Article
Pharmacology & Pharmacy
Mohd Aslam Saifi, Shivaraju Annaldas, Chandraiah Godugu
Summary: The study revealed the therapeutic effect of a direct thrombin inhibitor on tubulointerstitial fibrosis in chronic kidney disease by improving kidney injury and fibrosis through inhibition of thrombin-activated PAR-1 expression.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Shi-Jye Chu, Shih-En Tang, Hsin-Ping Pao, Shu-Yu Wu, Wen- Liao
Summary: This study demonstrates that the PAR-1 antagonist SCH530348 exerts protective effects by blocking PAR-1 expression and modulating the downstream PI3K, NF-kappa B, and MAPK pathways, reducing IR-induced acute lung injury. These findings suggest that PAR-1 antagonist could be a potential therapeutic candidate for lung protection following IR injury.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Elena Pompili, Valerio De Franchis, Claudia Giampietri, Stefano Leone, Elena De Santis, Francesco Fornai, Lorenzo Fumagalli, Cinzia Fabrizi
Summary: Schwann cells play a crucial role in peripheral nerve regeneration by promptly activating, dedifferentiating, and assisting axon regrowth after nerve injury. PAR1, a thrombin receptor present on Schwann cell plasma membrane, is emerging as a possible regulator of Schwann cells' pro-regenerative capacity. This review summarizes recent literature on the contribution of PAR1 and PAR1-activating proteases in regulating peripheral nerve regeneration.
Article
Hematology
Sujuan Li, Weili Wang, Lisha Lin, Lian Yang, Ying Cai, Xingzhi Yang, Taocui Zhang, Chuang Xiao, Hui Yan, Na Gao, Jinhua Zhao
Summary: An oligosaccharide HS-11, derived from sea cucumber Holothuria fuscopunctata, inhibits thrombin-mediated platelet activation and aggregation by directly binding to thrombin exosite II, demonstrating its antiplatelet and antithrombotic activity.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Sukanya Tripathy, Bader O. Almutairi, Sanjay Singh, Atul Rawat, Durgesh Dubey, Monisha Banerjee, Dinesh R. Modi, Anand Prakash
Summary: Thrombin-activated receptor-1 (PAR1) plays a crucial role in tumor angiogenesis, cell proliferation, and invasion. The present study investigated the expression of PAR1 in human glioma cell lines D54 and U87, as well as its downstream signaling pathway. The results showed that PAR1 was highly expressed in D54 cells compared to U87 cells. Activation of PAR1 led to increased ERK1/2 activity and enhanced migration and invasion. The antagonist SCH79797 significantly inhibited the migration and invasion of the glioma cell lines. Moreover, PAR1 activation affected intracellular Ca+2 concentration ([Ca+2]i). Thrombin and TFLLR induced an increase in [Ca+2]i, which was suppressed by the PAR1 inhibitor SCH79797. The study suggests that PAR1 signaling contributes to glioma progression and may serve as a potential therapeutic target for glioma prevention.
JOURNAL OF KING SAUD UNIVERSITY SCIENCE
(2022)
Article
Rheumatology
Meilang Xue, Haiyan Lin, Hai Po Helena Liang, Kelly McKelvey, Ruilong Zhao, Lyn March, Christopher Jackson
Summary: The study found that deficiency of PAR1 or PAR2 exacerbates inflammatory arthritis in CIA. The protective functions of PAR1 and PAR2 in CIA likely occur via differing mechanisms involving immune cell differentiation and cytokines/MMPs.
Review
Clinical Neurology
Fenghui Ye, Hugh J. L. Garton, Ya Hua, Richard F. Keep, Guohua Xi
Summary: Thrombin levels in the brain increase after stroke, contributing to brain pathology through harmful and protective mechanisms. Thrombin can affect brain injury via multiple pathways, linking the coagulation system to the immune system and potentially leading to short-term and long-term functional deficits.
TRANSLATIONAL STROKE RESEARCH
(2021)
Article
Hematology
Sonali R. Gnanenthiran, Gabrielle J. Pennings, Caroline J. Reddel, Heather Campbell, Maaike Kockx, Justin R. Hamilton, Vivien Chen, Leonard Kritharides
Summary: Aging is associated with increased basal platelet activation, ADP hyperreactivity, and thrombin resistance. In situ thrombin generation and systemic inflammation may be potential targets for preventing cardiovascular disease in the elderly.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Daisuke Asai, Naoko Inoue, Makiko Sugiyama, Tsugumi Fujita, Yutaka Matsuyama, Xiaohui Liu, Ayami Matsushima, Takeru Nose, Tommaso Costa, Yasuyuki Shimohigashi
Summary: This study verifies the importance of the position of benzene hydrogen atoms in activating the receptor, finding that benzene-hydrogen atoms at the ortho and meta positions, rather than the para position, play a crucial role in CH/pi interaction.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Immunology
Hannah Wilkinson, Hugh Leonard, Michael G. Robson, Richard Smith, ElLi Tam, John H. McVey, Daniel Kirckhofer, Daxin Chen, Anthony Dorling
Summary: TF-mediated PAR-1 and PAR-2 signaling determines the response of myeloid cells to IFN gamma in a homeostatic manner. The use of 3-MP, an agent that inhibits PAR-1 while delivering a PAR-2 signal, can effectively abolish immune responses dependent on M1 polarization, potentially providing therapeutic potential for various diseases.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Sanjay Goyal, Ankita Sood, Isha Gautam, Soumyadip Pradhan, Puskar Mondal, Gaaminepreet Singh, Ravinder Singh Jaura, Thakur Gurjeet Singh, Raminderpal Singh Sibia
Summary: This study found that elevated serum levels of PAR-1 in T2DM patients are positively correlated with increased body weight, BMI, HbA1c, and inflammatory cytokines. It suggests that elevated serum PAR-1 levels may serve as an independent predictor of inflammation in T2DM patients and have prognostic value for determining disease progression.
INFLAMMOPHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Hannah Wilkinson, Hugh Leonard, Daxin Chen, Toby Lawrence, Michael Robson, Pieter Goossens, John H. McVey, Anthony Dorling
Summary: Research has shown that in chronic inflammation, the PAR-1 signal is crucial for granuloma formation, with this signal acting on macrophages through the activation of Thrombin. The results of the experiment indicate that Thrombin signaling significantly enhances macrophage sensitivity to IFN-γ, leading to enhanced cell polarization.
Article
Clinical Neurology
Fenghui Ye, Jinting Yang, Ya Hua, Richard F. Keep, Guohua Xi
Summary: Using a Tmem119-EGFP transgenic mouse model, the study found that the number of perihematomal microglia significantly decreased on day 1 after ICH, but markedly increased by day 3 and day 7. Injection of iron or thrombin induced microglia death or proliferation, respectively.
Article
Gastroenterology & Hepatology
Jean-Paul Motta, Celine Deraison, Sylvie Le Grand, Bruno Le Grand, Nathalie Vergnolle
Summary: A new paradigm has been proposed for the treatment of inflammatory bowel diseases, focusing on tissue repair and mucosal healing in addition to resolving symptoms and inflammation. The PAR-1 antagonist has shown potential benefits in promoting mucosal repair in Crohn's disease patients, suggesting a new indication for IBD treatment.
INFLAMMATORY BOWEL DISEASES
(2021)
Article
Biochemistry & Molecular Biology
Michelle De Bruyn, Hannah Ceuleers, Nikita Hanning, Maya Berg, Joris G. De Man, Paco Hulpiau, Cedric Hermans, Ulf-Hakan Stenman, Hannu Koistinen, Anne-Marie Lambeir, Benedicte Y. De Winter, Ingrid De Meester
Summary: The study on protease activity in IBD and IBS explored cleavage patterns of bioactive peptides in colonic tissue, revealing potential therapeutic targets like thrombin, chymotrypsin-like proteases, and proteases with different specificities in acute colitis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Editorial Material
Clinical Neurology
Fenghui Ye, Yingfeng Wan, Sravanthi Koduri, Katherine G. Holste, Richard F. Keep, Ya Hua, Guohua Xi
TRANSLATIONAL STROKE RESEARCH
(2023)
Article
Clinical Neurology
Chaoyi Bian, Yingfeng Wan, Sravanthi Koduri, Ya Hua, Richard F. Keep, Guohua Xi
Summary: This study found that intraventricular iron injection in rats led to hydrocephalus and increased stromal macrophage number. Treatment with minocycline or clodronate liposomes improved iron-induced hydrocephalus and reduced the increase in stromal macrophages.
TRANSLATIONAL STROKE RESEARCH
(2023)
Article
Neurosciences
Yingfeng Wan, Katherine G. Holste, Ya Hua, Richard F. Keep, Guohua Xi
Summary: Intracerebral hemorrhage (ICH) is responsible for 10% of strokes in the USA, resulting in significant disability and mortality. It causes primary brain injury due to mechanical disruption and secondary injury through the release of clot-derived factors. ICH leads to brain edema and increased intracranial pressure, affecting patient prognosis. Currently, effective treatment methods for reducing perihematomal cerebral edema and intracranial pressure are limited. This review explores the mechanisms of edema formation, the influence of sex and age, and the progress in pharmacotherapy for ICH.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Endocrinology & Metabolism
Fenghui Ye, Jinting Yang, Katherine G. Holste, Sravanthi Koduri, Ya Hua, Richard F. Keep, Hugh J. L. Garton, Guohua Xi
Summary: Both monocyte-derived macrophages (MDMs) and brain resident microglia contribute to hematoma resolution after intracerebral hemorrhage (ICH). In this study, transgenic mice with enhanced green fluorescent protein (EGFP) labeled microglia were used to observe changes in MDMs and microglia after ICH. The results showed that MDMs entered the brain and formed a peri-hematoma cell layer by day 3 after ICH, and CD47 blocking antibody increased the number of MDMs around and inside the hematoma. These findings suggest that MDMs play an important role in phagocytosis after ICH and modulation of MDMs could be a potential therapeutic target.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2023)
Editorial Material
Neurosciences
Yejie Shi, Richard F. Keep
NEUROBIOLOGY OF DISEASE
(2023)
Review
Chemistry, Multidisciplinary
Jianming Xiang, Richard F. Keep
Summary: This mini-review provides an overview of the role of the solute carrier 15 (SLC15) family of proton-coupled oligopeptide transporters (POTs) in the brain, with a focus on Pept2 (Slc15A2) and PhT1 (Slc15A4). These transporters play a crucial role in the transport of di- and tripeptides, peptidomimetics, and drugs in the brain. The review highlights the pioneering work of David E. Smith in elucidating the impact of PepT2 at the choroid plexus and brain parenchymal cells, and discusses recent findings and future directions in brain POT research, including localization, regulatory pathways, transporter structure, species differences, and disease states.
