Role of E-cadherin in antimigratory and antiinvasive efficacy of silibinin in prostate cancer cells

The epithelial-to-mesenchymal transition (EMT) in prostate cancer (PCA) cells is considered prerequisite for acquiring migratory/invasive phenotype, and subsequent metastasis. We hypothesized that promoting the E-cadherin expression in PCA cells by using nontoxic phytochemicals, like silibinin, would prevent EMT and consequently invasiveness. Our results showed that silibinin treatment (5-90 μmol/L) significantly inhibits migratory and invasive potential of advance human PCA PC3, PC3MM2, and C4-2B cells in in vitro assays. Importantly, the antimigratory/antiinvasive efficacy of silibinin was not due to its cytotoxicity toward PCA cells. Molecular analyses showed that silibinin increases E-cadherin level that was localized mainly at cellular membrane as evidenced by subcellular fractional and confocal analyses in PC3 cells, which might be responsible for morphologically observed shift toward epithelial character. Silibinin also decreased the levels of Slug, Snail, phospho-Akt(ser(473)), nuclear β-catenin, phospho-Src(tyr(419)) and Hakai; together they play an important role in regulating E-cadherin expression/function and EMT. Similar silibinin effects on E-cadherin, β-catenin, phospho-Src(tyr(419)), and Hakai levels were also observed in PC3MM2 and C4-2B PCA cells. Selective Src inhibition by dasatinib also showed increased E-cadherin expression in PC3 cells suggesting a possible involvement of Src inhibition in silibinin-caused increase in E-cadherin level. Additional studies in PC3 cells with stable knock-down of E-cadherin expression revealed that antimigratory/antiinvasive efficacy of silibinin is in-part dependent on E-cadherin expression. Together, our results showing antimigratory/antiinvasive effects of silibinin and associated mechanisms suggest that silibinin should be tested further in clinically relevant animal models toward exploiting its potential benefits against metastatic PCA.     

Use of recombinant human activated protein C in nonmenstrual staphylococcal toxic shock syndrome

Toxic shock syndrome (TSS) is a serious, potentially life-threatening condition resulting from an overwhelming immunological response to an exotoxin released by Staphylococcus aureus and group A streptococci. High index of suspicion, early diagnosis and aggressive therapeutic measures must be instituted in view of high mortality of the TSS. In recent years, new agents have been tested to reduce morbidity and mortality in patients with severe sepsis, in addition to standard supportive measures. Among them, recombinant human activated protein C (rhAPC) has been reported to significantly reduce mortality and morbidity in patients with severe sepsis and two or more acute organ failures. We describe our experience with this drug in the early reversal of septic shock from TSS.     

Chronic mania: An unexpectidly long episode?

Mood disorders (unipolar and bipolar disorders) are one of the most distressing and disabling disorders known to man kind. Mood disorders may present as either a depressive phase or manic phase. Chronic mania by definition means presence of manic symptoms in excess of 2 yrs without remission. Chronic mania differs in its psychopathological presentation from the acute mania. Chronic mania also poses a diagnostic and management challenge. Along with the poor response to the treatment these patients are also likely to suffer from severe impairment in the social, familial, interpersonal and occupational functioning. These disturbances may add to the chronicity of the condition. This case underlines the significance of keeping possibility of chronic mania which has been overlooked in the recent literature.     

马蹄花提取物对大鼠的抗生育作用(英文)

AIM:To evaluate the anti-fertility effect of methanolic(MeTD) and aqueous(AqTD) flower extracts of Tabernaemon-tana divaricata in rats.METHODS:The anti-fertility activity of the extracts was evaluated using two experimental animal models:1) Estrogenic activity was carried out in immature female rats using ethinyl estradiol as standard.The evaluation parameters includes changes in uterine weight and histopathology of uterus.2) Anti-implantation and early abortifacient activity was performed in female Wistar rats.The number of implants and resorbtions were compared to vehicle control.RESULTS:Phytochemical analysis of MeTD and AqTD revealed the presence of carbohydrates,amino acids,steroids,glycosides,flavonoids,alkaloids and tannins.In estrogenic activity,the MeTD and AqTD were offered significant estrogen-like activity at 500 mg?kg-1,p.o.by increasing the uterine weight com-pared to vehicle control group.In Anti-implantation and early abortifacient activity study,MeTD(500 mg?kg-1,p.o.) showed significant effect and it was evident by decrease in the number of implants and increase in the number of resorbtions compared to vehicle control group.CONCLUSION:The MeTD at 500 mg?kg-1,p.o.possess significant estrogenic,anti-implantation and early abortifacient activ-ity,while the AqTD at 500 mg?kg-1,p.o.was found to possess significant estrogenic activity and the results are in consistent with the literature reports related to anti-fertility effect of flower extracts of Tabernaemontana divaricata.     

