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Elucidating specificity of an allosteric inhibitor WNK476 among WNK isoforms using molecular dynamic simulations.

Chem Biol Drug Des 2021 May 10. Epub 2021 May 10.

Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Indore-453552, Madhya Pradesh, India.

Specifically targeting the With-No-Lysine (WNK1) kinase, which is implicated in hypertension, renders a significant challenge in discovering competitive inhibitors due to the highly conserved ATP binding pocket. However, an allosteric inhibitor may impart high specificity against the WNK kinase isoforms since it targets the less conserved site and can provide greater efficacy even under high physiological ATP concentration. In the current study, we have investigated the structural and energetic basis of the specificity of the allosteric inhibitor WNK476 against WNK kinase isoforms by combining molecular dynamics simulations and free energy calculations using molecular mechanics Poisson-Boltzmann surface area (MMPBSA). Read More

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Novel benzenesulfonamides aryl and arylsulfone conjugates adopting tail/dual tail approaches: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies.

Eur J Med Chem 2021 Apr 27;221:113486. Epub 2021 Apr 27.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address:

New series of benzenesulfonamide and benzoic acid derivatives were designed and synthesized using tail/dual tail approach to improve potency and selectivity as carbonic anhydrase inhibitors. The synthesized compounds evaluated as CAIs against isoforms hCA I, II, IV and IX with acetazolamide (AAZ) as standard inhibitor. The benzenesulfonamide derivatives 7a-d, 8a-h, 12a-c, 13a and 15a-c showed moderate to potent inhibitory activity with selectivity toward isoform hCA II, especially, compound 13a with (K = 7. Read More

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The Zinc Finger Antiviral Protein ZAP Restricts Human Cytomegalovirus and Selectively Binds and Destabilizes Viral / Transcripts.

mBio 2021 05 4;12(3). Epub 2021 May 4.

Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany

Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonizes several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is less well understood. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. Read More

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Structural basis for positive allosteric modulation of AMPA and kainate receptors.

J Physiol 2021 May 2. Epub 2021 May 2.

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK- 2100, Denmark.

Key Points: AMPA and kainate receptors belong to the family of ionotropic glutamate receptors that are responsible for mediating the majority of fast excitatory neurotransmission. These receptors have been related to brain diseases, e.g. Read More

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Aurora kinase inhibitors in cancer.

Chem Biol Drug Des 2021 May 2. Epub 2021 May 2.

Department of Pharmaceutical Chemistry and Quality Assurance, Bhanuben Nanavati College of Pharmacy, SVKM's Dr, Mumbai, Maharashtra, India.

Aurora kinases (AURKs) are serine/threonine protein kinases that play a critical role during cell proliferation. Three isoforms of AURKs reported in mammals include AURKA, AURKB, AURKC, and all share a similar C-terminal catalytic domain with differences in their sub-cellular location, substrate specificity, and function. Recent research reports indicate an elevated expression of these kinases in several cancer types highlighting their role as oncogenes in tumorigenesis. Read More

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Novel 2,5-disubstituted-1,3,4-oxadiazole derivatives as MAO-B inhibitors: Synthesis, biological evaluation and molecular modeling studies.

Bioorg Chem 2021 Apr 16;112:104917. Epub 2021 Apr 16.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey. Electronic address:

Thirty novel 2,5-disubstituted-1,3,4-oxadiazole derivatives bearing urea moiety were designed and synthesized. IR, H-NMR, C-NMR and mass spectroscopic methods and elemental analysis were used to confirm the structures of the compounds. Their monoamine oxidase inhibitory activity was determined against the MAO-A and MAO-B isoforms. Read More

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A Special View of What Was Almost Forgotten: p38δ MAPK.

Cancers (Basel) 2021 Apr 25;13(9). Epub 2021 Apr 25.

Biotechnology Graduate Program, Universidade do Vale do Taquari (Univates), Lajeado, Rio Grande do Sul CEP 95914-014, Brazil.

The p38δ mitogen-activated protein kinase is an important signal transduction enzyme. p38δ has recently emerged as a drug target due to its tissue-specific expression patterns and its critical roles in regulation of cellular processes related to cancer and inflammatory diseases, such as cell proliferation, cell migration, apoptosis, and inflammatory responses. However, potent and specific p38δ inhibitors have not been defined so far. Read More

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Synthesis and Biological Evaluation of Coumarin-Linked 4-Anilinomethyl-1,2,3-Triazoles as Potent Inhibitors of Carbonic Anhydrases IX and XIII Involved in Tumorigenesis.

