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Porcine pleuropneumonia caused by Actinobacillus pleuropneumoniae (AP) infection leads to considerable financial loss in the swine industry worldwide. Multilocus sequence typing (MLST), a definitive molecular typing technique that is highly reproducible and is capable of comparing data across laboratories, has not been studied on AP. Therefore, the aim of this work is to develop a MLST assay to characterize AP isolates collected from Taiwan. A total of 85 AP isolates collected from pleuropneumonia of diseased pigs with respiratory symptoms and seven reference isolates from other countries were included for comparison. Seven housekeeping genes (recF, gly, rho, tpi, pyk, recN, and rpo) were selected for sequencing. Capsule types that determine serotypes and Apx toxins were analyzed by the polymerase chain reaction (PCR). The sequencing results showed that the 7 housekeeping genes differentiated the 92 isolates into 14 sequence types that belonged to three major clonal complexes and five singletons by eBURST. The 85 isolates assigned to detection of capsule types and Apx toxins showed that serotype 1 with Apx I, II, IV (55.3%) followed by serotype 5 with Apx I, II, IV (29.4%) were the most prevalent in Taiwan. Notably, serotype 15 was identified for the first time. Clonal complexes based on ST profiles from MLST analysis were highly associated with the distribution of capsule types, suggesting that MLST scheme was sufficient to identify DNA samples directly from AP. Therefore, MLST might be a useful tool for identification and further epidemiological assay of AP.

This case report describes New Neonatal Porcine Diarrhea Syndrome (NNPDS) caused by Enterococcus hirae. Four piglets at 3–5 days old with diarrhea were submitted for diagnostic investigation. The histopathological analysis revealed numerous large Gram-positive cocci adherent to the luminal surface from the tip to the base of the villi. The organisms were tightly adherent to enterocytes on the villous tips and exfoliated enterocytes within the luminal detritus. In situ hybridization revealed positive signals of E. hirae, the enteroadherent Gram-positive cocci, in the intestinal tissue. The swab of distal jejunum and gut content was cultured positive for E. hirae. Taken all results together, it was concluded that neonatal diarrhea in piglets was caused by E. hirae.

Obesity-associated hyperglycemia underlies insulin resistance, glucose intolerance, and related metabolic disorders including type 2 diabetes, renal damage, and nonalcoholic fatty liver disease. Turmeric root is commonly used in Asia, and curcumin, one of its pharmacological components, can play a role in preventing and treating certain chronic physiological disorders. Accordingly, this study examined how high-fat diet (HFD)-induced hyperglycemia and hyperlipidemia are reduced by curcumin through changes in fatty liver scores, chromium distribution, and renal injury in mice. Relative to the control group, also fed an HFD, the curcumin group weighed less and had smaller adipocytes, it also had lower daily food efficiency, blood urea nitrogen and creatinine levels, serum alanine aminotransferase and aspartate aminotransferase levels, serum and hepatic triglyceride levels, and hepatic lipid regulation marker expression. The curcumin-treated obese group exhibited significantly lower fasting blood glucose, was less glucose intolerant, had higher Akt phosphorylation and glucose transporter 4 (GLUT4) expression, and had greater serum insulin levels. Moreover, the group showed renal damage with lower TNF-α expression along with more numerous renal antioxidative enzymes that included superoxide dismutase, glutathione peroxidase, and catalase. The liver histology of the curcumin-treated obese mice showed superior lipid infiltration and fewer FASN and PNPLA3 proteins in comparison with the control mice. Curcumin contributed to creating a positive chromium balance by decreasing the amount of chromium lost through urine, leading to the chromium mobilization needed to mitigate hyperglycemia. Thus, the results suggest that curcumin prevents HFD-induced glucose intolerance, kidney injury, and nonalcoholic fatty liver disease.

Bivalves, such as freshwater clams (Corbicula fluminea) and hard clams (Meretrix lusoria), are the most extensive and widely grown shellfish in land-based ponds in Taiwan. However, few studies have examined the contamination of bivalves by quinolone and organophosphorus insecticides. Thus, we adapted an established procedure to analyze 8 quinolones and 12 organophosphorus insecticides using liquid and gas chromatography&ndash, tandem mass spectrometry. Surveys in Taiwan have not noted high residual levels of these chemicals in bivalve tissues. A total of 58 samples of freshwater or hard clams were obtained from Taiwanese aquafarms. We identified 0.03 mg/kg of enrofloxacin in one freshwater clam, 0.024 mg/kg of flumequine in one freshwater clam, 0.02 mg/kg of flumequine in one hard clam, 0.05 mg/kg of chlorpyrifos in one freshwater clam, 0.03 mg/kg of chlorpyrifos in one hard clam, and 0.02 mg/kg of trichlorfon in one hard clam. The results indicated that 5.17% of the samples had quinolone insecticide residues and 5.17% had organophosphorus residues. However, the estimated daily intake (EDI)/acceptable daily intake quotient (ADI) indicated no significant risk and no immediate health risk from the consumption of bivalves. These results provide a reference for the food-safety screening of veterinary drugs and pesticides in aquatic animals. Aquatic products should be frequently screened for residues of prohibited chemicals to safeguard human health.