Poly[3-(3, 4-dihydroxyphenyl) glyceric acid] from Comfrey exerts anti-cancer efficacy against human prostate cancer via targeting androgen receptor, cell cycle arrest and apoptosis

The major obstacles in human prostate cancer (PCA) treatment are the development of resistance to androgen ablation therapy leading to hormone-refractory state and the toxicity associated with chemotherapeutic drugs. Thus, the identification of additional non-toxic agents that are effective against both androgen-dependent and androgen-independent PCA is needed. In the present study, we investigated the efficacy of a novel phytochemical poly[3-(3, 4-dihydroxyphenyl)glyceric acid] (p-DGA) from Caucasian species of comfrey (Symphytum caucasicum) and its synthetic derivative syn-2, 3-dihydroxy-3-(3, 4-dihydroxyphenyl) propionic acid (m-DGA) against PCA LNCaP and 22Rv1 cells. We found that both p-DGA and m-DGA suppressed the growth and induced death in PCA cells, with comparatively lesser cytotoxicity towards non-neoplastic human prostate epithelial cells. Furthermore, we also found that both p-DGA and m-DGA caused G(1) arrest in PCA cells through modulating the expression of cell cycle regulators, especially an increase in CDKIs (p21 and p27). In addition, p-DGA and m-DGA induced apoptotic death by activating caspases, and also strongly decreased AR and PSA expression. Consistent with in vitro results, our in vivo study showed that p-DGA feeding strongly inhibited 22Rv1 tumors growth by 76% and 88% at 2.5 and 5mg/kg body weight doses, respectively, without any toxicity, together with a strong decrease in PSA level in plasma; and a decrease in PCNA, AR and PSA expression but increase in p21/p27 expression and apoptosis in tumor tissues from p-DGA-fed mice. Overall, present study identifies p-DGA as a potent agent against PCA without any toxicity, and supports its clinical application.     

Generation of reactive oxygen species by grape seed extract causes irreparable DNA damage leading to G2/M arrest and apoptosis selectively in head and neck squamous cell carcinoma cells

Head and neck squamous cell carcinoma (HNSCC) accounts for 6% of all malignancies in USA and unfortunately the recurrence of secondary primary tumors and resistance against conventional treatments decrease the overall 5 year survival rate in HNSCC patients. Thus, additional approaches are needed to control HNSCC. Here, for the first time, employing human HNSCC Detroit 562 and FaDu cells as well as normal human epidermal keratinocytes, we investigate grape seed extract (GSE) efficacy and associated mechanism in both cell culture and nude mice xenografts. GSE selectively inhibited the growth and caused cell cycle arrest and apoptotic death in both Detroit 562 and FaDu cells by activating DNA damage checkpoint cascade, including ataxia telangiectasia mutated/ataxia telangiectasia-Rad3-related-checkpoint kinase 1/2-cell division cycle 25C as well as caspases 8, 9 and 3. Consistent with these results, GSE treatment resulted in a strong DNA damage and a decrease in the levels of DNA repair molecules breast cancer gene 1 and Rad51 and DNA repair foci. GSE-caused accumulation of intracellular reactive oxygen species was identified as a major mechanism of its effect for growth inhibition, DNA damage and apoptosis, which was remarkably reversed by antioxidant N-acetylcysteine. GSE feeding to nude mice decreased Detroit 562 and FaDu xenograft tumor growth by 67 and 65% (P < 0.001), respectively. In immunohistochemical analysis, xenografts from GSE-fed groups showed decreased proliferation but increased DNA damage and apoptosis. Together, these findings show that GSE targets both DNA damage and repair and provide mechanistic insights for its efficacy selectively against HNSCC both in cell culture and mouse xenograft, supporting its translational potential against HNSCC.