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1.
Life Sci ; 272: 119206, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577854

RESUMO

AIMS: Enhanced aerobic glycolysis is a motivation of fibroblast-myofibroblast transdifferentiation (FMT), leading to kidney fibrosis. 3-Bromopyruvate (3-BrPA) is a glycolysis inhibitor and has fibrosis-protected effect in liver. This study aims to explore the effects of 3-BrPA on aerobic glycolysis and kidney fibrosis in a unilateral ureteral obstruction (UUO) mice model and transforming growth factor-ß1(TGF-ß1)-stimulated normal rat kidney fibroblast (NRK49F) cell model in vitro. MAIN METHODS: In vivo UUO mouse model and in vitro TGF-ß1 stimulated cell model were built. Immunohistochemical staining, Western blots, Real-time PCR and fluorescence microscopy were employed to detect extra cellular matrix (ECM) synthesis, fibroblast activation, aerobic glycolysis switch and related signaling pathways. KEY FINDINGS: HE and Masson's Trichrome staining showed that 3-BrPA substantially suppressed kidney injury and interstitial collagen production. 3-BrPA also attenuated ECM accumulation in a dose-dependent manner, as shown by immunohistochemistry staining, RT-PCR and western blot. Furthermore, 3-BrPA inhibited FMT, as indicated by α-SMA and PCNA immunofluorescence double staining. Additionally, the results of MTT assay indicated 3-BrPA prevented TGF-ß1 induced fibroblasts proliferation in a time- and dose-dependent manner. Mechanistically, molecular docking results showed that 3-BrPA effectively decreased the aerobic glycolysis related enzymes Hexokinase-2 (HK-2), Lactate dehydrogenase A (LDHA) and Pyruvate kinase isozymes M2 (PKM-2), as well as inhibited IL-1 receptor-associated kinase 4 (IRAK4)/MYC protein levels. SIGNIFICANCE: Our study highlighted that 3-BrPA is a potential reno-protective agent in kidney fibrosis through the inhibition of fibroblasts aerobic glycolysis might via IRAK4/MYC signal pathways.


Assuntos
Fibrose/tratamento farmacológico , Piruvatos/farmacologia , Obstrução Ureteral/tratamento farmacológico , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , China , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Rim/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Miofibroblastos/metabolismo , Piruvatos/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Sistema Urinário/patologia
2.
Chem Biol Interact ; 335: 109332, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387473

RESUMO

Renal fibrosis is a major cause of renal failure in diabetic nephropathy. Tropisetron is an antagonist of the 5HT3 receptor that exhibits anti-fibrosis effects. The present research aimed to investigate the protected role of tropisetron against renal fibrosis of diabetic nephropathy and its molecular mechanisms. For this purpose, male Wistar rats were allocated into 5 groups of control, tropisetron, diabetes, tropisetron + diabetes, and glibenclamide + diabetes (n = 7). After induction of type 1 diabetes with a single injection of STZ, tropisetron (3 mg/kg) and glibenclamide (1 mg/kg) were given to the rats daily by intraperitoneal injection for 2 weeks. The obtained data revealed that the treatment of diabetic rats with tropisetron led to a significant decrease in the elevated blood glucose, serum cystatin c, and urinary total protein (UTP) level, indicating the improvement of the impaired kidney function. Moreover, the results of Masson's trichrome staining showed that fibrosis attenuated in the kidney of diabetic rats after tropisetron treatment. RT-PCR and Western blotting revealed that TGF-ß1, the apoptotic mediator, and p53 were considerably declined in the kidney of diabetic rats in response to tropisetron treatment. Meanwhile, the expressions of matrix metalloproteinase-9 (MMP-9) and matrix metalloproteinase-2 (MMP-2) were increased. These notable effects were equipotent with glibenclamide, as a standard drug, suggesting that tropisetron can alleviate renal fibrosis in diabetic nephropathy. Our data indicate that tropisetron could improve kidney function and attenuate renal fibrosis through regulation of TGF-ß1, p53, and expression of extracellular matrix metalloproteinases.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Tropizetrona/uso terapêutico , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Fibrose/patologia , Fibrose/prevenção & controle , Glucose/metabolismo , Rim/patologia , Masculino , Proteínas/metabolismo , Ratos Wistar , Estreptozocina
3.
Int J Mol Sci ; 21(24)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33371319

