Video-Assisted Modified Ligation of the Intersphincteric Fistula Tract, an Integration of 2 Minimally Invasive Techniques for the Treatment of Parks Type II Anal Fistulas.

Introduction. Complex anal fistula (CAF) is a challenging anorectal condition. Although numerous treatments for its management have been proposed, none is ideal. Herein, we investigated the clinical efficacy of video-assisted modified ligation of the intersphincteric fistula tract (LIFT) in comparison with the incision-thread-drawing procedure for Parks type II anal fistulas. Methods. Male and female adult patients with Parks type II anal fistula who were randomized to receive one of two procedures in the Anorectal Surgery Unit of the Affiliated People's Hospital of Ningbo University: video-assisted modified LIFT (test group, 30 cases) or incision thread drawing (control group, 30 cases). Healing and recurrence, postoperative pain, and postoperative autonomous anal control ability were compared. Results. In the test group, the pain scores were significantly lower (P = .001) and wound healing was faster (P = .001). However, there were no marked differences between groups in operative efficacy or postoperative infection rate (all P > .05). We followed all the patients for more than 18 months, with the test group having lower Jorge-Wexner incontinence (P = .005) and fecal incontinence (FI) severity index (P = .000) scores. No significant difference in recurrence (χ2 = .351, P = .554) or healing (χ2 = 1.071, P = .301) rate was found between the 2 groups. Conclusions. We established that video-assisted modified LIFT is superior in repairing Parks type II anal fistulas, with less trauma, quicker recovery, and better anal function.

Antitumor activity of DMAKO-05, a novel shikonin derivative, and its metabolism in rat liver microsome.

The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.

[Antitumor effect research progress of shikonin and its derivatives].

Shikonin, the main active ingredient of Lithospermum, and its derivatives have been proved to have antitumor effects, and the anti-tumor mechanisms involve multiple targets. Based on recent literatures, this review focuses on the antitumor effects and its mechanisms. More emphases are given on the aspects of induction of apoptosis, induction of necrosis, acting on matrix metalloproteinase, acting on the protein tyrosine kinase and antiangiogenesis. The current status and problems of shikonin derivatives in antitumor effects are simply summarized and lookout for the development of antitumor drugs with shikonin as leading compounds.

Comparative study on enantiomeric excess of main akannin/shikonin derivatives isolated from the roots of three endemic Boraginaceae plants in China.

This work systematically investigated the enantiomeric excess (e.e.) of main components isolated from the roots of three endemic Boraginaceae plants distributed extensively in China, named Arnebia euchroma (Royle) Johnst (A.e.), Lithospermum erythrorhizon Sieb. et Zucc. (L.e.) and Onosma confertum W. W. Smith (O.c.), and the optical purity of their hydrolysis products separately, by means of three different approaches. The influence of HCl on the e.e. values of the major constituents was also studied. Analysis of the absolute configurations and e.e. values of all the derivatives acquired was performed by CD and chiral-HPLC respectively. The results of the main constituents demonstrated that A.e. mainly yields S-form naphthoquinone derivatives, while the R-form is predominant in the derivatives of L.e. and O.c. The optical purity of alkannin and shikonin and their derivatives was not influenced by acid treatment in the course of separation and hydrolysis. Additionally, it was found that 100% e.e. of shikinon could be acquired from a specific shikinon ester derivative, ß,ß-dimethylacrylshikonin occurring in the roots of O.c., as did 100% e.e. of alkannin from ß,ß-dimethylacrylalkannin contained in the roots of A.e.

Investigation of light absorption properties and acceptance angles of nanopatterned GZO/a-Si/p(+)-Si photodiodes.

In this work, n-GZO/a:amorphous-Si(i:intrinsic)/p( + )-Si photodiodes are fabricated. We employed a nanosphere lithographic technique to obtain nanoscale patterns on either the a-Si(i) or p( + )-Si surface. As compared with the planar n-GZO/p( + )-Si diode, the devices with nanopatterned a-Si(i) and nanopatterned p( + )-Si substrates show a 32% and 36.2% enhancement of photoresponsivity. Furthermore, the acceptance angle measurement reveals that the nanostructured photodiodes have larger acceptance angles than the planar structure. It also shows that the device with the nanocone structure has a higher acceptance angle than that with the nanorod structure.