Exposure to residues of antibiotics (e.g., sulfonamides) and insecticides (e.g., organophosphorus insecticides) in aquacultured food can adversely affect humans and animals and thus affect public health globally. Here, using a validated method, we examined the levels of residues of 12 sulfonamides as well as 18 organophosphorus insecticides in aquacultured fish in Taiwan. A total of 52 fish samples (i.e., 20 tilapia, 16 milk fish, and 16 perch samples) were obtained from Taiwanese aquafarms from June 2018 to October 2019. We detected 0.02 and 0.03 mg/kg of sulfamethazine (a sulfonamide) in one tilapia and one milk fish, respectively, and 0.02, 0.05, and 0.03 mg/kg of chlorpyrifos (an organophosphorus insecticide) in one tilapia, one milk fish, and one perch, respectively, thus, among the samples, 3.85% and 5.77% contained sulfonamides and organophosphorus insecticide residues, respectively. Furthermore, we assessed human health risk based on the estimated daily intakes (EDIs) of these residues: EDIs of sulfonamide and organophosphorus insecticide residues were &lt, 1.0% of the acceptable daily intake recommended by the Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Committee on Food Additives. The risk of exposure to sulfonamide and organophosphorus insecticide residue by consuming aquacultured fish in Taiwan was thus negligible, signifying no immediate health risk related to the consumption of fish. Our findings can constitute a reference in efforts geared toward ensuring food safety and monitoring veterinary drug and insecticide residue levels in aquacultured organisms. Residue levels in fish must be continually monitored to further determine possible effects of these residues on human health.

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.

Posttraumatic stress disorder (PTSD) gains a lot of attention due to high prevalence and strong psychological upset, but the etiology remains undefined and effective treatment is quite limited. Growing studies demonstrated the involvement of oxidative stress in various psychiatry diseases, suggesting anti-oxidation therapy might be a strategy for PTSD treatment. Free and Easy Wanderer (FAEW) is a poly-herbal drug clinically used in China for hundreds of years in the treatment of psychiatric disorder. We hypothesized that FAEW exerts clinical effects through the activity against oxidative stress with fluoxetine as antidepressant control drug. Our results revealed that FAEW significantly reduced both endogenous and H2O2-induced exogenous ROS levels in the human glioblastoma T98G and neuroblastoma SH-SY5Y cell lines. Transcriptome-wide microarray analysis indicated NRF2/HO-1 as the common target of FAEW and fluoxetine. Western blotting assay proved that the two drugs promoted NRF2 release from KEAP1 in the cytoplasm and translocation to the nuclei in a KEAP1-dependent manner, the expression of the protein HO-1 increased accordingly, suggesting the participation of KEAP1-NRF2/HO-1 pathway. The chemical constituents of FAEW (i.e. paeoniflorin, baicalin) bound to KEAP1 in silico, which hence might be the effective substances of FAEW. In conclusion, FAEW counteracted H2O2-induced oxidative stress through KEAP1-NRF2/HO-1 pathway.

Salvia miltiorrhiza Bunge (Lamiaceae) is a well-known Chinese herb that possesses numerous therapeutic activities, including anticancer effects. In this study, the cytotoxicity and the biological mechanisms of S. miltiorrhiza (SM) root extract on diverse resistant and sensitive cancer cell lines were investigated. CEM/ADR5000 cells were 1.68-fold resistant to CCRF-CEM cells, while HCT116 (p53[Formula: see text] and U87.MG[Formula: see text]EGFR cells were hypersensitive (collateral sensitive) compared to their parental cells. SM root extract stimulated ROS generation, cell cycle S phase arrest and apoptosis. The induction of the intrinsic apoptotic pathway was validated by increased cleavage of caspase 3, 7, 9 and poly ADP-ribose polymerase (PARP). MAP kinases including JNK, ERK1/2 and p38 were obviously phosphorylated and nuclear P65 was downregulated upon SM treatment. Transcriptome-wide COMPARE analysis revealed that the expression of encoding genes with diverse functions were associated with the cellular response to cryptotanshinone, one of the main constituents of SM root extract. In conclusion, SM root extract exerted profound cytotoxicity towards various sensitive and resistant cancer cells and induced the intrinsic apoptotic pathway.

Ethnopharmacological relevance Rosmarinic acid (RA), a major hydrosoluble bioactive compound found in the Chinese medicinal herb, Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine to treat various diseases, including cancer. However, the mechanisms have not been fully elucidated. Aim of the study Guided by microarray hybridization and Ingenuity Pathway Analysis, we identified modes of action of rosmarinic acid (RA) isolated from S. miltiorrhiza on acute lymphoblastic leukemia cells. Materials and methods Microarray data were verified by independent methods: Real-time RT-PCR (mRNA expression), resazurin assay (cytotoxicity of RA towards parental CCRF-CEM, multidrug-resistant CEM/ADR5000 cells and normal lymphocytes), flow cytometry (cell cycle arrest, apoptosis, necroptosis, generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential (MMP)), single cell gel electrophoresis (DNA damage), molecular docking and gene promoter binding motif analysis (NFκB), Western blotting (nuclear NFκB translocation, PARP cleavage, caspase 3/7/9 expression), and fibronectin-based cell adhesion assay. Results RA dose-dependently inhibited CCRF-CEM and CEM/ADR5000 cells, but caused less cytotoxicity towards normal lymphocytes. RA simultaneously induced apoptosis and necrosis, as shown by cell morphology and annexin V-PI assay. DNA damage was dose-dependently induced without ROS generation, which subsequently led to cell cycle arrest. RA-stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis. In accordance with molecular docking and gene promoter binding motif analyses, p65 translocation from the cytosol to the nucleus was blocked by RA, indicating a mechanistic role of the NFκB pathway to explain RA's action. RA affected cellular movement as evaluated by ameliorating cell adhesion to fibronectin. Conclusions RA induced apoptosis and necrosis in a ROS-independent DNA damage and caspase-independent manner. These results may contribute to the rationale use of S. miltiorrhiza and RA in traditional medicine of leukemia.

