Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Publication date: Available online 8 February 2017
Source:Free Radical Biology and Medicine
Author(s): Guang Xin, Zeliang Wei, Chengjie Ji, Huajie Zheng, Jun Gu, Limei Ma, Wenfang Huang, Susan L. Morris-Natschke, Jwu-Lai Yeh, Rui Zhang, Chaoyi Qin, Li Wen, Zhihua Xing, Yu Cao, Qing Xia, Ke Li, Hai Niu, Kuo-Hsiung Lee, Wen Huang
AimAs the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism.Approach and ResultsUsing ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner.ConclusionsXN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.

Graphical abstract

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Widespread hyperphosphorylated tau in the working memory circuit early after cortical impact injury of brain (Original study)

Publication date: 14 April 2017
Source:Behavioural Brain Research, Volume 323
Author(s): Zi-Ai Zhao, Ya-Lei Ning, Ping Li, Nan Yang, Yan Peng, Ren-Ping Xiong, Yan Zhao, Dong Liu, Xu-Jia Zeng, Jiang-Fan Chen, Yuan-Guo Zhou
A series of neurological and psychiatric symptoms occur after traumatic brain injury (TBI), with cognitive dysfunction being one of the most prominent sequela. Given that tau hyperphosphorylation is an important cause of cognitive impairment in patients of Alzheimer's disease, our present study detected the presence of hyperphosphorylated tau (p-tau), mainly at Ser404, in multiple brain regions, including the ipsilateral parietal cortex, contralateral hippocampus and prefrontal cortex, immediately after the injury in a mouse TBI model; these changes lasted for at least 4w. All of these brain regions play important roles in working memory. Hyperphosphorylated tau protein was primarily located in neurons and was accompanied by axonal injury and dendritic spine degeneration. Our study demonstrated that p-tau spreads gradually and selectively from the injured cortex to other brain regions after TBI and that all of the affected regions are part of the working memory circuit. These findings provide experimental support for the role of p-tau in cognitive impairment in the early phase after TBI.



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Mixed ligand coordination polymer based on 4,4′-sulfonyldibenzoic acid and 1,3-bis(2-methyl-1-imidazolyl)benzene: Synthesis, characterization, luminescent and proton conducting properties

Publication date: 15 May 2017
Source:Journal of Molecular Structure, Volume 1136
Author(s): Zhou Zhou, Ning-Ning Chen, Qiang Luo, Li-Yong Jia, Jun Wang, Jian-Qing Tao
A new proton-conductive Zn(II) coordination polymer, namely, [Zn(SDBA)(1,3-BMIB)·H2O]n (1) (1,3-BMIB = 1,3-bis(2-methyl-1-imidazolyl)benzene, H2SDBA = 4,4'-sulfonyldibenzoic acid)) has been synthesized under hydrothermal condition and characterized by elemental analysis, and single-crystal X-ray diffraction. Single-crystal X-ray diffraction study reveals that complex 1 features 2D (4, 4) grid layer. Complex 1 exhibits strong fluorescent emissions in the solid state at room temperature. Moreover, complex 1 also exhibits a proton conductivity of over 10⁻⁵ S cm⁻¹ at 328 K and 99% relative humidity.



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Atmospheric wet deposition of dissolved trace elements to Jiaozhou Bay, North China: Fluxes, sources and potential effects on aquatic environments

Publication date: May 2017
Source:Chemosphere, Volume 174
Author(s): Jianwei Xing, Jinming Song, Huamao Yuan, Qidong Wang, Xuegang Li, Ning Li, Liqin Duan, Baoxiao Qu
To analyze the fluxes, seasonal variations, sources and potential ecological effects of dissolved trace elements (TEs) in atmospheric wet deposition (AWD), one-year wet precipitation samples were collected and determined for nine TEs in Jiaozhou Bay (JZB) between June 2015 and May 2016. Both the volume-weighted mean (VWM) concentration and flux sequence for the measured TEs was Al > Mn > Zn > Fe > Pb > Se > Cr > Cd > Co. Al was the most abundant TE with a VWM concentration and wet flux of 33.8 μg L⁻¹ and 29.2 mg m⁻² yr⁻¹, which were 2 and 3 orders of magnitude higher than those of Co, respectively. The emission intensities of pollutants, rainfall amount and wind speed were the dominating factors influencing seasonal variations of TEs in AWD. Based on enrichment factors, correlation analysis and principal component analysis, most of the TEs in AWD were primarily originated from anthropogenic activities except for Al and Fe, which are typically derived from re-suspended soil dusts. Although the TE inputs by AWD were significantly lower than those by rivers, the TE inputs via short-term heavy rains would distinctly increase surface seawater TE concentrations and then pollute the marine environment of JZB. AWD would have both profound impacts on the biogeochemical cycles of TEs and dual ecological effects (nutrient and toxicity) on aquatic organisms.



