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Natural products are a great source of cancer chemotherapeutic agents. The present study was conducted to investigate whether cucurbitacin B (CuB), one of the most potent and widely used cucurbitacins, inhibits proliferation and induces apoptosis in the A549 lung cancer cell line. Furthermore, CuB induced apoptosis of A549 cells in a -concentration-dependent manner, as determined by fluorescence microscopy, flow cytometry and transmission electron microscopy. The present study also demonstrated that CuB dose-dependently inhibited lung cancer cell proliferation, with cell cycle inhibition and cyclin B1 downregulation. Apoptosis induced by CuB was shown to be associated with cytochrome c release, B-cell lymphoma 2 downregulation and signal transducer and activator of transcription 3 pathway inhibition. CuB may prove to be a useful approach for the chemotherapy of lung cancer.

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BACKGROUND: Breast cancer is one of the most common cancers in women in the world. Health-related quality of life (HRQL) at treatment endpoint in cancer clinical trials is widely considered to be increasingly important. The aim of this review was to provide a literature-based assessment of the validity, reliability and responsiveness of breast cancer-specific HRQL instruments in women breast cancer patients. MATERIALS AND METHODS: The databases consulted were Medline, PubMed, and Embase. The inclusion criteria required studies to: (1) involve use of HRQL measures; (2) cover women with breast cancer under standard treatment (surgery, radiation therapy, chemotherapy, hormone therapy, and targeted therapy); (3) involve the validity, reliability, or responsiveness of HRQL; (4) deal with validation of breast cancer-specific HRQL instruments. RESULTS: A total of 16 studies were identified through the literature search that met the 4 inclusion criteria. Some seven instruments were assessed among these 16 studies: EORTC QLQ-BR23, FACT-B, FACT-ES, HFRDIS, LSQ- 32, QLICP-BR, and SLDS-BC. EORTC QLQ-BR23, FACT-B, LSQ-32, QLICP-BR, and SLDS-BC are more general breast cancer-specific HRQL instruments. FACT-EB is the endocrine subscale combined with FACT-B in order to measure the side effects and putative benefits of hormonal treatment administered in breast cancer patients. HFRDIS is the HRQL measure focusing on hot flash concerns. CONCLUSIONS: This paper provides an overall understanding on the currently available breast cancer-specific HRQL instruments in women breast cancer patients.

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The herb of Hedyotis diffusa Willd (H. diffusa Willd), an annual herb distributed in northeastern Asia, has been known as a traditional oriental medicine for the treatment of cancer. Recently, Chinese researchers have discovered that two anthraquinones isolated from a water extract of H. diffusa Willd showed apoptosis-inducing effects against cancer cells. However, the cellular and molecular mechanisms responsible for this phenomenon are poorly understood. The current study determines the role of mitogen-activated protein kinases (MAPK) in human leukemic U937 cells apoptosis induced by 2-hydroxy-3-methylanthraquinone from H. diffusa. Our results showed that 2-hydroxy-3-methylanthraquinone decreased phosphorylation-ERK1/2 (p-ERK1/2), and increased p-p38MAPK, but did not affect expressions of p-JNK1/2 in U937 cells. Moreover, treatment of U937 cells with 2-hydroxy-3-methylanthraquinone resulted in activation of caspase-3. Furthermore, PD98059 (ERK1/2 inhibitor) significantly enhanced 2-hydroxy-3-methylanthraquinone-induced apoptosis in U937 cells, whereas caspase-3 inhibitor or SB203580 (p-p38MAPK inhibitor), decreased apoptosis in U937 cells. Taken together, our study for the first time suggests that 2-hydroxy-3-methylanthraquinone is able to enhance apoptosis of U937 cells, at least in part, through activation of p-p38MAPK and downregulation of p-ERK1/2. Moreover, the triggering of caspase-3 activation mediated apoptotic induction.

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Natural products isolated from Chinese medicinal herbs are useful sources of new drugs for cancer therapy. Tubeimoside-1 (TBMS1) is a natural compound isolated from the Chinese medicinal herb Bolbostemma paniculatum (Maxim.) Franquet (Cucurbitaceae). Studies have shown that TBMS1 has anticancer effects in various human cancer cell lines. However, the effect of TBMS1 on human gastric cancer cells is unknown. In the present study, it was observed that TBMS1 inhibited BGC823 gastric cancer cell proliferation in a concentration- and time-dependent manner. Fluorescent microscopy and flow cytometric analysis showed that TBMS1 induced BGC823 cell apoptosis in a concentration-dependent manner. Western blot analysis also showed that TBMS1 induced apoptosis by regulation of the Bcl-2 gene family in BGC823 cells. These findings indicate that TBMS1 may be developed as a possible therapeutic agent for the management of gastric cancer.