Glycine N-methyltransferase (GNMT) is abundantly expressed in normal livers and plays a protective role against tumor formation. GNMT depletion leads to progression of hepatocellular carcinoma (HCC). In this study, we investigated the activity of ectopic GNMT delivered using recombinant adeno-associated virus (AAV) gene therapy in mouse models of liver cirrhosis and HCC. Injection of AAV serotype 8 (AAV8) vector carrying the GNMT gene (AAV8-GNMT) in Gnmt−/− mice increased GNMT expression and downregulated pro-inflammatory responses, resulting in reduced liver damage and incidence of liver tumors. Moreover, AAV8-GNMT resulted in the amelioration of carbon tetrachloride (CCl4)-induced liver fibrosis in BALB/c mice. We showed that AAV8-GNMT protected hepatocytes from CCl4-induced liver damage. AAV8-GNMT significantly attenuated the levels of pro-fibrotic markers and increased efficiency of hepatocyte proliferation. These results suggest that correction of hepatic GNMT by gene therapy of AAV8-mediated gene enhancement may provide a potential strategy for preventing and delaying development of liver diseases.

Cryptotanshinone, a well-known diterpene quinone from a widely used traditional Chinese herb named Salvia miltiorrhiza, has been reported for its therapeutical potentials on diverse activities. In this study, pharmacological effects of cryptotanshinone on acute lymphoblastic leukemia cells were investigated. IC50 values of 5.0 and 4.8 were obtained in CEM/ADR5000 and CCRF-CEM. Microarray-based mRNA expression revealed that cryptotanshinone regulated genes associated with cell cycle, DNA damage, reactive oxygen species (ROS), NFκB signaling and cellular movement. The involvement of these pathways in the mode of action of cryptotanshinone was subsequently validated by additional independent in vitro studies. Cryptotanshinone stimulated ROS generation and induced DNA damage. It arrested cells in G2/M phase of the cell cycle and induced apoptosis as measured by annexin V-FITC-conjugating fluorescence. The induction of the intrinsic apoptotic pathway by cryptotanshinone was proved by loss of mitochondrial membrane potential and increased cleavage of caspase 3/7, caspase 9 and poly ADP ribose polymerase (PARP). DNA-binding motif analysis of the microarray-retrieved deregulated genes in the promoter region revealed NFκB as potential transcription factor involved in cryptotanshinone's mode of action. Molecular docking and Western blotting provided supportive evidence, suggesting that cryptotanshinone binds to IKK-β and inhibits the translocation of p65 from the cytosol to the nucleus. In addition, cryptotanshinone inhibited cellular movement as shown by a fibronectin-based cellular adhesion assay, indicating that this compound exerts anti-invasive features. In conclusion, cryptotanshinone exerts profound cytotoxicity, which is caused by multispecific modes of actions, including G2/M arrest, apoptosis and inhibition of cellular movement. The inhibitory activities of this compound may be explained by inhibition of NFκB, which orchestrates all these mechanisms.

Miltirone (1) is a diterpene quinone extracted from a well-known Chinese traditional herb (Salvia miltiorrhiza). We investigated the cytotoxic effects of miltirone toward sensitive and multidrug-resistant acute lymphoblastic leukemia cell lines. Miltirone inhibited multidrug-resistant P-glycoprotein (P-gp)-overexpressing CEM/ADR5000 cells better than drug-sensitive CCRF-CEM wild-type cells, a phenomenon termed collateral sensitivity. Flow cytometric analyses revealed that miltirone induced G2/M arrest and apoptosis. Furthermore, miltirone stimulated reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) disruption, which in turn induced DNA damage and activation of caspases and poly ADP-ribose polymerase (PARP). Downregulation of CCNB1 (cyclin B1) and CDC2 mRNA and upregulation of CDKN1A (p21) mRNA were in accord with miltirone-induced G2/M arrest. Moreover, miltirone decreased cell adherence to fibronectin. Molecular docking revealed that miltirone bound to the ATP-binding site of IKK-β. In conclusion, miltirone was collateral sensitive in multidrug-resistant P-gp-overexpressing cells, induced G2/M arrest, and triggered apoptosis via ROS-generated breakdown of MMP and DNA damage. Therefore, miltirone may be a promising candidate for cancer chemotherapy.

Posttraumatic stress disorder (PTSD) is a mental disorder developing after exposure to traumatic events. Although psychotherapy reveals some therapeutic effectiveness, clinically sustainable cure is still uncertain. Some Chinese herbal formulae are reported to work well clinically against mental diseases in Asian countries, but the safety and their mode of action are still unclear. In this study, we investigated the mechanisms of Chinese remedy free and easy wanderer (FAEW) on PTSD. We used a reverse pharmacology approach combining clinical data to search for mechanisms of PTSD with subsequent in vitro verification and bioinformatics techniques as follows: (1) by analyzing microarray-based transcriptome-wide mRNA expression profiling of PTSD patients; (2) by investigating the effect of FAEW and the antidepressant control drug fluoxetine on the transcription factor NF-κB using reporter cell assays and western blotting; (3) by performing molecular docking and literature data mining based on phytochemical constituents of FAEW. The results suggest an involvement of inflammatory processes mediated through NF-κB in the progression of PTSD. FAEW was non-cytotoxic in vitro and inhibited NF-κB activity and p65 protein expression. FAEW's anti-inflammatory compounds, i.e., paeoniflorin, isoliquiritin, isoliquiritin apioside and ononin were evaluated for binding to IκK and p65-RelA in a molecular docking approach. Paeoniflorin, albiflorin, baicalin, isoliquiritin and liquiritin have been reported to relieve depression in vivo or in clinical trials, which might be the active ingredients for FAEW against PTSD.

