抑制凝血酶诱导人血小板表面Ｐｓｅｌｅｃｔｉｎ的表达．结论：Ｔａｎ可抑制内皮细胞和血小板表达粘附分子．     

AQW051, a novel,potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation

Background and Purpose

Activation of the α7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7-nACh receptor agonist AQW051 as a promising drug candidate for this indication.

Experimental Approach

AQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects.

Key Results

In vitro, AQW051 bound with high affinity to α7-nACh receptors and stimulated calcium influx in cells recombinantly expressing the human α7-nACh receptor. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200 mg and multiple daily doses up to 75 mg. Once-daily oral administration of AQW051 resulted in continuous exposure and a two- to threefold accumulation compared with steady state was achieved by 1 week.

Conclusions and Implications

These data support further development of AQW051 as a cognitive-enhancing agent, as a therapeutic, for example, in Alzheimer''s disease or schizophrenia.     

Retymicin, galtamycin B, saquayamycin Z and ribofuranosyllumichrome, novel secondary metabolites from Micromonospora sp. Tü 6368. I. Taxonomy, fermentation, isolation and biological activities

A new xanthone compound named retymicin (1) was isolated together with galtamycin B (2) and saquayamycin Z (3), new members of the galtamycin and saquayamycin families, respectively, and the new lumichrome derivative 1-(alpha-ribofuranosyl)-lumichrome (4) from Micromonospora strain Tü 6368, isolated from a soil sample collected in Romania. Retymicin, galtamycin B and saquayamycin Z show cytostatic effects to various human tumor cell lines whereas saquayamycin Z is also active against Gram-positive bacteria.     

Arylomycins A and B,new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tü 6075. I. Taxonomy,fermentation, isolation and biological activities

New lipopeptide antibiotics, colourless arylomycins A series and yellow arylomycins B series were detected in the culture filtrate and mycelium extracts of Streptomyces sp. Tü 6075 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. Arylomycins are a family of lipohexapeptide antibiotics, which represent the first examples of biaryl-bridged lipopeptides. They show antibiotic activities against Gram-positive bacteria.     

Phase I trial and pharmacokinetic study of intravenous and oral α-Difluoromethylornithine

Eflornithine-HCl (-difluoromethylornithine or DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity in cell culture and animal tumor models. This phase I study was designed to determine and compare toxicity and the maximally tolerated dose of a 4-day course of DFMO given to patients in oral, continuous intravenous infusion or pulse intravenous infusion forms. Twenty-four patients were entered into this study: 8 received intravenous pulse drug, 10 intravenous continuous infusion of drug, and 6 oral DFMO. The most frequent toxicity was nausea and vomiting which occurred in 9 courses of oral drug. Only two patients receiving intravenous DFMO had nausea and vomiting. Clinically significant thrombocytopenia and audiometric abnormalities were not encountered in contrast to previous experience with 28-day courses of oral DFMO. The maximally tolerated dose of a four-day course of oral DFMO was 3.75 gm/M² every 6 hours. The maximally tolerated dose of intravenous pulse and continuous infusion DFMO was not attained. Pharmacokinetic studies demonstrated that the intravenous schedules achieved higher plasma levels of DFMO than those previously obtained with chronic oral dosing.Presented in part at the 20th Annual Meeting of the American Society of Clinical Oncology, May 1984, Toronto, Ontario, Canada     

46,X,I(Xq)1例

特纳(Turner)综合征是X染色体结构畸变综合征中的一种。本室发现一例特殊核型的Turner综合征46，X，I(Xq)。现报道如下：患者，女，19周岁，1.49米，体重35kg(出生时体重2.25kg)，生殖系统见幼稚型外生殖器，原发闭经；第二性征几乎不发育，无阴毛，腋毛稀少，乳头及乳腺发育差     

Phase I/II study of cisplatin, 5-fluorouracil and α-interferon for recurrent carcinoma of the head and neck

Summary Current chemotherapy regimens have failed to demonstrate a significant impact on the overall survival of patients with recurrent head and neck cancer; therefore, new agents or combinations of agents are necessary to improve outcome. Alpha-interferon potentiates the activity in vitro of both agents of one of the most active regimens currently available, cisplatin and 5-fluorouracil. The purpose of the current study was to evaluate the feasibility and efficacy in patients with recurrent head and neck cancer of adding -interferon to cisplatin 14 mg/m² daily and 5-fluorouracil 700 mg/m² daily for 5 days. No significant toxicity occurred with -interferon at dose level 0,1 × 10⁶ units/m² daily for five days. Of four patients treated at dose level +1, -interferon 3 × 10⁶ units/m², two developed prolonged grade III neutropenic following the fourth course. One of three patients developed grade IV thrombocytopenia and 6 of 13 courses at this dose level resulted in grade III neutropenia. A phase II study was performed in 19 patients with cisplatin 17 mg/m²/ day, 5-fluoruracil 700 mg/m²/day and a-interferon 3 × 10⁶ units/m²/day. During the phase II study grade III neutropenia occurred in 6 patients and grade IV neutropenia in another patient during at least one course. Grade III and IV thrombocytopenia occurred in one patient each during the phase II study. Overall, major responses occurred in 7 or 23 patients (30%): 5 in phase I and 2 in phase II.In conclusion, the addition of -interferon to cisplatin and 5-fluorouracil is feasible, but does not appear to increase response rates in recurrent head and neck cancer.     