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Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer

Abstract

Purpose

To investigate how curcumin alters the extracellular vesicles' (EVs) capability to ship drug resistance in ovarian cancer.

Methods

The EVs from cisplatin-resistant A2780cp cells with curcumin treatment (EVs-CU) or without curcumin treatment (EVs-N) were collected for lncRNA profiling. Curcumin's effect on MEG3 promoter methylation and MEG3 expression were studied by MSP and qRT-PCR, respectively. The regulative effect of MEG3 on miR-214 expression and the functional role of EVs mediated transfer of miR-214 in cisplatin resistance were further investigated.

Results

Curcumin weakened the EVs-N's capability to induce drug resistance and induced significant changes of lncRNAs in the EVs. MEG3 is one of the most upregulated lncRNAs. Curcumin led to demethylation in the promoter region of MEG3 and 5-AZA-dC treatment restored MEG3 expression in a dose dependent manner. There were at least two binding sites between MEG3 and miR-214. MEG3 restoration by curcumin significantly reduced miR-214 in cells and in EVs. Functionally, miR-214 inhibition weakened the EVs-N's capability to enhance chemoresistance, while miR-214 overexpression increased the capability of EVs-CU in inducing chemoresistance.

Conclusion

Curcumin can restore MEG3 levels via demethylation. MEG3 upregulation can decrease EVs mediated transfer of miR-214 in ovarian cancer cells, thereby reducing drug resistance.

http://ift.tt/2kHGKak

Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL)

Publication date: Available online 8 February 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): H. Lawall, A. Pokrovsky, P. Checinski, A. Ratushnyuk, G. Hamm, O. Randerath, F. Grieger, J.W.G. Bentz
ObjectivesThe aim was to assess the efficacy and safety of alprostadil in patients with peripheral arterial occlusive disease (PAOD) Fontaine Stage IV.MethodsThis was a multinational, prospective, randomised, double blind, placebo controlled, parallel group trial. Patients with Stage IV PAOD were equally randomised to either 4 weeks of alprostadil treatment twice daily or to placebo treatment twice daily. The primary efficacy variables were the rate of complete healing of all necrosis and ulceration 12 weeks after the end of treatment and the frequency of major amputations 24 weeks after the end of treatment.ResultsA total of 840 patients were randomised between 2004 and 2013. At baseline, no major differences between treatment groups were found. The rate of "complete healing" was 18.4% in patients on alprostadil and 17.2% in patients on placebo. The rates of "major amputations" were 12.6% in patients on alprostadil and 14.6% in patients on placebo. The adjusted difference between alprostadil and placebo including their 95% confidence intervals was 1.1 (−4.0 to 6.3) for "complete healing" and −2.1 (−6.7 to 2.5) for "major amputations." In the subgroup of diabetic patients the rates of major amputations were numerically lower in the alprostadil than placebo group (10.6% vs. 17.4%). Within the total cohort a non-significant difference in "decrease in ulcer area ≥50%" was reached in 30.2% of patients on alprostadil and in 24.3% of patients on placebo at end of treatment.ConclusionsIn this study, superiority of alprostadil over placebo could not be shown. Nevertheless, a slight numerical but not clinically relevant advantage for alprostadil emerged from the "area decrease of ulcers by ≥ 50%," indicating that a healing effect may have started. The results have to be considered in the light of several limitations in study design and conduct.



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Female Representation in the Academic Oncology Physician Workforce: Radiation Oncology Losing Ground to Hematology-Oncology