The invention of Social Networking Site not only changes the way people searching information and communicating, but also business marketing strategy. Before Social Networking Site came out, the usual way business marketing strategies are TV commercials, print advertisements and activities. After Social Networking Site got popular, more and more businesses turned to use the Internet as a strategy of marketing because the cost is inexpensive and it is easier to gain potential clients through the whole world. One of the Internet’s characteristics is virtually, which is a difficulty for business to run their website because they cannot actually observe their customers’ behavior. In this study, we try to use the data that we collect to analysis the behavior of iCook fan Page’s fans based on Dialogic Theory. Dialogic Theory has five facets, Dialogic Loop, Usefulness of Information, Generation of Return Visits, Ease of the Interface and Conservation of Visitors. Most of the studies used content analysis to analysis the criteria they defined, we define the criteria form user’s perspective and collect the data in a more convenient way. Moreover, we attempt to find out the relationship between Dialogic Theory and the change of fan number. The study found out that some criteria have relationship with fan’s number, which means if a business wants to improve their public strategy on fanpage, they can start from looking for these criteria. These criteria can help a business to run their fanpage more effectively; it also helps to gain fans’ value on the Internet.

Salvia miltiorrhiza Bunge (danshen) is a well-known traditional Chinese medicinal herb. The root part of the plant contains most of the bioactive ingredients, which mainly belong to two groups of compounds: hydrophilic phenolic acids and hydrophobic tanshinones. These bioactive compounds refer to as secondary metabolites and exert multiple therapeutic activities, such as anti-oxidative stress, anti-neurodegenerative, anti-inflammatory, and anti-hypertensive effects without showing serious side effects. Besides these pharmacological activities, anticancer effects have also attracted scientific attention. This review will provide an updated summary of the anticancer effects and the proposed mechanisms of the major bioactive compounds isolated from S. miltiorrhiza.

The natural compound 1,8-cineol, also known as eucalyptol, is a major constituent of eucalyptus oil. This epoxy-monoterpene is used as flavor and fragrance in consumer goods as well as medical therapies. Due to its anti-inflammatory properties, 1,8-cineol is also applied to treat upper and lower airway diseases. Despite its widespread use, only little is known about the genotoxicity of 1,8-cineol in mammalian cells. This study investigates the genotoxicity and cytotoxicity of 1,8-cineol in human and hamster cells. First, we observed a significant and concentration-dependent increase in oxidative DNA damage in human colon cancer cells, as detected by the Formamidopyrimidine-DNA glycosylase (Fpg)-modified alkaline comet assay. Pre-treatment of cells with the antioxidant N-acetylcysteine prevented the formation of Fpg-sensitive sites after 1,8-cineol treatment, supporting the notion that 1,8-cineol induces oxidative DNA damage. In the dose range of DNA damage induction, 1,8-cineol did neither reduce the viability of colon cancer cells nor affected their cell cycle distribution, suggesting that cells tolerate 1,8-cineol-induced oxidative DNA damage by engaging DNA repair. To test this hypothesis, hamster cell lines with defects in BRCA2 and Rad51, which are essentials players of homologous recombination (HR)-mediated repair, were treated with 1,8-cineol. The monoterpene induced oxidative DNA damage and subsequent DNA double-strand breaks in the hamster cell lines tested. Intriguingly, we detected a significant concentration-dependent decrease in viability of the HR-defective cells, whereas the corresponding wild-type cell lines with functional HR were not affected. Based on these findings, we conclude that 1,8-cineol is weakly genotoxic, inducing primarily oxidative DNA damage, which is most likely tolerated in DNA repair proficient cells without resulting in cell cycle arrest and cell death. However, cells with deficiency in HR were compromised after 1,8-cineol treatment, suggesting a protective role of HR in response to high doses of 1,8-cineol.

Green tea consumption is associated with chemoprevention of many cancer types. Fresh tea leaves are rich in polyphenolic catechins, which can constitute up to 30% of the dry leaf weight. While the polyphenols of green tea have been well investigated, it is still largely unknown, whether or not non-phenolic constituents also reveal chemopreventive and anti-metastatic effects. In this study, we investigated the effects of a fraction of green tea rich in phenolic compounds (PF), a non-phenolic fraction (NPF), which contains glyceroglycolipids (GGL), and a pure glyceroglycolipid compound isolated from the non-phenolic fraction in human cancer. Dried green tea leaves were extracted and applied to a Sephadex LH-20 column. The resazurin reduction assay was used to investigate the cytotoxicity of green tea samples towards human HepG2 hepatocellular carcinoma and normal AML12 hepatocytes cells. Gene expression profiling was performed by mRNA microarray hybridization and the microarray results were validated by RT-PCR. The scratch migration assay was used to investigate the effects of green tea samples on cell migration in vitro. The changes of microtubule dynamics were observed using fluorescence microscopy. PF and NPF were prepared from methanol extract of green tea. A GGL was isolated from NPF. All three green tea samples did not show significant cytotoxic activity up to 10 µg/mL in both HepG2 and AML12 cells, whereas cytotoxicity of the control drug doxorubicin was observed with both cell lines (IC50 on AML12: 0.024 µg/mL, IC50 on HepG2: 2.103 µg/mL). We identified three sets of genes differentially expressed upon treatment with the green tea samples. The genes were associated with cytoskeleton formation, cellular movement and morphology. The correlation coefficients between mRNA expression values determined by microarray and RT-PCR were R = 0.94. HepG2 and U2OS cells treated with green tea extracts showed the delayed closures. Besides, the number of distinct tubulin filaments decreased upon treatment with green tea samples. We identified not only PF, but also glyceroglycolipids in NPF as contributing factors to the chemopreventive effects of green tea. Both PF and NPF of green tea inhibited cancer cell migration by the disassembly of microtubules, even though they were not cytotoxic.