Metabolites 2021 Apr 7;11(4). Epub 2021 Apr 7.

Neurofarba Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.

A series of coumarin-linked 4-anilinomethyl-1,2,3-triazoles (-) was synthesized via a molecular hybridization approach, through carbon C-6 of the coumarin moiety. The synthesized compounds were evaluated for their inhibition of carbonic anhydrase (CA) isoforms I, II, IX and XIII. CAs IX and XIII were selectively inhibited over the off-target isoforms I and II. Read More

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Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition.

Bioorg Med Chem Lett 2021 Apr 19:128048. Epub 2021 Apr 19.

R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD salvage pathway. Since NAD plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators. Read More

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Bone Geometry Is Altered by Follistatin-Induced Muscle Growth in Young Adult Male Mice.

JBMR Plus 2021 Apr 3;5(4):e10477. Epub 2021 Mar 3.

Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences University of Melbourne Melbourne 3010 Australia.

The development of the musculoskeletal system and its maintenance depends on the reciprocal relationship between muscle and bone. The size of skeletal muscles and the forces generated during muscle contraction are potent sources of mechanical stress on the developing skeleton, and they shape bone structure during growth. This is particularly evident in hypermuscular global myostatin (Mstn)- mice, where larger muscles during development increase bone mass and alter bone shape. Read More

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Mouse gastric mucosal endocrine cells are sources and sites of action of Phoenixin-20.

Peptides 2021 Apr 17;141:170551. Epub 2021 Apr 17.

Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada. Electronic address:

Energy homeostasis is is determined by food intake and energy expenditure, which are partly regulated by the cross-talk between central and peripheral hormonal signals. Phoenixin (PNX) is a recently discovered pleiotropic neuropeptide with isoforms of 14 (PNX-14) and 20 (PNX-20) amino acids. It is a potent reproductive peptide in vertebrates, regulating the hypothalamo-pituitary-gonadal axis (HPG). Read More

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Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors.

Sci Rep 2021 Apr 15;11(1):8313. Epub 2021 Apr 15.

Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany.

The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. Read More

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CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment.

Front Genet 2021 23;12:649387. Epub 2021 Mar 23.

Department of Nutrition, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

The crosstalk between tumor cells and the tumor microenvironment (TME), triggers a variety of critical signaling pathways and promotes the malignant progression of cancer. The success rate of cancer therapy through targeting single molecule of this crosstalk may be extremely low, whereas co-targeting multiple components could be complicated design and likely to have more side effects. The six members of cellular communication network (CCN) family proteins are scaffolding proteins that may govern the TME, and several studies have shown targeted therapy of CCN family proteins may be effective for the treatment of cancer. Read More

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C-Phycocyanin-derived Phycocyanobilin as a Potential Nutraceutical Approach for Major Neurodegenerative Disorders and COVID-19-induced Damage to the Nervous System.

Curr Neuropharmacol 2021 Apr 8. Epub 2021 Apr 8.

Catalytic Longevity Foundation, 811 B Nahant Ct. San Diego, CA 92019. United States.

The edible cyanobacterium Spirulina platensis and its chief biliprotein C-Phycocyanin have shown protective activity in animal models of diverse human health diseases, often reflecting antioxidant and anti-inflammatory effects. The beneficial effects of C-Phycocyanin seem likely to be primarily attributable to its covalently attached chromophore Phycocyanobilin (PCB). Within cells, biliverdin is generated from free heme and it is subsequently reduced to bilirubin. Read More

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Prokineticin receptors interact unselectively with several G protein subtypes but bind selectively to β-arrestin 2.

Cell Signal 2021 Jul 31;83:110000. Epub 2021 Mar 31.

Istituto Superiore di Sanità, National Center for Drug Reserch and Evaluation, Viale Regina Elena, 299, 00161 Rome, Italy.

Prokineticin 1 (pk1) and prokineticin 2 (pk2) interact with two structurally related G-protein coupled receptors, prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). Cellular signalling studies show that the activated receptors can evoke Ca-mobilization, pertussis toxin-sensitive ERK phosphorylation, and intracellular cAMP accumulation, which suggests the partecipation of several G protein subtypes, such as G, G and G. However, direct interactions with these transduction proteins have not been studied yet. Read More

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In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates.

Molecules 2021 Mar 26;26(7). Epub 2021 Mar 26.

Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico.

CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. Read More

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Oral PI3K-δ,γ Inhibitor for the Management of People with Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Narrative Review on Duvelisib.

Onco Targets Ther 2021 25;14:2109-2119. Epub 2021 Mar 25.

CLL Research and Treatment Center, Division of Hematology-Oncology, Department of Medicine at Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.

The development of highly effective targeted therapies has led to a new treatment paradigm in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). Despite these advances, many patients will eventually require alternative treatment strategies due to the emergence of tolerability issues or resistance to these novel agents. Duvelisib is a first-in-class, potent oral agent with dual inhibitor activity against the δ and γ isoforms of phosphoinositide 3-kinase (PI3Kδ and PI3Kγ), which are specific to the hematopoietic system. Read More

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Identification and Kinetic Characterization of Serum- and Glucocorticoid-Regulated Kinase Inhibitors Using a Fluorescence Polarization-Based Assay.

SLAS Discov 2021 Mar 30:24725552211002465. Epub 2021 Mar 30.

Department of Chemistry, College of Natural Sciences, Keimyung University, Daegu, Republic of Korea.

The serum- and glucocorticoid-regulated kinase (SGK) family consists of three isoforms (SGK1, SGK2, and SGK3) that have been implicated in the regulation of tumor growth, metastasis, autophagy, and epithelial ion transport. SGK1 and SGK3 play essential roles in protein kinase B (AKT or PKB)-independent phosphoinositide 3-kinases (PI3K)-mediated tumorigenesis, as evidenced by the significantly elevated expression levels of SGK1 and SGK3 in many cancers, including prostate cancer, colorectal carcinoma, estrogen-dependent breast cancer, and glioblastoma. Therefore, SGK is a potential target for anticancer therapy. Read More

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Identification and characterization of novel candidate compounds targeting 6- and 7-transmembrane μ-opioid receptor isoforms.

Br J Pharmacol 2021 Mar 29. Epub 2021 Mar 29.

Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada.

Background And Purpose: The μ-opioid receptor (μ receptor) is the primary target for opioid analgesics. The 7-transmembrane (TM) and 6TM μ receptor isoforms mediate inhibitory and excitatory cellular effects. Here, we developed compounds selective for 6TM- or 7TM-μ receptors to further our understanding of the pharmacodynamic properties of μ receptors. Read More

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Expanding the scope of plant genome engineering with Cas12a orthologs and highly multiplexable editing systems.

Nat Commun 2021 03 29;12(1):1944. Epub 2021 Mar 29.

Department of Plant Science and Landscape Architecture, University of Maryland, College Park, MD, USA.

CRISPR-Cas12a is a promising genome editing system for targeting AT-rich genomic regions. Comprehensive genome engineering requires simultaneous targeting of multiple genes at defined locations. Here, to expand the targeting scope of Cas12a, we screen nine Cas12a orthologs that have not been demonstrated in plants, and identify six, ErCas12a, Lb5Cas12a, BsCas12a, Mb2Cas12a, TsCas12a and MbCas12a, that possess high editing activity in rice. Read More

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Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.

Bioorg Med Chem Lett 2021 Jun 26;41:127992. Epub 2021 Mar 26.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. Read More

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Fragment-Based Drug Design of Selective HDAC6 Inhibitors.

Methods Mol Biol 2021 ;2266:155-170

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.

Medicinal chemistry society has enough arguments to justify the usage of fragment-based drug design (FBDD) methodologies for the identification of lead compounds. Since the FDA approval of three kinase inhibitors - vemurafenib, venetoclax, and erdafitinib, FBDD has become a challenging alternative to high-throughput screening methods in drug discovery. The following protocol presents in silico drug design of selective histone deacetylase 6 (HDAC6) inhibitors through a fragment-based approach. Read More

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Induction of the endogenous sialoglycan ligand for eosinophil death receptor Siglec-8 in chronic rhinosinusitis with hyperplastic nasal polyposis.

Glycobiology 2021 Mar 20. Epub 2021 Mar 20.

Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21287, USA.

Siglec-8, an immune-inhibitory sialoglycan binding lectin (S8), is expressed on the surface of eosinophils and mast cells, potent mediators of allergic inflammation. When S8 engages endogenous sialoglycan ligands, eosinophils undergo apoptosis and mast cell mediator release is inhibited. In the human airway, Siglec-8 ligands (S8L) are sialylated keratan sulfate chains carried on isoforms of the protein Deleted in Malignant Brain Tumors-1 (DMBT1), an immunoregulatory protein that we recently identified as the endogenous ligand for S8, DMBT1S8. Read More

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Fluorescent- and tagged-protoxin II peptides: potent markers of the Na 1.7 channel pain target.

