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Platelets play a crucial role on hemostasis and are also involved in cardiovascular diseases, such as heart attack and stroke. Artesunate has been reported to possess multiple biological activities, including antitumor and anti-inflammatory activities. However, its effect on platelet activation remains unclear. Thus, we explored the detailed mechanisms underlying its antiplatelet effect. For the in vitro study, the data indicated that artesunate inhibited platelet aggregation induced by collagen, but not thrombin or U46619, indicating that artesunate may selectively inhibit collagen-mediated platelet activation Artesunate also blocked glycoprotein VI (GPVI) downstream signaling, including Syk, PLCγ2, PKC, Akt, and MAPKs. Moreover, artesunate could compete with collagen for binding to collagen receptor and bind to human recombinant GPVI with a high affinity (KD = 44 nM), indicating that it may directly interfere with GPVI. Artesunate also reduced collagen-induced granule release, calcium mobilization, and GPIIbIIIa activation. For the in vivo study, artesunate markedly prevented pulmonary thrombosis and delayed platelet thrombus formation in mesenteric veins and arteries but had minimal effects on hemostasis. In conclusion, we for the first time demonstrated that artesunate acts as a GPVI antagonist and effectively prevents platelet activation and thrombus formation with minimal risk of bleeding, highlighting its therapeutic potential in cardiovascular diseases.

Abstract Background Gastrointestinal injury following blunt abdominal trauma is uncommon; a combined stomach and duodenal perforating injury is even more rare. Because these two organs are located in different spaces in the abdomen, such injuries are difficult to identify. Case presentation A young woman involved in a motor vehicle crash presented to our emergency department with concerns of severe peritonitis. Contrast-enhanced computed tomography of the abdomen revealed pneumoperitoneum and retroperitoneal hematoma in zone 1. An emergency laparotomy was performed, revealing a stomach-perforating injury, which was resolved with primary repair. No obvious injury was observed on retroperitoneal exploration. However, peritonitis presented again on the second postoperative day, and a second laparotomy was performed, revealing a duodenum-perforating injury in its third portion. We performed primary repair with multi-tube-ostomy. The patient recovered well without permanent tube placement or internal bypass. Conclusions Assessing associated injuries in blunt abdominal trauma is crucial because they may be fatal if timely intervention is not undertaken. These types of complicated injuries require a feasible surgical strategy formulated by experienced surgeons, which gives the patient a better chance of survival.

Abstract Background The impact of liver cirrhosis on the outcomes of admission to intensive care unit (ICU) is not completely understood. Our purpose is to identify risk factors for mortality in ICU patients with liver cirrhosis. Methods Using reimbursement claims from Taiwan’s National Health Insurance Research Database from in 2006–2012, 1,250,300 patients were identified as having ICU stays of more than 1 day, and 37,197 of these had liver cirrhosis. With propensity score-matching for socioeconomic status, pre-existing medical conditions, and cirrhosis-related morbidities, 37,197 ICU patients without liver cirrhosis were selected for comparison. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of cirrhosis associated with 30-day, ICU, and one-year mortality were calculated. Results Compared with control, cirrhotic patients had higher 30-day mortality (aOR 1.60, 95% CI 1.53 to 1.68), particularly those with jaundice (aOR 2.23, 95% CI 2.03 to 2.45), ascites (aOR 2.32, 95% CI 2.19 to 2.46) or hepatic coma (aOR 2.21, 95% CI 2.07 to 2.36). Among ICU patients, liver cirrhosis was also associated with ICU mortality (aOR 144, 95% CI 1.38 to 1.51) and one-year mortality (aOR 1.40, 95% CI 1.35 to 1.46). Associations between cirrhosis of liver and increased 30-day mortality were significant in both sexes and every age group. Conclusions Liver cirrhosis was associated with 30-day mortality in ICU patients. Jaundice, ascites, hepatic coma, more than 4 admissions due to cirrhosis, and more than 30 days of hospital stay due to cirrhosis were exacerbated factors in cirrhotic ICU patients.

Pancreatic damage is the major causative agent in type 1 diabetes mellitus (DM). Several strategies have been suggested to regenerate pancreatic functions, such as stem cell transplantation and administration of active components isolating from natural herbals. This study aims to investigate if the synergistically protective effect on damaged pancreatic tissues can be observed in STZ-induced DM rats with autologous transplantation of adipose-derived stem cells (ADSC) coupling with oral administration of resveratrol. Pathological conditions can be recognized in DM rats with pancreatic damage, including reduction of islet size, suppression of survival markers, downregulation of AMPK/Sirt1 axis, and activation of apoptotic signaling. Autologous transplantation of ADSC slightly improves pancreatic functions, whereas autologous transplantation of ADSC coupling with oral administration of resveratrol significantly improves pancreatic functions in DM rats. We suggest that oral administration of resveratrol may enhance the therapeutic effect on DM patients receiving autologous transplantation of ADSC.

