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1.
Acta Pharmacol Sin ; 45(7): 1477-1491, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38538716

RESUMO

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Diabetes Mellitus Experimental , Transdução de Sinais , Cicatrização , Quinases Associadas a rho , Animais , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Cicatrização/efeitos dos fármacos , Humanos , Diabetes Mellitus Experimental/metabolismo , Masculino , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Camundongos , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por AMP/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III/metabolismo , Feminino
2.
Metab Brain Dis ; 39(7): 1335-1351, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39088109

RESUMO

Alzheimer's disease (AD) is characterized by cognitive decline stemming from the accumulation of beta-amyloid (Aß) plaques and the propagation of tau pathology through synapses. Exosomes, crucial mediators in neuronal development, maintenance, and intercellular communication, have gained attention in AD research. Yet, the molecular mechanisms involving exosomal miRNAs in AD remain elusive. In this study, we treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice, a model for AD, with either vehicle (ADNS) or fasudil (ADF), while C57BL/6 (control) mice received vehicle (WT). Cognitive function was evaluated using the Y-maze test, and AD pathology was confirmed through immunostaining and western blot analysis of Aß plaques and phosphorylated tau. Exosomal RNAs were extracted, sequenced, and analyzed from each mouse group. Our findings revealed that fasudil treatment improved cognitive function in AD mice, as evidenced by increased spontaneous alternation in the Y-maze test and reduced Aß plaque load and phosphorylated tau protein expression in the hippocampus. Analysis of exosomal miRNAs identified three miRNAs (mmu-let-7i-5p, mmu-miR-19a-3p, mmu-miR-451a) common to both ADNS vs ADF and WT vs ADNS groups. Utilizing miRTarBase software, we predicted and analyzed target genes associated with these miRNAs. Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of miRNA target genes indicated that mmu-miR-19a-3p and mmu-miR-451a are implicated in signal transduction, immune response, cellular communication, and nervous system pathways. Specifically, mmu-miR-19a-3p targeted genes involved in the sphingolipid signaling pathway, such as Pten and Tnf, while mmu-miR-451a targeted Nsmaf, Gnai3, and Akt3. Moreover, mmu-miR-451a targeted Myc in signaling pathways regulating the pluripotency of stem cells. In conclusion, fasudil treatment enhanced cognitive function by modulating exosomal MicroRNAs, particularly mmu-miR-451a and mmu-miR-19a-3p. These miRNAs hold promise as potential biomarkers and therapeutic targets for novel AD treatments.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Doença de Alzheimer , Cognição , Modelos Animais de Doenças , Exossomos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , MicroRNAs/genética , Camundongos , Exossomos/metabolismo , Exossomos/genética , Cognição/efeitos dos fármacos , Cognição/fisiologia , Masculino , Presenilina-1/genética , Precursor de Proteína beta-Amiloide/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos
3.
Biochem Biophys Res Commun ; 649: 32-38, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36739697

RESUMO

The small GTPase Rho and its effector Rho-kinase (ROCK) are activated in the diabetic kidney, and recent studies decade have demonstrated that ROCK signaling is an integral pathway in the progression of diabetic kidney disease. We previously identified the distinct role of ROCK1, an isoform of ROCK, in fatty acid metabolism in diabetic glomeruli. However, the effect of pharmacological intervention for ROCK1 is not clear. In the present study, we show that the inhibition of ROCK1 by Y-27632 and fasudil restores fatty acid oxidation in the glomeruli. Mechanistically, these compounds optimize fatty acid utilization and redox balance in mesangial cells via AMPK phosphorylation and the subsequent induction of PGC-1α. A further in vivo study showed that the inhibition of ROCK1 suppressed the downregulation of the fatty acid oxidation-related gene expression in glomeruli and mitochondrial fragmentation in the mesangial cells of db/db mice. These observations indicate that ROCK1 could be a promising therapeutic target for diabetic kidney disease through a mechanism that improves glomerular fatty acid metabolism.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Quinases Associadas a rho/metabolismo , Glomérulos Renais/metabolismo , Rim/metabolismo , Transdução de Sinais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Diabetes Mellitus/metabolismo
4.
Pharmacol Res ; 194: 106847, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37454916

RESUMO

Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.


