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  1. Article ; Online: Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword.

    Peh, Alex / O'Donnell, Joanne A / Broughton, Brad R S / Marques, Francine Z

    Stroke

    2022  Volume 53, Issue 5, Page(s) 1788–1801

    Abstract: Besides damaging the brain, stroke causes systemic changes, including to the gastrointestinal system. A growing body of evidence supports the role of the gut and its microbiota in stroke, stroke prognosis, and recovery. The gut microbiota can increase ... ...

    Abstract Besides damaging the brain, stroke causes systemic changes, including to the gastrointestinal system. A growing body of evidence supports the role of the gut and its microbiota in stroke, stroke prognosis, and recovery. The gut microbiota can increase the risk of a cerebrovascular event, playing a role in the onset of stroke. Conversely, stroke can induce dysbiosis of the gut microbiota and epithelial barrier integrity. This has been proposed as a contributor to systemic infections. In this review, we describe the role of the gut microbiota, microbiome and microbiota-derived metabolites in experimental and clinical stroke, and their potential use as therapeutic targets. Fourteen clinical studies have identified 62 upregulated (eg,
    MeSH term(s) Animals ; Brain ; Dysbiosis ; Fatty Acids, Volatile ; Gastrointestinal Microbiome ; Humans ; Mice ; Stroke/microbiology
    Chemical Substances Fatty Acids, Volatile
    Language English
    Publishing date 2022-02-09
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 80381-9
    ISSN 1524-4628 ; 0039-2499 ; 0749-7954
    ISSN (online) 1524-4628
    ISSN 0039-2499 ; 0749-7954
    DOI 10.1161/STROKEAHA.121.036800
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Optimising the photothrombotic model of stroke in the C57BI/6 and FVB/N strains of mouse.

    Knezic, Adriana / Broughton, Brad R S / Widdop, Robert E / McCarthy, Claudia A

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 7598

    Abstract: The photothrombotic stroke model relies on the interaction between photosensitive-dye and light for clot formation. Interestingly, the relationship between the length of light exposure and stroke-outcome has never been examined. This model has yet to be ... ...

    Abstract The photothrombotic stroke model relies on the interaction between photosensitive-dye and light for clot formation. Interestingly, the relationship between the length of light exposure and stroke-outcome has never been examined. This model has yet to be established in the FVB/N strain, even though stroke-outcomes are strain-specific. Therefore, this study aimed to examine the effect of different lengths of light exposure in two strains of mice on photothrombotic stroke. Male FVB/N and C57Bl/6 mice were subjected to stroke using 15, 18, or 20-min light exposure. Mice underwent functional testing for up to 7 days. Infarct volume was assessed with thionin staining, and cellular responses to injury analysed via immunofluorescence at 7-days post-stroke. Blood brain barrier (BBB) breakdown was assessed using Evans blue dye at 4.5-h post-stroke. Increasing light exposure from 15 to 20-min increased infarct volume but not functional deficit. Interestingly, there were strain-specific differences in functional outcomes, with FVB/N mice having less deficit on the hanging wire test than C57BI/6 after 15-min of light exposure. The opposite was seen in the adhesive removal test. There was no difference in the number of neurons, astrocytes, microglia, macrophages, and T cells between the strains, despite FVB/N mice demonstrating greater BBB breakdown and an enlarged spleen post-stroke. Increasing light exposure systematically increases infarct volume but does not worsen functional outcomes. FVB/N and C57Bl/6 mice exhibit subtle differences in functional outcomes post stroke, which highlights the need to choose tests which are appropriate for the mouse strain being used.
    MeSH term(s) Animals ; Blood-Brain Barrier/metabolism ; Infarction ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Stroke
    Language English
    Publishing date 2022-05-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-11793-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Hi1a Improves Sensorimotor Deficit following Endothelin-1-Induced Stroke in Rats but Does Not Improve Functional Outcomes following Filament-Induced Stroke in Mice.