Br J Pharmacol 2021 Mar 19. Epub 2021 Mar 19.

l'institut du thorax, INSERM, CNRS, UNIV NANTES, LabEx "Ion Channels, Science & Therapeutics", F-44007, Nantes, France.

Background And Purpose: Protoxin II (ProTx II) is a high affinity gating modifier that is thought to selectively block the Na 1.7 voltage-dependent Na channel, a major therapeutic target for the control of pain. We aimed at producing ProTx II analogues entitled with novel functionalities for cell distribution studies and biochemical characterization of its Na channel targets. Read More

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First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G.

J Immunother Cancer 2021 Mar;9(3)

Preclinical Department, Invectys, Paris, France

Background: CAR-T cells immunotherapy is a breakthrough in the treatment of hematological malignancies such as acute lymphoblastic leukemia (ALL) and B-cell malignancies. However, CAR-T therapies face major hurdles such as the lack of tumor-specific antigen (TSA), and immunosuppressive tumor microenvironment sometimes caused by the tumorous expression of immune checkpoints (ICPs) such as HLA-G. Indeed, HLA-G is remarkable because it is both a potent ICP and a TSA. Read More

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Discovery of Potent Carbonic Anhydrase Inhibitors as Effective Anticonvulsant Agents: Drug Design, Synthesis, and In Vitro and In Vivo Investigations.

J Med Chem 2021 Mar 15;64(6):3100-3114. Epub 2021 Mar 15.

Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Universitàdegli Studi di Firenze, Florence 50019, Italy.

Two sets of benzenesulfonamide-based effective human carbonic anhydrase (hCA) inhibitors have been developed using the tail approach. The inhibitory action of these novel molecules was examined against four isoforms: hCA I, hCA II, hCA VII, and hCA XII. Most of the molecules disclosed low to medium nanomolar range inhibition against all tested isoforms. Read More

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Carbonic anhydrase seven bundles filamentous actin and regulates dendritic spine morphology and density.

EMBO Rep 2021 Apr 15;22(4):e50145. Epub 2021 Mar 15.

Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland.

Intracellular pH is a potent modulator of neuronal functions. By catalyzing (de)hydration of CO , intracellular carbonic anhydrase (CA ) isoforms CA2 and CA7 contribute to neuronal pH buffering and dynamics. The presence of two highly active isoforms in neurons suggests that they may serve isozyme-specific functions unrelated to CO -(de)hydration. Read More

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Isoforms of IDH in breast carcinoma: IDH2 as a potent prognostic factor associated with proliferation in estrogen-receptor positive cases.

Breast Cancer 2021 Mar 12. Epub 2021 Mar 12.

Department of Pathology and Histotechnology, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Background: Isocitrate dehydrogenase (IDH) is an important enzyme that oxidatively decarboxylates isocitrate to α-ketoglutarate, and three isoforms (IDH1-3) have been identified. Overexpression and/or downregulation of IDH isoforms was reported in several human malignancies, suggesting importance of IDH in oncogenesis. However, significance of IDH isoforms remains largely unclear in the breast carcinoma. Read More

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Glabrone as a specific UGT1A9 probe substrate and its application in discovering the inhibitor glycycoumarin.

Eur J Pharm Sci 2021 Jun 6;161:105786. Epub 2021 Mar 6.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University, 38 Xueyuan Road, Beijing 100191, China. Electronic address:

UDP-glucuronosyltransferase 1A9 (UGT1A9) is one of the most important UGT isoforms, and plays an important role in the metabolic elimination of therapeutic drugs via glucuronidation. Herbal medicines affecting the activity of UGT1A9 may influence the metabolism of related drugs, thus causing herb-drug interactions and even adverse effects. However, few methods are available to evaluate the activity of UGT1A9. Read More

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Caldesmon: Biochemical and Clinical Implications in Cancer.

Front Cell Dev Biol 2021 18;9:634759. Epub 2021 Feb 18.

Department of Anorectal Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Caldesmon, an actin-binding protein, can inhibit myosin binding to actin and regulate smooth muscle contraction and relaxation. However, caldesmon has recently attracted attention due to its importance in cancer. The upregulation of caldesmon in several solid cancer tissues has been reported. Read More

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February 2021