PHARMACEUTICAL RESEARCH
(2023)
Article
Clinical Neurology
Anuska V. Andjelkovic, Muyu Situ, Ali Francisco Citalan-Madrid, Svetlana M. Stamatovic, Jianming Xiang, Richard F. Keep
Summary: Cerebral endothelial cells and their tight junctions form the blood-brain barrier (BBB), which is a unique, dynamic, and multi-functional interface. This review focuses on the changes in BBB and the neurovascular unit in normal aging and neurodegenerative disorders, particularly Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. Evidence suggests that BBB dysfunction contributes to neurodegeneration. The mechanisms underlying BBB dysfunction and its potential as a therapeutic target, including enhancing drug delivery, clearance of neurotoxic compounds, and preventing BBB dysfunction, are discussed. The need for novel biomarkers of BBB dysfunction is also addressed.
Editorial Material
Neurosciences
Richard F. Keep, Lester R. Drewes
FLUIDS AND BARRIERS OF THE CNS
(2023)
Editorial Material
Neurosciences
Richard F. Keep, Hazel C. Jones, Mark G. Hamilton, Lester R. Drewes
Summary: The aim of this editorial is to highlight the advancements in brain barrier and brain fluid research in 2022. It encompasses studies on blood-brain, blood-retina, and blood-CSF barriers (choroid plexus and meninges), as well as the signaling within the neurovascular unit and elements of the brain fluid systems. Furthermore, it discusses the impact of brain barriers and brain fluid systems on CNS diseases, their role in disease progression, and the progress being made in treating such diseases.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Article
Neurosciences
Chelsea M. Phillips, Svetlana M. Stamatovic, Richard F. Keep, Anuska V. Andjelkovic
Summary: This study examined the epigenetic and transcriptional profile of cerebral microvessels after stroke, revealing the role of DNA methylation in regulating blood-brain barrier (BBB) repair.
FLUIDS AND BARRIERS OF THE CNS
(2023)
Editorial Material
Neurosciences
Richard F. Keep, Hazel C. Jones, Lester R. Drewes
FLUIDS AND BARRIERS OF THE CNS
(2023)
Review
Clinical Neurology
Fenghui Ye, Richard F. Keep, Ya Hua, Hugh J. L. Garton, Guohua Xi
Summary: This article discusses the role of the glymphatic system in posthemorrhagic brain injury, especially posthemorrhagic hydrocephalus.
Article
Neurosciences
Jianming Xiang, Ya Hua, Guohua Xi, Richard F. Keep
Summary: This review evaluates the movement of fluid from blood to cerebrospinal fluid (CSF) and discusses the impact of ion transport in the choroid plexus (CP) epithelium and cerebral vasculature on fluid flow. It also addresses the potential targets for modulating CP fluid secretion, NKCC1 and TRPV4. Furthermore, it highlights the dynamic changes in fluid secretion and their role in the controversies over the CP's involvement in brain fluid secretion.
NEUROBIOLOGY OF DISEASE
(2023)
Editorial Material
Clinical Neurology
Momodou G. Bah, Katherine G. Holste, Guohua Xi, Richard F. Keep
TRANSLATIONAL STROKE RESEARCH
(2023)
Article
Neurosciences
Sara Diana Lolansen, Dagne Barbuskaite, Fenghui Ye, Jianming Xiang, Richard F. Keep, Nanna MacAulay
Summary: This study elucidated the molecular mechanisms underlying the development of hydrocephalus in spontaneously hypertensive rats (SHRs), and found that it is not associated with elevated intracranial pressure (ICP) and does not require increased cerebrospinal fluid (CSF) secretion or inefficient CSF drainage. This type of hydrocephalus is not life-threatening and occurs due to unknown disturbances in CSF dynamics.
FLUIDS AND BARRIERS OF THE CNS
(2023)