BackgroundDuring the COVID-19 pandemic, personal health records (PHRs) have enabled patients to monitor and manage their medical data without visiting hospitals and, consequently, minimize their infection risk. Taiwan’s National Health Insurance Administration (NHIA) launched the My Health Bank (MHB) service, a national PHR system through which insured individuals to access their cross-hospital medical data. Furthermore, in 2019, the NHIA released the MHB software development kit (SDK), which enables development of mobile apps with which insured individuals can retrieve their MHB data. However, the NHIA MHB service has its limitations, and the participation rate among insured individuals is low. ObjectiveWe aimed to integrate the MHB SDK with our developed blockchain-enabled PHR mobile app, which enables patients to access, store, and manage their cross-hospital PHR data. We also collected and analyzed the app’s log data to examine patients’ MHB use during the COVID-19 pandemic. MethodsWe integrated our existing blockchain-enabled mobile app with the MHB SDK to enable NHIA MHB data retrieval. The app utilizes blockchain technology to encrypt the downloaded NHIA MHB data. Existing and new indexes can be synchronized between the app and blockchain nodes, and high security can be achieved for PHR management. Finally, we analyzed the app’s access logs to compare patients’ activities during high and low COVID-19 infection periods. ResultsWe successfully integrated the MHB SDK into our mobile app, thereby enabling patients to retrieve their cross-hospital medical data, particularly those related to COVID-19 rapid and polymerase chain reaction testing and vaccination information and progress. We retrospectively collected the app’s log data for the period of July 2019 to June 2021. From January 2020, the preliminary results revealed a steady increase in the number of people who applied to create a blockchain account for access to their medical data and the number of app subscribers among patients who visited the outpatient department (OPD) and emergency department (ED). Notably, for patients who visited the OPD and ED, the peak proportions with respect to the use of the app for OPD and ED notes and laboratory test results also increased year by year. The highest proportions were 52.40% for ED notes in June 2021, 88.10% for ED laboratory test reports in May 2021, 34.61% for OPD notes in June 2021, and 41.87% for OPD laboratory test reports in June 2021. These peaks coincided with Taiwan’s local COVID-19 outbreak lasting from May to June 2021. ConclusionsThis study developed a blockchain-enabled mobile app, which can periodically retrieve and integrate PHRs from the NHIA MHB's cross-hospital data and the investigated hospital's self-pay medical data. Analysis of users’ access logs revealed that the COVID-19 pandemic substantially increased individuals’ use of PHRs and their health awareness with respect to COVID-19 prevention.

Fisetin, a naturally occurring flavonoid in fruits, nuts and vegetables possess antioxidant and anti-inflammatory properties. This study shows that fisetin exerts preventive and therapeutic effects on hypertension associated cardiac abnormalities in H9c2 cells and Spontaneously Hypertensive Rats (SHRs). For In vitro analysis, H9c2 cells were challenged with AngII and Fisetin (50 µM/mL) was administered either before 2 h or after 12 h of AngII challenge. For In vivo studies, SHRs received oral fisetin (10 mg/kg, twice a week for 6 weeks) and their cardiac function was analyzed by echocardiography. Histological studies and Western blotting were performed to assess the severity and the mechanism of the underlying cardiac abnormality. Fisetin effectively suppressed calcineurin-NFATC3 involved cellular hypertrophic effects as observed in H9c2 cells and in SHR hearts. Fisetin also enhanced cardiac function and restored cardiac morphology and therefore, fisetin is a potential agent against hypertension associated hypertrophy and cardiac deterioration.

Introduction: A third of the world's population is classified as having Metabolic Syndrome (MetS). Traditional diagnostic criteria for MetS are based on three or more of five components. However, the outcomes of patients with different combinations of specific metabolic components are undefined. It is challenging to be discovered and introduce treatment in advance for intervention, since the related research is still insufficient.Methods: This retrospective cohort study attempted to establish a method of visualizing metabolic components by using unsupervised machine learning and treemap technology to discover the relations between predicting factors and different metabolic components. Several supervised machine-learning models were used to explore significant predictors of MetS and to construct a powerful prediction model for preventive medicine.Results: The random forest had the best performance with accuracy and c-statistic of 0.947 and 0.921, respectively, and found that body mass index, glycated hemoglobin, and controlled attenuation parameter (CAP) score were the optimal primary predictors of MetS. In treemap, high triglyceride level plus high fasting blood glucose or large waist circumference group had higher CAP scores (>260) than other groups. Moreover, 32.2% of patients with high CAP scores during 3 years of follow-up had metabolic diseases are observed. This reveals that the CAP score may be used for detecting MetS, especially for the non-obese MetS phenotype.Conclusions: Machine learning and data visualization can illustrate the complicated relationships between metabolic components and potential risk factors for MetS.

