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Lead (Pb) is nonbiodegradable and toxic to the lungs. To investigate the potential mechanisms of Pb‐induced reactive oxygen species (ROS) accumulation and cell death in the lungs, human non‐small lung carcinoma H460 cells were stimulated with Pb(NO3)2 in this study. The results showed that Pb(NO3)2 stimulation increased cell death by inducing cell apoptosis which showed a reduced Bcl‐2 expression and an enhanced caspase 3 activation. Pb(NO3)2 also caused the production of H2O2 in H460 cells that triggering the buildup of ROS and mitochondrial membrane potential loss. We found that Pb(NO3)2 modulates oxidoreductive activity through reduced the glutathione‐disulfide reductase and glutathione levels in Pb(NO3)2‐exposed H460 cells. Furthermore, the superoxide dismutase (SOD) upstream molecule sirtuin 3 (SIRT3) was increased with Pb(NO3)2 dose. Collectively, these results demonstrate that Pb(NO3)2 promotes lung cell death through SIRT3/SOD‐mediated ROS accumulation and mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Aims: In contrast to Western patients with breast cancer, Asian patients are relatively younger at diagnosis, and most are free from traditional cardiovascular risk factors. Despite trastuzumab‐related major adverse cardiac and cerebrovascular event (MACCE) being reported, its incidence and predictors remain unknown in Taiwan. Methods and results: Through a three‐hospital retrospective cohort study, we analysed the incidence of MACCE in 386 breast cancer patients' exposure to trastuzumab from 2010 to 2018. To further reconfirm our findings, in a nationwide study using the Taiwanese National Health Insurance Research Database and National Cancer Registry, we identified 13 502 women diagnosed with breast cancer who received chemotherapy from 2010 to 2015 and found 6751 women who received initial treatment with trastuzumab. After 1:1 propensity score matching with trastuzumab non‐users, the incidence of MACCE was measured with a median follow‐up of 36 months. In the hospital‐based study, among 386 patients receiving trastuzumab, the 5‐year incidences of MACCE and heart failure (HF) were 5.4 and 2.8%, respectively. In the national cohort, the crude incidences of MACCEs and HF were 4.67 and 3.21%, respectively. After adjustment for age and comorbidities, the hazard ratio of MACCE was 1.485 (95% CI 1.246–1.769). Notably, among the endpoints, only the hazard ratio of HF was significantly higher in patients receiving trastuzumab than in nonusers. In the subgroup analysis, except for patients also using taxanes, those receiving trastuzumab had a higher risk of MACCE than non‐users. Conclusions: From clinical observations in a nationwide cohort, we found an increased risk of MACCE, especially HF, in patients receiving trastuzumab. Given that its cardiotoxicity is independent of traditional cardiovascular risks, our findings highlight critical concerns regarding the cardiac safety of trastuzumab use. [ABSTRACT FROM AUTHOR]

Prospective cohort studies have indicated that a highly nickel‐polluted environment may severely affect human health, resulting in such conditions as respiratory tract cancers. Such exposure can trigger vascular endothelial growth factor (VEGF) expression. However, the signal transduction pathways leading to VEGF induction by nickel compounds are not well understood. This study revealed the occurrence of VEGF induction in human non‐small‐cell lung cancer H460 cells exposed to NiCl2. Moreover, exposing H460 cells to NiCl2 activated extracellular signal‐regulated protein kinase (ERK), nuclear factor kappa B (NFκB), and protein kinase B (Akt) as well as downregulated AMP activated protein kinase (AMPK) expression. The mitogen‐activated protein kinase (MAPK) and ERK inhibitor significantly blocked NiCl2‐induced ERK activation and VEGF production. Pretreating H460 cells with a PI3K/Akt inhibitor substantially inhibited NiCl2‐induced VEGF expression and reduced Akt, ERK, and NFκB phosphorylation. Furthermore, 5‐aminoimidazole‐4‐carboxamide ribonucleoside‐induced AMPK activation improved VEGF expression in NiCl2‐treated H460 cells significantly. These results indicate that NiCl2 induces VEGF production through Akt, ERK, NFκB activation and AMPK suppression and mediates various types of pathophysiological angiogenesis. [ABSTRACT FROM AUTHOR]

