Article
Hematology
Rowan Frunt, Hinde El Otmani, Bubacarr Gibril Kaira, Steven de Maat, Coen Maas
Summary: Medical device associated thrombosis is a significant clinical issue caused by Factor XII binding to non-natural surface materials and activating the contact pathway. The absence of a publicly available crystal structure of full-length FXII has led to the exploration of the AlphaFold Protein Structure Database's model structure. By combining this model with previous studies, opportunities for selectively blocking FXII's contribution in medical device associated thrombosis can be identified.
THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Biology
Fatmah S. Alqahtany, Farjah H. Algahtani, Mashael M. Alshebly, Thamer S. Albegamy, Essam S. Alghamdi, Mohammed A. Alnakhli, Fatimah M. Madkhaly, Abdullah A. Alharbi, Nawaf A. Alqahtani
Summary: This study evaluated patients who opted for surgery and were found to have abnormal clotting profiles, showing the prevalence of FXII in the asymptomatic Saudi population. The results provide the normal range for FXII, serving as the basis for diagnosing FXII deficiency in the asymptomatic Saudi population.
SAUDI JOURNAL OF BIOLOGICAL SCIENCES
(2021)
Review
Hematology
Stephanie Demoulin, Edmond Godfroid, Cedric Hermans
Summary: The text addresses the critical unmet need in preventing medical device-associated thrombosis, highlighting the development of a new anticoagulant candidate Ir-CPI with a unique mechanism of action that inhibits clot formation without the risk of bleeding. It emphasizes the promising properties of Ir-CPI in the prevention of device-related thrombosis and the rationale for targeting upstream coagulation factors to achieve this goal.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Hematology
Aidan P. G. Walsh, Eefang Yu, James D. McFadyen, Viktoria Bongcaron, Mitchell J. Moon, Angela Huang, Jane F. Arthur, Ineke L. Muir, Veronika Rayzman, Con Panousis, Xiaowei Wang, Karlheinz Peter
Summary: Current clinical imaging of thromboembolic diseases often relies on indirect detection of thrombi, which may delay diagnosis and treatment. The development of targeted molecular imaging tools for direct imaging of thrombi using molecular imaging is highly desired. FXIIa targeting has been shown to be suitable for specific detection of venous and arterial thrombi, allowing for early imaging and monitoring of antithrombotic treatment.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Review
Hematology
Aleksandr Shamanaev, Maxim Litvak, David Gailani
Summary: This review focuses on the structure-function relationships of FXII and its potential implications for disease understanding and therapeutic development. The study identified key domains and their roles in FXII activation, shedding light on the molecular mechanisms underlying FXII-mediated pathologic processes.
CURRENT OPINION IN HEMATOLOGY
(2022)
Article
Hematology
Aleksandr Shamanaev, Maxim Litvak, Qiufang Cheng, Michal Ponczek, S. Kent Dickeson, Stephanie A. Smith, James H. Morrissey, David Gailani
Summary: The aim of this study was to identify the amino acids in the FXII EGF1 domain that are required for polyphosphate-dependent FXII functions. The results showed that Lys73, Lys74, Lys76, and Lys81 form a binding site for polyanionic substances, such as polyphosphate, which is crucial for surface-dependent FXII function.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Review
Chemistry, Medicinal
Dmitrii Kalinin
Summary: FXII is an emerging drug target with potential therapeutic agents being developed to treat thrombotic and inflammatory conditions. Patents over the last three decades have shown the development of various FXII-targeting agents, including small molecules, proteins, peptides, oligonucleotides, siRNAs, and monoclonal antibodies. Clinical trials of FXII inhibitors like Ir-CPI and CSL312 have shown efficacy in animal models, encouraging further development in this field.