Hypertension triggers oxidative stress, causing dysfunction in organs, including the brain, heart, and kidney. In this study, we examined the potential renal benefit of the soybean bioactive peptide VHVV by in silico analysis and in spontaneously hypertensive rats. Sixteen-week-old spontaneously hypertensive rats were divided into 3 groups and treated with or without VHVV or captopril. Age-matched Wistar-Kyoto rats were used as normotensive control group. The rats were sacrificed after 8 weeks of treatment, and kidneys were analyzed to demonstrate the efficacy of VHVV. In silico analysis confirmed the antihypertensive activity of VHVV. In animal study, VHVV induced antioxidant defense and modulated mitochondrial homeostasis in the hypertensive kidney via SIRT1-PGC1α/Nrf2 pathway. Hence, improvements in renal cells were attributed to the suppression of inflammation and apoptosis, and the architecture of the hypertensive kidney was restored after peptide treatment. Overall, VHVV exhibited therapeutic effects by decreasing renal damage caused by hypertension-induced free radicals.

Early and accurate prediction of endotracheal tube (ETT) location is pivotal for critically ill patients. Automatic and timely detection of faulty ETT locations from chest X-ray images may avert patients’ morbidity and mortality. Therefore, we designed convolutional neural network (CNN)-based algorithms to evaluate ETT position appropriateness relative to four detected key points, including tracheal tube end, carina, and left/right clavicular heads on chest radiographs. We estimated distances from the tube end to tracheal carina and the midpoint of clavicular heads. A DenseNet121 encoder transformed images into embedding features, and a CNN-based decoder generated the probability distributions. Based on four sets of tube-to-carina distance-dependent parameters (i.e., (i) 30–70 mm, (ii) 30–60 mm, (iii) 20–60 mm, and (iv) 20–55 mm), corresponding models were generated, and their accuracy was evaluated through the predicted L1 distance to ground-truth coordinates. Based on tube-to-carina and tube-to-clavicle distances, the highest sensitivity, and specificity of 92.85% and 84.62% respectively, were revealed for 20–55 mm. This implies that tube-to-carina distance between 20 and 55 mm is optimal for an AI-based key point appropriateness detection system and is empirically comparable to physicians’ consensus.

The coronavirus disease 2019 (COVID-19) has become a pandemic. Rapidly distinguishing COVID-19 from other respiratory infections is a challenge for first-line health care providers. This retrospective study was conducted at the Taipei Medical University Hospital, Taiwan. Patients who visited the outdoor epidemic prevention screening station for respiratory infection from February 19 to April 30, 2020, were evaluated for blood biomarkers to distinguish COVID-19 from other respiratory infections. Monocyte distribution width (MDW) ≥ 20 (odds ratio [OR]: 8.39, p = 0.0110, area under curve [AUC]: 0.703) and neutrophil-to-lymphocyte ratio (NLR) < 3.2 (OR: 4.23, p = 0.0494, AUC: 0.673) could independently distinguish COVID-19 from common upper respiratory tract infections (URIs). Combining MDW ≥ 20 and NLR < 3.2 was more efficient in identifying COVID-19 (AUC: 0.840). Moreover, MDW ≥ 20 and NLR > 5 effectively identified influenza infection (AUC: 0.7055). Thus, MDW and NLR can distinguish COVID-19 from influenza and URIs.

Summary: Background: Hemorrhoidectomy is commonly associated with postoperative pain. Calcium channel blockers are known to cause relaxation of gastrointestinal smooth muscle and oral diltiazem has also been shown to reduce the resting anal pressure. Objective: We attempted to analyze efficacy and side effects of topical diltiazem oint. in post-operative pain control. Methods: This is a meta-analysis of patients who underwent hemorrhoidectomy using topical diltiazem oint. versus placebo (Vaseline) for pain control. Patients with third or fourth degree hemorrhoids undergoing traditional hemorrhoidectomy were included. Procedures took place in the colorectal division of a hospital in 5 countries. Five randomized control trials (RCTs) published between 2005 and 2016 including 227 patients were included our meta-analysis (Diltiazem (calcium channel block) group = 137; Placebo (Vaseline) group = 90). Pain assessment was performed using a standardized Visual Analogue Scale. Any side effects of surgery or medication use, which were noted by the patient or the surgeon, also were recorded. Results: A total of 227 patients were included in the meta-analysis. The results revealed that Diltiazem ointment was statistically significant in reducing pain within 48 h, at 72 h, and more than 96 h after operation compared to the placebo group. Regarding overall complications (including headache), there was no statistical significance between diltiazem and placebo group. Conclusions: Topical application of diltiazem effectively relieves pain after hemorrhoidectomy with minimal side effects. Further large studies are needed to substantiate its value in clinical practice. Keywords: Hemorrhoidectomy, Post-hemorrhoidectomy, Diltiazem ointment, Calcium channel blocker, Meta-analysis

In association with the published article “Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy” (Huang et al., 2017) [1], this data article contains information about deSUMOylation of HSF2 on lysine 82 on angiotensin II (ANG II) -induced cardiac hypertrophy, which is mediated by MEL18. Isolated adult human whole heart tissue showed MEL18-mediated HSF2-IGF-IIR pathway is upregulated in hypertension human heart, compared to health human heart.