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Jolkinolide B from the roots of Euphorbia fischeriana Steud exhibits significant antitumor activities against several tumor lines. Previous study has shown that Jolkinolide B could induce apoptosis in human leukemia cells. However, the exact mechanism and signaling pathway involved in Jolkinolide B-induced apoptosis have not been fully elucidated. In the present study, we found that Jolkinolide B reduced cell viability and induced apoptosis in dose- and time-dependent manner in human leukemic HL-60 and THP-1 cells. The induction of apoptosis was accompanied by the downregulation of JAK2/STAT3. Our results also suggest that expression of Bcl-2 and mitochondrial cytochrome c was dosedependently reduced following Jolkinolide B-treated THP-1 and HL-60 cells, whereas Jolkinolide B up-regulated the expression of Bax and cytosolic cytochrome c. Moreover, we observed that Jolkinolide B treatment resulted in activation of caspase-3, -8, and -9. JSI-124, a STAT-3 inhibitor, was able to block the negative effect of Jolkinolide B on cell apoptosis. Taken together, our study for the first time suggests that Jolkinolide B is able to enhance apoptosis of human leukemic HL-60 and THP-1 cells, at least in part, through downregulation of JAK2/STAT3 and bcl-2, and upregulation of Bax and cytosolic cytochrome c. Moreover, the triggering of caspase-3, -8, and -9 activation mediated apoptotic induction.

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Natural compounds are a great source of cancer chemotherapeutic agents. Our investigation indicates that waltonitone, a triterpene extracted from medicinal plants, inhibits the proliferation of A549 cells in a concentration- and time-dependent manner. Waltonitone induced apoptosis of A549 cells in a concentration-dependent manner, as determined by fluorescence microscopy and flow cytometry. The apoptosis was accompanied by increased Bax protein levels and decreased Bcl-2 protein levels in A549 cells. Furthermore, the treatment of A549 cells with waltonitone altered the expression of miRNAs. We found that 27 miRNAs were differentially expressed in waltonitone-treated cells, of which 8 miRNAs target genes related to cell proliferation and apoptosis. In summary, our results demonstrate that waltonitone has a significant inhibitory effect on the proliferation of A549 cells. It is possible that upregulation of Bax/Bcl-2 and regulation of expression of specific miRNAs play a role in inhibition of proliferation and induction of apoptosis in waltonitone-treated cells. Waltonitone can be applied to lung carcinoma as a chemotherapeutic candidate.

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OBJECTIVE: To investigate the effect of SP600125, a specific c-jun N-terminal protein kinase (JNK) inhibitor, on Staphylococcus aureus (S. aureus)-induced U937 cell death and the underlying mechanism. METHODS: The human monocytic U937 cells were treated with S. aureus at different time with or without SP600125. Cell apoptosis was analyzed by flow cytometry. JNK, Bax, and caspase-3 activities were detected by Western blotting. RESULTS: S. aureus induced apoptosis in cultured U937 cells in a time-dependent manner. Expression of Bax and phospho-JNK significantly increased in S. aureus-treated U937 cells, and the level of activated caspase-3 also increased in a time-dependent manner. Inhibition of JNK with SP600125 significantly inhibited S. aureus-induced apoptosis in U937 cells. CONCLUSIONS: S. aureus can induce apoptosis in U937 cells by phosphorylation of JNK and activation of Bax and caspase-3. SP600125 protects U937 cells from apoptosis induced by S. aureus via inhibiting the activity of JNK.