RESUMO

Histamine is a basic amine stored in mast cells, with its release capable of activating one of four histamine receptors. The histamine 3 receptor (H3R) is known to be cardioprotective during acute ischemia by acting to limit norepinephrine release. However, a recent study reported that myofibroblasts isolated from the infarct zone of rat hearts responded to H3R activation by up-regulating collagen production. Thus, it is necessary to clarify the potential role of the H3R in relation to fibrosis in the heart. We identified that the mouse left ventricle (LV) expresses the H3R. Isolation of mouse cardiac fibroblasts determined that while angiotensin II (Ang II) increased levels of the H3R, these cells did not produce excess collagen in response to H3R activation. Using the Ang II mouse model of adverse cardiac remodeling, we found that while H3R blockade had little effect on cardiac fibrosis, activation of the H3R reduced cardiac fibrosis and macrophage infiltration. These findings suggest that when activated, the H3R is anti-inflammatory and anti-fibrotic in the mouse heart and may be a promising target for protecting against cardiac fibrosis.


Assuntos
Angiotensina II/farmacologia , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Receptores Histamínicos H3/metabolismo , Remodelação Ventricular/efeitos dos fármacos , Animais , Fibrose/metabolismo , Fibrose/patologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
4.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 193-196, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981270

RESUMO

Objective: To investigate the protective effect of spermine (Sp) on diabetic cardiomyopathy (DCM) and high glucose-induced cardiac fibroblasts (CFs), and to explore its mechanism.Methods: ①Animal experiments: 24 male Wistar rats were randomly divided into control group, type 1 diabetes group (TID) and spermine group (TID+Sp, each group n=8). TID rats were induced by streptozocin (STZ, 60 mg/kg), and TID+Sp rat were pretreated with spermine (Sp, 5 mg/(kg·d)) for 2 weeks before STZ injection. After 12 weeks of modeling, blood glucose, insulin levels, ejection fraction (EF) and shortening fraction (FS) were measured, and Masson staining and Sirius red staining were performed in the rat cardiac tissues. ②Cell experiments: primary CFs were extracted from newborn (1-3 d) Wistar rat hearts, and were randomly divided into control group, high-glucose group (HG) and HG+Sp group (n=6 per group). HG group was treated with 40 mmol/L glucose, and the HG+Sp group was pretreated with 5 µmol/L Sp for 30 min before HG treatment. The cell viability of CFs was detected by CCK8, the content of collagen in culture medium was analyzed by ELISA, and protein expressions of cell cycle related proteins (PCNA, CyclinD1 and P27) were detected by Western blot. Results: Compared with control group, the blood glucose and collagen content were increased, and the insulin level and heart function were decreased in the T1D group. Meanwhile, HG induced an increasing of the cell viability, the collagen content in the medium and the expressions of PCNA and CyclinD1, while the expression of P27 was down-regulated. Spermine could reduce the above changes, manifested as improving the cardiac function, regulating the expression of cyclin and reducing the level of myocardial fibrosis. Conclusion: Spermine can alleviate myocardial fibrosis in diabetic cardiomyopathy, which mechanism is related to the regulation of cell cycle.


Assuntos
Ciclo Celular , Complicações do Diabetes , Cardiomiopatias Diabéticas , Fibrose , Espermina , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complicações do Diabetes/induzido quimicamente , Complicações do Diabetes/tratamento farmacológico , Cardiomiopatias Diabéticas/induzido quimicamente , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Fibrose/etiologia , Glucose/toxicidade , Coração/efeitos dos fármacos , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Espermina/farmacologia , Espermina/uso terapêutico
5.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 207-210, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981273