Assuntos
Antineoplásicos , Neoplasias , Estados Unidos , Humanos , Inibidores de Proteínas Quinases/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Proteínas Quinases , Antineoplásicos/uso terapêutico
5.
J Neurochem ; 158(4): 980-996, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34033116

RESUMO

Postoperative delirium (POD) is a common post-operative complication in elderly patients that is associated with increased morbidity and mortality. However, the neuropathogenesis of this complication remains unknown. The blood-cerebrospinal fluid barrier (BCB) and brain-blood barrier (BBB) are composed of tight junctions between cells that form physical barriers, and BBB damage plays an important role in the neuropathogenesis of POD. Nevertheless, the role of BCB in POD remains to be elucidated. Herein, we investigated the effect of adenosine A2A receptor (A2A R), a key regulator of the permeability of barriers, on surgery-induced increased permeability of BCB and POD-like behaviors. Open field, buried food, and Y maze tests were used to evaluate behavioral changes in rats after surgery. Levels of tight junction proteins, adherens junction proteins, A2A R, GTP-RhoA, and ROCK2 in the choroid plexus were assessed by western blotting. The concentrations of NaFI and FITC-dextran in the cerebrospinal fluid (CSF) were detected by fluorescence spectrophotometry. Transmission electron microscopy was applied to observe the ultrastructure of the choroid plexus. Surgery/anesthesia decreased the levels of tight junction (e.g., ZO-1, occludin, and claudin1) proteins, increased concentrations of NaFI and FITC-dextran in CSF, damaged the ultrastructure of choroid plexus, and induced POD-like behaviors in rats. An A2A R antagonist alleviated POD-like behaviors in rats. Furthermore, the A2A R antagonist increased the levels of tight junction proteins and restored the permeability of BCB in rats with POD. Fasudil, a selective Rho-associated protein kinase 2 (ROCK2) inhibitor, ameliorated POD-like behaviors induced by A2A R activation. Moreover, fasudil also abolished the increased levels of GTP-RhoA/ROCK2, decreased levels of tight junction proteins, and increased permeability of BCB caused by A2A R activation. Our findings demonstrate that A2A R might participate in regulating BCB permeability in rats with POD via the RhoA/ROCK2 signaling pathway, which suggests the potential of A2A R as a therapeutic target for POD.


Assuntos
Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Delírio/tratamento farmacológico , Delírio/psicologia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/psicologia , Receptor A2A de Adenosina/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Plexo Corióideo/patologia , Delírio/induzido quimicamente , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Permeabilidade , Ratos , Ratos Sprague-Dawley , Fluoreto de Sódio/líquido cefalorraquidiano , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos
6.
Biochem Biophys Res Commun ; 526(3): 547-552, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32192772

RESUMO

Osteoclast and osteoblast are essential for proper bone development and remodeling as well as recovery of bone fracture. In this study, we seek chemical compounds that enhance turnover of bone metabolism for promoting bone healing. First, we screen a chemical library which includes 378 compounds by using murine pre-osteoclastic RAW264.7 cells to identify compounds that promote osteoclastic differentiation. We find that two ROCK (Rho-associated coiled-coil kinase) inhibitors, HA-1077 (Fasudil) and Y-27632, enhance osteoclastogenesis. Subsequently, we identify that these two compounds also increase osteoblastic differentiation of MC3T3-E1 cells. Finally, our in vivo experiment shows that the local administration of ROCK inhibitors accelerate the bone healing of the rat calvarial defect.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Amidas/farmacologia , Osteogênese/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/química , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Amidas/química , Amidas/uso terapêutico , Animais , Diferenciação Celular , Linhagem Celular , Consolidação da Fratura/efeitos dos fármacos , Masculino , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Crânio/efeitos dos fármacos , Crânio/lesões , Crânio/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Quinases Associadas a rho/metabolismo
7.
Molecules ; 25(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481507

