305 results match your criteria abrogated replacement

Penetrance of Severe Pulmonary Arterial Hypertension in Response to Vascular Endothelial Growth Factor Receptor 2 Blockade in a Genetically Prone Rat Model Is Reduced by Female Sex.

J Am Heart Assoc 2021 Jul 28:e019488. Epub 2021 Jul 28.

Sinclair Centre for Regenerative Medicine Ottawa Hospital Research Institute ON Canada.

Background We have previously reported important strain differences in response to SU5416 (SU, a vascular endothelial growth factor receptor 2 inhibitor) in rats and have identified a specific colony of Sprague-Dawley rats that are hyperresponsive (SD) to SU alone and develop severe pulmonary arterial hypertension (PAH) with a single injection of SU, even in the absence of hypoxia. Interestingly, SD rats exhibit incomplete penetrance of the severe PAH phenotype with an "all-or-none" response to SU alone, which provides a unique opportunity to assess the influence of female sex and sex hormones on susceptibility to PAH after endothelial injury in a genetically prone model. Methods and Results SD rats were injected with SU (20 mg/kg SC) and, in the absence of hypoxia, 72% of male but only 27% of female rats developed severe PAH at 7 weeks, which was associated with persistent endothelial cell apoptosis. Read More

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Estrogen normalizes maternal HFD-induced cardiac hypertrophy in offspring by regulating AT2R.

J Endocrinol 2021 06 16;250(1):1-12. Epub 2021 Jun 16.

Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of, Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Our previous study has demonstrated maternal high-fat diet (HFD) caused sex-dependent cardiac hypertrophy in adult male, but not female offspring. The present study tested the hypothesis that estrogen normalizes maternal HFD-induced cardiac hypertrophy by regulating angiotensin II receptor (ATR) expression in adult female offspring. Pregnant rats were divided into the normal diet (ND) and HFD (60% kcal fat) groups. Read More

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Simvastatin mitigates depressive-like behavior in ovariectomized rats: Possible role of NLRP3 inflammasome and estrogen receptors' modulation.

Int Immunopharmacol 2021 Jun 25;95:107582. Epub 2021 Mar 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address:

It is well known that females are more vulnerable than males to stress-related psychiatric disorders, particularly during perimenopausal and postmenopausal periods. Hormone replacement therapy (HRT) has been widely used for the management of postmenopausal depression. However, HRT could be associated with severe adverse effects, including increased risk for coronary heart disease, breast cancer and endometrial cancer. Read More

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MicroRNA-181a suppresses norethisterone-promoted tumorigenesis of breast epithelial MCF10A cells through the PGRMC1/EGFR-PI3K/Akt/mTOR signaling pathway.

Transl Oncol 2021 Jun 14;14(6):101068. Epub 2021 Mar 14.

Research Center of CHU Sainte-Justine, University of Montréal, 3175 Côte-Sainte-Catherine, Room 2.17.004, Montréal, Québec, Canada; Departments of Medicine, Pediatrics, Pharmacology, and Physiology, University of Montréal, Canada. Electronic address:

Background: Research suggests that hormone replacement therapy may increase the risk of breast cancer, and progestins such as norethisterone (NET) play a key role in this phenomenon. We have demonstrated that microRNA-181a (miR-181a) suppresses NET-promoted breast cancer cell survival. Nonetheless, the effects of NET and miR-181a on the tumorigenesis of human breast epithelial cells have not yet been elaborated. Read More

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2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase.

RSC Med Chem 2020 Jun 22;11(6):707-731. Epub 2020 May 22.

Cancer Research UK Newcastle Drug Discovery Unit , Chemistry, School of Natural and Environmental Sciences , Newcastle University , Newcastle upon Tyne , UK . Email: ; Tel: +44 (0)191 208 7060.

Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. Read More

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SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells.

Cell Death Dis 2021 01 20;12(1):101. Epub 2021 Jan 20.