RESUMO

Objective: To observe the protective effects of exogenous spermine on renal fibrosis induced by diabetic nephropathy (DN) and to explore its mechanism.Methods: Twenty-four male C57 mice were randomly divided into control group, type 1 diabetes group (TID) and spermine pretreatment group (TID+Sp, n=8 in each group). TID mice were induced by STZ (60 mg/kg), and TID+Sp mice were pretreated with spermine (5 mg/(kg·d)) for 2 weeks before STZ injection. The mice were killed at the 12th week. The renal function was determined by serum creatinine and urea nitrogen. HE, PAS and Masson staining were used to evaluate renal tissue injury and fibrosis. The expressions of matrix metalloproteinase (MMP-2, MMP-9) and collagen IV (Coll-IV) in the kidney of mice were detected by Western blot. Results: Compared with the control group, the blood glucose (5.67±0.22 vs 28.40±0.57 mmol/L), creatinine (14.33±1.22 vs 30.67±4.73 µmol/L) and urea nitrogen (6.93±4.94 vs 22.00±1.04 mmol/L) in the T1D group were increased significantly (P<0.05), the glomerular basement membrane was thickened, the collagen was significantly increased, the expressions of MMP-2, MMP-9 and Coll-IV protein were increased (0.57±0.07 vs 1.06±0.20, 47.00±0.04 vs 1.29±0.09 and 0.42±0.16 vs 0.95±0.18,P<0.05). Exogenous spermine significantly alleviates the above-mentioned changes. Conclusion: Exogenous spermine pretreatment could significantly alleviate renal fibrosis in diabetic mice by regulating the balance between MMPs and collagen.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Espermina , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Fibrose/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Distribuição Aleatória , Espermina/farmacologia , Espermina/uso terapêutico
6.
Environ Health Prev Med ; 25(1): 53, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917140

RESUMO

BACKGROUND: Pilea umbrosa (Urticaceae) is used by local communities (district Abbotabad) for liver disorders, as anticancer, in rheumatism and in skin disorders. METHODS: Methanol extract of P. umbrosa (PUM) was investigated for the presence of polyphenolic constituents by HPLC-DAD analysis. PUM (150 mg/kg and 300 mg/kg) was administered on alternate days for eight weeks in rats exposed with carbon tetrachloride (CCl4). Serum analysis was performed for liver function tests while in liver tissues level of antioxidant enzymes and biochemical markers were also studied. In addition, semi quantitative estimation of antioxidant genes, endoplasmic reticulum (ER) induced stress markers, pro-inflammatory cytokines and fibrosis related genes were carried out on liver tissues by RT-PCR analysis. Liver tissues were also studied for histopathological injuries. RESULTS: Level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione (GSH) decreased (p < 0.05) whereas level of thiobarbituric acid reactive substance (TBARS), H2O2 and nitrite increased in liver tissues of CCl4 treated rat. Likewise increase in the level of serum markers; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin was observed. Moreover, CCl4 caused many fold increase in expression of ER stress markers; glucose regulated protein (GRP-78), x-box binding protein1-total (XBP-1 t), x-box binding protein1-unspliced (XBP-1 u) and x-box binding protein1-spliced (XBP-1 s). The level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) was aggregated whereas suppressed the level of antioxidant enzymes; γ-glutamylcysteine ligase (GCLC), protein disulfide isomerase (PDI) and nuclear erythroid 2 p45-related factor 2 (Nrf-2). Additionally, level of fibrosis markers; transforming growth factor-ß (TGF-ß), Smad-3 and collagen type 1 (Col1-α) increased with CCl4 induced liver toxicity. Histopathological scrutiny depicted damaged liver cells, neutrophils infiltration and dilated sinusoids in CCl4 intoxicated rats. PUM was enriched with rutin, catechin, caffeic acid and apigenin as evidenced by HPLC analysis. Simultaneous administration of PUM and CCl4 in rats retrieved the normal expression of these markers and prevented hepatic injuries. CONCLUSION: Collectively these results suggest that PUM constituted of strong antioxidant chemicals and could be a potential therapeutic agent for stress related liver disorders.