    Knezic, Adriana / Budusan, Elena / Saez, Natalie J / Broughton, Brad R S / Rash, Lachlan D / King, Glenn F / Widdop, Robert E / McCarthy, Claudia A

    ACS pharmacology & translational science

    2024  Volume 7, Issue 4, Page(s) 1043–1054

    Abstract: Activation of acid-sensing ion channel 1a (ASIC1a) plays a major role in mediating acidosis-induced neuronal injury following a stroke. Therefore, the inhibition of ASIC1a is a potential therapeutic avenue for the treatment of stroke. Venom-peptide Hi1a, ...

    Abstract Activation of acid-sensing ion channel 1a (ASIC1a) plays a major role in mediating acidosis-induced neuronal injury following a stroke. Therefore, the inhibition of ASIC1a is a potential therapeutic avenue for the treatment of stroke. Venom-peptide Hi1a, a selective and highly potent ASIC1a inhibitor, reduces the infarct size and functional deficits when injected into the brain after stroke in rodents. However, its efficacy when administered using a clinically relevant route of administration remains to be established. Therefore, the current investigation aims to examine the efficacy of systemically administered Hi1a, using two different models of stroke in different species. Mice were subjected to the filament model of middle cerebral artery occlusion (MCAO) and treated with Hi1a systemically using either a single- or multiple-dosing regimen. 24 h poststroke, mice underwent functional testing, and the brain infarct size was assessed. Rats were subjected to endothelin-1 (ET-1)-induced MCAO and treated with Hi1a intravenously 2 h poststroke. Rats underwent functional tests prior to and for 3 days poststroke, when infarct volume was assessed. Mice receiving Hi1a did not show any improvements in functional outcomes, despite a trend toward reduced infarct size. This trend for reduced infarct size in mice was consistent regardless of the dosing regimen. There was also a trend toward lower infarct size in rats treated with Hi1a. More specifically, Hi1a reduced the amount of damage occurring within the somatosensory cortex, which was associated with an improved sensorimotor function in Hi1a-treated rats. Thus, this study suggests that Hi1a or more brain-permeable ASIC1a inhibitors are a potential stroke treatment.
    Language English
    Publishing date 2024-03-14
    Publishing country United States
    Document type Journal Article
    ISSN 2575-9108
    ISSN (online) 2575-9108
    DOI 10.1021/acsptsci.3c00328
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Optimising the photothrombotic model of stroke in the C57BI/6 and FVB/N strains of mouse

    Adriana Knezic / Brad R. S. Broughton / Robert E. Widdop / Claudia A. McCarthy

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 11

    Abstract: Abstract The photothrombotic stroke model relies on the interaction between photosensitive-dye and light for clot formation. Interestingly, the relationship between the length of light exposure and stroke-outcome has never been examined. This model has ... ...

    Abstract Abstract The photothrombotic stroke model relies on the interaction between photosensitive-dye and light for clot formation. Interestingly, the relationship between the length of light exposure and stroke-outcome has never been examined. This model has yet to be established in the FVB/N strain, even though stroke-outcomes are strain-specific. Therefore, this study aimed to examine the effect of different lengths of light exposure in two strains of mice on photothrombotic stroke. Male FVB/N and C57Bl/6 mice were subjected to stroke using 15, 18, or 20-min light exposure. Mice underwent functional testing for up to 7 days. Infarct volume was assessed with thionin staining, and cellular responses to injury analysed via immunofluorescence at 7-days post-stroke. Blood brain barrier (BBB) breakdown was assessed using Evans blue dye at 4.5-h post-stroke. Increasing light exposure from 15 to 20-min increased infarct volume but not functional deficit. Interestingly, there were strain-specific differences in functional outcomes, with FVB/N mice having less deficit on the hanging wire test than C57BI/6 after 15-min of light exposure. The opposite was seen in the adhesive removal test. There was no difference in the number of neurons, astrocytes, microglia, macrophages, and T cells between the strains, despite FVB/N mice demonstrating greater BBB breakdown and an enlarged spleen post-stroke. Increasing light exposure systematically increases infarct volume but does not worsen functional outcomes. FVB/N and C57Bl/6 mice exhibit subtle differences in functional outcomes post stroke, which highlights the need to choose tests which are appropriate for the mouse strain being used.
    Keywords Medicine ; R ; Science ; Q
    Subject code 590
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Post-stroke administration of H2 relaxin reduces functional deficits, neuronal apoptosis and immune cell infiltration into the mouse brain.