Institute of Dermatology, Xinhua Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education and Department of Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Leukemia arises from blockage of the differentiation/maturation of hematopoietic progenitor cells at different stages with uncontrolled proliferation of leukemic cells. However, the signal pathways that block cell differentiation remain unclear. Herein we found that SUMOylation of the M2 isoform of pyruvate kinase (PKM2), a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, is prevalent in a variety of leukemic cell lines as well as primary samples from patients with leukemia through multiple-reaction monitoring based targeted mass spectrometry analysis. Read More

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January 2021

Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.

J Clin Lipidol 2021 Jan-Feb;15(1):151-161.e0. Epub 2020 Nov 24.

Diabetes Institute, Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, 750 Republican St, Seattle WA 98109, USA. Electronic address:

Background: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown.

Objective: To determine the effects of transdermal ERT on HDL composition and cholesterol efflux capacity (CEC), as well as the relationships between these metrics and CV risk factors. Read More

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November 2020

Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice.

Front Aging Neurosci 2020 4;12:240. Epub 2020 Aug 4.

Department of Physiology, Nanjing Medical University, Nanjing, China.

It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer's disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-month-old female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). Read More

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Fat-Free Mass Is Better Related to Serum Uric Acid Than Metabolic Homeostasis in Prader-Willi Syndrome.

Nutrients 2020 08 25;12(9). Epub 2020 Aug 25.

Division of Auxology, IRCCS Istituto Auxologico Italiano, 28824 Piancavallo (VB), Italy.

: Prader-Willi syndrome (PWS) is conventionally regarded as a model of genetic obesity carrying a metabolically healthier profile and fat compartmentalization than subjects with non-syndromic obesity. Serum uric acid (sUA) is a recognized surrogate marker of metabolic derangement. As no information is currently available on sUA levels in adults with PWS, we aimed to analyze sUA in a large cohort of adult patients with PWS in comparison to a control counterpart; secondly, we aimed to investigate the metabolic and non-metabolic determinants of sUA in PWS. Read More

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Multicopy Suppressor Analysis of Strains Lacking Cytoplasmic Peptidyl-Prolyl Isomerases Identifies Three New PPIase Activities in That Includes the DksA Transcription Factor.

Int J Mol Sci 2020 Aug 14;21(16). Epub 2020 Aug 14.

Unit of Bacterial Genetics, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, Poland.

Consistent with a role in catalyzing rate-limiting step of protein folding, removal of genes encoding cytoplasmic protein folding catalysts belonging to the family of peptidyl-prolyl isomerases (PPIs) in confers conditional lethality. To address the molecular basis of the essentiality of PPIs, a multicopy suppressor approach revealed that overexpression of genes encoding chaperones (DnaK/J and GroL/S), transcriptional factors (DksA and SrrA), replication proteins Hda/DiaA, asparatokinase MetL, Cmk and acid resistance regulator (AriR) overcome some defects of Δ6 strains. Interestingly, viability of Δ6 bacteria requires the presence of transcriptional factors DksA, SrrA, Cmk or Hda. Read More

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Does the severity of low-gradient aortic stenosis classified by computed tomography-derived aortic valve calcification determine the outcome of patients after transcatheter aortic valve implantation (TAVI)?

Eur Radiol 2021 Jan 8;31(1):549-558. Epub 2020 Aug 8.

Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, 61231, Bad Nauheim, Germany.

Objectives: Aortic valve calcification (AVC) determined by computed tomography has emerged as a complementary measure of aortic stenosis (AS) severity and as a predictor of adverse events. Thus, AVC can guide further treatment decisions in patients with low-gradient AS (LG-AS). We compared the symptomatic and prognostic outcome of patients with low vs. Read More

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January 2021

Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility.

Arterioscler Thromb Vasc Biol 2020 09 9;40(9):2143-2158. Epub 2020 Jul 9.

From the INSERM-UPS UMR U1048, Institut des Maladies Métaboliques et Cardiovasculaires (M.A., C.F., R.Z., M.B., R.S., T.A., F.B., P.G., H.L., C.F., J.-F.A., F.L.), Université de Toulouse, France.