To investigate the association between cardiorespiratory fitness and hospitalization events in a cohort of large voluntary arm forces in Taiwan.The cardiorespiratory fitness and hospitalization events in armed forces (CHIEF) is a retrospective cohort consisting of more than 4000 professional military members aged 18-50 years in Eastern Taiwan. All participants received history taking, physical examination, chest radiography, 12-lead electrocardiography, blood tests for cell counts and fasting glucose, lipid profiles, uric acid, renal function and liver function in the Hualien Armed Forces General Hospital during 2014. In addition, participants were required to undergo two indoor resistant exercise tests including 2-min push-up and 2-min sit-up, both scored by infrared sensing, and one outdoor endurance 3000-m none weight-bearing running test, the main indicator of cardiorespiratory fitness in the Military Physical Training and Testing Center in Eastern Taiwan in 2014.Hospitalization events for cardiovascular disease, acute kidney injury, rhabdomyolysis, severe infectious disease, acute psychiatric illness, diabetes, orthopedic surgery and mortality will be identified in the National Insurance Research Database for 10 years.CHIEF will be among the largest Eastern Asian armed forces cohort, in which physical status was strictly evaluated to follow up the hospitalization events for severe illness.

Made available in DSpace on 2018-11-26T16:27:45Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-02-15 Deutsche Forschungsgemeinschaft Background: Biopiracy mainly focuses on the use of biological resources and/or knowledge of indigenous tribes or communities without allowing them to share the revenues generated out of economic exploitation or other non-monetary incentives associated with the resource/knowledge. Methods: Based on collaborations of scientists from five continents, we have created a communication platform to discuss not only scientific topics, but also more general issues with social relevance. This platform was termed 'PhytCancer -Phytotherapy to Fight Cancer' (www.phyt-cancer.uni-mainz.de). As a starting point, we have chosen the topic biopiracy, since we feel this is of pragmatic significance for scientists working with medicinal plants. Results: It was argued that the patenting of herbs or natural products by pharmaceutical corporations disregarded the ownership of the knowledge possessed by the indigenous communities on how these substances worked. Despite numerous court decisions in U.S.A. and Europe, several international treaties, (e.g. from United Nations, World Health Organization, World Trade Organization, the African Unity and others), sharing of a rational set of benefits amongst producers (mainly pharmaceutical companies) and indigenous communities is yet a distant reality. In this paper, we present an overview of the legal frameworks, discuss some exemplary cases of biopiracy and bioprospecting as excellent forms of utilization of natural resources. Conclusions: We suggest certain perspectives, by which we as scientists, may contribute towards prevention of biopiracy and also to foster the fair utilization of natural resources. We discuss ways, in which the interests of indigenous people especially from developing countries can be secured. (C) 2015 Elsevier GmbH. All rights reserved. Johannes Gutenberg Univ Mainz, Dept Pharmaceut Biol, Inst Pharm & Biochem, Staudinger Weg 5, D-55128 Mainz, Germany Johannes Gutenberg Univ Mainz, Dept English & Linguist, D-55128 Mainz, Germany Johannes Gutenberg Univ Mainz, Med Ctr, Inst Hist Theory & Eth Med, D-55128 Mainz, Germany Univ Khartoum, Fac Sci, Dept Bot, Khartoum, Sudan Univ Nairobi, Dept Vet Anat & Physiol, Nairobi, Kenya Al Balqa Appl Univ, Shoubak Univ Coll, Salt, Jordan Wilderness Int, Dresden, Germany Wilderness Int, Stony Plain, AB, Canada Ft McPherson, Fort McPherson, NT, Canada Curtin Univ, Fac Hlth Sci, Ctr Hlth Innovat Res Inst, Perth, WA 6845, Australia SASTRA Univ, Sch Chem & Biotechnol, Thanjavur 613401, TN, India Sao Paulo State Univ, Inst Chem, Dept Organ Chem, Araraquara, Brazil Univ Philippines, Dept Biol, Manila, Philippines Univ Philippines, Inst Biol, Quezon City 1101, Philippines NN Blokhin Russian Canc Res Ctr, Moscow, Russia Univ Porto, Biomed Sci Inst Abel Salazar, Rua Campo Alegre 823, P-4100 Oporto, Portugal Heidelberg Sch Chinese Med, Heidelberg, Germany Southwest Ctr Nat Prod Res & Commercializat, Sch Nat Resources & Environm, Tucson, AZ USA Univ Western Cape, Dept Chem, Bellville, South Africa Mehmet Akif Ersoy Univ, Dept Biol, Burdur, Turkey Univ Khartoum, Dept Pharmacognosy, Khartoum, Sudan Univ Dschang, Dept Biochem, Fac Sci, Dschang, Cameroon Chonnam Natl Univ, Coll Pharm, Gwangju, South Korea Macao Univ Sci & Technol, Macau, Peoples R China Univ Nairobi, Dept Chem, Nairobi, Kenya Rodrigo Facio Univ, Fac Microbiol, San Jose, Costa Rica Chubu Univ, Coll Biosci & Biotechnol, Dept Appl Biol Chem, Kasugai, Aichi 487, Japan Tokyo Inst Technol, Grad Sch Biosci & Biotechnol, Dept Biomol Engn, Yokohama, Kanagawa 227, Japan Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania Mahidol Univ, Fac Pharm, Dept Pharmacognosy, Bangkok 10700, Thailand Rajamangala Univ Technol Thayaburi, Tradit Med Coll, Pathum Thani, Thailand King Saud Univ, Coll Pharm, Dept Pharmacognosy, Riyadh, Saudi Arabia Natl Res Ctr, Phytochem Dept, Cairo, Egypt Lebanese Univ, Dept Chem, Fac Sci 2, Beirut, Lebanon Fed Govt Sudan, Khartoum, Sudan Zhejiang Chinese Med Univ, Hangzhou, Zhejiang, Peoples R China Sao Paulo State Univ, Inst Chem, Dept Organ Chem, Araraquara, Brazil Deutsche Forschungsgemeinschaft: CRK2015/1