Vincristine is a clinically used antimicrotubule drug for treating patients with lymphoma. Due to its property of increasing platelet counts, vincristine is also used to treat patients with immune thrombocytopenia. Moreover, antiplatelet agents were reported to be beneficial in thrombotic thrombocytopenic purpura (TTP). Therefore, we investigated the detailed mechanisms underlying the antiplatelet effect of vincristine. Our results revealed that vincristine inhibited platelet aggregation induced by collagen, but not by thrombin, arachidonic acid, and the thromboxane A2 analog U46619, suggesting that vincristine exerts higher inhibitory effects on collagen-mediated platelet aggregation. Vincristine also reduced collagen-mediated platelet granule release and calcium mobilization. In addition, vincristine inhibited glycoprotein VI (GPVI) signaling, including Syk, phospholipase Cγ2, protein kinase C, Akt, and mitogen-activated protein kinases. In addition, the in vitro PFA-100 assay revealed that vincristine did not prolong the closure time, and the in vivo study tail bleeding assay showed that vincristine did not prolong the tail bleeding time; both findings suggested that vincristine may not affect normal hemostasis. In conclusion, we demonstrated that vincristine exerts antiplatelet effects at least in part through the suppression of GPVI signaling. Moreover, this property of antiplatelet activity of vincristine may provide additional benefits in the treatment of TTP.

Abstract Background To define the benefits of different methods for diagnosis of pediatric appendicitis in Taiwan, a nationwide cohort study was used for analysis. Methods We identified 44,529 patients under 18 years old who had been hospitalized with a diagnosis of acute appendicitis between 2003 and 2012. We analyzed the percentages of cases in which ultrasound (US) and/or computed tomography (CT) were performed and non-perforated and perforated appendicitis were diagnosed for each year. Multivariate logistic regression analyses were performed to evaluate risk factors for perforated appendicitis. Results There were more cases of non-perforated appendicitis (N = 32,491) than perforated appendicitis (N = 12,038). The rate of non-perforated cases decreased from 0.068% in 2003 to 0.049% in 2012; perforated cases remained relatively stable at 0.024%~0.023% from 2003 to 2012. The percentage of CT evaluation increased from 3% in 2003 to 20% in 2012; the rates of US or both US and CT evaluations were similar annually. The percentage of neither CT nor US evaluation gradually decreased from 97% in 2003, to 79% in 2012. The odds ratios of a perforated appendix for those patients diagnosed by US, CT, or both US and CT were 1.227 (95% confidence interval (CI) 0.91, 1.65; p = 0.173), 2.744 (95% CI 2.55, 2.95; p

Abstract Background Targeted superparamagnetic iron oxide (SPIO) nanoparticles have emerged as a promising biomarker detection tool for molecular magnetic resonance (MR) image diagnosis. To identify patients who could benefit from Epidermal growth factor receptor (EGFR)-targeted therapies, we introduce lipid-encapsulated SPIO nanoparticles and hypothesized that anti-EGFR antibody cetuximab conjugated of such nanoparticles can be used to identify EGFR-positive glioblastomas in non-invasive T2 MR image assays. The newly introduced lipid-coated SPIOs, which imitate biological cell surface and thus inherited innate nonfouling property, were utilized to reduce nonspecific binding to off-targeted cells and prevent agglomeration that commonly occurs in nanoparticles. Results The synthesized targeted EGFR-antibody-conjugated SPIO (EGFR-SPIO) nanoparticles were characterized using dynamic light scattering, zeta potential assays, gel electrophoresis mobility shift assays, transmission electron microscopy (TEM) images, and cell line affinity assays, and the results showed that the conjugation was successful. The targeting efficiency of the synthesized EGFR-SPIO nanoparticles was confirmed through Prussian blue staining and TEM images by using glioblastoma cell lines with high or low EGFR expression levels. The EGFR-SPIO nanoparticles preferentially targeted U-251 cells, which have high EGFR expression, and were internalized by cells in a prolonged incubation condition. Moreover, the T2 MR relaxation time of EGFR-SPIO nanoparticles could be used for successfully identifying glioblastoma cells with elevated EGFR expression in vitro and distinguishing U-251 cells from U-87MG cells, which have low EFGR expression. Conclusion These findings reveal that the lipid-encapsulated EGFR-SPIO nanoparticles can specifically target cells with elevated EGFR expression in the three tested human glioblastoma cell lines. The results of this study can be used for noninvasive molecular MR image diagnosis in the future.

