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https://www.readbyqxmd.com/read/28636269/commentary-on-r-d-trends-away-from-general-medicine-cardiovascular-drugs-can-the-fda-help-reverse-the-trend
#1
R J Meyer
In the latter part of the 20th century, drug development in cardiovascular diseases (CVDs) was a paragon of "modern" therapeutics, bringing about a substantial number of effective, well-tolerated agents targeting some of the most prevalent diseases of the Western world. These drugs were often examples of rational drug development targeting specific pathophysiologic pathways previously elucidated through basic research (e.g., targeting of the renin-angiotensin system or the cholesterol synthesis pathway). The widespread adoption of these ground-breaking medications in practice and into medical guidelines undoubtedly played a role in the fall of morbidity and mortality from CVD in the United States in recent decades...
June 21, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28636232/a-genetic-stochastic-process-model-for-genome-wide-joint-analysis-of-biomarker-dynamics-and-disease-susceptibility-with-longitudinal-data
#2
Liang He, Ilya Zhbannikov, Konstantin G Arbeev, Anatoliy I Yashin, Alexander M Kulminski
Unraveling the underlying biological mechanisms or pathways behind the effects of genetic variations on complex diseases remains one of the major challenges in the post-GWAS (where GWAS is genome-wide association study) era. To further explore the relationship between genetic variations, biomarkers, and diseases for elucidating underlying pathological mechanism, a huge effort has been placed on examining pleiotropic and gene-environmental interaction effects. We propose a novel genetic stochastic process model (GSPM) that can be applied to GWAS and jointly investigate the genetic effects on longitudinally measured biomarkers and risks of diseases...
June 21, 2017: Genetic Epidemiology
https://www.readbyqxmd.com/read/28636229/recovery-from-reproductive-and-morphological-abnormalities-in-medaka-oryzias-latipes-following-a-14-day-exposure-to-diclofenac
#3
Hirofumi Yokota, Kaho Higashi, Erina Hanada, Ei Matsuzaki, Yukinari Tsuruda, Tomoko Suzuki, Eiko Nakano, Sayaka Eguchi
Mating pairs of medaka (Oryzias latipes) were exposed to diclofenac (DCF) at measured concentrations of 0 (control), 7.1, 37, and 78 µg/L for 14 d under static-renewal conditions. Effects on reproductive success, as well as morphological abnormalities, of the fish were assessed. During the exposure period, both fecundity and fertility were significantly decreased in the 37 and 78 µg/L treatments groups, and swollen abdomens in females were observed in all exposure groups. Notably, a defect of the lower jaw also was observed in four male fish: two at 37 µg/L, and the others at 78 µg/L of DCF...
June 21, 2017: Environmental Toxicology and Chemistry
https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#4
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28636034/upregulation-of-heme-oxygenase-1-mediates-the-anti-inflammatory-activity-of-casein-glycomacropeptide-gmp-hydrolysates-in-lps-stimulated-macrophages
#5
Tiange Li, Xue Cheng, Min Du, Bin Chen, Xueying Mao
Recently, we have shown that casein glycomacropeptide hydrolysates (GHP) exhibit both anti-inflammatory and anti-oxidative activities in vitro. However, whether heme oxygenase-1 (HO-1) is involved in the cytoprotective effect of GHP against the inflammatory status remains unclear. Therefore, we hypothesized that HO-1 is a potential target of GHP, which mediates its anti-inflammatory effect. Here, GHP inhibited the intracellular reactive oxygen species (ROS) accumulation and NADPH oxidase 2 (NOX2) expression and enhanced reduced glutathione (GSH) levels in LPS-stimulated RAW264...