Paroxysmal atrial fibrillation (PAF) carries an equally high annual stroke rate as chronic atrial fibrillation (AF). Furthermore, the frequency and duration of PAF are thought to be associated with stroke risk. In this pilot study, a trans-telephonic electrocardiograph (TTE) monitoring system was used to detect asymptomatic PAF and to study the relationship between ischemic stroke and the frequency of PAF. Between December 2004 and April 2006, 70 patients enrolled in the TTE monitoring program. Patients either transmitted electrocardiograms (ECGs) daily or upon experiencing cardiac symptoms. Of the 70 patients included, 25 were diagnosed with PAF. In total, 11% (855/7,768) of the recordings were diagnosed as PAF, yet less than 2% of total calls collected and less than 17% of all the calls with PAF were associated with obvious symptoms. Four patients developed five ischemic strokes resulting in a calculated annual stroke rate of 0.56%. Patients with stroke had more episodes of AF (56.5±106.3 versus 6.7±85.9, p=0.685) and symptomatic AF episodes (9.8±17.5 versus 4.9±8.1, p=0.381) than the patients who did not have a stroke, but the differences were not statistically significant because of the low numbers of patients and episodes. Most PAF episodes were asymptomatic, and the TTE system could easily detect these episodes. Furthermore, these four patients tended to have more episodes of PAF and more symptomatic attacks of PAF than patients who did not have a stroke.

Sunitinib malate, an oral multitargeted tyrosine kinase inhibitor (TKI), has been approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. It is supposed that this targeted approach improves antitumor activity with less toxicity than traditional chemotherapy. However, unanticipated cardiotoxicity related to TKIs has been reported. Less well described are the treatment and prognosis of patients with sunitinib-related cardiogenic shock. Here, we report a successfully treated case. In contrast to previous case reports, the shock status did not allow for standard heart failure treatment with angiotensin-converting enzyme inhibitor or beta-blocker. We used intra-aortic balloon counterpulsation, and the patient survived. Twenty-four days after onset, the patient's left ventricular ejection fraction had improved from 20% to 48%. To the best of our knowledge, this is the first case report of severe heart failure after sunitinib treatment in Taiwan. As the clinical application of TKIs expands, cardiologists and oncologists should be alert to the possible adverse cardiovascular effects and be ready to institute prompt treatment.

This paper investigates the feasibility of applying Tomlinson-Harashima precoding (THP) to multicarrier code-division multiple-access (MC-CDMA) system downlinks, in which multiple-access interference and possible complexity in the mobile terminal (MT) are major burdens. A THP based on the minimum mean-square error (MMSE) criterion is also presented, making it possible to realize a low-complexity receiver at the MT. The hardware architecture of the MMSE THP with modified QR decomposition at the transmitter is presented, along with the required word length analyzed. Pipeline and parallel schemes are adopted to reduce the execution time. For a generic square matrix of order for RQ decomposition, the required latency is time units, which is based on the modified Gram-Schmidt algorithm.

Background: Unfolded protein responses (UPR) determine cell fate and are recognized as anticancer targets. In a previous research, we reported that cryptotanshinone (CPT) exerted cytotoxic effects toward acute lymphoblastic leukemia cells through mitochondria-mediated apoptosis. Purpose: In the present study, we further investigated the role of UPR in CPT-induced cytotoxicity on acute lymphoblastic leukemia cells by applying tools of pharmacogenomics and bioinformatics. Methods: Gene expression profiling was performed by mRNA microarray hybridization. Potential transcription factor binding motifs were identified in the promoter regions of the deregulated genes by Cistrome software. Molecular docking on eIF-4A and PI3K was performed to investigate the inhibitory activity of CPT on translation initiation. Results: CPT regulated genes related to UPR and eIF2 signaling pathways. The DNA-Damage-Inducible Transcript 3 (DDIT3) gene, which is activated as consequence of UPR malfunction during apoptosis, was induced and validated by in vitro experiments. Transcription factor binding motif analysis of the microarrary-retrieved deregulated genes in the promoter region emphasized the relevance of transcription factors, such as ATF2, ATF4 and XBP1, regulating UPR and cell apoptosis. Molecular docking suggested inhibitory effects of CPT by binding to eIF-4A and PI3K providing evidence for a role of CPT's in the disruption of protein synthesis. Conclusion: CPT triggered UPR and inhibited protein synthesis via eIF-mediated translation initiation, potentially supporting CPT-induced cytotoxic effects toward acute leukemia cells.