Abstract Background It is known that the medicinal herb Alpinia oxyphylla Miq. is widely used as a remedy for diarrhea as well as the symptoms accompanying hypertension and cerebrovascular disorders. Moreover, it has also been reported that Alpinia oxyphylla Miq. has beneficial effects on anti-senescence and neuro-protection. This study focuses on the molecular mechanisms by which the Alpinia oxyphylla Miq. fruits promote neuron regeneration. Methods A piece of silicone rubber was guided across a 15 mm gap in the sciatic nerve of a rat. This nerve gap was then filled with various doses of Alpinia oxyphylla Miq. fruits to assess their regenerative effect on damaged nerves. Further, we investigated the role of Alpinia oxyphylla Miq. fruits in RSC96 Schwann cell proliferation. Results Our current results showed that treatment with the extract of Alpinia oxyphylla Miq. fruits triggers the phosphorylated insulin-like growth factor-1 receptor- phosphatidylinositol 3-kinase/serine-threonine kinase pathway, and up-regulated the proliferating cell nuclear antigen in a dose-dependent manner. Cell cycle analysis on RSC96 Schwann cells showed that, after exposure to Alpinia oxyphylla Miq. fruit extract, the transition from the first gap phase to the synthesis phase occurs in 12–18 h. The expression of the cell cycle regulatory proteins cyclin D1, cyclin E and cyclin A increased in a dose-dependent manner. Transfection with a small interfering RNA blocked the expression of phosphatidylinositol 3-kinase and induced down-regulation both on the mRNA and protein levels, which resulted in a reduction of the expression of the survival factor B-cell lymphoma 2. Conclusion We provide positive results that demonstrate that Alpinia oxyphylla Miq. fruits facilitate the survival and proliferation of RSC96 cells via insulin-like growth factor-1 signaling.

Stress-induced cardiac hypertrophy leads to heart failure. Our previous studies demonstrate that insulin-like growth factor-II receptor (IGF-IIR) signaling is pivotal to hypertrophy regulation. In this study, we show a novel IGF-IIR alternative spliced transcript, IGF-IIRα (150 kDa) play a key role in high-salt induced hypertrophy mechanisms. Cardiac overexpression of IGF-IIRα and high-salt diet influenced cardiac dysfunction by increasing pathophysiological changes with up-regulation of hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We found that, cardiac hypertrophy under high-salt conditions were amplified in the presence of IGF-IIRα overexpression. Importantly, high-salt induced angiotensin II type I receptor (AT1R) up regulation mediated IGF-IIR expressions via upstream mitogen activated protein kinase (MAPK)/silent mating type information regulation 2 homolog 1 (SIRT1)/heat shock factor 1 (HSF1) pathway. Further, G-coupled receptors (Gαq) activated calcineurin/nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3)/protein kinase C (PKC) signaling was significantly up regulated under high-salt conditions. All these effects were observed to be dramatically over-regulated in IGF-IIRα transgenic rats fed with a high-salt diet. Altogether, from the findings, we demonstrate that IGF-IIRα plays a crucial role during high-salt conditions leading to synergistic cardiac hypertrophy.

Probiotics are reported to provide protective health benefits against various disorders. In this study, we established a high-calorie diet animal model with a diet prepared by fortifying normal diet with soybean oil and condensed milk and the animals were supplemented with different dose of probiotic Lactobacillus reuteri GMNL-263(Lr263) for 8 weeks to investigate the protective function. We measured the lipid levels in plasma, liver and faecal; heart weight, function and collagen accumulation and biochemical markers of cardiac disease. Lr263 reversed high-calorie diet-induced cardiac weight gain, systolic malfunction and prevented heart inflammation by decreasing inflammation proteins NF-κB and COX-2. Moreover, Lr263 reduced cardiac eccentric hypertrophy and the levels of cardiac fibrosis markers CTGF and SP1 in high-calorie diet-fed rat hearts. Thus, Lr263 is considered as a functional food that provides anti-inflammatory, anti-hypertrophic, anti-fibrotic functions and identified specific biologic effects in reducing the characteristics of the high-calorie diet-induced progression to heart failure.

Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson’s disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD), and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD). Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263) probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD)-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day) were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor β (TGF-β) expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease.

