Kevin C Allan, Lucille R Hu, Marissa A Scavuzzo, Andrew R Morton, Artur S Gevorgyan, Erin F Cohn, Benjamin L L Clayton, Ilya R Bederman, Stevephen Hung, Cynthia F Bartels, Mayur Madhavan, Paul J Tesar
Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2...
October 10, 2020: Cell Stem Cell
Marvin Korff, Lukas Imberg, Jonas M Will, Nico Bückreiß, Svetlana A Kalinina, Benjamin M Wenzel, Gregor A Kastner, Constantin G Daniliuc, Maximilian Barth, Ruzanna A Ovsepyan, Kirill R Butov, Hans-Ulrich Humpf, Matthias Lehr, Mikhail A Panteleev, Antti Poso, Uwe Karst, Torsten Steinmetzer, Gerd Bendas, Dmitrii V Kalinin
We herein report the conventional and microscale parallel synthesis of selective inhibitors of human blood coagulation factor XIIa and thrombin exhibiting a 1,2,4-triazol-5-amine scaffold. Structural variations of this scaffold allowed identifying derivative 21i , a potent 29 nM inhibitor of FXIIa, with improved selectivity over other tested serine proteases and also finding compound 21m with 27 nM inhibitory activity toward thrombin. For the first time, acylated 1,2,4-triazol-5-amines were proved to have anticoagulant properties and the ability to affect thrombin- and cancer-cell-induced platelet aggregation...
October 22, 2020: Journal of Medicinal Chemistry
Daniel Patiño-García, Leonor Cruz-Fernandes, Julio Buñay, Renán Orellana, Ricardo D Moreno
Reproductive hormone imbalance in infertile women is correlated to high levels of phthalates and alkylphenols, which are among endocrine-disrupting chemicals (EDCs). Previous studies have shown that they interfere with gene expression by deregulating levels of microRNAs (miRs), small non-coding RNAs targeting mRNAs encoding enzymes in the hormone biosynthesis pathway. However, this effect depends on the target organ, dose and whether or not they are alone or in mixtures. Our goal was to study whether the biosynthesis, and a specific group of miRs targeting mRNAs encoding enzymes in steroid hormone biosynthesis, are deregulated in the ovaries of female mice chronically exposed to a mixture of three phthalates (DEHP+DBP+BBP) and two alkylphenols (NP+OP) at a human environmentally relevant dose...
November 2020: Journal of Molecular Endocrinology
Xuan Kuo, Deron R Herr, Wei-Yi Ong
Clinacanthus nutans (Lindau) (C. nutans) has diverse uses in traditional herbal medicine for treating skin rashes, insect and snake bites, lesions caused by herpes simplex virus, diabetes mellitus and gout in Singapore, Malaysia, Indonesia, Thailand and China. We previously showed that C. nutans has the ability to modulate the induction of cytosolic phospholipase A2 (cPLA2 ) expression in SH-SY5Y cells through the inhibition of histone deacetylases (HDACs). In the current study, we elucidated the effect of C...
October 21, 2020: Neuromolecular Medicine
M V Kravchik, I A Novikov, A M Subbot, A A Antonov, S Yu Petrov, N A Pakhomova
PURPOSE: To analyze the chemical composition of the sclera and trabecular meshwork in patients with primary open-angle glaucoma (POAG) and to assess the impact of corneal-compensated intraocular pressure (IOP) on the chemistry of the drainage area. MATERIAL AND METHODS: Biopsy specimens of the trabecular meshwork (89 specimens) and sclera (41 specimens) obtained from patients with POAG on maximal medical therapy were analyzed to determine the content of certain chemical elements - carbon (C), nitrogen (N), oxygen (O), aluminum (Al), calcium (Ca), chlorine (Cl), potassium (K), magnesium (Mg), sodium (Na), phosphorus (P), silicon (Si) and sulfur (S)...
2020: Vestnik Oftalmologii
Stephanie Cicalese, Keisuke Okuno, Satoru Eguchi
Disruption of protein quality control occurs with aging and cardiovascular pathologies including arterial stiffness and hypertension. Angiotensin II (Ang II) is believed to induce endoplasmic reticulum stress in vascular smooth muscle cells (VSMC), thus contributing to vascular remodeling and dysfunction. However, whether Ang II increases formation of protein aggregates and mediates proteotoxicity in VSMCs remain obscure. Accordingly, the present study aimed to establish a quantitative method of protein aggregate detection induced by Ang II, and to investigate their potential involvement in inflammatory and senescence responses...
October 15, 2020: Journal of Cardiovascular Pharmacology
Yu-Jhou Chen, Chen-June Seak, Shih-Ching Kang, Tsung-Hsing Chen, Chien-Cheng Chen, Chip-Jin Ng, Chao-Wei Lee, Ming-Yao Su, Hsin-Chih Huang, Pin-Cheng Chen, Chun-Hsiang Ooyang, Sen-Yung Hsieh, Hao-Tsai Cheng
INTRODUCTION: Caustic substance ingestion is frequently life-threatening, and its pathological mechanisms of tissue damage are well documented. However, few studies have assessed the combined effects of pH and the ingested dose on patient outcomes. Additionally, the miscellaneous chemical properties are not immediately available for providing predictive insights to physicians. This study aimed to provide a new perspective of the risk assessment of caustic substance ingestion based on the pH and dose...