RESUMO

Parkinson's disease (PD) is a multifactorial neurodegenerative disease. In recent years, several studies demonstrated that the gastroenteric system and intestinal microbiome influence central nervous system function. The pathological mechanisms triggered thereby change neuronal function in neurodegenerative diseases including dopaminergic neurons in Parkinson´s disease. In this study, we employed a model system for PD of cultured primary mesencephalic cells and used the pesticide rotenone to model dopaminergic cell damage. We examined neuroprotective effects of the Rho kinase inhibitor Fasudil and the short chain fatty acid (SCFA) propionic acid on primary neurons in cell morphological assays, cell survival, gene and protein expression. Fasudil application resulted in significantly enhanced neuritic outgrowth and increased cell survival of dopaminergic cells. The application of propionic acid primarily promoted cell survival of dopaminergic cells against rotenone toxicity and increased neurite outgrowth to a moderate extent. Interestingly, Fasudil augmented gene expression of synaptophysin whereas gene expression levels of tyrosine hydroxylase (TH) were substantially increased by propionic acid. Concerning protein expression propionic acid treatment increased STAT3 levels but did not lead to an increased phosphorylation indicative of pathway activation. Our findings indicate that both Fasudil and propionic acid treatment show beneficial potential in rotenone-lesioned primary mesencephalic cells.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Propionatos/farmacologia , Rotenona/toxicidade , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Imuno-Histoquímica , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Gravidez , Propionatos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/metabolismo , Quinases Associadas a rho/metabolismo
8.
Stroke ; 50(3): 738-744, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30744543

RESUMO

Background and Purpose- Previously, murine models Krit1 +/- Msh2 -/- and Ccm2 +/- Trp53 -/- showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods- The murine models, Pdcd10 +/- Trp53 -/- and Pdcd10 +/- Msh2 -/-, were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results- The Pdcd10 +/- Trp53 -/- /Msh2 -/- models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P=0.027) by fasudil, and to 0.0047 ( P=0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions- These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Hemorragias Intracranianas/tratamento farmacológico , Hemorragias Intracranianas/genética , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Proteínas Reguladoras de Apoptose , Atorvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hemorragias Intracranianas/diagnóstico por imagem , Proteína KRIT1/genética , Camundongos , Camundongos Knockout , Sinvastatina/uso terapêutico , Microtomografia por Raio-X
9.
Clin Immunol ; 201: 35-47, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30660624

RESUMO

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system characterized by oligodendrocyte loss and progressive neurodegeneration. The cuprizone (CPZ)-induced demyelination is widely used to investigate the demyelination/remyelination. Here, we explored the therapeutic effects of Hydroxyfasudil (HF), an active metabolite of Fasudil, in CPZ model. HF improved behavioral abnormality and reduced myelin damage in the corpus callosum. Splenic atrophy and myelin oligodendrocyte glycoprotein (MOG) antibody were observed in CPZ model, which were partially restored and obviously inhibited by HF, therefore reducing pathogenic binding of MOG antibody to oligodendrocytes. HF inhibited the percentages of CD4+IL-17+ T cells from splenocytes and infiltration of CD4+ T cells and CD68+ macrophages in the brain. HF also declined microglia-mediated neuroinflammation, and promoted the production of astrocyte-derived brain derived neurotrophic factor (BDNF) and regeneration of NG2+ oligodendrocyte precursor cells. These results provide potent evidence for the therapeutic effects of HF in CPZ-induced demyelination.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Doenças Desmielinizantes/tratamento farmacológico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Cuprizona , Citocinas/imunologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia
10.
Bioorg Med Chem Lett ; 29(14): 1812-1818, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31088713