Cardiovascular diseases are the leading cause of death of death in Taiwan. Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death. Coronary heart disease (CHD) occurs when plaque builds up in the coronary arteries to cause the ischemic heart disease which will enhance myocardial remodeling and also induce myocardial hypoxia. High density lipoprotein (HDL) has been proposed to have cardio-protective effects. Under hypoxic conditions (1%O2 for 24hr), in H9c2 cells, reactive oxygen species (ROS) is induced which leads to cardiomyocyte apoptosis and cardiac dysfunction. Therefore, the present study described the protective effect of HDL on hypoxia-induced cardiomyocyte damage. We investigated the NADPH oxidase-produced ROS-related signaling pathways and apoptosis in cardiomyocytes under hypoxia conditions. Results showed that the ROS mediated cardiac damage might occur via AT1 and PKC activation. Furthermore, hypoxia downregulated the survival protein (p-AKTser473) and anti-apoptotic protein (BCL2), whereas pro-apoptotic protein, Bax and caspase 3 were upregulated. These detrimental effects by ROS and apoptosis were prevented by HDL pretreatment. Our findings revealed the underlying molecular mechanism by which HDL suppresses the hypoxia-induced cardiomyocyte dysfunction. Further, we elucidated the role of HDL on preventing hypoxia induced cardiomyocyte apoptosis is mediated through the inhibition of NADPH oxidase-derived ROS.

Fourteen-day rehospitalization with new traumatic spinal cord injury (tSCI) diagnosis is used as an indicator for the diagnostic quality of the first hospitalization. In this nationwide population-based cohort study, we identified risk factors for this indicator.We conducted a nested case-control study by using the data of patients who received a first hospitalization for trauma between 2001 and 2011. The data were retrieved from Taiwan's National Health Insurance Research Database. Variables including demographic and trauma characteristics were compared between patients diagnosed with tSCI at the first hospitalization and those receiving a 14-day rehospitalization with new tSCI diagnosis.Of the 23 617 tSCI patients, 997 had 14-day rehospitalization with new tSCI diagnosis (incidence rate, 4.22%). The risk of 14-day rehospitalization with new tSCI diagnosis was significantly lower in patients with severe (injury severity score [ISS] = 16-24; odds ratio [OR], 0.17; 95% confidence interval [CI], 0.13-0.21) and profound (ISS > 24; OR, 0.11; 95% CI, 0.07-0.18) injuries. Interhospital transfer (OR, 8.20; 95% CI, 6.48-10.38) was a significant risk factor, along with injuries at the thoracic (OR, 1.62; 95% CI, 1.21-2.18), lumbar (OR, 1.30; 95% CI, 1.02-1.65), and multiple (OR, 3.23; 95% CI, 1.86-5.61) levels. Brain (OR, 2.82), chest (OR, 2.99), and abdominal (OR, 2.74) injuries were also identified as risk factors. In addition, the risk was higher in patients treated at the orthopedic department (OR, 2.26; 95% CI, 1.78-2.87) and those of other surgical disciplines (OR, 1.89; 95% CI, 1.57-2.28) than in those treated at the neurosurgery department.Delayed tSCI diagnoses are not uncommon, particularly among trauma patients with ISSs < 16 or those who are transferred from lower-level hospitals. Further validation and implementation of evidence-based decision rules is essential for improving the diagnostic quality of traumatic thoracolumbar SCI.

Systemic lupus erythematosus (SLE) is a disease that mostly affects women. Accelerated atherosclerosis is a high-risk factor associated with SLE patients. SLE associated with cardiovascular disease is one of the most important causes of death. In this study, we demonstrated that Lactobacillus paracasei GMNL-32 (GMNL-32), a probiotic species, exhibits anti-fibrosis and anti-apoptotic effects on the cardiac tissue of NZB/WF1 mice. Female NZB/W F1 mice, a well-known and commonly used lupus-prone mouse strain, were treated with or without GMNL-32 administration for 12 weeks. Oral administration of GMNL-32 to NZB/WF1 mice significantly increased the ventricular thickness when compared to that of NZB/WF1 mice. Administration of GMNL-32 significantly attenuated the cardiac cell apoptosis that was observed in exacerbate levels in the control NZB/WF1 mice. Further, the cellular morphology that was slightly distorted in the NZB/WF1 was effectively alleviated in the treatment group mice. In addition, GMNL-32 reduced the level of Fas death receptor-related pathway of apoptosis signaling and enhanced anti-apoptotic proteins. These results indicate that GMNL-32 exhibit an effective protective effect on cardiac cells of SLE mice. Thus, GMNL-32 may be a potential therapeutic strategy against SLE associated arthrosclerosis.