June 21, 2017: Food & Function
https://www.readbyqxmd.com/read/28636017/effect-of-cisplatin-on-the-transport-activity-of-pii-type-atpases
#6
Francesco Tadini-Buoninsegni, Giacomo Sordi, Serena Smeazzetto, Giovanni Natile, Fabio Arnesano
Cisplatin (cis-diamminedichlorido-Pt(ii)) is extensively used as a chemotherapeutic agent against various types of tumors. However, cisplatin administration causes serious side effects, including nephrotoxicity, ototoxicity and neurotoxicity. It has been shown that cisplatin can interact with P-type ATPases, e.g., Cu(+)-ATPases (ATP7A and ATP7B) and Na(+),K(+)-ATPase. Cisplatin-induced inhibition of Na(+),K(+)-ATPase has been related to the nephrotoxic effect of the drug. To investigate the inhibitory effects of cisplatin on the pumping activity of PII-type ATPases, electrical measurements were performed on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) and Na(+),K(+)-ATPase embedded in vesicles/membrane fragments adsorbed on a solid-supported membrane...
June 21, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28635651/effects-of-tetrodotoxin-in-mouse-models-of-visceral-pain
#7
Rafael González-Cano, Miguel Ángel Tejada, Antonia Artacho-Cordón, Francisco Rafael Nieto, José Manuel Entrena, John N Wood, Cruz Miguel Cendán
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis...
June 21, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28635609/gastroprotective-effect-of-ghrelin-against-indomethacin-induced-gastric-injury-in-rats-possible-role-of-heme-oxygenase-1-pathway
#8
Mona M Allam, Ola A El-Gohary
Ghrelin has been shown to ameliorate gastric injury by several mechanisms in experimental animal models. The present study aimed to investigate the effect of pretreatment with ghrelin on indomethacin-induced gastric injury in rats and the role of heme oxygenase-1(HO-1) pathway as a novel mechanism underlying the gastroprotective effect of ghrelin. In all groups studied, ulcer score (U.S), ulcer index (U.I) and preventive index (P.I) were evaluated and the gastric inflammatory biomarkers including levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and myeloperoxidase (MPO) activity as well as prostaglandin E2 (PGE2), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), HO-1 and bilirubin as an indicator of heme oxygenase activity were measured...
July 2017: General Physiology and Biophysics
https://www.readbyqxmd.com/read/28635540/reduced-serum-vgf-levels-were-reversed-by-antidepressant-treatment-in-depressed-patients
#9
Haitang Jiang, Suzhen Chen, Na Lu, Yingying Yue, Yingying Yin, Yuqun Zhang, Wenhao Jiang, Jinfeng Liang, Yonggui Yuan
OBJECTIVES: VGF, a non-acronymic neuropeptide, is important in the pathogenesis of major depressive disorder (MDD) and in the functioning and efficacy of some antidepressant drugs. In this study we assessed whether serum VGF levels change in MDD patients and if antidepressant treatments can restore these changes. METHODS: We measured serum VGF concentrations using sandwich ELISA in drug-free MDD patients before treatment began (n = 26) and at 8 weeks after antidepressant treatment (n = 26) with escitalopram and duloxetine, two common antidepressants...
September 22, 2016: World Journal of Biological Psychiatry
https://www.readbyqxmd.com/read/28635401/inhibition-of-long-non-coding-rna-ror-reverses-resistance-to-tamoxifen-by-inducing-autophagy-in-breast-cancer
#10
Yuehua Li, Baohong Jiang, Hongbo Zhu, Xiaofei Qu, Liqin Zhao, Yeru Tan, Yiling Jiang, Mingchu Liao, Xiaoping Wu
This study explored the mechanism underlying long non-coding RNA ROR regulating autophagy on Tamoxifen resistance in breast cancer. Cancer tissues and adjacent normal tissues were collected from 74 breast cancer patients. Human breast cancer BT474 cells were assigned into blank, phosphate buffered saline, Tamoxifen, negative control + Tamoxifen, siROR + Tamoxifen, 3-methyladenine + Tamoxifen, and siROR + 3-methyladenine + TA groups. The expression of long non-coding RNA ROR and expressions of multi-drug resistance-associated P-glycoprotein and glutathione S-transferase-π messenger RNA were detected using quantitative real-time polymerase chain reaction...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28635374/sepsis-favors-high-on-clopidogrel-platelet-reactivity
#11
Karolina Akinosoglou, Angelos Perperis, Spyridoula Theodoraki, Dimitrios Alexopoulos, Charalambos Gogos
High-on-treatment platelet reactivity (HPR) is associated with ischemic events in patients on antiplatelet therapy with a history of cardiovascular disease. On the other hand, recent data have associated sepsis with adverse cardiovascular events in patients admitted with bacteremia or respiratory infection. We aimed to assess P2Y12-mediated platelet reactivity (PR) during sepsis and recovery in patients under clopidogrel. This was a prospective observational study. Incoming patients presenting with signs/symptoms of sepsis already on a maintenance dose of clopidogrel of 75 mg qd for cardiovascular events were included in this study...