Kaempferol is a flavonoid with anticancer and anti‐metastasis activity in different cancer‐cell lines. However, the underlying mechanisms by which kaempferol acts on human retinal pigment epithelial (ARPE‐19) cells remain unclear. In this study, we demonstrated that kaempferol inhibited migration and invasion in ARPE‐19 cells at non‐toxic dosages. We discovered that kaempferol obviously reduced the enzyme activity and protein expression of matrix metalloproteinase‐2 by increasing the phosphorylated levels of extracellular signal‐regulated kinases 1/2 (ERK1/2) signaling pathways. Additionally, ERK1/2‐specific inhibitor PD98059 significantly reversed kaempferol's inhibitory effects on migration and expression of MMP‐2 in ARPE‐19 cells. Overall, our results are the first to demonstrate that kaempferol is capable of inhibiting cell migration by targeting ERK1/2 signaling in human retinal pigment epithelial cells. [ABSTRACT FROM AUTHOR]

Dihydromyricetin (DHM), a flavanonol compound in Ampelopsis grossedentata, possesses several biological activities. However, the molecular mechanism underlying the effects of DHM on human proliferative vitreoretinopathy (PVR) remains unclear. We explored the effects of DHM on cell migration and the metastasis‐promoting proteins in human retinal pigment epithelial (RPE) cells (ARPE‐19 cells). Our results revealed that DHM attenuated ARPE‐19 cell invasion and migration by reducing matrix metalloproteinase‐2 (MMP‐2) expression. Furthermore, a Western blot analysis revealed that DHM significantly reduced levels of phosphorylated c‐Jun N‐terminal kinase 1/2, but not those of extracellular signal‐regulated kinase 1/2 and p38. In conclusion, our findings shown that DHM inhibits human RPE cell migration through the inhibition of MMP‐2 expression; therefore, DHM may have potential therapeutic value in treating PVR as adjuvant therapy. [ABSTRACT FROM AUTHOR]

Abstract: Coronarin D, a diterpene derived from the rhizomes of Hedychium coronarium, has been used to treat inflammatory diseases. Coronarin D can exert strong anticancer effects through cell growth prevention and cell cycle arrest in many cancer cells. In this study, we investigated the molecular mechanism through which coronarin D suppresses cell proliferation and triggers cell death in human hepatocellular carcinoma (HCC) cells. Treatment of Huh7 and Sk‐hep‐1 cells with coronarin D resulted in a significantly increased loss of mitochondrial membrane potential, leading to the cleavage and activation of caspase‐9, caspase‐8, and caspase‐3 and changes in Bax, Bcl‐2, and Bcl‐xL protein levels. Coronarin D significantly induced autophagy by increasing the expression of Beclin‐1 and LC3‐II and reducing the expression of p62. Moreover, Huh7 and Sk‐hep‐1 cells exposed to coronarin D had decreased expression of phosphorylated AKT, p38, and ERK and increased expression of phosphorylated JNK. Exposure of cells to the JNK‐specific inhibitor SP600125 attenuated the apoptotic effects of coronarin D. Taken together, this is the first study to report that coronarin D may effectively inhibit cell growth through apoptosis. We have provided evidence indicating that coronarin D induces cell death through the upregulation of JNK mitogen‐activated protein kinases in human HCC cells. [ABSTRACT FROM AUTHOR]