Objective: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17β-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Read More

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September 2020

Genistein Attenuates Acute Cerebral Ischemic Damage by Inhibiting the NLRP3 Inflammasome in Reproductively Senescent Mice.

Front Aging Neurosci 2020 17;12:153. Epub 2020 Jun 17.

Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Postmenopausal women have a higher incidence of stroke compared to the age-matched males, and the estrogen was thought to be the main cause of such difference. However, estrogen replacement therapy for the prevention of postmenopausal stroke shows controversial results and is widely disputed because of its serious side effects after chronic administration. Genistein (Gen), a natural phytestrogen with fewer side effects, has a protective effect against cerebral ischemia damage. Read More

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Nuclear localization of ING3 is required to suppress melanoma cell migration, invasion and angiogenesis.

Biochem Biophys Res Commun 2020 06 22;527(2):418-424. Epub 2020 Apr 22.

Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Inhibitor of growth family member 3 (ING3), a tumor suppressor, plays crucial roles in cell cycle regulation, apoptosis and transcription. Previous studies suggest important roles of nuclear ING3, however, the nuclear localization sequence (NLS) of ING3 is not defined and its biological functions remain to be elucidated. In this study, various ING3 mutants were generated to identify its NLS. Read More

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Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis.

Gut 2021 Feb 23;70(2):388-400. Epub 2020 Apr 23.

CIBEREHD, Madrid, Spain

Objective: Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. Read More

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February 2021

Regulatory T cells promote remyelination in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis following human neural stem cell transplant.

Neurobiol Dis 2020 07 8;140:104868. Epub 2020 Apr 8.

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, United States of America. Electronic address:

Multiple sclerosis (MS) is a chronic, inflammatory autoimmune disease that affects the central nervous system (CNS) for which there is no cure. In MS, encephalitogenic T cells infiltrate the CNS causing demyelination and neuroinflammation; however, little is known about the role of regulatory T cells (Tregs) in CNS tissue repair. Transplantation of neural stem and progenitor cells (NSCs and NPCs) is a promising therapeutic strategy to promote repair through cell replacement, although recent findings suggest transplanted NSCs also instruct endogenous repair mechanisms. Read More

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Ovariectomy provokes inflammatory and cardiovascular effects of endotoxemia in rats: Dissimilar benefits of hormonal supplements.

Toxicol Appl Pharmacol 2020 04 21;393:114928. Epub 2020 Feb 21.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. Electronic address:

The female gender is protected against immunological complications of endotoxemia. Here we investigated whether gonadal hormone depletion by ovariectomy (OVX) uncovers inflammatory and cardiovascular effects of endotoxemia and whether these effects are reversed by hormone replacement therapies. Changes in inflammatory cytokines, blood pressure (BP), left ventricular (LV) function, and cardiac autonomic activity caused by lipopolysaccharide (LPS) in conscious female rats with different hormonal states were determined. Read More

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Antiplatelet therapy abrogates platelet-assisted Staphylococcus aureus infectivity of biological heart valve conduits.

J Thorac Cardiovasc Surg 2021 06 23;161(6):e457-e472. Epub 2019 Nov 23.

Cardiovascular Developmental Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Objective: Although recent advances in pulmonary valve replacement have enabled excellent hemodynamics, infective endocarditis remains a serious complication, particularly for implanted bovine jugular vein (BJV) conduits.

Methods: We investigated contributions by platelets and plasma fibrinogen to endocarditis initiation on various grafts used for valve replacement. Thus, adherence of Staphylococcus aureus and platelets to 5 graft tissues was studied quantitatively in perfusion chambers, assisted by microscopic analysis. Read More

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Brake dust exposure exacerbates inflammation and transiently compromises phagocytosis in macrophages.

Metallomics 2020 03;12(3):371-386

Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, London, SE1 9NH, UK.