June 21, 2017: Platelets
https://www.readbyqxmd.com/read/28635361/role-of-licochalcone-a-in-vegf-induced-proliferation-of-human-airway-smooth-muscle-cells-implications-for-asthma
#12
Sung-Ho Kim, Qing-Mei Pei, Ping Jiang, Min Yang, Xue-Jiao Qian, Jiang-Bo Liu
Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling, which is associated with increased airway smooth muscle (ASM) mass. Licochalcone A is the predominant characteristic chalcone in licorice root. We found that licochalcone A inhibited vascular endothelial growth factor (VEGF)-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed via inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity, but not that of Akt...
February 2017: Growth Factors
https://www.readbyqxmd.com/read/28635346/effect-of-drug-related-cues-on-response-inhibition-through-abstinence-a-pilot-study-in-male-heroin-abstainers
#13
Bobo Su, Ling Yang, Grace Y Wang, Sha Wang, Shaomei Li, Hua Cao, Yan Zhang
BACKGROUND: Chronic heroin use can cause a deficit of inhibitory function, leading to a loss of control over drug use. Exposure to drug-related cues is considered as one of the contributing factors. However, it is unclear whether there are dynamic changes on the effect of drug-related cues on response inhibition following prolonged abstinence. OBJECTIVE: The present study investigated the effect of drug-related cues on response inhibition in heroin abstainers at different abstinent phases...
February 17, 2017: American Journal of Drug and Alcohol Abuse
https://www.readbyqxmd.com/read/28634798/value-of-biochars-from-miscanthus-x-giganteus-cultivated-on-contaminated-soils-to-decrease-the-availability-of-metals-in-multicontaminated-aqueous-solutions
#14
Adeline Janus, Aurélie Pelfrêne, Karin Sahmer, Sophie Heymans, Christophe Deboffe, Francis Douay, Christophe Waterlot
The objective of this study was to evaluate the sorption efficiency of eight biochars, made from Miscanthus x giganteus cultivated on contaminated agricultural soil, in aqueous solutions contaminated with metals alone or mixed with polycyclic aromatic hydrocarbons. These biochars were produced in different pyrolysis conditions (temperature, 400/600 °C; heating rate, 5/10 °C min(-1); duration, 45/90 min) and compared with an uncontaminated commercialized biochar made of wood. The physicochemical characterization of the Miscanthus biochars confirmed the impact of the pyrolysis on the biochar parameters with substantial differences between the biochars in terms of pH, cation exchange capacity, and specific surface area...
June 20, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28634786/inhibition-of-nf-%C3%AE%C2%BAb-activity-by-aminoguanidine-alleviates-neuroinflammation-induced-by-hyperglycemia
#15
Yuanjian Song, Fang Zhang, Changjiang Ying, Kiran Ashok Kumar, Xiaoyan Zhou
Neuroinflammation is a key feature of cerebral complication which is associated with diabetes mellitus (DM). Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of neuroinflammation. However, how iNOS facilitates the development of inflammation in brain is still unidentified. The aim of the present study was to investigate the association of iNOS and neuroinflammation in diabetic mice, and elucidate the potential mechanisms underlying aminoguanidine (AG), the selective inhibitor of iNOS, protected neurons against inflammation in diabetic mice...