"Should I stay or should I go?" Coming off methadone and buprenorphine treatment

Background

This study aimed to investigate patient perspectives regarding coming off maintenance opioid substitution treatment (OST). The study explored previous experiences, current interest and concerns about stopping treatment, and perceptions of how and when coming off treatment should be supported.

Methods

A cross-sectional survey was used. Participants were 145 patients receiving OST at public opioid treatment clinics in Sydney, Australia.

Results

Sixty-two percent reported high interest in coming off treatment in the next 6 months. High interest was associated with having discussed coming off treatment with a greater number of categories of people (OR = 1.72), not citing concern about heroin relapse (OR = 3.18), and shorter duration of current treatment episode (OR = 0.99). Seventy-one percent reported previous withdrawal attempts and 23% had achieved opioid abstinence for ≥3 months following a previous withdrawal attempt. Attempts most commonly involved jumping off (59%), and doctor-controlled (52%) or self-controlled (48%) gradual reduction. For future attempts respondents were most interested in doctor-controlled (68%) or self-controlled (41%) gradual reduction. Concerns regarding coming off treatment included withdrawal discomfort (68%), increased pain (50%), and relapse to heroin use (48%).

Conclusion

While some patients may require lifetime maintenance, the issue of coming off treatment is important to many patients and should be discussed regularly throughout treatment and where appropriate supported by a menu of clinical options.     

Subchronic Toxicity of 3,3′,4,4′,5-Pentachlorobiphenyl in the Rat: I. Clinical,Biochemical, Hematological,and Histopathological Changes

Subchronic Toxicity of 3,3′,4,4′,5-Pentachlorobiphenyl in the Rat. I. Clinical, Biochemical, Hematological, and Histopathological Changes. Chu, I., Villeneuve, D.C., Yagminas, A., LeCavalier, P., Poon, R., Feeley, M., Kennedy, S. W., Seegal, R. F., Häkansson, H., Ahlborg, U. G., and Valli, V. E. (1994). Fundam. Appl. Toxicol. 22, 457-468.The systemic toxicity of 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) following subchronic dietary exposure was investigated in Sprague-Dawley rats. PCB 126 was administered to rats of both sexes at concentrations of 0.1, 1.0, 10, or 100 ppb in their diet for 13 weeks. Another group of rats received a loading dose of 5 μg PCB/kg body wt at the start of the feeding period followed by exposure to 10 ppb PCB diet for the same period of time as the other groups. Growth suppression and decreased food consumption were observed in the highest dose groups of both sexes. Increased organ/body weight ratios for the liver occurred in the 10 and 100 ppb groups of both sexes. Rats of both sexes exposed to the highest dose of the PCB also exhibited increased relative kidney, spleen, and brain weights. Hematological and most serum biochemical changes were confined to the 100 ppb groups. These included elevated alkaline phosphatase, bilirubin, cholesterol, and aspartate aminotransferase, and decreased serum glucose, hemoglobin, erythrocytes, hematocrit, and platelets. A dose-dependent increase in liver ethoxyresorufin-O-deethylase activity was observed in rats of both sexes starting at 0.1 ppb. A dose-dependent increase in liver uroporphyrin levels was observed in both sexes and significant changes occurred in the female rats at 1.0 ppb and higher dose groups. Decreased liver vitamin A was observed in the 10 ppb group and higher in both sexes. Kidney vitamin A was elevated in the 100 ppb group. No statistically significant changes were noted in concentrations of brain biogenic amines. PCB 126 residues were 10-fold higher in liver than in fat. Treatment-related histopathological changes were observed in the thymus, thyroid, bone marrow, and liver of rats exposed to the 10 ppb diet, but increased frequency of mild changes was observed in most of these tissues at the 1.0 ppb level. Based on the above data, the no adverse effect level was judged to be 0.1 ppb in the diet or 0.01 μg/kg body wt/day.     

Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tü 6040. I. Taxonomy, fermentation, isolation and biological activities

Two novel angucyclinone-type antibiotics, simocyclinones D4 and D8, were detected in the mycelium extract of Streptomyces antibioticus Tü 6040 by HPLC-diode-array and HPLC-electrospray-mass-spectrometry screening. The compounds show antibiotic activities against Gram-positive bacteria and cytostatic effects on various tumor cell lines.     

Stimulation of tanshinone production in Salvia miltiorrhiza hairy roots by β -cyclodextrin-coated silver nanoparticles

Diterpenoid tanshinones, major bioactive constituents of Salvia miltiorrhiza roots are drug candidates against cardiocerebral diseases. To develop sustainable and effective elicitation strategies for the enhanced production of tanshinones, the spherical shaped β-cyclodextrin-coated silver nanoparticles (AgNP-β-CDs, Ø35.3 ± 8.3 nm) were synthesized and applied as elicitor to hairy root cultures of S. miltiorrhiza. The content of total tanshinones including tanshinone I, IIA and cryptotanshinone in the cultures was stimulated by AgNP- β-CD at 30 mg/L. The elicitation effects of AgNP-β-CD on tanshinone were found to be related to the released dissolved Ag⁺ and nanoparticle bumping to the root surface in the cultures. AgNP-β-CD treatment induced reactive oxygen species (ROS) including H₂O₂ and O₂^? production in the hairy roots, leading to enhance activities of superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX), and up-regulated expressions of key biosynthetic genes for tanshinones in hairy roots. The nano-elicitor increased total production of tanshinones in 18-day-old hairy root cultures to 10.8 mg/L, a 1.8-fold over that of the control. These results indicate that AgNP- β-CD could be a novel effective elicitor in hairy root cultures for the production of pharmaceutical secondary metabolites.