Assuntos
Tetracloreto de Carbono/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Urticaceae/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose/genética , Inflamação/genética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
7.
Am J Physiol Renal Physiol ; 319(1): F139-F148, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538151

RESUMO

Inflammation is a major determinant for the progression of chronic kidney disease (CKD). NF-κB is a master transcription factor upregulated in CKD that promotes inflammation and regulates apoptosis and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-κB p50 subunit (p50i) fused to a protein carrier [elastin-like polypeptide (ELP)] and equipped with a cell-penetrating peptide (SynB1). We hypothesized that intrarenal SynB1-ELP-p50i therapy would inhibit NF-κB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 wk, pigs received single intrarenal SynB1-ELP-p50i therapy (10 mg/kg) or placebo (n = 7 each). Renal hemodynamics were quantified in vivo using multidetector computed tomography before and 8 wk after treatment. Pigs were then euthanized. Ex vivo experiments were performed to quantify renal activation of NF-κB, expression of downstream mediators of NF-κB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-κB signaling and downstream mediators (e.g., TNF-α, monocyte chemoattractant protein-1, and IL-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction versus controls. All of these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 wk after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-κB pathway using novel drug delivery technology in a translational model of CKD.


Assuntos
Rim/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Rim/metabolismo , Rim/patologia , Circulação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Suínos
8.
Arch Med Res ; 51(6): 524-534, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32473749

RESUMO

OBJECTIVE: To investigate the effects and molecular mechanism of melatonin (MT) on NF-κB and TGF-ß/Smad3 signaling pathways in db/db diabetic mice. METHODS: db/db diabetic mice were divided into five groups treated with melatonin at doses of 50, 100, 200 µg/kg, the urinary concentration was detected by ELISA, renal histology was observed in PAS paining. Mouse mesangial cells were divided into mannitol control group, normal control group, normal control + MT group, high glucose group, high glucose + different concentrations (10, 100, 1000) µmol/L MT group. The proliferation of mesangial cells was detected by EdU kit; the expression of NF-κBp65, ColⅣ and Fn were detected by laser confocal system; the concentrations and mRNA levels of ColⅣ and Fn were detected by ELISA and qRT-PCR. the expressions of ColⅣ, Fn, IκB, p-IκB, TGF-ß1, Smad3 and p-Smad3 were detected by Western blot in renal tissues and mesangial cells. RESULTS: MT treatment could markedly improve the kidney histopathologic lesions. Compared with the db/m mice, 24 h urinary albumin excretion rate (UAER) and the expressions of ColIV, Fn, p-IκB/IκB, NF-κBp65, TGF-ß1 and p-Smad3/Smad3 were decreased after melatonin treatment (p <0.05). Compared with the control group, the proliferation function of mesangial cells in high glucose group was significantly enhanced, and the expressions of ColIV, Fn, p-IκB/IκB, NF-κBp65, TGF-ß1 and p-Smad3/Smad3 in mesangial cells were significantly up-regulated (p <0.05), and these changes were significantly lowered in MT treatment. CONCLUSION: Melatonin can inhibit renal inflammation and fibrosis by inhibiting the NF-κB and TGF-ß1/Smad3 signaling pathways, and melatonin may be a promising therapeutic target in diabetic nephropathy.


Assuntos
Depressores do Sistema Nervoso Central/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Fibrose/tratamento farmacológico , Rim/patologia , Melatonina/uso terapêutico , NF-kappa B/efeitos dos fármacos , Proteína Smad3/efeitos dos fármacos , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Animais , Depressores do Sistema Nervoso Central/farmacologia , Diabetes Mellitus Experimental , Nefropatias Diabéticas/patologia , Masculino , Melatonina/farmacologia , Camundongos , NF-kappa B/antagonistas & inibidores , Proteína Smad3/antagonistas & inibidores , Fator de Crescimento Transformador beta1/antagonistas & inibidores
9.
Aliment Pharmacol Ther ; 51(12): 1233-1246, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32406116

RESUMO

BACKGROUND: Medical therapy and/or endoscopic balloon dilation with intralesional therapies are options for the treatment of small bowel fibrostenotic Crohn's disease (CD). AIM: To perform a systematic review summarising evidence for efficacy of systemic and endoscopic intralesional medical therapy in established small bowel strictures in adult CD patients. METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL and Scopus was conducted. Primary outcomes were rates of surgical resection and repeat endoscopic dilation. Pooled event rates from random effects models across studies with 95% confidence intervals were reported. RESULTS: Ten studies describing systemic medical therapy and eight studies of intralesional injection were included. One randomised controlled trial each for systemic therapy and intrastricture injection were identified. Only observational studies were found for systemic biologic therapies, which exclusively included tumour necrosis factor (TNF) antagonists, while intralesional therapies all involved corticosteroids except for one study that evaluated infliximab. Pooled event rates for surgical resection after systemic and intralesional therapy were 28.3% (95% CI: 18.2%-41.3%) and 18.5% (95% CI: 8.3%-36.2%), respectively over a median follow-up of 23 months (range 5.5-105.8), and 21.8 months (range 5-47). Risk of repeat endoscopic balloon dilation in those with intralesional therapy was 58.3% (95% CI: 36.6%-77.3%) over a median follow-up of 21.8 months (range 5-47). CONCLUSIONS: There are no favoured therapies for patients with stricturing small bowel CD. Data are lacking for ustekinumab and vedolizumab. No endoscopic intralesional medications provided a clear benefit for prevention of repeat EBD or surgery.