RESUMO

Given the therapeutic efficacy of fasudil hydrochloride (F) and dichloroacetate (DCA) on pulmonary arterial hypertension (PAH), a new salt fasudil dichloroacetate (FDCA) was designed, synthesized and biologically evaluated. FDCA exhibited comparable ROCK II inhibitory activity relative to fasudil hydrochloride, and suppressed the expression of TNF-α and IL-6 in both PDGF-BB and hypoxia-treated pulmonary arterial smooth muscle cells (PASMCs) and endothelial cells (PAECs). Significantly, FDCA lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), and decreased right ventricular hypertrophy (RVH) in monocrotaline (MCT)-induced PAH rats. Meanwhile, FDCA remarkably decreased pulmonary artery medial thickness (PAMT) and hyperplasia, restoring the elasticity of elastic fiber, reduced cardiac hypertrophy, and attenuated fibrosis of heart and lung. Collectively, FDCA exhibited triple activities of pulmonary vasodilation, vascular remodeling inhibition and RVH inhibition, suggesting that it may be a promising agent for PAH intervention.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Administração Oral , Animais , Masculino , Inibidores de Proteínas Quinases/farmacologia , Ratos
11.
Int J Mol Sci ; 20(23)2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31771203

RESUMO

There are three critical pathways for the pathogenesis and progression of pulmonary arterial hypertension (PAH): the prostacyclin (prostaglandin I2) (PGI2), nitric oxide (NO), and endothelin pathways. The current approved drugs targeting these three pathways, including prostacyclin (PGI2), phosphodiesterase type-5 (PDE5) inhibitors, and endothelin receptor antagonists (ERAs), have been shown to be effective, however, PAH remains a severe clinical condition and the long-term survival of patients with PAH is still suboptimal. The full therapeutic abilities of available drugs are reduced by medication, patient non-compliance, and side effects. Nanoparticles are expected to address these problems by providing a novel drug delivery approach for the treatment of PAH. Drug-loaded nanoparticles for local delivery can optimize the efficacy and minimize the adverse effects of drugs. Prostacyclin (PGI2) analogue, PDE5 inhibitors, ERA, pitavastatin, imatinib, rapamycin, fasudil, and oligonucleotides-loaded nanoparticles have been reported to be effective in animal PAH models and in vitro studies. However, the efficacy and safety of nanoparticle mediated-drug delivery systems for PAH treatment in humans are unknown and further clinical studies are required to clarify these points.


Assuntos
Nanopartículas/química , Hipertensão Arterial Pulmonar/tratamento farmacológico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Mesilato de Imatinib/uso terapêutico , Quinolinas/uso terapêutico
12.
Mol Cancer ; 17(1): 40, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29455651

RESUMO

Atypical Chronic Myeloid Leukemia (aCML) is a myeloproliferative neoplasm characterized by neutrophilic leukocytosis and dysgranulopoiesis. From a genetic point of view, aCML shows a heterogeneous mutational landscape with mutations affecting signal transduction proteins but also broad genetic modifiers and chromatin remodelers, making difficult to understand the molecular mechanisms causing the onset of the disease. The JAK-STAT, MAPK and ROCK pathways are known to be responsible for myeloproliferation in physiological conditions and to be aberrantly activated in myeloproliferative diseases. Furthermore, experimental evidences suggest the efficacy of inhibitors targeting these pathways in repressing myeloproliferation, opening the way to deep clinical investigations. However, the activation status of these pathways is rarely analyzed when genetic mutations do not occur in a component of the signaling cascade. Given that mutations in functionally unrelated genes give rise to the same pathology, it is tempting to speculate that alteration in the few signaling pathways mentioned above might be a common feature of pathological myeloproliferation. If so, targeted therapy would be an option to be considered for aCML patients.