Publication date: Available online 8 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Awad A. Ahmed, Wei-Ting Hwang, Emma B. Holliday, Christina H. Chapman, Reshma Jagsi, Charles R. Thomas, Curtiland Deville
PurposeOur purpose was to assess comparative female representation trends for trainees and full-time faculty in the US academic Radiation- and Hematology-Oncology workforce over three decades.Methods and MaterialsSimple linear regression models with year as the independent variable were used to determine changes in female percentage representation per year and associated 95% confidence intervals for trainees and full-time faculty in each specialty.ResultsPeak representation was 48.4% (801/1654) in 2013 for Hematology-Oncology trainees, 39.0% (585/1499) in 2014 for Hematology-Oncology full-time faculty, 34.8% (202/581) in 2007 for Radiation-Oncology trainees, and 27.7% (439/1584) in 2015 for Radiation-Oncology full-time faculty. Representation significantly increased for trainees and full-time faculty in both specialties at approximately 1%/yr for Hematology-Oncology trainees and full-time faculty and 0.3%/yr for Radiation-Oncology trainees and full-time faculty. Compared to Radiation-Oncology, the rates were 3.84 and 2.94 times greater for Hematology-Oncology trainees and full-time faculty, respectively.ConclusionDespite increased female trainee and full-time faculty representation over time in the academic oncology physician workforce, Radiation Oncology is lagging behind Hematology-Oncology with trainees declining in recent years in Radiation Oncology suggesting a de-facto ceiling in female representation. Whether such issues as delayed or insufficient exposure, inadequate mentorship, or specialty competitiveness disparately affect female representation in Radiation Oncology compared to Hematology-Oncology are under-explored and require continued investigation to ensure that the future oncologic physician workforce reflects the diversity of the population it serves.



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Novel bone metabolism-associated hormones: the importance of the pre-analytical phase for understanding their physiological roles

Abstract

The endocrine function of bone is now a recognized feature of this tissue. Bone-derived hormones that modulate whole-body homeostasis, are being discovered as for the effects on bone of novel and classic hormones produced by other tissues become known. Often, however, the data regarding these last generation bone-derived or bone-targeting hormones do not give about a clear picture of their physiological roles or concentration ranges. A certain degree of uncertainty could stem from differences in the pre-analytical management of biological samples. The pre-analytical phase comprises a series of decisions and actions (i.e., choice of sample matrix, methods of collection, transportation, treatment and storage) preceding analysis. Errors arising in this phase will inevitably be carried over to the analytical phase where they can reduce the measurement accuracy, ultimately, leading discrepant results. While the pre-analytical phase is all important, in routine laboratory medicine, it is often not given due consideration in research and clinical trials. This is particularly true for novel molecules, such as the hormones regulating the endocrine function of bone. In this review we discuss the importance of the pre-analytical variables affecting the measurement of last generation bone-associated hormones and describe their, often debated and rarely clear physiological roles.

http://ift.tt/2k459F6

Low-after-high glucose down-regulated Cx43 in H9c2 cells by autophagy activation via cross-regulation by the PI3K/Akt/mTOR and MEK/ERK 1/2 signal pathways

Abstract

Purpose

Hypoglycemia in diabetes is a strong predictor of cardiovascular events. High-glucose have been reported to alter connexin43 expression and to promote autophagy in cardiomyocytes. We investigated whether low-after-high glucose would influence connexin43 expression and autophagy in H9c2 cells.

Methods

H9c2 cells were incubated in 33.3 mM glucose for 24 h followed by 2.5 mM glucose for 2, 4, 6, or 12 h with or without chloroquine (autophagy inhibitor), U0126 (MEK_1/2 inhibitor) or LY294002 (PI3K inhibitor). Cells incubated in 5.5, 33.3, or 2.5 mM glucose with or without inhibitors and in the presence of mannitol were used as controls. Protein expression was assayed by western blot, apoptosis was assayed by flow cytometry, cell proliferation was determined by MTT assays, and cytotoxicity was assayed by lactate dehydrogenase measurement.

Results

Cytotoxicity and early apoptosis were increased and cell proliferation was decreased after exposure to low-after-high glucose, and these results were reversed by chloroquine and U0126 but were aggravated by LY294002. Connexin43 expression was downregulated in a time-dependent manner and was accompanied by upregulated expression of LC3-II, Beclin-1, p62, p-Akt, p-mTOR, and p-ERK_1/2. Chloroquine suppressed autophagy and reversed the downregulation of connexin43. U0126 inhibited ERK activation and decreased autophagy proteins expression but increased connexin43 expression. LY294002 suppressed p-Akt, activated autophagy, and decreased connexin43 expression. Interestingly, MEK_1/2 inhibition also increased p-Akt expression, but inhibition of PI3K led to p-ERK downregulation.

