: New treatments are needed to reduce myocardial infarct size (MI) and prevent heart failure (HF) following acute myocardial infarction (AMI), which are the leading causes of death and disability ...worldwide. Studies in rodent AMI models showed that genetic and pharmacological inhibition of mitochondrial fission, induced by acute ischemia and reperfusion, reduced MI size. Whether targeting mitochondrial fission at the onset of reperfusion is also cardioprotective in a clinically-relevant large animal AMI model remains to be determined.
: Adult pigs (30-40 kg) were subjected to closed-chest 90-min left anterior descending artery ischemia followed by 72 h of reperfusion and were randomized to receive an intracoronary bolus of either mdivi-1 (1.2 mg/kg, a small molecule inhibitor of the mitochondrial fission protein, Drp1) or vehicle control, 10-min prior to reperfusion. The left ventricular (LV) size and function were both assessed by transthoracic echocardiography prior to AMI and after 72 h of reperfusion. MI size and the area-at-risk (AAR) were determined using dual staining with Tetrazolium and Evans blue. Heart samples were collected for histological determination of fibrosis and for electron microscopic analysis of mitochondrial morphology.
: A total of 14 pigs underwent the treatment protocols (eight control and six mdivi-1). Administration of mdivi-1 immediately prior to the onset of reperfusion did not reduce MI size (MI size as % of AAR: Control 49.2 ± 8.6 vs. mdivi-1 50.5 ± 11.4; p = 0.815) or preserve LV systolic function (LV ejection fraction %: Control 67.5 ± 0.4 vs. mdivi-1 59.6 ± 0.6; p = 0.420), when compared to vehicle control. Similarly, there were no differences in mitochondrial morphology or myocardial fibrosis between mdivi-1 and vehicle control groups.
: Our pilot study has shown that treatment with mdivi-1 (1.2 mg/kg) at the onset of reperfusion did not reduce MI size or preserve LV function in the clinically-relevant closed-chest pig AMI model. A larger study, testing different doses of mdivi-1 or using a more specific Drp1 inhibitor are required to confirm these findings.
Sinularin is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigated the effects of sinularin on two human gastric cancer cell lines, AGS and ...NCI-N87. Our results demonstrated that sinularin suppressed the proliferation of gastric cancer cells in a dose-dependent manner and induced apoptosis. In addition, the loss of mitochondrial membrane potential, the release of cytochrome C, the activation of Bax, Bad and caspase-3/9, and the suppression of p-Bad, Bcl-xL and Bcl-2 were observed in the cells treated with sinularin. This finding suggests that sinularin-induced apoptosis is associated with mitochondria-mediated apoptosis and occurs through caspase-dependent pathways. Furthermore, sinularin inhibited the phosphoinositol 3-kinase/Akt/mechanistic target of the rapamycin signaling pathway. Taken together, our results show that sinularin-induced apoptosis is mediated by activation of the caspase cascade and mitochondrial dysfunction. Our findings suggest that sinularin merits further evaluation as a chemotherapeutic agent for human gastric cancer.
Urothelial carcinoma (UC) is the most common type of genitourinary cancer with high incidence and mortality rates in men. In this study, we used the BFTC-905 and T24 bladder cancer cell lines as in ...vitro models to investigate the pathways involved in flaccidoxide-induced apoptosis.
We utilized MTT assays, colony assays, wound-healing assays and fluorescence with TUNEL to confirm the cytotoxicity of flaccidoxide in bladder cancer cell lines. Potential proliferative and apoptotic molecular mechanisms were evaluated by western blotting.
The expression of anti-apoptotic proteins Bcl-2 and phosphorylated Bad (p-Bad) was attenuated with an increasing flaccidoxide concentration, while the expression of proapoptotic proteins Bax, Bad, cleaved caspase-3, cleaved caspase-9 and cleaved PARP-1 was found increased. Additionally, phosphorylation of phosphoinositide 3-kinases (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in the PI3K/AKT/mTOR pathway was reduced, leading to a reduction in the phosphorylation of downstream 70-kDa ribosomal protein S6 kinase 1 (p70S6K), S6 ribosomal protein (S6) and eukaryotic translation initiation factor 4B (eIF4B). However, eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) protein phosphorylation was increased due to attenuation of the upstream phosphorylation of mTOR protein.
Flaccidoxide-induced apoptosis in BFTC-905 and T24 cells is mediated by mitochondrial dysfunction and down-regulation the PI3K/AKT/mTOR/p70S6K signaling pathway.
Hypertension and cancer are frequently found comorbidity occurring in same individual. This study was intended to evaluate the anticancer effects of commonly used antihypertensive medications and ...chemotherapy on chemoresistant lung cancer cells.