Assuntos
Janus Quinases/metabolismo , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Humanos , Janus Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação/genética , Nitrilas , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Pirimidinas , Pirimidinonas/uso terapêutico , Transdução de Sinais/genética , Quinases Associadas a rho/genética
13.
Annu Rev Med ; 67: 355-74, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26768244

RESUMO

The Rho kinases, or ROCKs, are a family of serine-threonine kinases that serve as key downstream effectors for Rho GTPases. The ROCKs are increasingly recognized as critical coordinators of a tissue response to injury due to their ability to modulate a wide range of biological processes. Dysregulated ROCK activity has been implicated in several human pathophysiological conditions ranging from cardiovascular and renal disorders to fibrotic diseases. In recent years, an important role for the ROCKs in the regulation of immune responses is also being uncovered. We provide an overview of the role of the ROCKs in immune cells and discuss studies that highlight the emerging involvement of this family of kinases in the pathogenesis of autoimmune diseases. Given the potential promise of the ROCKs as therapeutic targets, we also outline the approaches that could be employed to inhibit the ROCKs in autoimmune disorders.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos T/imunologia , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/imunologia , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Amidas/uso terapêutico , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Linfócitos B/imunologia , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Citoesqueleto/metabolismo , Expressão Gênica , Arterite de Células Gigantes/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Células Mieloides/imunologia , Osteoartrite/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/efeitos dos fármacos , Quinases Associadas a rho/genética
14.
Dig Dis Sci ; 63(10): 2653-2661, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29767392

RESUMO

BACKGROUND: Benign biliary stricture (BBS) is highly refractory. Currently, there is no effective strategy for prevention of BBS recurrence. The aim of this study is to establish a novel BBS rabbit model and to investigate the efficacy of biliary infusion with anti-proliferative medications for treating BBS. METHOD: A BBS model was established via surgical injury and biliary infection. The biliary infusion tube was inserted into the common bile duct via the stump of cystic duct after cholecystectomy. Biliary infusions with Rapamycin, Pirfenidone and Fasudil were performed daily during the 4 weeks following the surgery. The wall thickness and luminal area of the bile duct were assessed. RESULTS: All rabbits formed BBS after surgery. The mortality rate was 13% (8/60) and tube withdrawal rate was 4% (2/48). The thickness of the bile duct wall was significantly reduced; whereas the luminal area of the bile duct was dramatically enlarged in the Rapamycin or the Pirfenidone treated group, compared to the saline treated group. Furthermore, the local treatment significantly decreased the levels of proliferation makers, including PCNA, Collagen I and fibrogenic mediators, including ACTA2 and TGF-beta. CONCLUSION: We have established a novel animal model for BBS formation. We have further demonstrated that biliary infusion with Rapamycin or Pirfenidone limits the biliary strictures through inhibiting the proliferation of the bile duct wall in this model. This may represent a new avenue for preventing biliary restenosis.


Assuntos
Doenças Biliares , Modelos Animais de Doenças , Coelhos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Constrição Patológica , Avaliação Pré-Clínica de Medicamentos , Piridonas/uso terapêutico , Prevenção Secundária , Sirolimo/uso terapêutico , Vasodilatadores/uso terapêutico
15.
Stroke ; 48(1): 187-194, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27879448