    Truong, Shirley H T / Bonnici, Benjamin / Rupasinghe, Samoda / Kemp-Harper, Barbara K / Samuel, Chrishan S / Broughton, Brad R S

    Pharmacological research

    2022  Volume 187, Page(s) 106611

    Abstract: Brain inflammation and apoptosis contribute to neuronal damage and loss following ischaemic stroke, leading to cognitive and functional disability. It is well-documented that the human gene-2 (H2)-relaxin hormone exhibits pleiotropic properties via its ... ...

    Abstract Brain inflammation and apoptosis contribute to neuronal damage and loss following ischaemic stroke, leading to cognitive and functional disability. It is well-documented that the human gene-2 (H2)-relaxin hormone exhibits pleiotropic properties via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), including anti-inflammatory and anti-apoptotic effects, thus making it a potential therapeutic for stroke. Hence, the current study investigated whether post-stroke H2-relaxin administration could improve functional and histological outcomes. 8-12-week-old male C57BL/6 mice were subjected to sham operation or photothrombotic stroke and intravenously-administered with either saline (vehicle) or 0.02, 0.2 or 2 mg/kg doses of recombinant H2-relaxin at 6, 24 and 48 h post-stroke. Motor function was assessed using the hanging wire and cylinder test pre-surgery, and at 24 and 72 h post-stroke. Brains were removed after 72 h and infarct volume was assessed via thionin staining, and RXFP1 expression, leukocyte infiltration and apoptosis were determined by immunofluorescence. RXFP1 was identified on neurons, astrocytes and macrophages, and increased post-stroke. Whilst H2-relaxin did not alter infarct volume, it did cause a dose-dependent improvement in motor function at 24 and 72 h post-stroke. Moreover, 2 mg/kg H2-relaxin significantly decreased the number of apoptotic cells as well as macrophages and neutrophils within the ischaemic hemisphere, but did not alter T or B cells numbers. The anti-inflammatory and anti-apoptotic effects of H2-relaxin when administered at 6 h post-cerebral ischaemia may provide a novel therapeutic option for patients following ischaemic stroke.
    MeSH term(s) Mice ; Animals ; Humans ; Male ; Relaxin/pharmacology ; Relaxin/therapeutic use ; Brain Ischemia/drug therapy ; Receptors, G-Protein-Coupled/metabolism ; Receptors, Peptide/chemistry ; Receptors, Peptide/metabolism ; Mice, Inbred C57BL ; Stroke/drug therapy ; Brain/metabolism ; Apoptosis ; Infarction ; Ischemic Stroke ; Anti-Inflammatory Agents
    Chemical Substances Relaxin (9002-69-1) ; Receptors, G-Protein-Coupled ; Receptors, Peptide ; Anti-Inflammatory Agents
    Language English
    Publishing date 2022-12-14
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1003347-6
    ISSN 1096-1186 ; 0031-6989 ; 1043-6618
    ISSN (online) 1096-1186
    ISSN 0031-6989 ; 1043-6618
    DOI 10.1016/j.phrs.2022.106611
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Simultaneous late-gadolinium enhancement and T1 mapping of fibrosis and a novel cell-based combination therapy in hypertensive mice.

    Li, Yifang / Zheng, Gang / Salimova, Ekaterina / Broughton, Brad R S / Ricardo, Sharon D / de Veer, Michael / Samuel, Chrishan S

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2022  Volume 158, Page(s) 114069

    Abstract: Fibrosis is a hallmark of chronic hypertension and disrupts the viability of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) post-transplantation. This study thus, determined whether the anti-fibrotic drug, serelaxin (RLX), could enhance ... ...