October 20, 2020: Clinical Toxicology
Inna Sabdyusheva Litschauer, Klaus Becker, Saiedeh Saghafi, Simone Ballke, Christine Bollwein, Meraaj Foroughipour, Julia Gaugeler, Massih Foroughipour, Viktória Schavelová, Viktória László, Balazs Döme, Christine Brostjan, Wilko Weichert, Hans-Ulrich Dodt
Here, we describe a novel approach that allows pathologists to three-dimensionally analyse malignant tissues, including the tumour-host tissue interface. Our visualization technique utilizes a combination of ultrafast chemical tissue clearing and light-sheet microscopy to obtain virtual slices and 3D reconstructions of up to multiple centimetre sized tumour resectates. For the clearing of tumours we propose a preparation technique comprising three steps: (a) Fixation and enhancement of tissue autofluorescence with formalin/5-sulfosalicylic acid...
October 19, 2020: Scientific Reports
Šidlová Henrieta, Očko Peter, Mikuláš Ubomír, Šikuta Ján, Šidlo Jozef
Uterine rupture in pregnancy belongs to acute conditions in gynaecology and obstetrics. It is a life-threatening complication for both mother and foetus. The occurrence of fatal consequences in developed countries is very rare. The causes of rupture include scarring after the caesarean section, fibroid enucleation, rough curettage, muscular insufficiency in uterine developmental defects, uterine wall damage due to inflammation, uterine hypoplasia, elevated intrauterine pressure during contraction, cephalopelvic disproportion, previous fibroid, prostaglandin or oxytocin administration, etc...
2020: Soudní Lékarství
Michele M Salzman, Jason A Bartos, Demetris Yannopoulos, Matthias L Riess
Reperfusion injury is a complex pathological event involving processes that can lead to further disruption of the cell membrane and function following an ischemic event. Return of blood flow allows for the needed reperfusion; however, for a period of time before remaining viable cells stabilize, reperfusion results in additional cellular injury. In cardiomyocytes, loss of membrane integrity allows abnormal influx of extracellular calcium, leading to hyper-contracture and cell death. Methods to improve the membrane integrity of cardiomyocytes overwhelmed by pathological disruptions, such as reperfusion injury, are needed to prevent cell death, because of the myocardium's limited ability to regenerate...
December 2020: Pharmacology Research & Perspectives
Lei Zhang, Jia-Qin Yuan, Fu-Chen Song, Mei-Dong Zhu, Qi Li, Sheng-Hua Liu, Kai Zhao, Cheng Zhao
CONTEXT: Qing-Mai-Yin (QMY) is a clinically used herbal formula for treating arteriosclerosis obliterans (ASO). OBJECTIVE: To evaluate the chemical constituents and effects of QMY on ASO rabbit model. MATERIALS AND METHODS: Forty-eight New Zealand rabbits were divided into six groups ( n  = 8): normal (normal rabbits treated with 0.5% CMC-Na), vehicle (ASO rabbits treated with 0.5% CMC-Na), positive (simvastatin, 1.53 mg/kg), and QMY treatment (300, 600, and 1200 mg/kg)...
December 2020: Pharmaceutical Biology
Alessio Smeraldo, Paolo A Netti, Enza Torino
Nowadays, magnetic resonance imaging (MRI) is the first diagnostic imaging modality for numerous indications able to provide anatomical information with high spatial resolution through the use of magnetic fields and gradients. Indeed, thanks to the characteristic relaxation time of each tissue, it is possible to distinguish between healthy and pathological ones. However, the need to have brighter images to increase differences and catch important diagnostic details has led to the use of contrast agents (CAs)...
2020: Contrast Media & Molecular Imaging
Beniamino Palmieri, Veronica Corazzari, Maria Vadalaʹ, Annamaria Vallelunga, Julio César Morales-Medina, Tommaso Iannitti
Multiple chemical sensitivity (MCS) is characterised by non-specific and recurring symptoms affecting multiple organs and associated with exposure to chemicals, even at low concentrations, which are, under normal circumstances, harmless to the general population. Symptoms include general discomfort, cardiovascular instability, irritation of the sensory organs, breath disorders, hypersensitivity affecting the skin and epithelial lining of the gut, throat and lungs, anxiety, and learning and memory loss. Chemical intolerance is a key distinguishing feature of MCS, limiting considerably patients' lifestyle with serious social, occupational and economic implications...