EXPERT OPINION ON THERAPEUTIC PATENTS
(2021)
Article
Hematology
Erica M. Sparkenbaugh, Michael W. Henderson, Megan Miller-Awe, Christina Abrams, Anton Ilich, Fatima Trebak, Nirupama Ramadas, Shantel Vital, Dillon Bohinc, Kara L. Bane, Chunsheng Chen, Margi Patel, Michael Wallisch, Thomas Renne, Andras Gruber, Brian Cooley, David Gailani, Malgorzata Kasztan, Gregory M. Vercellotti, John D. Belcher, Felicity E. Gavins, Evi X. Stavrou, Nigel S. Key, Rafal Pawlinski
Summary: A hypercoagulable state, chronic inflammation, and increased risk of venous thrombosis and stroke are observed in patients with sickle cell disease (SCD). Activation of coagulation factor XII (FXII) and the contact pathway is increased in SCD, leading to enhanced thrombin generation and systemic inflammation. Inhibition of FXII effectively reduces experimental thromboinflammation and vascular complications in a mouse model of SCD, suggesting that it may provide a safe approach for interfering with inflammation, thrombotic complications, and vaso-occlusion in patients with SCD.
Review
Biochemistry & Molecular Biology
Reiner K. Mailer, Chandini Rangaswamy, Sandra Konrath, Jonas Emsley, Thomas Renne
Summary: The plasma protein factor XII, as the liver-derived zymogen of serine protease FXIIa, plays a key role in thrombosis and inflammation. Growing evidence suggests that FXIIa-mediated thrombo-inflammation is crucial in various pathological states, and increased FXIIa levels are associated with hypercholestemlemia and hypertriglyceridemia.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Review
Pharmacology & Pharmacy
Ju-Xian Song, Jia Liu, Yimin Jiang, Zi-Ying Wang, Min Li
Summary: TFEB as a master regulator of the autophagy-lysosomal pathway holds therapeutic potential for neurodegenerative disorders, with small molecules identified as TFEB activators showing promise in protecting against these diseases. Research is ongoing and the development of specific and potent TFEB activators with ideal brain bioavailability could provide a method for treating neurodegenerative disorders.
DRUG DISCOVERY TODAY
(2021)
Article
Hematology
Aleksandr Shamanaev, Ivan Ivanov, Mao-Fu Sun, Maxim Litvak, Priyanka Srivastava, Bassem M. Mohammed, Rabia Shaban, Ashoka Maddur, Ingrid M. Verhamme, Owen J. T. McCarty, Ruby H. P. Law, David Gailani
Summary: Factor XII (FXII) is a plasma protease that contributes to bradykinin generation. Its conversion to FXIIa enhances when it binds to negatively charged surfaces. The heavy chain of FXII plays a key role in surface binding and activation, while also restricting activation when not bound to a surface. Different domains within the heavy chain have varying importance in FXII function, such as EGF1 being required for surface-dependent activation and KNG and FN2 influencing activation in the absence of a surface.
Article
Hematology
Aleksandr Shamanaev, Ivan Ivanov, Mao-Fu Sun, Maxim Litvak, Priyanka Srivastava, Bassem M. Mohammed, Rabia Shaban, Ashoka Maddur, Ingrid M. Verhamme, Owen J. T. McCarty, Ruby H. P. Law, David Gailani
Summary: Factor XII (FXII) is a plasma zymogen that contributes to bradykinin production. The activation of FXII is enhanced when it binds to negatively charged surfaces such as polymeric orthophosphate. The heavy chain of FXII promotes surface-binding and activation, while restricting activation in the absence of a surface. EGF1, KNG, and FN2 domains play important roles in FXII function.
Editorial Material
Immunology
Sven-Eric Jordt
Summary: The study demonstrates that a novel TRPA1 inhibitor can suppress inflammation and airway smooth muscle contraction in several preclinical species, offering a new possibility for asthma treatment.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Review
Hematology
James C. Fredenburgh, Jeffrey Weitz
Summary: The article discusses the rationale for developing factor XI inhibitors, identifies the most advanced stage agents, describes the results of completed clinical trials and ongoing trials, highlighting opportunities and challenges for this new generation of anticoagulants.