June 20, 2017: Metabolic Brain Disease
https://www.readbyqxmd.com/read/28634761/unveiling-the-compositional-variety-of-cardiolipins-in-rhodobacter-sphaeroides-by-liquid-chromatography-with-electrospray-ionization-and-multistage-collision-induced-dissociation-mass-spectrometry
#16
Sara Granafei, Ilario Losito, Massimo Trotta, Angela Agostiano, Francesco Palmisano, Tommaso R I Cataldi
Cardiolipins (CL) contained in the lipid extracts of the photosynthetic bacterium Rhodobacter sphaeroides (strain R26) were systematically characterized by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry, performed in single (MS), tandem (MS/MS) and sequential (MS(3)) modes using a linear ion trap mass spectrometer. The total number of carbon atoms and C=C bonds of each CL and, subsequently, those related to each of the constituting phosphatidic acid (PA) units, along with the location of the latter on the central glycerol backbone, were inferred from MS and MS/MS data, respectively...
June 20, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28634711/%C3%AE-pyrone-derivatives-from-a-streptomyces-strain-resensitize-tamoxifen-resistance-in-breast-cancer-cells
#17
Rui-Min Yang, Xiu-Lei Zhang, Li Wang, Jian-Ping Huang, Jing Yang, Yi-Jun Yan, Jian-Ying Luo, Xiang-Ting Wang, Sheng-Xiong Huang
Tamoxifen resistance (TamR) is the underlying cause of treatment failure in many breast cancer patients receiving tamoxifen. In order to look for noncytotoxic natural products with the ability to reverse TamR, an extract from strain Streptomyces sp. KIB-H0495 was detected to be active. Subsequent large scale fermentation and isolation led to the isolation of four α-pyrone derivatives including two new compounds, violapyrones J (2) and K (3), and two known analogues, violapyrones B (1) and I (4). Further bioactivity assays indicated that only 1 and 3 exerted potent resensitization effects on MCF-7/TamR cells at a concentration of 1 μM...
June 20, 2017: Natural Products and Bioprospecting
https://www.readbyqxmd.com/read/28634592/euglycemic-diabetic-ketoacidosis-with-prolonged-glucosuria-associated-with-the-sodium-glucose-cotransporter-2-canagliflozin
#18
Daniel A Kelmenson, Kelsey Burr, Yusra Azhar, Paul Reynolds, Chelsea A Baker, Neda Rasouli
Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control by a reversible inhibition of the sodium-glucose cotransporters in the renal proximal tubules resulting in increased urinary glucose. This unique mechanism, independent of insulin secretion and beta cell function, has made this class of medication desirable in patients with type 2 diabetes. However in May 2015, the US Food and Drug Administration issued a safety warning pertaining to the development of diabetic ketoacidosis (DKA) with the use of SGLT2 inhibitors...
April 2017: Journal of Investigative Medicine High Impact Case Reports
https://www.readbyqxmd.com/read/28634550/sortilin-related-receptor-expression-in-human-neural-stem-cells-derived-from-alzheimer-s-disease-patients-carrying-the-apoe-epsilon-4-allele
#19
Alen Zollo, Zoe Allen, Helle F Rasmussen, Filomena Iannuzzi, Yichen Shi, Agnete Larsen, Thorsten J Maier, Carmela Matrone
Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28634514/cystic-lesions-of-peripheral-nerves-are-we-missing-the-diagnosis-of-the-intraneural-ganglion-cyst
#20
Jyoti Panwar, Anil Mathew, Binu P Thomas
AIM: To highlight the salient magnetic resonance imaging (MRI) features of the intraneural ganglion cyst (INGC) of various peripheral nerves for their precise diagnosis and to differentiate them from other intra and extra-neural cystic lesions. METHODS: A retrospective analysis of the magnetic resonance (MR) images of a cohort of 245 patients presenting with nerve palsy involving different peripheral nerves was done. MR images were analyzed for the presence of a nerve lesion, and if found, it was further characterized as solid or cystic...
May 28, 2017: World Journal of Radiology
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