Calcium channel blockers (CCBs), including Verapamil, Diltiazem, and Nifedipine, either alone or combined with docetaxel (DOC) or vincristine (VCR) were used to treat A549 lung adenocarcinoma chemoresistant sublines. Cell viability was determined by MTT assay, and colony formation assay was used to demonstrate the long-term effect of CCBs on proliferation of the sublines. Apoptosis was evaluated by Annexin V assay and autophagy intensity was quantitated from acidic vesicular organelle formation. Pan-caspase inhibitor, shATG5 interference and chloroquine were applied to study the roles of Verapamil on apoptosis and autophagy, with related proteins verified by Western blot analysis.
Results show that 10 μM of Verapamil and Diltiazem, but not Nifedipine, differentially induce autophagy in DOC-resistant or VCR-resistant A549 cells, respectively. When CCBs are combined with DOC or VCR to treat the sublines, 10 μM of Verapamil induces autophagy more significantly than Diltiazem and Nifedipine, respectively, in DOC-resistant (54.91±0.76, 18.03±0.69, 7.05±0.30) or VCR-resistant A549 (32.41±1.04, 21.51±0.63, 7.14±0.24) cells. Inhibition of apoptosis by pan-caspase inhibitor partly reduced cell death indicates association of caspase-dependent cell death but with persistence of autophagy. Inhibition of autophagy by interfering ATG5 expression reduced c-PARP level and apoptotic cells suggest a pro-death role of autophagy. Chloroquine treatment enhanced autophagosome accumulation and cell death but with reduced c-PARP level suggests that mechanism of caspase-independent cell death also contributes to Verapamil/chemotherapy-induced anticancer effects.
Verapamil combined with DOC or VCR induces chemoresistant lung cancer cells to death through autophagy burst and apoptosis more strongly than Diltiazem and Nifedipine. Administering Verapamil or Diltiazem individually with chemotherapy, but not Nifedipine, can be considered in lung cancer patients with hypertension.
Chemical examination of the Taiwanese soft coral Sinularia flexibilis led to the isolation of five cembrane-based diterpenoids 1-5, including two new metabolites, 11-acetylsinuflexolide (1) and ...11-acetyldihydrosinuflexolide (2). The structures of the new metabolites were determined based on extensive spectroscopic analysis, particularly mass spectrometry and 2D NMR (1H-1H COSY, HMQC, HMBC, and NOESY) spectroscopy. Metabolites 1, 3 and 4 exhibited moderate to weak cytotoxicity to human tumor cell lines, HeLa, HEp-2, MCF-7 and MDA-MB-231.
Background: In the past decade, accidents have been one of the top 10 causes of death in Taiwan. Head trauma caused by accidents has been an issue of concern in Taiwan. Although serious long-term ...effects have been documented, research on mild traumatic brain injury (mTBI) remains scarce. Thus, the main purpose of this study was to analyze post-concussion symptome (PCS) and the relevant impact on physical, emotional, and cognitive functions.
Materials and Methods: During 2012-2013, 105 patients with mTBI in a single hospital were surveyed based on the Rivermead postconcussion symptoms questionnaire in 1 week, and their postinjury status was followed 1 month later. The collected data were analyzed using the paired t-test and descriptive statistics.
Results: The collected data were included patient demographics and pretrauma risk factors. A total of 101 patients were subject to mTBI. The rate increased among males and the population aged from 21 to 44 years old. The most common cause of injury was the motorcycle accident, where half of the patients had an initial loss of consciousness and posttraumatic amnesia. Partial resolution of symptoms was noted within 1 month for all participants, but some symptoms persisted (P < 0.0001). In general, patients (especially females) recovered faster from physical impairment. The analysis provides information about the impacts and shows the increased risk of neurocranial traumas related to mTBI.
Conclusion: This study presents patients' PCS symptoms in different periods. Those symptoms improved gradually in 1 month, but some symptoms persisted, especially those affecting emotional and cognitive functions. Most patients in this study were young, and the illness had impact on the patients' daily life. As shown by the results, the risk factors were associated with prolonged PCS among females. Aside from physical symptoms, special attention should be paid to mental care as well. More predictors for mTBI may improve medical care quality and reduce losses of medical resources.