    Abstract Fibrosis is a hallmark of chronic hypertension and disrupts the viability of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) post-transplantation. This study thus, determined whether the anti-fibrotic drug, serelaxin (RLX), could enhance the therapeutic effects of BM-MSCs or BM-MSC-derived exosomes (BM-MSC-EXO) in hypertensive mice. Left ventricular (LV) fibrosis in particular was assessed using conventional histological staining and non-invasive cardiac magnetic resonance imaging (CMRI). CMRI was employed using a novel magnetisation prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence to simultaneously perform late gadolinium enhancement imaging and T1 mapping. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and saline to drink (1 K/DOCA/salt) for 21 days, whilst control mice were given normal drinking water for the same time-period. On day 14 post-injury, subgroups of 1 K/DOCA/salt-hypertensive mice were treated with RLX alone or in combination with BM-MSCs or BM-MSC-EXO; or the mineralocorticoid receptor antagonist, spironolactone. At day 21 post-injury, LV and kidney histopathology was assessed, whilst LV fibrosis and function were additionally analysed by CMRI and echocardiography. 1 K/DOCA/salt-hypertensive mice developed kidney tubular injury, inflammation, fibrosis, and more moderate LV hypertrophy, fibrosis and diastolic dysfunction. RLX and BM-MSCs combined provided optimal protection against these pathologies and significantly reduced picrosirius red-stained organ fibrosis and MP2RAGE analysis of LV fibrosis. A significant correlation between MP2RAGE analysis and histologically-stained interstitial LV fibrosis was detected. It was concluded that the MP2RAGE sequence enhanced the non-invasive CMRI detection of LV fibrosis. Furthermore, combining RLX and BM-MSCs may represent a promising treatment option for hypertensive cardiorenal syndrome.
    Language English
    Publishing date 2022-12-08
    Publishing country France
    Document type Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2022.114069
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Comparing the renoprotective effects of BM-MSCs versus BM-MSC-exosomes, when combined with an anti-fibrotic drug, in hypertensive mice.

    Li, Yifang / Chakraborty, Amlan / Broughton, Brad R S / Ferens, Dorota / Widdop, Robert E / Ricardo, Sharon D / Samuel, Chrishan S

    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

    2021  Volume 144, Page(s) 112256

    Abstract: Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, ... ...

    Abstract Fibrosis, a hallmark of chronic kidney disease (CKD), impairs the viability of human bone marrow derived-mesenchymal stromal cells (BM-MSCs) post-transplantation. To address this, we demonstrated that combining BM-MSCs with the anti-fibrotic drug, serelaxin (RLX), enhanced BM-MSC-induced renoprotection in preclinical CKD models. Given the increased interest and manufacturing advantages to using stem cell-derived exosomes (EXO) as therapeutics, this study determined whether RLX could enhance the therapeutic efficacy of BM-MSC-EXO, and compared the renoprotective effects of RLX and BM-MSC-EXO versus RLX and BM-MSCs in mice with hypertensive CKD. Adult male C57BL/6 mice were uninephrectomised, received deoxycorticosterone acetate and given saline to drink (1K/DOCA/salt) for 21 days. Control mice were uninephrectomised and given normal drinking water for the same time-period. Subgroups of 1K/DOCA/salt-hypertensive mice were then treated with either RLX (0.5 mg/kg/day) or BM-MSC-EXO (25 μg/mouse; equivalent to 1-2 × 10
    MeSH term(s) Animals ; Antifibrotic Agents/pharmacology ; Antihypertensive Agents/pharmacology ; Blood Pressure/drug effects ; Cells, Cultured ; Combined Modality Therapy ; Desoxycorticosterone Acetate ; Disease Models, Animal ; Exosomes/metabolism ; Exosomes/transplantation ; Fibrosis ; Hypertension/metabolism ; Hypertension/pathology ; Hypertension/physiopathology ; Hypertension/therapy ; Kidney/drug effects ; Kidney/metabolism ; Kidney/pathology ; Macrophages/drug effects ; Macrophages/metabolism ; Male ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/metabolism ; Mice, Inbred C57BL ; Mineralocorticoid Receptor Antagonists/pharmacology ; Nephrectomy ; Recombinant Proteins/pharmacology ; Relaxin/pharmacology ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/pathology ; Renal Insufficiency, Chronic/physiopathology ; Renal Insufficiency, Chronic/prevention & control ; Sodium Chloride, Dietary ; Spironolactone/pharmacology ; T-Lymphocytes/drug effects ; T-Lymphocytes/metabolism ; Mice
    Chemical Substances Antifibrotic Agents ; Antihypertensive Agents ; Mineralocorticoid Receptor Antagonists ; Recombinant Proteins ; Sodium Chloride, Dietary ; serelaxin protein, human ; Spironolactone (27O7W4T232) ; Desoxycorticosterone Acetate (6E0A168OB8) ; Relaxin (9002-69-1)
    Language English
    Publishing date 2021-10-01
    Publishing country France
    Document type Comparative Study ; Journal Article
    ZDB-ID 392415-4
    ISSN 1950-6007 ; 0753-3322 ; 0300-0893
    ISSN (online) 1950-6007
    ISSN 0753-3322 ; 0300-0893
    DOI 10.1016/j.biopha.2021.112256
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Platelet-targeted thrombolysis for treatment of acute ischemic stroke.

