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Elbadr MM, Galal HA, Hetta HF, Elfadil H, Alanazi FE, Fawzy S, Aljohani HM, Abd Ellah NH, Ali MF, Dyab AK, Ahmed EA. Immunomodulatory Effect of Rivaroxaban Nanoparticles Alone and in Combination with Sitagliptin on Diabetic Rat Model. Diseases 2025; 13:87. [PMID: 40136627 PMCID: PMC11941519 DOI: 10.3390/diseases13030087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Chronic inflammation and immune dysregulation are key drivers of diabetes complications. Rivaroxaban (RX) and sitagliptin (SITA) are established therapies for thromboembolism and glycemic control, respectively. This study evaluated the novel therapeutic potential of nano-rivaroxaban (NRX) alone and in combination with sitagliptin (SITA) in mitigating inflammation and restoring immune balance in streptozotocin (STZ)-induced diabetic rats. METHODS Type 2 diabetes was induced in rats using a single injection of STZ (60 mg/kg). Animals were divided into five groups: control, STZ-diabetic, RX-treated (5 mg/kg), NRX-treated (5 mg/kg), and NRX+SITA-treated (5 mg/kg + 10 mg/kg). After 4 weeks of treatment, blood glucose, coagulation markers, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10) were analyzed. Histopathological examination of the liver, kidney, pancreas, and spleen was conducted. Immunohistochemistry was used to assess hepatic NF-κB expression. RESULTS STZ significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10), along with increased hepatic NF-κB expression and histopathological abnormalities in immune organs. NRX significantly reduced inflammatory cytokines, improved histopathological changes in organs, and decreased hepatic NF-κB expression. The combination therapy (NRX + SITA) achieved superior immune modulation, with enhanced cytokine profile restoration, reduced hepatic NF-κB expression, and near-complete histopathological normalization. CONCLUSIONS This study underscores the promise of combining nanoparticle-based drug delivery with established therapies like sitagliptin to achieve superior immune modulation and inflammation control, presenting a potential therapeutic strategy for managing diabetes complications.
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Affiliation(s)
- Mohamed M. Elbadr
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; (M.M.E.)
| | - Heba A. Galal
- Department of Pharmacology, Faculty of Veterinary Medicine, Assiut University, Assiut 71515, Egypt;
| | - Helal F. Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Hassabelrasoul Elfadil
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Fawaz E. Alanazi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Shereen Fawzy
- Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Hashim M. Aljohani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madina 41477, Saudi Arabia;
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Noura H. Abd Ellah
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Badr University in Assiut, Naser City 2014101, Assiut, Egypt;
- Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71515, Egypt
| | - Marwa F. Ali
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut 71515, Egypt;
| | - Ahmed K. Dyab
- Department of Medical Parasitology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt;
| | - Esraa A. Ahmed
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt; (M.M.E.)
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Heitzer M, Winnand P, Bock A, Ooms M, Katz MS, Kniha K, Grottke O, Hölzle F, Modabber A. Evaluation of the Hemostatic Effect of an Innovative Tissue Adhesive during Extraction Therapy under Rivaroxaban in a Rodent Model. J Funct Biomater 2023; 14:333. [PMID: 37504828 PMCID: PMC10381264 DOI: 10.3390/jfb14070333] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023] Open
Abstract
An increase in rivaroxaban therapies is associated with increased numbers of postoperative bleeding despite the use of hemostatic sponges, which are currently the gold standard treatment. VIVO has shown promising hemostatic results, favorable tissue properties, and ease of application, although it has not yet been used in the oral cavity. The aim of this study was to evaluate the hemostatic properties of VIVO in the extraction sockets of 31 rodents and compare this to gelatin sponge (GSP) therapy. At rivaroxaban concentrations of 264.10 ± 250.10 ng/mL, 62 extraction sockets were generated, of which 31 were treated with VIVO and 31 with GSP. The duration time, early and late bleeding events, and wound healing score were determined. Histologic examinations of the tissues were performed after 5 days. VIVO presented a longer procedure, 1.26 ± 0.06 min, but a significantly shorter bleeding time, 0.14 ± 0.03 min. There was no difference between the two groups in terms of the severity and timing of bleeding. More minor early bleeding events were observed for GSP. VIVO showed a significantly better healing score, with favorable histological results. In an animal study, VIVO showed promising hemostatic properties after tooth extraction under ongoing anticoagulative therapy.