RESUMO

BACKGROUND AND PURPOSE: We sought to compare the effect of chronic treatment with commonly tolerated doses of Fasudil, a specific RhoA kinase (ROCK) inhibitor, and simvastatin (with pleiotropic effects including ROCK inhibition) on cerebral cavernous malformation (CCM) genesis and maturation in 2 models that recapitulate the human disease. METHODS: Two heterozygous murine models, Ccm1+/-Msh2-/- and Ccm2+/-Trp53-/-, were treated from weaning to 4 to 5 months of age with Fasudil (100 mg/kg per day), simvastatin (40 mg/kg per day) or with placebo. Mouse brains were blindly assessed for CCM lesion burden, nonheme iron deposition (as a quantitative measure of chronic lesional hemorrhage), and ROCK activity. RESULTS: Fasudil, but not simvastatin, significantly decreased mature CCM lesion burden in Ccm1+/-Msh2-/- mice, and in meta-analysis of both models combined, when compared with mice receiving placebo. Fasudil and simvastatin both significantly decreased the integrated iron density per mature lesion area in Ccm1+/-Msh2-/- mice, and in both models combined, compared with mice given placebo. ROCK activity in mature lesions of Ccm1+/-Msh2-/- mice was similar with both treatments. Fasudil, but not simvastatin, improved survival in Ccm1+/-Msh2-/- mice. Fasudil and simvastatin treatment did not affect survival or lesion development significantly in Ccm2+/-Trp53-/- mice alone, and Fasudil benefit seemed limited to males. CONCLUSIONS: ROCK inhibitor Fasudil was more efficacious than simvastatin in improving survival and blunting the development of mature CCM lesions. Both drugs significantly decreased chronic hemorrhage in CCM lesions. These findings justify the development of ROCK inhibitors and the clinical testing of commonly used statin agents in CCM.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Neoplasias Encefálicas/tratamento farmacológico , Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Sinvastatina/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Neoplasias Encefálicas/patologia , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Camundongos , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sinvastatina/farmacologia
16.
Blood ; 125(24): 3760-8, 2015 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-25931586

RESUMO

Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within an individual patient's mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral loss-of-function RNA interference (RNAi) screen in primary leukemic cells. Stringent validation identified 6 genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression, and although some of the candidates seemed to be rather patient specific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1 inhibition did not foster growth of immature malignant progenitors but was toxic to this cell fraction in feeder coculture and xenotransplant experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large-scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Inibidores de Proteínas Quinases/uso terapêutico , Interferência de RNA , Quinases Associadas a rho/genética , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Apoptose/efeitos dos fármacos , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Células Tumorais Cultivadas , Quinases Associadas a rho/antagonistas & inibidores
17.
Int J Neuropsychopharmacol ; 20(4): 336-345, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27927737

RESUMO

Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss. Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed. Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration. Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Dendritos/efeitos dos fármacos , Depressão/patologia , Depressão/prevenção & controle , Hipocampo/patologia , Células Piramidais/ultraestrutura , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Fatores de Despolimerização de Actina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dendritos/ultraestrutura , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Resposta de Imobilidade Tônica/efeitos dos fármacos , Quinases Lim/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteína Fosfatase 1/metabolismo , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Restrição Física/efeitos adversos , Natação/psicologia
18.
J Cardiovasc Pharmacol ; 70(2): 102-109, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28437280

RESUMO

Chronic intermittent hypoxia (CIH), the hallmark of obstructive sleep apnea syndrome (OSAS), has been reported to play a key role in the development of OSAS-associated cardiovascular diseases including cardiac remodeling. RhoA/Rho-kinase (ROCK) pathway has also been implicated in myocardial remodeling, but the exact mechanisms are not fully elucidated. This study's purpose is to investigate the influence of fasudil, a selective ROCK inhibitor, on CIH-induced left ventricular remodeling in rats and its possible mechanisms. Adult male Sprague-Dawley rats suffered from CIH or normoxia stimulus and were intervened with vehicle or fasudil (10 mg·kg·d, intraperitoneal injection) for 6 weeks. In this study, treatment with fasudil significantly reversed intermittent hypoxia-induced histopathological transformations and ultrastructural changes in rat myocardium. Moreover, fasudil downregulated the protein levels of RhoA and phosphorylation of myosin phosphatase targeting subunit-1 (MYPT1), thus effectively inhibited the activation of RhoA/ROCK signaling pathway. Simultaneously, activity of nuclear factor (NF)-kB was suppressed by fasudil, which was accompanied by reduced NF-kB downstream inflammatory genes including interleukin-6, tumor necrosis factor-a and monocyte chemotactic protein-1, and apoptosis. These results suggest that fasudil attenuates myocardial remodeling in CIH rats, at least partly by suppressing activation of NF-kB. Inhibition of the RhoA/ROCK pathway could become an important therapeutic target in the prevention of OSAS-related cardiomyopathy.