    Palazzolo, Jason S / Ale, Anukreity / Ho, Heidi / Jagdale, Shweta / Broughton, Brad R S / Medcalf, Robert L / Wright, David K / Alt, Karen / Hagemeyer, Christoph E / Niego, Be'eri

    Blood advances

    2022  Volume 7, Issue 4, Page(s) 561–574

    Abstract: Thrombolysis with tissue-type plasminogen activator (tPA) remains the main treatment for acute ischemic stroke. Nevertheless, tPA intervention is limited by a short therapeutic window, low recanalization rates, and a risk of intracranial hemorrhage (ICH), ...

    Abstract Thrombolysis with tissue-type plasminogen activator (tPA) remains the main treatment for acute ischemic stroke. Nevertheless, tPA intervention is limited by a short therapeutic window, low recanalization rates, and a risk of intracranial hemorrhage (ICH), highlighting the clinical demand for improved thrombolytic drugs. We examined a novel thrombolytic agent termed "SCE5-scuPA," comprising a single-chain urokinase plasminogen activator (scuPA) fused with a single-chain antibody (SCE5) that targets the activated glycoprotein IIb/IIIa platelet receptor, for its effects in experimental stroke. SCE5-scuPA was first tested in a whole blood clot degradation assay to show the benefit of platelet-targeted thrombolysis. The tail bleeding time, blood clearance, and biodistribution were then determined to inform the use of SCE5-scuPA in mouse models of photothrombotic stroke and middle cerebral artery occlusion against tenecteplase. The impacts of SCE5-scuPA on motor function, ICH, blood-brain barrier (BBB) integrity, and immunosuppression were evaluated. Infarct size was measured by computed tomography imaging and magnetic resonance imaging. SCE5-scuPA enhanced clot degradation ex vivo compared with its nonplatelet-targeting control. The maximal SCE5-scuPA dose that maintained hemostasis and a rapid blood clearance was determined. SCE5-scuPA administration both before and 2 hours after photothrombotic stroke reduced the infarct volume. SCE5-scuPA also improved neurologic deficit, decreased intracerebral blood deposits, preserved the BBB, and alleviated immunosuppression poststroke. In middle cerebral artery occlusion, SCE5-scuPA did not worsen stroke outcomes or cause ICH, and it protected the BBB. Our findings support the ongoing development of platelet-targeted thrombolysis with SCE5-scuPA as a novel emergency treatment for acute ischemic stroke with a promising safety profile.
    MeSH term(s) Mice ; Animals ; Ischemic Stroke/complications ; Ischemic Stroke/drug therapy ; Infarction, Middle Cerebral Artery/complications ; Infarction, Middle Cerebral Artery/drug therapy ; Tissue Distribution ; Thrombolytic Therapy/adverse effects ; Fibrinolytic Agents/therapeutic use ; Stroke/etiology ; Urokinase-Type Plasminogen Activator ; Thrombosis/drug therapy ; Platelet Glycoprotein GPIIb-IIIa Complex
    Chemical Substances Fibrinolytic Agents ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73) ; Platelet Glycoprotein GPIIb-IIIa Complex
    Language English
    Publishing date 2022-04-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2021006691
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  9. Article ; Online: Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.