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Affiliation(s)
- Marius Heitzer
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Philipp Winnand
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Anna Bock
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Mark Ooms
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Marie Sophie Katz
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Kristian Kniha
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Oliver Grottke
- Clinic for Anesthesiology/Operative Intensive Care Medicine, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Frank Hölzle
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
| | - Ali Modabber
- Department of Oral and Cranio-Maxillofacial Surgery, University Hospital RWTH Aachen, Pauwelstraße 30, 52074 Aachen, Germany
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Matrix Metalloproteinases in Cardioembolic Stroke: From Background to Complications. Int J Mol Sci 2023; 24:ijms24043628. [PMID: 36835040 PMCID: PMC9959608 DOI: 10.3390/ijms24043628] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/20/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases participating in physiological processes of the brain, maintaining the blood-brain barrier integrity and playing a critical role in cerebral ischemia. In the acute phase of stroke activity, the expression of MMPs increase and is associated with adverse effects, but in the post-stroke phase, MMPs contribute to the process of healing by remodeling tissue lesions. The imbalance between MMPs and their inhibitors results in excessive fibrosis associated with the enhanced risk of atrial fibrillation (AF), which is the main cause of cardioembolic strokes. MMPs activity disturbances were observed in the development of hypertension, diabetes, heart failure and vascular disease enclosed in CHA2DS2VASc score, the scale commonly used to evaluate the risk of thromboembolic complications risk in AF patients. MMPs involved in hemorrhagic complications of stroke and activated by reperfusion therapy may also worsen the stroke outcome. In the present review, we briefly summarize the role of MMPs in the ischemic stroke with particular consideration of the cardioembolic stroke and its complications. Moreover, we discuss the genetic background, regulation pathways, clinical risk factors and impact of MMPs on the clinical outcome.
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AKKAYA Ö, AYDOĞAN E. APIXABAN'ın DOZA BAĞLI ANTİANJİYOJENİK POTANSİYELİ: Deneysel bir bakış. ACTA MEDICA ALANYA 2022. [DOI: 10.30565/medalanya.1129978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Amaç: Direkt oral antikoagülanlar (DOAK'lar), tromboembolizmin tedavisi ve önlenmesi için geleneksel tıbbi rejimlere iyi alternatiflerdir. Apixaban, bu yeni geliştirilen ilaçların daha popüler varyasyonlarından biridir. Antikoagülan potansiyelinin yanı sıra, olası hücresel etkiler gelecekteki çalışmaların konusu olmaya devam etmektedir. Bu çalışmanın amacı, korioallantoik membran (CAM) modelinde apiksaban'ın olası antianjiyogenik etkilerini araştırmaktı.
Yöntem: Apixaban'ın 10-4, 10-5 ve 10-6 M konsantrasyonlarında ilaç peletleri hazırlandı ve yumurta inkübasyonunun dördüncü gününde korioallantoik membrana yerleştirildi. Sekizinci günde, membranların tüm vasküler yoğunlukları, bilinen bir monoklonal, insanlaştırılmış, vasküler endotelyal büyüme faktörü inhibitörü olan 10-6 M'lik bir bevacizumab konsantrasyonu ile karşılaştırıldı.
Sonuçlar: 10-4 M apiksaban konsantrasyonunun, bevacizumabınkine benzer güçlü bir antianjiyogenik potansiyele sahip olduğunu bulduk. Bununla birlikte, daha düşük bir apiksaban dozunda (10-5 M, 10-6 M) orta düzeyde antianjiyogenik potansiyel vardı. Daha yüksek antianjiyogenik potansiyel dozlarının (10-4 M konsantrasyon) daha düşük dozlarda apiksaban (10-5 M, 10-6 M) ile karşılaştırılması, önemli istatistiksel farklılıklar ortaya çıkardı (p < 0.05).
Sonuç: Sonuçlarımız, yüksek doz apiksaban'ın güçlü antianjiyogenik potansiyele sahip olduğunu göstermektedir. Bu etkinin kesin mekanizması bilinmemektedir. Bu pilot sonuçlar, DOAK'lara yeni bir bakış elde etmek için daha ileri çalışmalarla doğrulanmalıdır.