Studies have emphasised the importance of combustion-derived particles in eliciting adverse health effects, especially those produced by diesel vehicles. In contrast, few investigations have explored the potential toxicity of particles derived from tyre and brake wear, despite their significant contributions to total roadside particulate mass. The objective of this study was to compare the relative toxicity of compositionally distinct brake abrasion dust (BAD) and diesel exhaust particles (DEP) in a cellular model that is relevant to human airways. Read More

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Raloxifene inhibits adipose tissue inflammation and adipogenesis through Wnt regulation in ovariectomized rats and 3 T3-L1 cells.

J Biomed Sci 2019 Aug 31;26(1):62. Epub 2019 Aug 31.

Department and Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.

Background: Loss of ovarian function, as in menopause or after ovariectomy (OVX), is closely associated with obesity and white adipose tissue (WAT) inflammation. Estrogen replacement protects against postmenopausal obesity but increases the risks of carcinogenesis. In the present study, we investigated the effects of long-term treatment of raloxifene (RAL), a selective estrogen receptor modulator, on the features of estrogen deficiency-induced obesity and explored the involvement of canonical and non-canonical Wnt regulation in vivo and in vitro. Read More

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Developmental plasticity of epithelial stem cells in tooth and taste bud renewal.

Proc Natl Acad Sci U S A 2019 09 19;116(36):17858-17866. Epub 2019 Aug 19.

School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332;

In Lake Malawi cichlids, each tooth is replaced in one-for-one fashion every ∼20 to 50 d, and taste buds (TBs) are continuously renewed as in mammals. These structures are colocalized in the fish mouth and throat, from the point of initiation through adulthood. Here, we found that replacement teeth (RT) share a continuous band of epithelium with adjacent TBs and that both organs coexpress stem cell factors in subsets of label-retaining cells. Read More

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September 2019

Impaired ligand-dependent MET activation caused by an extracellular SEMA domain missense mutation in lung cancer.

Cancer Sci 2019 Oct 13;110(10):3340-3349. Epub 2019 Aug 13.

Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Aberrant activation of the MET/hepatocyte growth factor (HGF) receptor participates in the malignant behavior of cancer cells, such as invasion-metastasis and resistance to molecular targeted drugs. Many mutations in the MET extracellular region have been reported, but their significance is largely unknown. Here, we report the dysregulation of mutant MET originally found in a lung cancer patient with Val370 to Asp370 (V370D) replacement located in the extracellular SEMA domain. Read More

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October 2019

Yangonin protects against estrogen-induced cholestasis in a farnesoid X receptor-dependent manner.

Eur J Pharmacol 2019 Aug 17;857:172461. Epub 2019 Jun 17.

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, 116044, China; Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian, 116044, China. Electronic address:

Estrogen-induced cholestasis is a common etiology of hepatic diseases in women with contraceptives administration, pregnancy or hormone replacement therapy. Farnesoid X receptor (FXR) is a member of nuclear receptor super family of ligand-activated transcription factors that is highly expressed in liver. FXR is acknowledged to contribute to the bile acid homeostasis, as well as the pathogenesis and progression of cholestasis. Read More

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Estradiol Protects Neuropeptide Y/Agouti-Related Peptide Neurons against Insulin Resistance in Females.

Neuroendocrinology 2020 19;110(1-2):105-118. Epub 2019 Jun 19.

Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, Oregon, USA,

When it comes to obesity, men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage wanes in postmenopausal women. A key diagnostic of the metabolic syndrome is insulin resistance in both peripheral tissues and brain, especially in the hypothalamus. Since the anorexigenic hormone 17β-estradiol (E2) regulates food intake in part by inhibiting the excitability of the hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons, we hypothesized that E2 would protect against insulin resistance in NPY/AgRP neurons with diet-induced obesity (DIO). Read More

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February 2021

Hepatoprotection of auraptene from the peels of citrus fruits against 17α-ethinylestradiol-induced cholestasis in mice by activating farnesoid X receptor.