    Royce, Simon G / Rele, Siddharth / Broughton, Brad R S / Kelly, Kilian / Samuel, Chrishan S

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2017  Volume 31, Issue 9, Page(s) 4168–4178

    Abstract: Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed ... ...

    Abstract Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the
    MeSH term(s) Administration, Intranasal ; Airway Remodeling ; Animals ; Female ; Goblet Cells ; Hypersensitivity ; Mesenchymal Stromal Cells ; Metaplasia ; Mice ; Mice, Inbred BALB C ; Ovalbumin ; Pulmonary Fibrosis/therapy ; Respiratory Hypersensitivity/chemically induced ; Respiratory Hypersensitivity/immunology ; Respiratory Hypersensitivity/therapy ; Stem Cell Transplantation/methods
    Chemical Substances Ovalbumin (9006-59-1)
    Language English
    Publishing date 2017-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.201700178R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Combining mesenchymal stem cells with serelaxin provides enhanced renoprotection against 1K/DOCA/salt-induced hypertension.

    Li, Yifang / Shen, Matthew / Ferens, Dorota / Broughton, Brad R S / Murthi, Padma / Saini, Sheetal / Widdop, Robert E / Ricardo, Sharon D / Pinar, Anita A / Samuel, Chrishan S

    British journal of pharmacology

    2021  Volume 178, Issue 5, Page(s) 1164–1181

    Abstract: Background and purpose: Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This study determined whether combining bone marrow-derived ... ...

    Abstract Background and purpose: Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This study determined whether combining bone marrow-derived mesenchymal stem cells (BM-MSCs) with the renoprotective effects of recombinant human relaxin (serelaxin) could therapeutically reduce renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)-induced hypertension, compared with the effects of the ACE inhibitor, perindopril.
    Experimental approach: Adult male C57BL/6 mice were uni-nephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt) for 21 days. Control mice were uni-nephrectomised but received water over the same time period. Sub-groups of 1K/DOCA/salt-injured mice (n = 5-8 per group) were treated with either serelaxin (0.5 mg·kg
    Key results: 1K/DOCA/salt-injured mice developed elevated BP and hypertension-induced renal damage, inflammation and fibrosis. BM-MSCs alone reduced the injury-induced fibrosis and attenuated BP to a similar extent as perindopril. Serelaxin alone modestly reduced renal fibrosis and effectively reduced tubular injury. Strikingly, the combined effects of BM-MSCs (at both doses) with serelaxin significantly inhibited renal fibrosis and proximal tubular epithelial injury while restoring renal architecture, to a greater extent than either therapy alone, and over the effects of perindopril.
    Conclusion and implications: Combining BM-MSCs and serelaxin provided broader renoprotection over either therapy alone or perindopril and might represent a novel treatment for hypertensive CKD.
    MeSH term(s) Animals ; Blood Pressure ; Desoxycorticosterone ; Desoxycorticosterone Acetate ; Hypertension/chemically induced ; Hypertension/drug therapy ; Hypertension, Renal ; Kidney ; Male ; Mesenchymal Stem Cells ; Mice ; Mice, Inbred C57BL
    Chemical Substances Desoxycorticosterone (40GP35YQ49) ; Desoxycorticosterone Acetate (6E0A168OB8)
    Language English
    Publishing date 2021-02-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80081-8
    ISSN 1476-5381 ; 0007-1188
    ISSN (online) 1476-5381
    ISSN 0007-1188
    DOI 10.1111/bph.15361
    Database MEDical Literature Analysis and Retrieval System OnLINE

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