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Bian Z, Liu X, Feng T, Yu H, Hu X, Hu X, Bian Y, Sun H, Tadokoro K, Takemoto M, Yunoki T, Nakano Y, Fukui Y, Morihara R, Abe K, Yamashita T. Protective Effect of Rivaroxaban Against Amyloid Pathology and Neuroinflammation Through Inhibiting PAR-1 and PAR-2 in Alzheimer's Disease Mice. J Alzheimers Dis 2022; 86:111-123. [PMID: 35001892 DOI: 10.3233/jad-215318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer's disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. OBJECTIVE The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. METHODS In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. RESULTS Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. CONCLUSION The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.
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Affiliation(s)
- Zhihong Bian
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Xia Liu
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Tian Feng
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Haibo Yu
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Xiao Hu
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Xinran Hu
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Yuting Bian
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Hongming Sun
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Koh Tadokoro
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Mami Takemoto
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Taijun Yunoki
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Yumiko Nakano
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Yusuke Fukui
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Ryuta Morihara
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
| | - Koji Abe
- National Center Hospital, National Center of Neurology and Psychiatry, Kodaira-shi, Tokyo, Japan
| | - Toru Yamashita
- Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama, Japan
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Zhong TT, Wang G, Wang XQ, Kong WD, Li XY, Xue Q, Zou YA. Serum calcium, albumin, globulin and matrix metalloproteinase-9 levels in acute cerebral infarction patients. World J Clin Cases 2021; 9:9070-9076. [PMID: 34786389 PMCID: PMC8567529 DOI: 10.12998/wjcc.v9.i30.9070] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hemorrhagic transformation (HT) is a common complication in patients with cerebral infarction. However, its pathogenesis is poorly understood. The knowledge of factors that may increase risk for HT may help in improving the safety of thrombolytic therapy.
AIM To investigate the predictive value of serum calcium, albumin, globulin and matrix metalloproteinase-9 (MMP-9) levels for HT after intravenous thrombolysis (IVT) in patients with acute cerebral infarction.
METHODS Five hundred patients with acute cerebral infarction who received IVT with alteplase within 4.5 h after the onset of disease between January 2018 and January 2021 at our hospital were selected as the study subjects. They were divided into groups based on computed tomography scan results of the brain made within 36 h after thrombolysis. Forty patients with HT were enrolled in an observation group and 460 patients without HT were enrolled in a control group. Serum calcium, albumin, globulin and MMP-9 levels were compared between the two groups. Regression analysis was used to discuss the relationship between these indices and HT.
RESULTS The previous history of hypertension, diabetes, atrial fibrillation, cerebrovascular diseases, smoking and alcohol intake were not associated with HT after IVT in patients with acute cerebral infarction (all P > 0.05). The National Institutes of Health stroke scale (NHISS) score was associated with HT after IVT in patients with acute cerebral infarction (P < 0.05). The serum calcium and albumin levels were lower in the observation group than in the control group (all P < 0.05). The levels of globulin and MMP-9 were significantly higher in the observation group than in the control group (all P < 0.05). Logistic regression analysis showed that NHISS score, serum calcium, albumin, globulins and MMP-9 were independent factors influencing the occurrence of HT following IVT in patients with cerebral infarction (P < 0.05).
CONCLUSION Serum calcium, albumin, globulin and MMP-9 levels are risk factors for HT after IVT in patients with acute cerebral infarction. Moreover, NHISS score can be used as a predictor of post-thrombolytic HT.