[Gender-based analyses of intervention outcome in non-ST segment elevation acute coronary syndrome].

OBJECTIVE: To investigate the impact of gender on outcomes in patients with non-ST segment elevation acute coronary syndrome undergoing intervention treatment. METHODS: In a multi-center randomized trial, the patients diagnosed as non-ST segment elevation acute coronary syndrome were randomly assigned to undergo early intervention (coronary angiography ≤ 24 h after randomization) or delayed intervention (coronary angiography ≥ 36 h after randomization). The primary outcome was a composite of death, myocardial infarction or stroke at 180 days. The secondary outcomes were death, myocardial infarction, refractory ischemia, stroke or revascularization at 180 days. RESULTS: Among 815 patients (545 males, 270 females), the incidences of primary and secondary outcome were equivalent for both genders (P > 0.05). Males of the early intervention group had a greater incidence of the primary outcome (7.1% vs 14.8%, P = 0.00). The secondary outcome was a composite of death, myocardial infarction or refractory ischemia occurring in 12.5% of males in early intervention group and 21.2% in delayed intervention group. Significant difference existed (P = 0.00). The incidence of another secondary outcome as a composite of death, myocardial infarction, refractory ischemia, stroke or revascularization was equivalent for males in early intervention group and delayed intervention group (26.8% vs 32.4%, P > 0.05). The incidences of primary outcome (12.6% vs 14.3%, P > 0.05) and secondary outcome (18.5% vs 23.5% P > 0.05; 28.5% vs 27.7% P > 0.05) were equivalent for females in early intervention group and delayed intervention group (P > 0.05). CONCLUSION: Patients with non-ST segment elevation acute coronary syndrome undergoing intervention demonstrate no significant gender differences in efficacy and safety. Early intervention reduces the rate of myocardial infarction for males, but it is not superior to delayed intervention for females.

[Progress in the study of drug delivery system based on nanoparticles to overcome multi-drug resistance].

Multi-drug resistance (MDR) of cancer cells is a major cause of failure in chemotherapy. To the majority of anti-cancer drugs, tumor cells are able to generate a multi-drug resistance; but there is no common views on the mechanism of MDR. This review summarizes the use of drug delivery system based on nanoparticles to overcome MDR in recent years. Three kinds including non-modified, ligand-modified and multifunctional drug delivery systems are described. Especially, the mechanism of reversing MDR based on nanoparticles is covered. Through efficiently offsetting and antagonizing the action of pumping drugs out of the tumor cells, drug delivery system based on nanoparticles can increase the concentration of the drug in tumors, while reduce the side effects on normal cells and overcome multi-drug resistance. The use of drug-loaded nanoparticles, which combines nanotechnology with the strategy of active and passive targeting administration, has shown significant prospect improving cancer therapy.

Melocochines A and B, Two Alkaloids from the Fruits of Melodinus cochinchinensis.

Melocochines A (1) and B (2), one pair of epimers with an unprecedented skeleton, were isolated from Melodinus cochinchinensis. Their structures and absolute configurations were established by a combination of MS, NMR, and single-crystal X-ray diffraction analyses. Compounds 1 and 2 represent a class of novel alkaloids, characterized by a rare 1H-benzo[b]azepane ring system within monoterpenoid indole alkaloid categories. Compounds 1 and 2 enhanced lysosomal biogenesis with LysoTracker staining intensities of 139.7% and 119.0%, respectively.

Discovery and synthesis of sulfur-containing 6-substituted 5,8-dimethoxy-1,4-naphthoquinone oxime derivatives as new and potential anti-MDR cancer agents.

Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ±â€¯0.01 to 1.33 ±â€¯0.05 µM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.

Advance in Anti-tumor Mechanisms of Shikonin, Alkannin and their Derivatives.

Shikonin, alkannin and their derivatives, the main ingredient of Lithospermum erythrorhizon and Arnebia euchroma (Royle) Johnst native to Inner Mongolian and Northwest of China respectively, hold promising potentials for antitumor effects via multiple-target mechanisms. This review will emphasize the importance of their antitumor activity in apoptosis, necroptosis and immunogenic cell death, and expound the relationship of their antitumor activity and naphthoquinone scaffold that could generate ROS and alkylating agent. Meanwhile, the antitumor mechanisms of naturally-occurring shikonin, alkannin and their derivatives, which were divided into the direct interaction involved in alkylating agent, covalently binding the DNA and protein, as well as the indirect interaction mediated by ROS, nonspecifically influencing the mitochondria or multiple signal pathways, will be systematically summarized and discussed.