Food Funct 2019 Jul;10(7):3839-3850

Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China. and Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China.

Cholestatic liver injury induced by estrogen is a common clinical syndrome in women undergoing oral administration of contraceptives, pregnancy or hormone replacement therapy. Estrogen-induced cholestasis is associated with the accumulation of endogenous bile acids, which play critical roles in the disease progression and symptoms. In the present study, we described the protective effect of auraptene, a simple coumarin present in the peels of citrus fruits, such as grapefruit, against 17α-ethinylestradiol (EE)-induced cholestasis, and further elucidated the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect. Read More

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Potential Role of H-Ferritin in Mitigating Valvular Mineralization.

Arterioscler Thromb Vasc Biol 2019 03;39(3):413-431

From the HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian, Academy of Sciences, Debrecen (K.É.S., L.P., M.O., N.P., G.B., J.B.), Faculty of Medicine, University of Debrecen, Hungary.

Objective- Calcific aortic valve disease is a prominent finding in elderly and in patients with chronic kidney disease. We investigated the potential role of iron metabolism in the pathogenesis of calcific aortic valve disease. Approach and Results- Cultured valvular interstitial cells of stenotic aortic valve with calcification from patients undergoing valve replacement exhibited significant susceptibility to mineralization/osteoblastic transdifferentiation in response to phosphate. Read More

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Parathyroid hormone initiates dynamic NHERF1 phosphorylation cycling and conformational changes that regulate NPT2A-dependent phosphate transport.

J Biol Chem 2019 03 29;294(12):4546-4571. Epub 2019 Jan 29.

From the Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology,

Na-H exchanger regulatory factor-1 (NHERF1) is a PDZ protein that scaffolds membrane proteins, including sodium-phosphate co-transport protein 2A (NPT2A) at the plasma membrane. NHERF1 is a phosphoprotein with 40 Ser and Thr residues. Here, using tandem MS analysis, we characterized the sites of parathyroid hormone (PTH)-induced NHERF1 phosphorylation and identified 10 high-confidence phosphorylation sites. Read More

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p47 licenses activation of the immune deficiency pathway in the tick .

Proc Natl Acad Sci U S A 2019 01 17;116(1):205-210. Epub 2018 Dec 17.

Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201

The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick How XIAP activates the IMD pathway in response to microbial infection remains ill defined. Here, we identified the XIAP enzymatic substrate p47 as a positive regulator of the IMD network. XIAP polyubiquitylates p47 in a lysine 63-dependent manner and interacts with the p47 ubiquitin-like (UBX) module. Read More

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January 2019

Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus.

PLoS Pathog 2018 06 29;14(6):e1007135. Epub 2018 Jun 29.

Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.

The RNA helicase LGP2 (Laboratory of Genetics and Physiology 2) is a non-signaling member of the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), whose pivotal role on innate immune responses against RNA viruses is being increasingly uncovered. LGP2 is known to work in synergy with melanoma differentiation-associated gene 5 (MDA5) to promote the antiviral response induced by picornavirus infection. Here, we describe the activity of the foot-and-mouth disease virus (FMDV) Leader protease (Lpro) targeting LGP2 for cleavage. Read More

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Structure-activity relationship investigation of coumarin-chalcone hybrids with diverse side-chains as acetylcholinesterase and butyrylcholinesterase inhibitors.

Mol Divers 2018 Nov 22;22(4):893-906. Epub 2018 Jun 22.

College of Pharmacy, Hu'nan University of Chinese Medicine, Changsha, 410208, China.

Chalcones containing tertiary amine side-chains have potent activity as acetylcholinesterase (AChE) inhibitors. However, the effects of the location of the tertiary amine groups as well as of other groups on AChE and butyrylcholinesterase (BChE) activity have not been reported. Here, we report the synthesis and testing of 36 new coumarin-chalcone hybrids (5d-7j, 9d-11f, 12k-13m) against AChE and BChE. Read More

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November 2018