BackgroundRelevant clinical studies have been small and have not convincingly demonstrated whether the perioperative initiation of beta‐blockers should be considered in patients with diabetes mellitus undergoing noncardiac surgery. Methods and ResultsIn this nationwide propensity score–matched study, we included patients with diabetes mellitus undergoing noncardiac surgery between 2000 and 2011 from Taiwan's National Health Insurance Research Database. Patients were classified as beta‐blocker and non–beta‐blocker cohorts. We further stratified beta‐blocker users into cardioprotective beta‐blocker (atenolol, bisoprolol, metoprolol, or carvedilol) and other beta‐blocker users. To investigate time of initiation of beta‐blocker use, initiation time was stratified into 2 periods (>30 and ≤30 days preoperatively). The outcomes of interest were in‐hospital and 30‐day mortality. After propensity score matching, we identified 50 952 beta‐blocker users and 50 952 matched controls. Compared with non–beta‐blocker users, cardioprotective beta‐blocker users were associated with lower risks of in‐hospital (odds ratio 0.75, 95% CI 0.68–0.82) and 30‐day (odds ratio 0.75, 95% CI 0.70–0.81) mortality. Among initiation times, only the use of cardioprotective beta‐blockers for >30 days was associated with decreased risk of in‐hospital (odds ratio 0.72, 95% CI 0.65–0.78) and 30‐day (odds ratio 0.72, 95% CI 0.66–0.78) mortality. Of note, use of other beta‐blockers for ≤30 days before surgery was associated with increased risk of both in‐hospital and 30‐day mortality. ConclusionsThe use of cardioprotective beta‐blockers for >30 days before surgery was associated with reduced mortality risk, whereas short‐term use of beta‐blockers was not associated with differences in mortality in patients with diabetes mellitus.

Background: Major trauma remains a significant medical concern, leading to about 10,000 deaths annually in Taiwan. Trauma system implementation has been shown to improve the outcomes in different countries. Using the National Health Insurance data, our study examined the influence of age and other factors on the outcomes of trauma patients. Materials and methods: We collected the original claim data of 1 million beneficiaries who enrolled in the National Health Insurance program from 2006 to 2008. ICDMAP-90 was used for calculating the Injury Severity Score (ISS), which was required for assessing the disease severity and implementing appropriate control measures. Other variables included age, sex, triage classifications, pre-existing comorbidities, and hospital levels. The Charlson Comorbidity Index for the year of admission was used for adjusting comorbid conditions. Results: A total of 2497 major trauma patients (ISS >15) were identified in our database. After controlling all the variables in a logistic regression model, for all the major trauma patients, a significant difference was observed between different hospital levels. Compared with the trauma centers, the risk of mortality in nontrauma centers was 1.58 times that in trauma centers (p = 0.004). In the younger groups (aged

Cardiovascular diseases have a high prevalence worldwide and constitute the leading causes of mortality. Recently, malfunctioning of β-catenin signaling has been addressed in hypertensive heart condition. Ang-II is an important mediator of cardiovascular remodeling processes which not only regulates blood pressure but also leads to pathological cardiac changes. However, the contribution of Ang-II/β-catenin axis in hypertrophied hearts is ill-defined. Employing in vitro H9c2 cells and in vivo spontaneously hypertensive rats (SHR) cardiac tissue samples, western blot analysis, luciferase assays, nuclear-cytosolic protein extracts, and immunoprecipitation assays, we found that under hypertensive condition β-catenin gets abnormally induced that co-activated LEF1 and lead to cardiac hypertrophy changes by up-regulating the IGF-IIR signaling pathway. We identified putative LEF1 consensus binding site on IGF-IIR promoter that could be regulated by β-catenin/LEF1 which in turn modulate the expression of cardiac hypertrophy agents. This study suggested that suppression of β-catenin expression under hypertensive condition could be exploited as a clinical strategy for cardiac pathological remodeling processes.

Tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) are elevated in pleural fluids of tuberculous pleuritis (TBP) where pleural mesothelial cells (PMCs) conduct the first-line defense against Mycobacterium tuberculosis (MTB). However, the clinical implication of TNF-α and MMPs in TBP and the response of PMCs to MTB infection remain unclear.We measured pleural fluid levels of TNF-α and MMPs in patients with TBP (n = 18) or heart failure (n = 18) as controls. Radiological scores for initial effusion amount and residual pleural fibrosis at 6-month follow-up were assessed. In vitro human PMC experiments were performed to assess the effect of heat-killed M. tuberculosis H37Ra (MTBRa) on the expression of TNF-α and MMPs.As compared with controls, the effusion levels of TNF-α, MMP-1 and MMP-9 were significantly higher and correlated positively with initial effusion amount in patients with TBP, while TNF-α and MMP-1, but not MMP-9, were positively associated with residual pleural fibrosis of TBP. Moreover, effusion levels of TNF-α had positive correlation with those of MMP-1 and MMP-9 in TBP. In cultured PMCs, MTBRa enhanced TLR2 and TLR4 expression, activated ERK signaling, and upregulated TNF-α mRNA and protein expression. Furthermore, knockdown of TLR2, but not TLR4, significantly inhibited ERK phosphorylation and TNF-α expression. Additionally, both MTBRa and TNF-α markedly induced MMP-1 and MMP-9 synthesis in human PMCs, and TNF-α neutralization substantially reduced the production of MMP-1, but not MMP-9, in response to MTBRa stimulation.MTBRa activates TLR2/ERK signalings to induce TNF-α and elicit MMP-1 and MMP-9 in human PMCs, which are associated with effusion volume and pleural fibrosis and may contribute to pathogenesis of TBP. Further investigation of manipulation of TNF-α and MMP expression in pleural mesothelium may provide new insights into the mechanisms and rational treatment strategies for TBP.