Conclusion

Culturing H9c2 cells under low-after-high glucose downregulated connexin43 by promoting autophagy through a mechanism involving the PI3K/Akt/mTOR and MEK/ERK_1/2 signaling pathways.

http://ift.tt/2kOLCNw

The complex interplay among hepatocytes and immune cells at the crossroad between inflammation and cholesterol metabolism in hyperglycemia

Abstract

An intriguing piece of evidence for the inflammatory story of type 2 diabetes has come to the light. A recent study by Okin and colleagues adds new clues to the interplay between cholesterol metabolism and immunity and how it impacts glucose homeostasis in inflammatory conditions. But some questions are a still unsolved conundrum. Here we suggest to better dissect the regulatory mechanism of Mevalonate pathway and to underpin a new causative link between immunometabolic dysregulation and diabetes.

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Development and Clinical Validation of a Novel Photography-based Skin Erythema Evaluation System: A Comparison with the Calculated Consensus of Dermatologists

Abstract

Erythema is the most common presenting sign of skin conditions [1,2]. Erythema reflects the degree of inflammation associated with various diseases, such as atopic dermatitis, psoriasis, and lupus erythematosus; it is also cosmetically troublesome in subjects with flushing, rosacea, and photoaging [3,4]. In addition, there are vascular disorders that present with erythema, such as nevus flammeus, telangiectasia, and post-acne erythema [5]. Various therapeutic devices, medicines, and cosmetics have been developed to improve these dermatological conditions [6,7]. These modalities need to be validated objectively for dermatologists, patients, and regulatory agencies [8–10]. Various studies are in progress on both improvement of skin conditions and their objective measurement [11,12]. The evaluation of skin condition is highly dependent on dermatologists' judgments based on naked eyes, and the results can vary depending on the dermatologists' expertise and bias [13,14]. It is convenient to perform an evaluation using photographs, but this approach is affected by variation in the environment, such as uneven brightness and light type [15].

This article is protected by copyright. All rights reserved.

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A New Mode of Mitotic Surveillance

Publication date: Available online 7 February 2017
Source:Trends in Cell Biology
Author(s): Bramwell G. Lambrus, Andrew J. Holland
Cells have evolved certain precautions to preserve their genomic content during mitosis and avoid potentially oncogenic errors. Besides the well-established DNA damage checkpoint and spindle assembly checkpoint (SAC), recent observations have identified an additional mitotic failsafe referred to as the mitotic surveillance pathway. This pathway triggers a cell cycle arrest to block the growth of potentially unfit daughter cells and is activated by both prolonged mitosis and centrosome loss. Recent genome-wide screens surprisingly revealed that 53BP1 and USP28 act upstream of p53 to mediate signaling through the mitotic surveillance pathway. Here we review advances in our understanding of this failsafe and discuss how 53BP1 and USP28 adopt noncanonical roles to function in this pathway.



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Post-translational Modification of Caspases: The Other Side of Apoptosis Regulation

Publication date: Available online 7 February 2017
Source:Trends in Cell Biology
Author(s): Alexey V. Zamaraev, Gelina S. Kopeina, Evgeniia A. Prokhorova, Boris Zhivotovsky, Inna N. Lavrik
Apoptosis is a crucial program of cell death that controls development and homeostasis of multicellular organisms. The main initiators and executors of this process are the Cysteine-dependent ASPartate proteASES – caspases. A number of regulatory circuits tightly control caspase processing and activity. One of the most important, yet, at the same time still poorly understood control mechanisms of activation of caspases involves their post-translational modifications. The addition and/or removal of chemical groups drastically alters the catalytic activity of caspases or stimulates their nonapoptotic functions. In this review, we will describe and discuss the roles of key caspase modifications such as phosphorylation, ubiquitination, nitrosylation, glutathionylation, SUMOylation, and acetylation in the regulation of apoptotic cell death and cell survival.



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Parathyroid Cancer Versus Atypical Parathyroid Neoplasm; Investigating Their Clinical Characteristics and Biological Behavior

Conditions:   Parathyroid Carcinoma;   Parathyroid Neoplasm
Intervention:   Other: Chart Review
Sponsor:   M.D. Anderson Cancer Center
Recruiting - verified February 2017

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Radiotherapy Related Skin Toxicity: Mepitel® vs. Standard Care in Patients With Locally Advanced Head-and-Neck Cancer

Condition:   Head and Neck Neoplasms
Interventions:   Other: Mepitel® Film;   Other: Standard Care
Sponsor:   University of Schleswig-Holstein
Not yet recruiting - verified February 2017

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Informed Consent and Assent in Pediatric Oncology Trials

Publication date: Available online 8 February 2017
Source:Clinical Therapeutics
Author(s): Richard I. Shader, Cynthia H. Livingston




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A Review of the Clinical Efficacy and Safety of Insulin Degludec and Glargine 300 U/mL in the Treatment of Diabetes Mellitus