Synthesis and biological evaluation of sulfur-containing shikonin oxime derivatives as potential antineoplastic agents.

As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC50 ranging from 0.27 ± 0.02 to 9.23 ± 0.12 µM. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro. Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent.

Sensitized photooxidation of furanoeremophilane with singlet oxygen and their biogenetic relationship.

In an attempt to explore the biogenetic relationship of furanoeremophilane derivatives and eremophilan-8alpha,12-olides, produced in Ligularia and their structure-activity relationship, we studied the photosensitized oxidation of furanoeremophilane-type sesquiterpenes. Under the condition of several solvents solution Irradiation with a 200 W incandescent lamp of furanoeremophilan-14beta,6alpha-olide isolated from Ligularia vellerea, in various solutions with methylene blue, rose bengal, toluidine blue and safranine T gave several products. The products were isolated by chromatographic procedure and their structures were elucidated as eremophilan-14beta,6alpha,8alpha,12-diolide derivatives by NMR, IR and MS methods. A reaction mechanism has been proposed.

A novel bieremophilanolide from Ligularia lapathifolia.

A new bieremophilanolide was isolated from the roots and rhizomes of Ligularia lapathifolia. Its structure was established as 8,8'-bi-3beta-angeloyloxy-eremophil-7(11)-en-12,8alpha(14beta,6alpha)-diolide (1) by IR, MS, 1D, and 2D NMR experiments.

Shikonin Derivative DMAKO-05 Inhibits Akt Signal Activation and Melanoma Proliferation.

DMAKO-05((S)-1-((5E,8E)-5,8-bis(hydroxyimino)-1,4-dimethoxy-5,8-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-methylbutanoate) is a novel oxime derivative of shikonin, the major component extracted from Chinese herb Lithospermun erythrorhizon. Here, we report that DMAKO-05 had an antitumor activity against mouse melanoma cell line B16F0. Our studies indicated that DMAKO-05 not only inhibited B16F0 proliferation and migration but also led to cell cycle arrest at G1 phase and cell apoptosis, in which DMAKO-05 triggered mitochondrial-mediated apoptosis signal including caspase-9/3 and PARP. In response to DMAKO-05 treatment, the Akt-mediated survival signals were remarkably attenuated in B16F0 cells. Collectively, DMAKO-05 has a strong cytotoxicity in B16F0 cells via inhibiting Akt activation, inducing G1 arrest, and promoting B16F0 cell apoptosis. DMAKO-05 might serve as a potential candidate lead compound for melanoma.

A new silymarin preparation based on solid dispersion technique.

Silymarin is a hepatoprotective agent that is poorly soluble in water. The present study describes a new preparation of solid dispersions in the form of "dripping pills" designed to enhance solubility. Dripping pills of silymarin were prepared at a 1:4 ratio by the traditional fusion method with the use of a mixture of silymarin and polyethylene glycol 6000 (PEG 6000). The prepared dripping pills were spherical and 3 to 4 mm in diameter, with an average weight of 30 mg per pill and with each pill containing 5 mg of silymarin. The dissolution rates of silymarin in dripping pill and of 3 other silymarin preparations, including Yiganling Film-Coating Tablet, Yiganling Sugar-Coating Tablet, and Legalon Capsule, were determined in pH 1.2 medium. The dissolution rate (T50) of the silymarin dripping pill was found to be significantly higher (by a factor of 7.5-11) than those of the other 3 preparations.

[Studies on dissolution rate in vitro of silymarin dropping pill].