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Affiliation(s)
- Ting-Ting Zhong
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Gang Wang
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Xiao-Qin Wang
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Wei-Dan Kong
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Xiao-Yu Li
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Qian Xue
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
| | - Yu-An Zou
- Department of Neurology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China
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Abdelzaher WY, Mohammed HH, Welson NN, Batiha GES, Baty RS, Abdel-Aziz AM. Rivaroxaban Modulates TLR4/Myd88/NF-Kβ Signaling Pathway in a Dose-Dependent Manner With Suppression of Oxidative Stress and Inflammation in an Experimental Model of Depression. Front Pharmacol 2021; 12:715354. [PMID: 34630092 PMCID: PMC8497790 DOI: 10.3389/fphar.2021.715354] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/10/2021] [Indexed: 01/10/2023] Open
Abstract
Depression is a common mental illness leading to upset or anxiety, with a high incidence rate in the world. Depression can lead to suicidal thoughts and behavior. The present study aimed to evaluate the effect of the direct oral anticoagulant rivaroxaban (RVX), in the model of depression induced by chronic unpredicted mild stress (CUMS) in rats. Fifty-six male Wister rats were randomly divided into seven experimental groups (8 rats/group); Group 1: Control group given vehicle per oral (p.o.), Group 2: RVXL-control group (received rivaroxaban 20 mg/kg/day, p.o..), Group 3: RVXH-control group (received rivaroxaban 30 mg/kg/day, p.o.), Group 4: chronic unpredictable mild stress (CUMS) group, Group 5: FLX-treated CUMS group (received fluoxetine 10 mg/kg/day, p.o..), Group 6: RVXL-treated CUMS group (received rivaroxaban 20 mg/kg/day, p.o.), and Group 7: RVXH-treated CUMS group (received rivaroxaban 30 mg/kg/day, p.o.). The rats received the drugs from the first day of the experiment and continued till 4 weeks-the duration of the study. The following were measured: monoamine neurotransmitters, malondialdehyde (MDA), total nitrite/nitrate (NOx), reduced glutathione (GSH), superoxide dismutase (SOD), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor-A (VEGF-A). A forced swimming test (FST) was done. Furthermore, histological changes and glial fibrillary acidic protein (GFAP) immunoexpression were evaluated. CUMS showed a significant decrease in hypothalamic neurotransmitters, hippocampal GSH, SOD, BNDF, and VEGF-A with a significant increase in hippocampal MDA, NOx, NF-kβ, Myd88, TLR4, TNF-α, and GFAP immunoexpression. RVX showed significant improvement in all parameters (p -value < 0.0001). In conclusion, RVX in a dose-dependent manner possesses potent ameliorative effects against depression by reducing the oxidative stress and inflammatory process, through the regulation of the TLR4/Myd88/NF-kβ signaling pathway.
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Affiliation(s)
| | - Hanaa H Mohammed
- Department of Histology, Faculty of Medicine, Minia University, Minia, Egypt
| | - Nermeen N Welson
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Roua S Baty
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
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Bieber M, Foerster KI, Haefeli WE, Pham M, Schuhmann MK, Kraft P. Treatment with Edoxaban Attenuates Acute Stroke Severity in Mice by Reducing Blood-Brain Barrier Damage and Inflammation. Int J Mol Sci 2021; 22:ijms22189893. [PMID: 34576055 PMCID: PMC8464921 DOI: 10.3390/ijms22189893] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 11/16/2022] Open
Abstract
Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood–brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.
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Affiliation(s)
- Michael Bieber
- Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany; (M.B.); (M.K.S.)
| | - Kathrin I. Foerster
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (K.I.F.); (W.E.H.)
| | - Walter E. Haefeli
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, Germany; (K.I.F.); (W.E.H.)
| | - Mirko Pham
- Department of Neuroradiology, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Michael K. Schuhmann
- Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany; (M.B.); (M.K.S.)
| | - Peter Kraft
- Department of Neurology, University Hospital Würzburg, 97080 Würzburg, Germany; (M.B.); (M.K.S.)
- Department of Neurology, Klinikum Main-Spessart, 97816 Lohr, Germany
- Correspondence: ; Tel.: +49-9352-505-1501
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Chen S, Yang F, Xu T, Wang Y, Zhang K, Fu G, Zhang W. Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study. Front Genet 2021; 12:619536. [PMID: 34122499 PMCID: PMC8189424 DOI: 10.3389/fgene.2021.619536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 04/13/2021] [Indexed: 12/28/2022] Open
Abstract
Background Although several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk. Methods A two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10–8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy. Results In total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy. Conclusions This two-sample MR analysis found no evidence to support causal association of Hcy with AF.
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Affiliation(s)
- Songzan Chen
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Fangkun Yang
- Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tian Xu
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yao Wang
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Kaijie Zhang
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guosheng Fu
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Wenbin Zhang
- Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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10
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Andjelkovic AV, Stamatovic SM, Phillips CM, Martinez-Revollar G, Keep RF. Modeling blood-brain barrier pathology in cerebrovascular disease in vitro: current and future paradigms. Fluids Barriers CNS 2020; 17:44. [PMID: 32677965 PMCID: PMC7367394 DOI: 10.1186/s12987-020-00202-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
The complexity of the blood-brain barrier (BBB) and neurovascular unit (NVU) was and still is a challenge to bridge. A highly selective, restrictive and dynamic barrier, formed at the interface of blood and brain, the BBB is a "gatekeeper" and guardian of brain homeostasis and it also acts as a "sensor" of pathological events in blood and brain. The majority of brain and cerebrovascular pathologies are associated with BBB dysfunction, where changes at the BBB can lead to or support disease development. Thus, an ultimate goal of BBB research is to develop competent and highly translational models to understand mechanisms of BBB/NVU pathology and enable discovery and development of therapeutic strategies to improve vascular health and for the efficient delivery of drugs. This review article focuses on the progress being made to model BBB injury in cerebrovascular diseases in vitro.