Abstract: Fisetin, a diatery flavonoid, been reported that possess anticancer effects in various cancers. The purpose of the study was to investigate the antitumor effects of fisetin in cultured uveal melanoma cell lines and compared with normal retinal pigment epithelial (RPE) cells. MTT assay was used for evaluating cytotoxic effects of fisetin. Flow cytometry study was used for the determination of apoptosis. JC‐1 fluorescent reader was used to determine mitochondrial transmembrane potential changes. The results shown that fisetin dose‐dependently decreased the cell viability of uveal melanoma cells but not influenced the cell viability of RPE cells. Apoptosis of uveal melanoma cells was induced by fisetin efficiently. Fisetin inhibited antiapoptotic Bcl‐2 family proteins and damaged the mitochondrial transmembrane potential. The levels of proapoptotic Bcl‐2 proteins, cytochrome c, and various caspase activities were increased by fisetin. In conclusion, fisetin induces apoptosis of uveal melanoma cells selectively and may be a promising agent to be explored for the treatment of uveal melanoma. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to investigate the risk of stroke in patients with cerebral palsy (CP), based on nationwide data in Taiwan.Method: This prospective cohort study was comprised of patients recorded on the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005) who had a diagnosis of CP (n=1975) in records between 1 January 2004 and 31 December 2007. A comparison group (1:5) drawn from the same database was matched for age and sex (n=9875). Each patient was tracked by data until the development of stroke or the end of 2008. Cox proportional-hazards regression analysis was used to evaluate the hazard ratios after adjusting for potential confounding factors.Results: Patients with CP were more likely to suffer stroke than the comparison population, after adjusting for potential confounding factors (adjusted hazard ratio: 2.17; 95% confidence interval [CI]: 1.74-2.69). The hazard ratio of stroke was 4.78 (95% CI: 3.18-7.17) and 1.57 (95% CI: 1.20-2.05) for patients with CP aged 50 years and under, and over 50 years respectively.Interpretation: Cerebral palsy is a risk factor or marker for stroke that is independent of traditional stroke risk factors. Further research in this area is warranted. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by varied clinical symptoms and can be comorbid with neuropsychiatric disorders. However, the association between SLE and dementia risk in patients with SLE remains unclear. In this study, we evaluated the incidence of dementia in patients with SLE.Methods: Patients were recruited from a nationwide cohort in 2004-2008 and categorized as SLE (n = 1,074; patients diagnosed with SLE) or non-SLE (n = 5,370; age- and sex-matched controls). Each patient was followed for up to 7 years, until either receiving a diagnosis of dementia or until December 31, 2010. Data were analyzed using the Kaplan-Meier method and Cox regression analysis.Results: The incidence rate of dementia was higher in the SLE cohort (357 per 100,000 person-years) than in the non-SLE cohort (180 per 100,000 person-years). Patients with SLE had a higher risk of dementia than did those without SLE (crude hazard ratio [HR] 1.92; P < 0.05). Cox regression analysis revealed an adjusted HR for dementia in the SLE cohort of 2.14 (P < 0.001), after adjustment for other comorbid diseases and variables.Conclusion: Patients with SLE have a higher risk of dementia. [ABSTRACT FROM AUTHOR]

Background To investigate the incidence and risk of hip fracture among dementia patients Methods This is a retrospective population-based 7-year cohort study using case-control matched analysis database from Taiwan's Longitudinal Health Insurance Database 2005. Patients were diagnosed with codes or International Classification of Diseases-9-CM codes of dementia, between 1 January 2004 and 31 December 2006. The prevalence and the adjusted odds ratio of hip fracture among dementia patients and the controls were estimated. Results We enrolled 3101 patients with dementia in the dementia cohort and 12,404 (1:4) patients in the control group. Of these, 202 patients experienced hip fractures. The incidence of hip fracture was 1178 per 100,000 person-years in the dementia cohort and 624 per 100,000 person-years in the comparison cohort. The hip fracture hazard ratio during the follow-up period was 1.89 (95% confidence interval [CI] 1.60-2.23, p < 0.001) for dementia patients. After adjusting for the covariates, the hazard ratio of hip fracture was 1.41 (95% CI, 1.19-1.69, p < 0.001) for dementia patients. Conclusion People with dementia experience an increased incidence of hip fracture and are at a higher risk of sustaining a hip fracture in the future. Proper and effective hip fracture-prevention strategies are essential for dementia patients. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the contribution to glucose intolerance and metabolic syndrome of obesity combined with the diagnostic criteria of polycystic ovary syndrome (PCOS). Design. Prospective study. Setting. University teaching hospital from 31 August 2010 to 31 August 2011. Population. Two hundred and twenty women with PCOS and seventy normal control women. Methods. The clinical and biochemical characteristics of women with PCOS and control women were evaluated. Main outcome measures. The impact of obesity, hyperandrogenism, oligo-anovulation and polycystic ovary morphology on impaired glucose tolerance and metabolic disturbances. Results. Obese women with PCOS had significantly higher insulin resistance than obese normal control women. Logistic regression analysis showed that obesity was the only factor that predicted impaired glucose tolerance and metabolic syndrome. Use of the area under the receiver operating characteristic curve (AUROC) for the body mass index to predict impaired glucose tolerance and metabolic syndrome was more accurate than AUROCs for serum total testosterone level and the average menstrual interval. Conclusions. Body weight status was the major factor determining the risk of impaired glucose tolerance and metabolic syndrome in women with PCOS. Obesity should be treated as the major factor determining long-term health consequences associated with PCOS. [ABSTRACT FROM AUTHOR]