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AIM: To investigate the effects of imidapril (IMI) on effective refractory period (ERP) and sodium current (I(Na)) of myocytes in ventricular noninfarction zone of healed myocardial infarction (HMI) in rabbit models. METHODS: Rabbits with left coronary artery ligation were prepared and IMI (0.625 mg x kg(-1) x d(-1), 8 weeks) was orally administered. The ERP and sodium current were recorded. RESULTS: The ERP in HMI heart was prolonged. The ERP in IMI group was lower significantly than that of HMI group. The I(Na) density of myocyte in HMI ventricle decreased obviously. V 1/2 of steady state inactivation of I(Na) shifted to hyperpolarization, and time constant (tau) of recovery from inactivation in HMI ventricular myocyte was longer than that of sham ventricular myocyte. I(Na) density in IMI group increased markedly as compared with that of HMI group. CONCLUSION: IMI was shown to reverse the abnormal prolongation of ERP in rabbit heart with the HMI and increase I(Na) density. It may be the mechanism of IMI preventing against antiarrhythmia in healed myocardical infarction.

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OBJECTIVE: To establish an experimental endometriosis model using nude mouse as a xenographic host for relative biological behavior study of endometriosis. METHODS: Nude mice of experimental group were implanted with the late secretory endometrium of patients with endometriosis (n = 24) or without endometriosis (n = 24) into pelvic and abdominal cavities. Nude mice of control group (n = 3) were implanted with the greater omentum. Nude mice were killed at 5, 15 and 30 d randomly to observe the growth of endometriotic lesions. The morphological changes of endometriotic lesions from different sources and at different time points of growth were examined by light microscopy and electron microscopy; the expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) of eutopic endometrium and endometriotic lesions were detected by RT-PCR method, and the expressions of steroid hormone receptors by immunohistochemistry method. RESULTS: Endometriotic lesions were found from 5 d with rich blood supply, endometrial glands and stroma under light microscope. And the adhesion to mouse tissues became more severe with time. Under electron microscope, proliferation and infiltration of inflammatory cells were most striking at 15 d. At 30 d the organellae of gland cells were disappeared and there was nuclear chromatin aggregation with apoptosis tendency, but secretory granules still could be seen. The expressions of VEGF and MMP-9 mRNA were increased in endometriotic lesions compared with eutopic endometrium (P < 0.05), and were strongest at 15 d (EM group: 1.11 +/- 0.13/1.00 +/- 0.11; NEM group: 1.10 +/- 0.11/0.99 +/- 0.08) and decreased at 30 d (EM group: 0.85 +/- 0.11/0.77 +/- 0.13; NEM group: 0.86 +/- 0.14/0.76 +/- 0.11). Immunochemistry revealed the positive rate of estrogen and progestogen receptors at 30 d (EM group: 4/8 and 4/8; NEM group: 5/8 and 4/8) was lower than that at 5 d (EM group: 7/8 and 7/8; NEM group: 8/8 and 7/8) and 15 d (EM group: 7/8 and 7/8; NEM group: 7/8 and 8/8), and the expressions of steroid hormone receptors were mostly weak. There was no differences in expression of VEGF and MMP-9 mRNA, estrogen and progestogen between endometriotic lesions implanted with normal endometrium and endometrium from patients with endometriosis. CONCLUSIONS: The nude mouse is an appropriate model for the study of the early phase of endometriosis, and the genesis and development of endometriotic lesions are similar to that of human endometriosis. Endometriosis is associated with multiple factors.