In this study the isolated compound 11-dehydrosinulariolide from soft coral Sinularia leptoclados possessed anti-proliferative, anti-migratory and apoptosis-inducing activities against A2058 melanoma ...cells. Anti-tumor effects of 11-dehydrosinulariolide were determined by MTT assay, cell migration assay and flow cytometry. Growth and migration of melanoma cells were dose-dependently inhibited by 2-8 μg/mL 11-dehydrosinulariolide. Flow cytometric data indicated that 11-dehydrosinulariolide induces both early and late apoptosis in melanoma cells. It was found that the apoptosis induced by 11-dehydrosinulariolide is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by loss of mitochondrial membrane potential (∆Ψm), release of cytochrome C, activation of caspase-3/-9 and Bax as well as suppression of Bcl-2/Bcl-xL. The cleavage of PARP-1 suggested partial involvement of caspase-independent pathways. Immunoblotting data displayed up-regulations of PERK/eIF2α/ATF4/CHOP and ATF6/CHOP coupling with elevation of ER stress chaperones GRP78, GRP94, calnexin, calreticulin and PDI, implicating the involvement of these factors in ER stress-mediated apoptosis induced by 11-dehydrosinulariolide. The abolishment of apoptotic events after pre-treatment with salubrinal indicated that ER stress-mediated apoptosis is also induced by 11-dehydrosinulariolide against melanoma cells. The data in this study suggest that 11-dehydrosinulariolide potentially induces apoptosis against melanoma cells via mitochondrial dysregulation and ER stress pathways.
Both the root and stem bark of
Mahonia species were popular folk medicines. The plant has several proven biological activities including anti-bacterial, anti-fungal, and anti-inflammatory effects. ...However,
Mahonia has not been studied for its anticancer effects. In the present study, we made extracts from
Mahonia oiwakensis (MOE), a selected species in Taiwan, and investigated their effects on various human lung cells. We found that MOE-induced apoptotic death in human A549 non-small-cell lung carcinoma (NSCLC) cells in a dose- and time-dependent manner. Treatment with the extracts also caused an increase in the sub-G1 fraction of cells, chromosome condensation, and DNA fragmentation. The mitochondrial-mediated pathway was implicated in this MOE-induced apoptosis as evidenced by the activation of the caspase cascade, cleavage of poly (ADP-ribose) polymerase (PARP), disruption of mitochondrial membrane potential, and release of cytochrome
C. A higher ratio of Bax/Bcl-2 proteins and cleavage of Bid were also observed in MOE-induced cell apoptosis. In A549 tumor-xenografted nude mice, MOE also retarded
in vivo proliferation (
P
<
0.05) and induced apoptosis in tumor cells, as shown by a decrease in Ki-67-positive staining (
P
<
0.05) and increased transferase-mediated dUTP nick-end labeling (TUNEL)-positive staining (
P
<
0.05). In conclusion, MOE inhibits the growth of human lung cancer cells
in vitro and
in vivo, suggesting that it may have therapeutic potential against human lung cancer.
The incidence of seizures in patients undergoing burr-hole crainiostomy with closed-system drainage for chronic subdural hematoma (CSDH) is low. The post-operative use of anticonvulsants is, thus, ...controversial. In this study, we tried to correlate pre-operative computed tomographic (CT) appearance of the CSDH with the need for post-operative seizure prophylaxis. From April 1998 to November 2001, 128 cases of CSDH surgically treated at our hospital were studied. All patients underwent burr-hole craniostomy with closed system drainage. All CSDHs were classified as low-density, isodense, and mixed-density lesions according to CT findings. The incidence of early post-operative seizures (within 3 weeks of surgery) among all patients was 5.4% (7/128). In the subgroups by lesion density, the incidences were 6.2% (1/16) in the low-density group, 2.4% (2/83) in the isodense group, and 13.7% (4/29) in the mixed-density group (all
p<0.05). The mean age among the seven patients (five males and two females) who had seizures was 71 years. The locations of the CSDHs among the 128 patients were the left side of the brain in 53 (41.4%) patients, right side in 45 (35.2%), and bilateral in 30 (23.4%) patients. Among the seven patients who suffered from post-operative seizures, five (71.4%) had left side CSDHs, one (14.2%) had a right side CSDH, and one (14.2%) had bilateral CSDHs. We concluded that the post-operative seizure rate appeared high in the group with mixed-density type lesions on CT, and in those with left unilateral CSDH. We suggest the use of prophylactic anticonvulsants for patients with mixed-density lesions on pre-operative CT.
碩士
高雄醫學大學
醫務管理學研究所碩士在職專班
98
Objectives
Stroke ranks the second leading cause of death in Taiwan. Ruptured intracranial aneurysm is one of the main factors of hemorrhagic stroke. Aneurysm surgery can ...be done by traditional craniotomy with external clipping of the aneurysm. Recently, study of relevant literature review that a new surgical treatment of intracranial aneurysm by using minimally invasive intravascular embolization may provide patients with better outcome and shorter recovery time. However, the used of platinum coils for embolization is more expensive than the aneurysm clips. The National Health Insurance restricted the use of these platinum coils clinically. The purpose of this study is to compare these two types of procedures in their clinical outcomes and medical utilizations. And to provide information for the medical resource planning while making the health care policy.
Methods
According to the current literature of intracranial aneurysms treatment, we divided the traditional craniotomy surger
PDF