Platelet activation is involved in cardiovascular diseases, such as atherosclerosis and ischemic stroke. Licochalcone A (LA), an active ingredient of licorice, exhibits multiple biological activities such as anti-oxidation and anti-inflammation. However, its role in platelet activation remains unclear. Therefore, the study investigated the antiplatelet mechanism of LA. Our data revealed that LA (2–10 μM) concentration dependently inhibited platelet aggregation induced by collagen, but not thrombin and U46619. LA markedly attenuated collagen-stimulated ATP release, P-selectin secretion, calcium mobilization, and GPIIbIIIa activation, but did not interfere with the collagen binding to platelets. Moreover, LA significantly reduced the activation of PLCγ2, PKC, Akt and MAPKs. Thus, LA attenuates platelet activation, possibly by inhibiting collagen receptor downstream signaling but not by blocking the collagen receptors. In addition, LA prevented adenosine diphosphate (ADP)-induced acute pulmonary thrombosis, fluorescein sodium-induced platelet thrombus formation, and middle cerebral artery occlusion/reperfusion-induced brain injury in mice, but did not affect normal hemostasis. This study demonstrated that LA effectively reduced platelet activation and thrombus formation, in part, through the inhibition of PLCγ2–PKC, Akt, and MAPK pathways, without the side effect of bleeding. These findings also indicate that LA may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders such as stroke.

Metastasis is the most dangerous risk faced by patients with hereditary non-polyposis colon cancer (HNPCC). The expression of matrix metalloproteinases (MMPs) has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with various concentrations of prostaglandin E2 (PGE2; 0, 1, 5 or 10 μM) promotes the migration ability of the human LoVo colon cancer cell line. As demonstrated by mRNA and protein expression analyses, EP2 and EP4 are the major PGE2 receptors expressed on the LoVo cell membrane. The Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt cell survival pathway was upregulated by EP2 and EP4 activation. Following the activation of the PI3K/Akt pathway, β-catenin translocated into the nucleus and triggered COX2 transcription via LEF-1 and TCF-4 and its subsequent translation. COX2 expression correlated with the elevation in the migration ability of LoVo cells. The experimental evidence shows a possible mechanism by which PGE2 induces cancer cell migration and further suggests PGE2 to be a potential therapeutic target in colon cancer metastasis. On inhibition of PGE2, in order to determine the downstream pathway, the levels of PI3K/Akt pathway were suppressed and the β-catenin expression was also modulated. Inhibition of EP2 and EP4 shows that PGE2 induces protein expression of COX-2 through EP2 and EP4 receptors in LoVo colon cancer cells.

Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2), for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs). In addition, protein phosphatase such as protein phosphatase 1 (PP1) and calcineurin (PP2B) are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO)-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage.

Aging, a natural biological/physiological phenomenon, is accelerated by reactive oxygen species (ROS) accumulation and identified by a progressive decrease in physiological function. Several studies have shown a positive relationship between aging and chronic heart failure (HF). Cardiac apoptosis was found in age-related diseases. We used a traditional Chinese medicine, Alpinate Oxyphyllae Fructus (AOF), to evaluate its effect on cardiac anti-apoptosis and pro-survival. Male eight-week-old Sprague–Dawley (SD) rats were segregated into five groups: normal control group (NC), d-Galactose-Induced aging group (Aging), and AOF of 50 (AL (AOF low)), 100 (AM (AOF medium)), 150 (AH (AOF high)) mg/kg/day. After eight weeks, hearts were measured by an Hematoxylin–Eosin (H&E) stain, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-assays and Western blotting. The experimental results show that the cardiomyocyte apoptotic pathway protein expression increased in the d-Galactose-Induced aging groups, with dose-dependent inhibition in the AOF treatment group (AL, AM, and AH). Moreover, the expression of the pro-survival p-Akt (protein kinase B (Akt)), Bcl-2 (B-cell lymphoma 2), anti-apoptotic protein (Bcl-xL) protein decreased significantly in the d-Galactose-induced aging group, with increased performance in the AOF treatment group with levels of p-IGFIR and p-PI3K (Phosphatidylinositol-3′ kinase (PI3K)) to increase by dosage and compensatory performance. On the other hand, the protein of the Sirtuin 1 (SIRT1) pathway expression decreased in the aging groups and showed improvement in the AOF treatment group. Our results suggest that AOF strongly works against ROS-induced aging heart problems.