Article
Chemistry, Medicinal
Vanessa Carle, Yuteng Wu, Rakesh Mukherjee, Xu-Dong Kong, Chloe Rogg, Quentin Laurent, Enza Cecere, Camille Villequey, Madhuree S. Konakalla, Tamara Maric, Christina Lamers, Cristina Diaz-Perlas, Kaycie Butler, Junko Goto, Bernd Stegmayr, Christian Heinis
Summary: A cyclic peptide-based FXI inhibitor has been developed, which selectively and effectively inhibits activated FXI with anticoagulation effects comparable to heparin but with a broader therapeutic range.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Gastroenterology & Hepatology
Thorben Fruendt, Niko Schroeder, Angelique Hoelzemer, Hans Pinnschmidt, Jocelyn de Heer, Berit C. Behrends, Thomas Renne, Anne Lautenbach, Ansgar W. Lohse, Joerg Schrader
Summary: Background: Diabetes mellitus is a major risk factor for chronic kidney injury or cardiovascular disease, but little is known about the prevalence of undiagnosed diabetes in gastroenterology inpatients. Objective: To improve detection of undiagnosed diabetes, a routine screening procedure for gastroenterology inpatients was established. Results: The prevalence of undiagnosed diabetes in gastroenterology inpatients is markedly elevated, with a substantial number of patients in a prediabetic status, and PSC-related liver cirrhosis is an independent risk factor for undiagnosed diabetes.
ZEITSCHRIFT FUR GASTROENTEROLOGIE
(2022)
Review
Biochemistry & Molecular Biology
Reiner K. Mailer, Chandini Rangaswamy, Sandra Konrath, Jonas Emsley, Thomas Renne
Summary: The plasma protein factor XII, as the liver-derived zymogen of serine protease FXIIa, plays a key role in thrombosis and inflammation. Growing evidence suggests that FXIIa-mediated thrombo-inflammation is crucial in various pathological states, and increased FXIIa levels are associated with hypercholestemlemia and hypertriglyceridemia.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Letter
Cell Biology
Martin Zickler, Stephanie Stanelle-Bertram, Sandra Ehret, Fabian Heinrich, Philine Lange, Berfin Schaumburg, Nancy Mounogou Kouassi, Sebastian Beck, Michelle Y. Jaeckstein, Oliver Mann, Susanne Krasemann, Maria Schroeder, Dominik Jarczak, Axel Nierhaus, Stefan Kluge, Manuela Peschka, Hartmut Schlueter, Thomas Renne, Klaus Pueschel, Andreas Kloetgen, Ludger Scheja, Benjamin Ondruschka, Joerg Heeren, Guelsah Gabriel
Article
Cardiac & Cardiovascular Systems
Elina Larissa Petersen, Alina Gossling, Gerhard Adam, Martin Aepfelbacher, Christian-Alexander Behrendt, Ersin Cavus, Bastian Cheng, Nicole Fischer, Juergen Gallinat, Simone Kuehn, Christian Gerloff, Uwe Koch-Gromus, Martin Haerter, Uta Hanning, Tobias B. Huber, Stefan Kluge, Johannes K. Knobloch, Piotr Kuta, Christian Schmidt-Lauber, Marc Luetgehetmann, Christina Magnussen, Carola Mayer, Kai Muellerleile, Julia Muench, Felix Leonard Naegele, Marvin Petersen, Thomas Renne, Katharina Alina Riedl, David Leander Rimmele, Ines Schaefer, Holger Schulz, Enver Tahir, Benjamin Waschki, Jan-Per Wenzel, Tanja Zeller, Andreas Ziegler, Goetz Thomalla, Raphael Twerenbold, Stefan Blankenberg
Summary: This study comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection and found subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function. However, there were no signs of structural brain damage, neurocognitive impairment, or quality-of-life impairment.