Publication date: Available online 7 February 2017
Source:Clinical Therapeutics
Author(s): Vincent C. Woo
PurposeThe treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) using insulin is not ideal at this time. Despite advances made with basal insulin analogues, many individuals achieve less than optimal glycemic control or are at risk for hypoglycemia. Currently available basal insulin analogues do not deliver steady, peakless, continuous insulin for >24 hours and are associated with adverse events, including hypoglycemia. The objective of this paper was to review the clinical efficacy and safety of upcoming long-acting insulin analogues such as insulin degludec and insulin glargine 300 U/mL (Gla-300).MethodsA comprehensive literature search of PubMed and Google Scholar was conducted from 1966 to 2015. The search included randomized controlled trials that specifically assessed the efficacy and safety of insulin degludec and Gla-300 in patients with T1DM and T2DM.FindingsThe efficacy of insulin degludec and Gla-300 in achieving glycemic control has been reported in clinical trials in adults with T1DM and T2DM. Not only did a large number of patients succeed in meeting glycosylated hemoglobin targets, but they also experienced reductions in hypoglycemic events. These 2 therapies are associated with a reduced risk of nocturnal hypoglycemia and are generally well tolerated.ImplicationsThe long-acting insulin analogues insulin degludec and Gla-300 are promising therapies in the treatment of T1DM and T2DM. Their improved insulin delivery for >24 hours offers glycemic control with a good safety profile.



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Corrigendum to ‘Demographic and Clinical Characteristics of Type 2 Diabetes Mellitus Patients Initiating Dipeptidyl Peptidase-4 Inhibitors - A Retrospective Study of UK General Practice’ Clin Ther 2016;8:1825–1832.e15

Publication date: Available online 8 February 2017
Source:Clinical Therapeutics
Author(s): Abigail Tebboth, Sally Lee, Anna Scowcroft, Paula Bingham-Gardiner, William Spencer, John Bolodeoku, Syed Wasi Hassan




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Anesthesia, Brain Changes, and Behavior: Insights from Neural Systems Biology

Publication date: Available online 8 February 2017
Source:Progress in Neurobiology
Author(s): Elisabeth Colon, Edward A. Bittner, Barry Kussman, Mary Ellen McCann, Sulpicio Soriano, David Borsook
Long-term consequences of anesthetic exposure in humans are not well understood. It is possible that alterations in brain function occur beyond the initial anesthetic administration. Research in children and adults has reported cognitive and/or behavioral changes after surgery and general anesthesia that may be short lived in some patients, while in others, such changes may persist. The changes observed in humans are corroborated by a large body of evidence from animal studies that support a role for alterations in neuronal survival (neuroapoptosis) or structure (altered dendritic and glial morphology) and later behavioral deficits at older age after exposure to various anesthetic agents during fetal or early life. The potential of anesthetics to induce long-term alterations in brain function, particularly in vulnerable populations, warrants investigation. In this review, we critically evaluate the available preclinical and clinical data on the developing and aging brain, and in known vulnerable populations to provide insights into potential changes that may affect the general population of patients in a more, subtle manner. In addition this review summarizes underlying processes of how general anesthetics produce changes in the brain at the cellular and systems level and the current understanding underlying mechanisms of anesthetics agents on brain systems. Finally, we present how neuroimaging techniques currently emerge as promising approaches to evaluate and define changes in brain function resulting from anesthesia, both in the short and the long-term.



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A critical overview of the current myofascial pain literature – March 2017

Publication date: Available online 7 February 2017
Source:Journal of Bodywork and Movement Therapies
Author(s): Jan Dommerholt, Rob Grieve, Todd Hooks, Michelle Finnegan
After two years of having contributed to this overview series of articles, we sadly say goodbye to Dr. Rob Grieve. We would like to thank Dr. Grieve for his insightful contributions and analyses of the myofascial pain literature. Dr. Grieve would have preferred to continue, but his many university and research responsibilities had to take priority. We are looking forward to reviewing his future research endeavors in this article. We are pleased that Dr. Li-Wei Chou, MD, PhD has agreed to replace Dr. Grieve and join our team. Dr. Chou is Assistant Professor at China Medical University in Taichung, Taiwan and he has an impressive publication record with many research studies and book chapters.In this edition of the overview article, we once again have included articles from around the world with a combination of basic research and clinical studies and case reports. The majority of papers deal with dry needling, but there are also several more basic research studies and manual therapy papers.



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