Assuntos
Apoptose/fisiologia , Hipóxia/metabolismo , Miocárdio/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Remodelação Ventricular/fisiologia , Quinases Associadas a rho/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Hipóxia/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Miocárdio/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores
19.
RNA Biol ; 14(7): 963-971, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28387604

RESUMO

Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long ncRNAs (lncRNAs), are important players in diseases and emerge as novel drug targets. Thus, unraveling the relationships between ncRNAs and other biomedical entities in cells are critical for better understanding ncRNA roles that may eventually help develop their use in medicine. To support ncRNA research and facilitate retrieval of relevant information regarding miRNAs and lncRNAs from the plethora of published ncRNA-related research, we developed DES-ncRNA ( www.cbrc.kaust.edu.sa/des_ncrna ). DES-ncRNA is a knowledgebase containing text- and data-mined information from public scientific literature and other public resources. Exploration of mined information is enabled through terms and pairs of terms from 19 topic-specific dictionaries including, for example, antibiotics, toxins, drugs, enzymes, mutations, pathways, human genes and proteins, drug indications and side effects, mutations, diseases, etc. DES-ncRNA contains approximately 878,000 associations of terms from these dictionaries of which 36,222 (5,373) are with regards to miRNAs (lncRNAs). We provide several ways to explore information regarding ncRNAs to users including controlled generation of association networks as well as hypotheses generation. We show an example how DES-ncRNA can aid research on Alzheimer disease and suggest potential therapeutic role for Fasudil. DES-ncRNA is a powerful tool that can be used on its own or as a complement to the existing resources, to support research in human ncRNA. To our knowledge, this is the only knowledgebase dedicated to human miRNAs and lncRNAs derived primarily through literature-mining enabling exploration of a broad spectrum of associated biomedical entities, not paralleled by any other resource.


Assuntos
Mineração de Dados , Bases de Conhecimento , MicroRNAs/genética , RNA Longo não Codificante/genética , Software , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Dicionários como Assunto , Progressão da Doença , Ontologia Genética , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo
20.
Am J Ther ; 24(6): e676-e680, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26825486

RESUMO

To investigate the effects of topical administration of a selective Rho-associated kinase (ROCK) inhibitor, fasudil 0.5% and 1.2% in glaucomatous patients. In this interventional case series study, 4 eyes of 4 patients with unilateral end-stage primary open-angle glaucoma and no light perception vision were assigned to receive topical fasudil 0.5% (in 3 eyes) or 1.2% (in 1 eye) ophthalmic solution twice daily for 8 weeks. At weeks 1, 2, 3, 4, and 8, intraocular pressure (IOP) and adverse events were evaluated. Baseline mean IOP was 53.5 ± 3.4 mm Hg and mean IOP reductions of the last visit were -8.25 ± 1.2 mm Hg at 2 hours and -8.75 ± 2.2 mm Hg at 4 hours. Mean IOP reductions were clinically and statistically significant with 0.5% and 1.2% fasudil and peak effects occurred 2-4 hours after application (P = 0.0002). The largest IOP reductions were produced by 1.2% fasudil (up to -12 mm Hg). Conjunctival hyperemia was found in 1 patient with 1.2% fasudil. Topical administration of fasudil in end-stage primary open-angle glaucoma patients, caused reduction in IOP and was well tolerated. ROCK inhibitors could be considered as a candidate for glaucoma therapy in future.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Glaucoma de Ângulo Aberto/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Soluções Oftálmicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Administração Oftálmica , Idoso , Túnica Conjuntiva/irrigação sanguínea , Túnica Conjuntiva/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Hiperemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Tonometria Ocular
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