October 19, 2020: Reviews on Environmental Health
Qing Hua, Ondrej Adamovsky, Hana Vespalcova, Jonna Boyda, Jordan T Schmidt, Marianne Kozuch, Serena L M Craft, Pamela E Ginn, Stanislav Smatana, Eva Budinska, Maria Persico, Joseph H Bisesi, Christopher J Martyniuk
Dietary exposure to chemicals alters the diversity of microbiome communities and can lead to pathophysiological changes in the gastrointestinal system. The organochlorine pesticide dieldrin is a persistent environmental contaminant that bioaccumulates in fatty tissue of aquatic organisms. The objectives of this study were to determine whether environmentally-relevant doses of dieldrin altered gastrointestinal morphology and the microbiome of zebrafish. Adult zebrafish at ∼4 months of age were fed a measured amount of feed containing either a solvent control or one of two doses of dieldrin (measured at 16, and 163...
October 5, 2020: Environmental Pollution
Kilmer S McCully
A century ago a fat-soluble vitamin from leafy vegetables, later named vitamin E, was discovered to enhance fertility in animals. Vitamin E consists of 8 isomers of tocopherols and tocotrienols, each containing chromanol groups that confer antioxidant properties and differ only in the 15-carbon saturated phytyl poly-isoprenoid side chain of tocopherols and the 15-carbon unsaturated farnesyl poly-isoprenoid side chain of tocotrienols. Although tocotrienol was first isolated from rubber plants in 1964, its importance in multiple disease processes was not recognized until two decades later, when the cholesterol-lowering and anti-cancer effects were first reported...
September 2020: Annals of Clinical and Laboratory Science
Sara Ciulli, Enrico Volpe, Rubina Sirri, Giorgia Tura, Francesca Errani, Gianpiero Zamperin, Anna Toffan, Marina Silvi, Andrea Renzi, Miriam Abbadi, Lorena Biasini, Tobia Pretto, Pietro Emmanuele, Antonio Casalini, Giuseppe Sarli, Patrizia Serratore, Oliviero Mordenti, Luciana Mandrioli
This investigation focused on an episode of chronic mortality observed in juvenile Huso huso sturgeons. The examined subjects underwent pathological, microbiological, molecular, and chemical investigations. Grossly severe body shape deformities, epaxial muscle softening, and multifocal ulcerative dermatitis were the main observed findings. The more constant histopathologic findings were moderate to severe rarefaction and disorganization of the lymphohematopoietic lymphoid tissues, myofiber degeneration, atrophy and interstitial edema of skeletal epaxial muscles, and degeneration and atrophy of the gangliar neurons close to the myofibers...
October 13, 2020: Animals: An Open Access Journal From MDPI
Paolo Fattorini, Cristina Forzato, Domenico Tierno, Eleonora De Martino, Eros Azzalini, Vincenzo Canzonieri, Giorgio Stanta, Serena Bonin
RNA isolated from fixed and paraffin-embedded tissues is widely used in biomedical research and molecular pathology for diagnosis. In the present study, we have set-up a method based on high performance liquid chromatography (HPLC) to investigate the effects of different fixatives on RNA. By the application of the presented method, which is based on the Nuclease S1 enzymatic digestion of RNA extracts followed by a HPLC analysis, it is possible to quantify the unmodified nucleotide monophosphates (NMPs) in the mixture and recognize their hydroxymethyl derivatives as well as other un-canonical RNA moieties...
October 13, 2020: International Journal of Molecular Sciences
Cristina Risi, Luisa U Schäfer, Betty Belknap, Ian Pepper, Howard D White, Gunnar F Schröder, Vitold E Galkin
Heart contraction depends on a complicated array of interactions between sarcomeric proteins required to convert chemical energy into mechanical force. Cyclic interactions between actin and myosin molecules, controlled by troponin and tropomyosin, generate the sliding force between the actin-based thin and myosin-based thick filaments. Alterations in this sophisticated system due to missense mutations can lead to cardiovascular diseases. Numerous structural studies proposed pathological mechanisms of missense mutations at the myosin-myosin, actin-tropomyosin, and tropomyosin-troponin interfaces...
October 10, 2020: Structure
Stephen T McSorley, Jayne Digby, Danielle Clyde, Neil Cruickshank, Paul Burton, Louise Barker, Judith A Strachan, Callum G Fraser, Karen Smith, Craig Mowat, Jack Winter, Robert Jc Steele
BACKGROUND: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). This study examined the diagnostic yield of colonoscopy by faecal haemoglobin concentration (f-Hb) in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). METHODS: In three Scottish NHS Boards, FIT kits (HM-JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by GPs to guide referrals for patients with lower GI symptoms (lab data studied for 12 months from December 2015 onward in Tayside, 18 months from June 2018 onward in Fife, and 5 months from September 2018 onward in Greater Glasgow and Clyde)...
October 16, 2020: Colorectal Disease
Yuexian Cui, Xuelian Jin, Jun Young Choi, Byung Gon Kim
Subcortical ischemic white matter injury (SIWMI), pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging, is a common cause of cognitive decline in elderly. Despite its high prevalence, it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model. The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components...
April 2021: Neural Regeneration Research
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