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Affiliation(s)
- Anuska V Andjelkovic
- Department of Pathology, University of Michigan Medical School, 7520 MSRB I, 1150 West Medical Center Dr, Ann Arbor, MI, 48109-5602, USA.
| | - Svetlana M Stamatovic
- Department of Pathology, University of Michigan Medical School, 7520 MSRB I, 1150 West Medical Center Dr, Ann Arbor, MI, 48109-5602, USA
| | - Chelsea M Phillips
- Graduate Program in Neuroscience, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Gabriela Martinez-Revollar
- Department of Pathology, University of Michigan Medical School, 7520 MSRB I, 1150 West Medical Center Dr, Ann Arbor, MI, 48109-5602, USA
| | - Richard F Keep
- Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Molecular Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
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11
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Wang Q, Reps JM, Kostka KF, Ryan PB, Zou Y, Voss EA, Rijnbeek PR, Chen R, Rao GA, Morgan Stewart H, Williams AE, Williams RD, Van Zandt M, Falconer T, Fernandez-Chas M, Vashisht R, Pfohl SR, Shah NH, Kasthurirathne SN, You SC, Jiang Q, Reich C, Zhou Y. Development and validation of a prognostic model predicting symptomatic hemorrhagic transformation in acute ischemic stroke at scale in the OHDSI network. PLoS One 2020; 15:e0226718. [PMID: 31910437 PMCID: PMC6946584 DOI: 10.1371/journal.pone.0226718] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 12/02/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND PURPOSE Hemorrhagic transformation (HT) after cerebral infarction is a complex and multifactorial phenomenon in the acute stage of ischemic stroke, and often results in a poor prognosis. Thus, identifying risk factors and making an early prediction of HT in acute cerebral infarction contributes not only to the selections of therapeutic regimen but also, more importantly, to the improvement of prognosis of acute cerebral infarction. The purpose of this study was to develop and validate a model to predict a patient's risk of HT within 30 days of initial ischemic stroke. METHODS We utilized a retrospective multicenter observational cohort study design to develop a Lasso Logistic Regression prediction model with a large, US Electronic Health Record dataset which structured to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). To examine clinical transportability, the model was externally validated across 10 additional real-world healthcare datasets include EHR records for patients from America, Europe and Asia. RESULTS In the database the model was developed, the target population cohort contained 621,178 patients with ischemic stroke, of which 5,624 patients had HT within 30 days following initial ischemic stroke. 612 risk predictors, including the distance a patient travels in an ambulance to get to care for a HT, were identified. An area under the receiver operating characteristic curve (AUC) of 0.75 was achieved in the internal validation of the risk model. External validation was performed across 10 databases totaling 5,515,508 patients with ischemic stroke, of which 86,401 patients had HT within 30 days following initial ischemic stroke. The mean external AUC was 0.71 and ranged between 0.60-0.78. CONCLUSIONS A HT prognostic predict model was developed with Lasso Logistic Regression based on routinely collected EMR data. This model can identify patients who have a higher risk of HT than the population average with an AUC of 0.78. It shows the OMOP CDM is an appropriate data standard for EMR secondary use in clinical multicenter research for prognostic prediction model development and validation. In the future, combining this model with clinical information systems will assist clinicians to make the right therapy decision for patients with acute ischemic stroke.