Salvia miltiorrhiza (SM) Bunge is one of the widely-used Chinese medicinal herbs. In this study, the chemical constituents and anticancer potential of SM stems and leaves were examined with those of respective callus cultures. The callus culture for stem and leaf explants was initiated in modified Murashige and Skoog (MS) medium. Active constituents of respective extracts were analyzed by high performance liquid chromatography coupled with DAD and MS (HPLC-DAD-MS). Rosmarinic acid (RA) and salvianolic acid B (Sal B) were determined to be the main phenolic compounds. Quantitative analyses revealed that callus stem extracts produced higher amount of RA and Sal B (stem RA: 1.27±0.38%; stem Sal B: 0.87±0.20%) than callus leaf did (leaf RA: 0.28±0.02%; leaf Sal B: 0.07±0.03%). Stem and leaf callus extracts exerted cytotoxic effects towards CCRF-CEM cells (stem: 13.1±0.90 μg/ml; leaf: 18.1±0.33 μg/ml). As expected, stem extract with higher amount of RA and Sal B showed lower IC50 value than leaf extract. These findings suggest the possibility to isolate bioactive constituents with anticancer properties from in vitro callus cultures of stems and leaves of SM.

Background Resistance of cancer cells towards chemotherapeutics represents a major cause of therapy failure. The objective of our study was to evaluate cellular defense strategies in response to the novel vacuolar H+-ATPase inhibitor, archazolid B. Experimental approach: The effects of archazolid B on T24 bladder carcinoma cells were investigated by combining “omics” technologies (transcriptomics (mRNA and miRNA) and proteomics). Free cholesterol distribution was determined by filipin staining using flow cytometry and fluorescence microscopy. Flow cytometry was performed for LDLR surface expression studies. Uptake of LDL cholesterol was visualized by confocal microscopy. SREBP activation was determined performing Western Blotting. The efficiency of archazolid B/fluvastatin combination was tested by cytotoxicity assays. Results Archazolid B led to accumulation of free cholesterol within intracellular compartments and drastic disturbances in cholesterol homeostasis resulting in activation of SREBP-2 (sterol regulatory element-binding protein 2) and up-regulation of target genes including HMGCR (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. LDLR surface expression was reduced and LDL uptake was completely inhibited after 24 h, indicating newly synthesized cholesterol to be the main source of cholesterol in archazolid B treated cells. By combining archazolid B with the HMGCR inhibitor fluvastatin, cholesterol was reduced and cell viability decreased by about 20% compared to archazolid B treatment alone. Conclusions Our study revealed cholesterol biosynthesis as an important resistance mechanism in T24 cells after archazolid B treatment. The combination of archazolid B with statins may be an attractive strategy to potentiate archazolid B induced cell killing by affecting cholesterol biosynthesis.

Hepatitis C virus core protein (HCVcp), which is secreted by infected cells, is reported as an immunomodulator in immune cells. However, the effects of HCVcp on hepatic stellate cells (HSCs), the key cells in liver fibrosis, still remain unclear. In this study, we investigated the effects of HCVcp on obese receptor (ObR) related downstream signaling pathways and fibrogenic gene expression in HSCs. LX-2, a human HSC line, was incubated with HCVcp. Inhibitors and short interfering RNAs were used to interrogate the mechanisms of HCVcp action on HSCs. HCVcp (20-100 ng/ml) concentration-dependently stimulated α-smooth muscle actin (α-SMA) protein expression and mRNA expression of α-SMA, procollagen α2(I) and TGF-β1 genes, with a plateau of 220% of controls at 100 ng/ml. HCVcp induced mRNA and protein expression of ObR. Blocking of Ob-Rb with a neutralizing antibody inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and AMPKα stimulated by HCVcp. Furthermore, knockdown of Ob-Rb down-regulated HCVcp-induced STAT3, AKT, and AMPKα phosphorylation, and reversed HCVcp-suppressed mRNA expression of matrix metalloproteinase (MMP)-1, peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element binding protein-1c (SREBP-1c) genes. AMPKα signaling blockade reversed HCVcp-suppressed SREBP-1c mRNA expression. HCVcp stimulated reactive oxygen species formation and gp91(phox) (a component of NADPH oxidase) protein expression, together with AKT phosphorylation, leading to suppression of PPARγ and SREBP-1c genes. Our results provide a new finding that HCVcp induced ObR-dependent Janus Kinase (JAK) 2-STAT3, AMPKα, and AKT signaling pathways and modulated downstream fibrogenetic gene expression in HSCs.

Background and Aims: In chronic liver injury, hepatic stellate cells (HSCs) acquire an activated phenotype, migrate to the injured region in response to chemotactic factors, and produce extracellular matrix proteins including collagen. In this study, we investigated the effects of rhubarb (Rheum palmatum L.) on transforming growth factor (TGF)-β1-induced expressions of α-smooth-muscle actin (SMA) and collagen, and the migration of HSCs. Methods: HSC-T6, a cell line of rat HSCs, was used in the in vitro experiments. An enzyme-linked immunosorbent assay and Sircol red assay were used to detect the expressions of α-SMA and collagen, respectively. HSC-T6 migration was assayed with a transwell apparatus. Phosphorylations of Smad2/3 and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) 1/2, p38, and c-jun N-terminal kinase (JNK), were analyzed with Western blotting. Matrix metalloproteinase (MMP)-2 activity was examined by gelatin zymography. Results: The results revealed that a rhubarb extract concentration-dependently attenuated TGF-β1-induced α-SMA and collagen expressions and migration of HSCs. The inhibitory effect of rhubarb was associated with (i) down-regulation of the phosphorylation of Smad2/3 and JNK, and (ii) attenuation of MMP-2 activity. Within the working concentrations used, the rhubarb extract did not affect cell viability of HSCs. Conclusion: The results suggest that rhubarb attenuated TGF-β1-mediated migration of HSCs possibly by interfering with Smad2/3 phosphorylation, the MAPK pathway, and MMP-2 activity.

