Vasorelaxant activity of indole alkaloids from Tabernaemontana dichotoma.

The aim of this study was to search for bioactive natural products from medicinal plants targeting vasorelaxant activity and we found the methanol extract from bark of Tabernaemontana dichotoma showed vasorelaxant activity on rat aorta. We isolated eight indole alkaloids including 10-methoxyalstonerine (1), a new macroline type indole alkaloid, from bark of T. dichotoma. These were respectively identified as 10-methoxyaffinisine (2), lochnerine (3), cathafoline (4), (−)-alstonerine (5), 19,20-dehydro-10-methoxytalcarpine (6), alstonisine (7), and alstonal (8) based on spectroscopic analysis. Among them, sarpagine type (2 and 3), akuammiline type (4), and macroline oxindole type (7 and 8) showed potent vasorelaxant activity. Mechanism of action on vasorelaxant activity of 10-methoxyaffinisine (2), cathafoline (4), and alstonisine (7) was clarified. Effects of 10-methoxyaffinisine (2), cathafoline (4), and alstonisine (7) were partially mediated the NO release from endothelial cells. Furthermore, 10-methoxyaffinisine (2) and alstonisine (7) attribute to the inhibitory effect of VDC and ROC, and cathafoline (4) have inhibitory effect on Ca2+ influx via ROC. In addition, 10-methoxyaffinisine (2) as a major compound from bark of T. dichotoma showed hypotensive effect on normotensive rats in vivo

Is there a role for melatonin in fibromyalgia?

Fibromyalgia, characterised by persistent pain, fatigue, sleep disturbance and cognitive dysfunction, is a central sensitivity syndrome that also involves abnormality in peripheral generators and in the hypothalamic pituitary adrenal axis. Heterogeneity of clinical expression of fibromyalgia with a multifactorial aetiology has made the development of effective therapeutic strategies challenging. Physiological properties of the neurohormone melatonin appear related to the symptom profile exhibited by patients with fibromyalgia and thus disturbance of it’s production would be compatible with the pathophysiology. Altered levels of melatonin have been observed in patients with fibromyalgia which are associated with lower secretion during dark hours and higher secretion during daytime. However, inconsistencies of available clinical evidence limit conclusion of a relationship between levels of melatonin and symptom profiles in patients with fibromyalgia. Administration of melatonin to patients with fibromyalgia has demonstrated suppression of many symptoms and an improved quality of life consistent with benefit as a therapy for the management of this condition. Further studies with larger samples, however, are required to explore the potential role of melatonin in the pathophysiology of fibromyalgia and determine the optimal dosing regimen of melatonin for the management of fibromyalgia

Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study.

BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low-/middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112

Host-Guest Complexation of [60]Fullerenes and Porphyrins Enabled by “Click Chemistry”

Herein the synthesis, characterization, and organization of a first-generation dendritic fulleropyrrolidine bearing two pending porphyrins are reported. Both the dendron and the fullerene derivatives were synthesized by Cu(I) -catalyzed alkyne-azide cycloaddition (CuAAC). The electron-donor-acceptor conjugate possesses a shape that allows the formation of supramolecular complexes by encapsulation of C60 within the jaws of the two porphyrins of another molecule. The interactions between the two photoactive units (i.e., C60 and Zn-porphyrin) were confirmed by cyclic voltammetry as well as by steady-state and time-resolved spectroscopy. For example, a shift of about 85 mV was found for the first reduction of C60 in the electron-donor-acceptor conjugate compared with the parent molecules, which indicates that C60 is included in the jaws of the porphyrin. The fulleropyrrolidine compound exhibits a rich polymorphism, which was corroborated by AFM and SEM. In particular, it was found to form supramolecular fibrils when deposited on substrates. The morphology of the fibrils suggests that they are formed by several rows of fullerene-porphyrin complexes

Identification of Prognostic Molecular Features in the Reactive Stroma of Human Breast and Prostate Cancer

Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value

Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Praziquantel has been used as first-line drug for chemotherapy of schistosomiasis since 1984. Besides praziquantel, artemether and artesunate have also been used for the control of this infectious disease since late 1990s. In this article, we conducted a systematic review and meta-analysis to evaluate the antischistosomal efficacy of different medication strategies including monotherapy or combination therapies of these drugs.</p> <p>Results</p> <p>A number of 52 trials from 38 articles published in peer-reviewed journals before July 2011 were selected for analysis after searching the following literature databases: the Cochrane Library, PubMed/Medline, ISI Web of Science, Chinese Biomedicine Literature Database, and China National Knowledge Infrastructure. Our meta-analyses showed that a dosage of 30-60 mg/kg praziquantel compared with placebo produced a protection rate of about 76% (95% CI: 67%-83%) for treating human schistosomiasis, which varied from 70% to 76% with no significant differences among the subspecies <it>S. haematobium</it>, <it>S. japonicum </it>or <it>S. mansoni</it>. Protection rates were higher when praziquantel doses were elevated, as concluded from the nRCTs results: the protection rate of praziquantel at 40 mg/kg was 52% (95% CI: 49%-55%), and it increased to 91% (95% CI: 88%-92%) when the dosages were elevated to 60/80/100 mg/kg divided two or more doses. Multiple doses of artemether or artesunate over 1- or 2-week intervals resulted in protection rates of 65% to 97% for preventing schistosomiasis, and increased doses and shorter medication intervals improved their efficacies. Praziquantel and artemisinin derivatives (artemether or artesunate) in combination resulted in a higher protection rate of 84% (95% CI: 64%-91%) than praziquantel monotherapy for treatment. praziquantel and artesunate in combination had a great protection rate of 96% (95% CI: 78%-99%) for preventing schistosomes infection.</p> <p>Conclusions</p> <p>According to the results, praziquantel remains effective in schistosomiasis treatment, and multiple doses would improve its efficacy; meanwhile, praziquantel is also a good drug for preventing acute schistosomiasis morbidity. It's better to use multiple doses of artemether or artesunate with 1- or 2-week intervals for prevention against schistosome infection. Praziquantel and artemether or artesunate in combination perform better in treatment than praziquantel monotherapy, and they are especially suitable for treating the patients with repeated exposure to infected water.</p

Tools to Support Policy Decisions Related to Treatment Strategies and Surveillance of Schistosomiasis Japonica towards Elimination

Immunodiagnostic assays are widely applied in the field to control schistosomiasis in P.R. China as the prevalence and infection intensity of schistosome infections decrease. Field evaluations are urgently needed before they can be adopted to support policy decisions of the national programme for the control and elimination of schistosomiasis in P.R. China. We carried out a large scale cross-sectional survey in field settings with different transmission situations to validate immunodiagnostic tools that can be used to formulate new schistosomiasis elimination strategy in P.R. China. Regarding stool examination as gold reference, the validity and screening efficacy of each immunodiagnostic kit were calculated and compared with each other. The association of the prevalence of schistosomiasis and antibody positive rates determined by immunoassays were analyzed using Pearson's correlation coefficient values. The study indicates that which test to use with the elimination strategy is dependent on the purpose of testing, the endemic status of community and the resources available. And more sensitive methods need to be explored and used to target infected individuals for treatment or to eliminate schistosomiasis

S100A14 Stimulates Cell Proliferation and Induces Cell Apoptosis at Different Concentrations via Receptor for Advanced Glycation End Products (RAGE)

S100A14 is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effects on different types of cells. However, exact extracellular roles of S100A14 have not been clarified yet. Here we investigated the effects of S100A14 on esophageal squamous cell carcinoma (ESCC) cell lines. Results demonstrated that low doses of extracellular S100A14 stimulate cell proliferation and promote survival in KYSE180 cells through activating ERK1/2 MAPK and NF-κB signaling pathways. Immunoprecipitation assay showed that S100A14 binds to receptor for advanced glycation end products (RAGE) in KYSE180 cells. Inhibition of RAGE signaling by different approaches including siRNA for RAGE, overexpression of a dominant-negative RAGE construct or a RAGE antagonist peptide (AmphP) significantly blocked S100A14-induced effects, suggesting that S100A14 acts via RAGE ligation. Furthermore, mutation of the N-EF hand of S100A14 (E39A, E45A) virtually reduced 10 µg/ml S100A14-induced cell proliferation and ERK1/2 activation. However, high dose (80 µg/ml) of S100A14 causes apoptosis via the mitochondrial pathway with activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase. High dose S100A14 induces cell apoptosis is partially in a RAGE-dependent manner. This is the first study to demonstrate that S100A14 binds to RAGE and stimulates RAGE-dependent signaling cascades, promoting cell proliferation or triggering cell apoptosis at different doses

Preface paper to the Semi-Arid Land-Surface-Atmosphere (SALSA) Program special issue

The Semi-Arid Land-Surface-Atmosphere Program (SALSA) is a multi-agency, multi-national research effort that seeks to evaluate the consequences of natural and human-induced environmental change in semi-arid regions. The ultimate goal of SALSA is to advance scientific understanding of the semi-arid portion of the hydrosphere–biosphere interface in order to provide reliable information for environmental decision making. SALSA approaches this goal through a program of long-term, integrated observations, process research, modeling, assessment, and information management that is sustained by cooperation among scientists and information users. In this preface to the SALSA special issue, general program background information and the critical nature of semi-arid regions is presented. A brief description of the Upper San Pedro River Basin, the initial location for focused SALSA research follows. Several overarching research objectives under which much of the interdisciplinary research contained in the special issue was undertaken are discussed. Principal methods, primary research sites and data collection used by numerous investigators during 1997–1999 are then presented. Scientists from about 20 US, five European (four French and one Dutch), and three Mexican agencies and institutions have collaborated closely to make the research leading to this special issue a reality. The SALSA Program has served as a model of interagency cooperation by breaking new ground in the approach to large scale interdisciplinary science with relatively limited resources