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Affiliation(s)
- Qiong Wang
- Biomedical Engineering School, Sun Yat-Sen University, Guangzhou, China
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
| | - Jenna M. Reps
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Janssen Research and Development, Raritan, New Jersey, United States of America
| | - Kristin Feeney Kostka
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- IQVIA, Durham, North Carolina, United States of America
| | - Patrick B. Ryan
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Janssen Research and Development, Raritan, New Jersey, United States of America
- Department of Biomedical Informatics, Columbia University, New York, New York, United States of America
| | - Yuhui Zou
- Department of Neurosurgery, General Hospital of Southern Theatre Command, Guangzhou, China
| | - Erica A. Voss
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Janssen Research and Development, Raritan, New Jersey, United States of America
- Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Peter R. Rijnbeek
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - RuiJun Chen
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Department of Biomedical Informatics, Columbia University, New York, New York, United States of America
- Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America
| | - Gowtham A. Rao
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Janssen Research and Development, Raritan, New Jersey, United States of America
| | - Henry Morgan Stewart
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- IQVIA, Durham, North Carolina, United States of America
| | - Andrew E. Williams
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Tufts Medical Center, Institute for Clinical Research and Health Policy Studies, Boston, Massachusetts, United States of America
| | - Ross D. Williams
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mui Van Zandt
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- IQVIA, Durham, North Carolina, United States of America
| | - Thomas Falconer
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Department of Biomedical Informatics, Columbia University, New York, New York, United States of America
| | - Margarita Fernandez-Chas
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- IQVIA, Durham, North Carolina, United States of America
| | - Rohit Vashisht
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Stanford Center for Biomedical Informatics Research, Stanford, California, United States of America
| | - Stephen R. Pfohl
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Stanford Center for Biomedical Informatics Research, Stanford, California, United States of America
| | - Nigam H. Shah
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Stanford Center for Biomedical Informatics Research, Stanford, California, United States of America
| | - Suranga N. Kasthurirathne
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Center for Biomedical Informatics, Regenstrief Institute, Indianapolis, Indiana, United States of America
- Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, United States of America
| | - Seng Chan You
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- Department of Biomedical informatics, Ajou University School of Medicine, Suwon, Korea
| | - Qing Jiang
- Biomedical Engineering School, Sun Yat-Sen University, Guangzhou, China
| | - Christian Reich
- Observational Health Data Sciences and Informatics, New York, New York, United States of America
- IQVIA, Durham, North Carolina, United States of America
| | - Yi Zhou
- Department of Biomedical Engineering, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
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12
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Abouhussein DMN, Bahaa El Din Mahmoud D, Mohammad F E. Design of a liquid nano-sized drug delivery system with enhanced solubility of rivaroxaban for venous thromboembolism management in paediatric patients and emergency cases. J Liposome Res 2019; 29:399-412. [PMID: 30720378 DOI: 10.1080/08982104.2019.1576732] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The increasing incidence of venous thromboembolism (VTE) in paediatric population has stimulated the development of liquid anticoagulant formulations. Thus our goal is to formulate a liquid formulation of poorly-water soluble anticoagulant, rivaroxaban (RIVA), for paediatric use and to assess the possibility of its intravenous administration in emergencies. Self-nanoemulsifying drug delivery systems (SNEDDSs) were developed and characterized. SNEDDS constituents were estimated from the saturated solubility study followed by plotting the corresponding ternary phase diagrams to determine the best self-emulsified systems. Thermodynamic stability, emulsification, dispersibility, robustness to dilution tests, in vitro dissolution, particle size, and zeta potential were executed to optimize the formulations. The optimized formulation, that composed of Capryol 90:Tween 20:PEG 300 (5:45:50), increased RIVA solubility (285.7-fold than water), it formed nanoemulsion with a particle size of 16.15 nm, PDI of 0.25 and zeta potential of -21.8. It released 100.83 ± 2.78% of RIVA after 5 min. SNEDDS was robust to dilution with oral and parenteral fluids and showed safety to human RBCs. SNEDDS showed enhanced bioavailability after oral and intravenous administration than the oral drug suspension (by 1.25 and 1.26-fold, respectively). Moreover, it exhibited enhanced anticoagulant efficacy in the prevention and treatment of carrageenan-induced thrombosis rat model.
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Affiliation(s)
- Dalia M N Abouhussein
- Pharmaceutics Department, National Organization for Drug Control and Research (NODCAR) , Giza , Egypt
| | - Dina Bahaa El Din Mahmoud
- Pharmaceutics Department, National Organization for Drug Control and Research (NODCAR) , Giza , Egypt
| | - Ebtehal Mohammad F
- Department of Pharmacology, National Organization for Drug Control and Research (NODCAR) , Giza , Egypt
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