EUROPEAN HEART JOURNAL
(2022)
Editorial Material
Hematology
Andreas Greinacher, Florian Langer, Linda Schoenborn, Thomas Thiele, Munif Haddad, Thomas Renne, Jerome Rollin, Yves Gruel, Theodore E. Warkentin
Review
Hematology
Reiner K. Mailer, Piotr Kuta, Thomas Renne
Summary: Blood coagulation is essential for maintaining the integrity of the circulatory system, but it can also lead to thrombosis. Existing anticoagulant treatments increase the risk of bleeding, necessitating the development of drugs targeting novel mechanisms. Recent studies have shown that intervention in contact system proteins can provide effective and safe thromboprotection without increasing bleeding risk.
Article
Endocrinology & Metabolism
Lena Rass, Amir-Hossein Rahvar, Jakob Matschke, Wolfgang Saeger, Thomas Renne, Jens Aberle, Joerg Flitsch, Roman Rotermund
Summary: The study aimed to analyze the expression of SSTR2a and 5 in somatotrophic pituitary adenomas and associate it with tumor size, clinical, biochemical, and histological parameters, as well as response to SA therapy. The results showed no significant relationship between receptor subtype expression rates and the parameters analyzed.
HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM
(2022)
Article
Medicine, General & Internal
Bastian F. J. Plochg, Hanna Englert, Chandini Rangaswamy, Sandra Konrath, Mandy Malle, Sibylle Lampalzer, Claudia Beisel, Salma Wollin, Maike Frye, Jens Aberle, Johannes Kluwe, Thomas Renne, Reiner K. Mailer
Summary: Our study reveals that liver damage promotes pro-inflammatory ApoB100-specific T-cell populations, providing a cellular mechanism for increased CVD risk in liver disease patients.
JOURNAL OF INTERNAL MEDICINE
(2022)
Article
Genetics & Heredity
Mojgan Masoodi, Manuela Peschka, Stefan Schmiedel, Munif Haddad, Maike Frye, Coen Maas, Ansgar Lohse, Samuel Huber, Paulus Kirchhof, Jerzy-Roch Nofer, Thomas Renne
Summary: This study found significant differences in plasma metabolic signatures between COVID-19 patients and control group, primarily in lipid and amino acid metabolism. Protein systems biology analysis revealed that COVID-19 mainly impacted sphingolipid, tryptophan, tyrosine, glutamine, arginine, and arachidonic acid metabolism pathways. Additionally, decreased levels of GABA could serve as a potential biomarker and therapeutic target for COVID-19 patients.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2022)
Article
Hematology
Wariya Sanrattana, Simone Smits, Arjan D. Barendrecht, Nadine D. van Kleef, Hinde El Otmani, Minka Zivkovic, Mark Roest, Thomas Renne, Chantal C. Clark, Steven de Maat, Coen Maas
Summary: TaSER fusion protein has antithrombotic properties by interfering with platelet-driven thrombin formation, inhibiting thrombin activity on platelet surface, blocking VWF binding, and disassembling platelet agglutinates. It delays tissue factor-triggered thrombin generation in a targeted manner. TaSER limits platelet adhesion and aggregate formation, as well as thrombus formation, through targeted inhibition of platelet-dependent thrombin activity.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Hematology
Stuart Wallis, Nina Wolska, Hanna Englert, Mareike Posner, Abhishek Upadhyay, Thomas Renne, Ian Eggleston, Stefan Bagby, Giordano Pula
Summary: In this study, Efb(68-87) was identified as a novel selective platelet-binding peptide that directly binds to P-selectin and inhibits interactions between platelets and leukocytes leading to PLAs and NETs formation. This peptide has the potential to become a selective inhibitor of the proinflammatory activity of platelets, which play a key role in thromboinflammation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Review
Medicine, Legal
Johann Zwirner, Rachel Kulakofsky, Antonia Fitzek, Ann Sophie Schroeder, Simone Bohnert, Heike Franke, Thomas Renne, Rexson Tse, Benjamin Ondruschka
Summary: Traumatic brain injury (TBI) is a major cause of death and its accurate diagnosis is challenging in cases where clear signs of head trauma are lacking. Post-mortem studies suggest that biomarkers could be used to provide objective evidence for cause of death, estimation of survival time, and time since death in TBI cases. However, current biomarkers have low specificity for TBI and limited information regarding survival time and time since death. Future research should explore accessible samples like urine and vitreous humor, combine established biomarkers, and utilize novel approaches such as metabolomics and mi-RNAs.