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In order to verify the hypothesis that left ventricular epicardial (LV-Epi) pacing and biventricular (BiV) pacing unavoidably influence the myocardial electrophysiological characters and may result in high risk of malignant ventricular arrhythmia, we calculated, in both normal mongrel dogs and dog models with rapid-right-ventricular-pacing induced dilated cardiomyopathy congestive heart failure (DCM-CHF), the monophasic action potential duration (MAPD) and the transmural dispersion of repolarization (TDR) in intracardiac electrogram together with the QT interval and T(peak)-T(end) (T(p(-T(e)) interval in surface electrocardiogram (ECG) during LV-Epi and BiV pacing, compared with those during right ventricular endocardial (RV-Endo) pacing. To prepare the DCM-CHF dog model, rapid right ventricular pacing (250 bpm) was performed for 23.6+/-2.57 days to the dog. All the normal and DCM-CHF dogs were given radio frequency catheter ablation (RFCA) to His bundle with the guide of X-ray fluoroscopy. After the RFCA procedures, the animals were under the situation of complete atrioventricular block so that the canine heart rates could be voluntarily controlled in the following experiments. After a thoracotomy, ECG and monophasic action potentials (MAP) of subendocardial, subepicardial and mid-layer myocardium were recorded synchronously in 8 normal and 5 DCM-CHF dogs during pacing from endocardium of RV apex (RV-Endo), epicardium of LV anterior wall (LV-Epi) and simultaneously both of the above (biventricular, BiV), the later was similar to the ventricular resynchronization therapy to congestive heart failure patients in clinic. The Tp-Te) meant the interval from the peak to the end of T wave, which was a representative index of TDR in surface ECG. The TDR was defined as the difference between the longest and the shortest MAPD of subendocardial, subepicardial and mid-layer myocardium. Our results showed that in normal dogs, pacing participating of LV (LV-Epi, BiV) prolonged MAPD of all the three layers of the myocardium (P<0.05) with the character that mid-layer MAPD was the longest and subepicardial MAPD was the shortest following subendocardial MAPD. At the same time, TDR prolonged from 26.75 ms at RV-Endo pacing to 37.54 ms at BiV pacing and to 47.16 ms at LV-Epi pacing (P<0.001). Meanwhile in surface ECG, BiV and LV-Epi pacing resulted in a longer Tp-Te) interval compared with RV-Endo pacing (P<0.01), without parallel QT interval prolongation. Furthermore, all the DCM-CHF model dogs showed manifestations of congestive heart failure and enlargement of left ventricles. Based on the lengthening of mid-layer MAPD from 257.35 ms to 276.30 ms (P<0.0001) and increase of TDR from 27.58 ms to 33.80 ms (P equals;0.002) in DCM-CHF model due to the structural disorders of myocardium compared with the normal dog, LV-Epi and BiV pacing also led to the effect of prolonging MAPD of three layers of the myocardium and enlarging TDR. From these results we make the conclusions that prolongation of MAPD of subendocardial, subepicardial and mid-layer myocardium and increase in TDR during pacing participating of LV (LV-Epi, BiV) may contribute to the formation of unidirectional block and reentry, which play roles or at least are the high risk factors in the development of malignant ventricular arrhythmia, especially in case of structural disorders of myocardium. These findings must be considered seriously when ventricular resynchronization therapy is performed to congestive heart failure patients.

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AIM: To investigate the transmural heterogeneous change of slow component of delayed rectifying potassium current in rabbit left ventricular hypertrophic myocytes and the effect of long-term treatment with imidapril (Imi). METHODS: Rabbits were divided into hypertrophy group (left ventricular hypertrophy induced by partial ligation of abdominal aorta), Imi-treated group (surgical treatment as hypertrophy group was treated with Imi), and Sham-operated group as control. Whole-cell patch-clamp technique was used to record potassium currents. RESULTS: (1) Membrane capacitance was larger in hypertrophic cells than in sham-operated and Imi-treated cells. Action potential durations (APD) of epicardium (Epi), midmyocardium (M), and endocardium (Endo) were remarkably longer in hypertrophic cells than those in Imi-treated and sham-operated cells. The prolongation of APD90 of M was the most pronounced in three layer myocytes of hypertrophic group. (2) The densities of I(Ks,tail) of hypertrophic cells were reduced by Epi 25.3 %+/-2.9 %, M 38.0 %+/-3.7 % and Endo 20.3 %+/-4.7 % compared with those of sham-operated cells. The decrease of IKs,tail density was more pronounced in M than in Epi and Endo (n = 13, P<0.01 vs Epi or Endo). (3) The density of I(Kr,tail) in Imi-treated cells was not different from that in sham-operated cells significantly (n=10). CONCLUSION: Imi reduced prolongation of APD and inhibited the heterogeneous change of I(Ks,tail) in rabbit left ventricular hypertrophic myocytes.

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Experiments were performed to investigate the heterogeneity of the action potential and ion currents in left ventricular myocytes of the rabbit. Myocytes were isolated by enzymatic method. The sub-endocardial (Endo) and sub-epicardium (Epi) tissues were separated from the other region (midmyocardium, M) with a razor. Single cells in each region were obtained by gentle shaking and dispersing in a chamber filled with normal Tyrode's solution. The results showed that the action potential and the ion currents in the three layers were significantly different. M cells had a more pronounced spike-and-dome configuration, with a significantly larger phase 1 magnitude and plateau voltage. Action potential duration (APD) in M cells was longer than that in Epi or Endo cells. I(Ca, L) and I(to) in M cells were higher than those of Epi and Endo. On the contrary, I(K,s) in M cells was the minimum compared with those in the three LV walls. The differences in ion currents may well explain the heterogeneity of action potentials in M layers of the rabbit heart.

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