OBJECTIVE: To test the dissolution rate of silymarin dropping pill as well as to be compared with other three commercial products of the silymarin. METHOD: By UV spectrophotometry, we studied the dissolution conditions of silymarin dropping pill and compared its dissolution rate with Yiganling tablets (film-coating, sugar-coating) and Legalon capsule which are available in the market. RESULT: The dissolution parameters T50 and Td of silymarin dropping pill, Yiganling tablet (film-coating), Yiganling tablet (sugar-coating) and Legalon capsule are 6.78, 9.85 min, 51.01, 73.78 min, 74.35, 86.97 min and 53.10, 72.65 min. CONCLUSION: The dissolution rate of silymarin dropping pill is superior to that of two kinds of Yiganling tablets and Legalon capsule.

Cytotoxic indole alkaloids from the fruits of Melodinus cochinchinensis.

Eight indole alkaloids, melosines A-H, together with 13 known alkaloids, were isolated from the fruits of Melodinus cochinchinensis. The structure elucidation of isolated secondary metabolites was based on comprehensive spectroscopic data analysis. Melosine B showed moderate cytotoxic activity against five human cancer cell lines, HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 1.6 to 8.1µM.

Prevalence, histologic and clinical characteristics of heterotopic gastric mucosa in Chinese patients.

AIM: To determine the prevalence, demographic, clinical and histopathologic features of heterotopic gastric mucosa (HGM) in Chinese patients. METHODS: Patients referred to three endoscopy units were enrolled in this study. The macroscopic characteristics of HGM were documented. Biopsies were obtained and observed using hematoxylin and eosin staining. Helicobacter pylori colonization was examined by Whartin-Starry staining. RESULTS: HGM was observed in 420 Chinese patients, yielding a prevalence of 0.4%. The majority of patients had a single patch (300/420; 71.4%), while the remainder had two (84/420; 20%) or multiple patches (36/420; 8.6%). The size of the patches and the distance from the patch to the frontal incisor teeth varied significantly. The large majority of HGM patches were flat (393/420; 93.6%), whereas the remaining patches were slightly elevated. The primary histological characteristic was fundic-type (216/420; 51.4%) within the HGM patch, and antral- (43/420; 10.2%) and transitional-type (65/420; 15.5%) mucosa were also observed. The prevalence of intestinal metaplasia was 3.1% (13/420) and the prevalence of dysplasia was 1.4% (6/420), indicating the necessity for endoscopic follow-up in patients with HGM. Esophageal and extraesophageal complaints were also observed in patients with HGM. Dysphagia and epigastric discomfort (odds ratios: 6.836 and 115.826, respectively; Ps < 0.05) were independent risk factors for HGM. CONCLUSION: Clinical complaints should be considered to improve the detection rate of HMG. The prevalence of intestinal metaplasia and dysplasia also indicates a need for endoscopic follow-up.

Design, synthesis, and biological evaluation of shikonin and alkannin derivatives as potential anticancer agents via a prodrug approach.

To minimize the cytotoxicity of shikonin and alkannin that arises through the generation of reactive oxygen species (ROS) and alkylation of the naphthazarin ring, two series of novel core-scaffold-modified shikonin and alkannin derivatives were designed. These derivatives, which differ in their configurational and positional isomerism (R-, S-, and 2- and 6-isomers) were synthesized in high enantiomeric excess (>99 % ee). The selectivity of the dimethylated derivatives was significantly higher than the parent shikonin in vitro, but some side effects were still observed in vivo. Surprisingly, the dimethylated diacetyl derivatives with poor anticancer activity in vitro showed tumor-inhibiting effects similar to paclitaxel without any toxicity in vivo. The anticancer activity of these derivatives is in agreement with their low ROS generation and alkylating capacity, emphasizing their potential as prodrugs. This strategy provides means to address the nonspecific cytotoxicity of naphthazarin analogues toward normal cells.

Synthesis and antitumour activity of ß-hydroxyisovalerylshikonin analogues.

A series of novel ß-hydroxyisovalerylshikonin analogues bearing oxygen-containing substituents at the side-chain hydroxyl of shikonin were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against multi-drug resistant (MDR) cell lines DU-145 and HeLa. Most compounds exhibited significant inhibitory activity on both cell lines. The structure-activity relationship showed the analogues with ether substituents displayed the most potent antitumour activity and selective cytotoxicity towards DU-145. Among the compounds with ether substituents, increasing the steric hindrance in the carbon bearing ß-hydroxyl or replace the ß-hydroxyl with acetoxy or methoxy would lead to the decline of cytotoxicity.