INTERNATIONAL JOURNAL OF LEGAL MEDICINE
(2022)
Article
Hematology
Reiner K. Mailer, Sandra Konrath, Lydia Zhan, Hanna Thode, Manu Beerens, Maike Frye, Daniel F. J. Ketelhuth, Thomas Renne, Goeran K. Hansson
Summary: Inflammation caused by LDL deposition in the arterial wall leads to atherosclerosis. Regulatory T cells inhibit vascular inflammation by inducing immune tolerance towards LDL-related antigens. However, the mechanisms that promote the generation of LDL-specific regulatory T cells in vivo are still unclear.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Review
Cell Biology
Peter M. Benz, Timo Froemel, Hebatullah Laban, Joana Zink, Lea Ulrich, Dieter Groneberg, Reinier A. Boon, Philip Poley, Thomas Renne, Cor de Wit, Ingrid Fleming
Summary: Actin binding proteins are crucial for the regulation of actin cytoskeletal dynamics and play a role in various cellular processes. The Ena/VASP family of proteins enhance actin filament assembly and link kinase signaling pathways to actin organization. They are involved in processes such as membrane protrusions, cell adhesions, and mechanical tension. This review provides an overview of the functions and molecular mechanisms of Ena/VASP proteins in cardiovascular cells.
Article
Hematology
Steven de Maat, Chantal C. Clark, Arjan D. Barendrecht, Simone Smits, Nadine D. van Kleef, Hinde El Otmani, Manon Waning, Marc van Moorsel, Michael Szardenings, Nicolas Delaroque, Kristof Vercruysse, Rolf T. Urbanus, Silvie Sebastian, Peter J. Lenting, Christoph Hagemeyer, Thomas Renne, Karen Vanhoorelbeke, Claudia Tersteeg, Coen Maas
Summary: Thrombotic microangiopathies are characterized by attacks of disseminated microvascular thrombosis. This study developed a fusion protein called Microlyse that can target and activate plasminogen on microthrombi, showing greater efficacy for the treatment of TTP compared to current methods.
Review
Pharmacology & Pharmacy
Karlie R. Sharma, Christine M. Colvis, Griffih P. Rodgers, Douglas M. Sheeley
Summary: There are many genes within the druggable genome that have not been studied, and the US National Institutes of Health's program provides resources to explore these genes, with the potential for rapid impact on human health.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Mohammad Sameer Khan, B. H. Jaswanth Gowda, Waleed H. Almalki, Tanuja Singh, Amirhossein Sahebkar, Prashant Kesharwani
Summary: Mitochondria-specific functional liposomes hold great potential for cancer therapy. This review discusses the association between mitochondria and tumor formation, as well as the advantages of liposomes in delivering drugs to mitochondria.
DRUG DISCOVERY TODAY
(2024)
Review
Pharmacology & Pharmacy
Choong Yong Ung, Cristina Correia, Hu Li, Christopher M. Adams, Jennifer J. Westendorf, Shizhen Zhu
Summary: With increasing human life expectancy, the global medical burden of chronic diseases is growing. Chronic diseases often involve malfunctioning of multiple organs, and understanding the interorgan crosstalk is crucial to understanding the etiology of chronic diseases. Researchers have proposed the locked-state model (LoSM) and cutting-edge systems biology and artificial intelligence strategies to decipher chronic multiorgan locked states. The findings have important clinical implications for improving treatments for chronic diseases.
DRUG DISCOVERY TODAY
(2024)