In liver injury, hepatic stellate cells (HSCs) acquire an activated phenotype, migrate to the injured region in response to chemotactic factors and produce extracellular matrix (ECM) proteins including alpha-smooth muscle actin (alpha-SMA) and collagen in order to repair the damage. HSC-T6, a cell line of rat HSCs, was used in in vitro experiments. TGF-beta1 was used as a chemoattractant. The expression of alpha-SMA was used as a marker of activated hepatic stellate cells and cell migration was assayed with the Transwell method to investigate the active principles of the roots of Rheum palmatum L. (Dahuang), a well-known traditional Chinese herb used for treating liver diseases. Under cell activation and chemotaxis-directed fractionation and purification, four anthraquinones, rhein ( 1), emodin ( 2), chrysophanol ( 3) and physcion ( 4), and four phenylbutanoids, lindleyin ( 5), isolindleyin ( 7), 4-(4'-hydroxyphenyl)-2-butanone 4'- O-beta- D-glucopyranoside ( 8), and 4-(4'-hydroxyphenyl)-2-butanone ( 9), and a stilbene, 3,5,4'-trihydroxystilbene 4'- O-beta- D-glucopyranoside 6'- O-gallate ( 6) were isolated from the active fractions. Among them, compounds 1 and 2 inhibited alpha-SMA expression. However, compounds 3, 4, 6 and 8 attenuated chemotactic migration, but not alpha-SMA expression.

Tetrandrine (Tet) (C38H42O8N2; molecular weight, 622), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit anti-inflammatory and anti-fibrotic effects in pulmonary diseases, but the mechanism of action has yet to be investigated. In this study, we tested whether Tet exerts anti-fibrotic effects on rat hepatic fibrosis through anti-NFκB pathways. After bile-duct ligation, rats were given Tet (1 or 5 mg/kg) or silymarin (50 mg/kg, as a positive control) by gavage twice daily for 3 weeks. Liver sections were taken for Sirius red quantitative scoring, immunofluorescence double staining of α-smooth muscle actin (α-SMA) and NFκB, and for quantitative determinations of the mRNA expression levels of TGF-β1, α-SMA, collagen 1α2, inducible nitric oxide synthase (iNOS), intercellular adhesion molecule 1 (ICAM-1), metallothionein, vascular endothelial growth factor (VEGF), and VEGF type II receptor (VEGFR2) genes. The results showed that both Tet and silymarin treatment significantly reduced the fibrosis scores and hepatic collagen content of BDL rats, compared with no treatment. Both Tet and silymarin treatments decreased the number of α-SMA- and NFκB-positive cells in fibrotic livers. Moreover, Tet and silymarin treatments attenuated the mRNA expression levels of TGF-β1,α-SMA, collagen 1α2, iNOS, ICAM-1, VEGF, and VEGFR2 genes, and induced the mRNA expression of the metallothionein gene. This study suggests that the anti-fibrotic effects of Tet were related to the reduction of fibrosis-related gene transcription, the attenuation of NFκB-activated pathways, and the induction of metallothionein gene transcription in the livers of BDL rats.

Background Anti-inflammation strategies are one of the proposed therapeutic approaches to hepatic fibrosis. Tetrandrine (C(38)H(42)O(8)N(2), molecular weight: 622; Tet), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to exert anti-inflammatory activity in pulmonary diseases. The purpose of the present study was to investigate the in vitro and in vivo effects of Tet on hepatic fibrosis. Methods A cell line of rat hepatic stellate cells (HSC-T6) was stimulated with transforming growth factor-beta1 (TGF-beta1) or tumor necrosis factor-alpha (TNF-alpha). The inhibitory effects of Tet on the nuclear factor kappaB (NFkappaB) signaling cascade and molecular markers including intercellular adhesion molecule-1 (ICAM-1) and alpha-smooth muscle actin (alpha-SMA) secretion were assessed. Fibrosis was induced by dimethylnitrosamine (DMN) administration in rats for 4 weeks. Fibrotic rats were randomly assigned to one of the four groups: vehicle (0.7% carboxyl methyl cellulose, CMC), Tet (1 mg/kg), Tet (5 mg/kg), or silymarin (50 mg/kg), each given by gavage twice daily for 3 weeks starting after 1 week of DMN administration. At the end of the study, liver tissues were scored for fibrosis and analyzed for molecular markers of fibrosis. Results Tetrandrine (0.5-5.0 micromol/L) concentration-dependently inhibited NFkappaB transcriptional activity induced by TNF-alpha, including IkappaBalpha phosphorylation and mRNA expressions of ICAM-1 in HSC-T6 cells. In addition, Tet also inhibited TGF-beta1-induced alpha-SMA secretion and collagen deposition in HSC-T6 cells. Fibrosis scores of livers from DMN-treated rats with high-dose Tet (1.3 +/- 0.3) were significantly reduced in comparison with DMN-treated rats receiving saline (2.0 +/- 0.2). Hepatic collagen content of DMN rats was significantly reduced by either Tet or silymarin treatment. Double-staining results showed that alpha-SMA- and NFkappaB-positive cells were decreased in the fibrotic livers by Tet and silymarin treatment. In addition, mRNA expression of ICAM-1, alpha-SMA, and TGF-beta1 was attenuated by Tet treatment. Moreover, levels of plasma aspartate aminotransferase and alanine aminotransferase activities were reduced by Tet and silymarin treatment. Conclusion Tetrandrine exerts antifibrotic effects in both HSC-T6 cells and in rats with DMN-induced fibrosis.