Assuntos
Doença de Crohn/tratamento farmacológico , Obstrução Intestinal/tratamento farmacológico , Corticosteroides/administração & dosagem , Terapia Combinada/estatística & dados numéricos , Constrição Patológica/complicações , Constrição Patológica/tratamento farmacológico , Constrição Patológica/epidemiologia , Constrição Patológica/cirurgia , Doença de Crohn/complicações , Doença de Crohn/epidemiologia , Doença de Crohn/cirurgia , Dilatação/métodos , Dilatação/estatística & dados numéricos , Endoscopia Gastrointestinal/métodos , Endoscopia Gastrointestinal/estatística & dados numéricos , Fibrose/complicações , Fibrose/tratamento farmacológico , Fibrose/epidemiologia , Fibrose/cirurgia , Humanos , Infusões Intralesionais , Obstrução Intestinal/complicações , Obstrução Intestinal/epidemiologia , Obstrução Intestinal/cirurgia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
12.
Invest Ophthalmol Vis Sci ; 61(4): 15, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32298438

RESUMO

Purpose: Pathological neovascularization and fibrosis are common pathological changes of many retinal diseases, such as proliferative retinopathy (PR) and age-related macular degeneration (AMD). Treatment modalities for these pathological changes are limited. The purpose of the present study was to test the effects of palmitoylethanolamide (PEA), an endocannabinoid mimetic amide, on retinal neovascularization and fibrosis and to determine its molecular mechanism of action. Methods: A rat Müller cell line (rMC-1), a mouse model of oxygen-induced retinopathy (OIR), and the very-low-density lipoprotein receptor (VLDLR) knockout mouse model were used. PEA was intraperitoneally injected or orally administrated in animal models. Inflammation and profibrotic changes were evaluated by western blot analysis. Glial fibrillary acidic protein (GFAP) and peroxisome proliferator-activated receptor alpha (PPARα) were measured by RT-PCR and western blot analysis. Results: Profibrotic changes were present in OIR and Vldlr-/- retinas. PEA significantly alleviated inflammation and inhibited neovascularization in OIR and Vldlr-/- retinas and suppressed profibrotic changes in OIR and Vldlr-/- retinas. Moreover, PEA potently suppressed Müller gliosis in these retinas. In rMC-1 cells, PEA suppressed Müller gliosis, reduced inflammatory cytokines, and attenuated profibrotic changes. Further, both mRNA and protein levels of PPARα were elevated in the retina under PEA treatment, and the effects of PEA were abolished in Pparα-/- OIR mice. Conclusions: PEA reduced retinal neovascularization and fibrotic changes and suppressed Müller gliosis in experimental PR and neovascular AMD by activating PPARα. PEA may be a potential treatment for retinopathies with pathological neovascularization and fibrosis.


Assuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Etanolaminas/uso terapêutico , Gliose/tratamento farmacológico , PPAR alfa/metabolismo , Ácidos Palmíticos/uso terapêutico , Retina/patologia , Neovascularização Retiniana/tratamento farmacológico , Administração Oral , Amidas , Animais , Western Blotting , Linhagem Celular , Modelos Animais de Doenças , Células Ependimogliais/efeitos dos fármacos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/patologia , Marcação In Situ das Extremidades Cortadas , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigênio/toxicidade , PPAR alfa/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de LDL/genética , Retina/metabolismo , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia
13.
PLoS One ; 15(4): e0230392, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275672

RESUMO

OBJECTIVES: High-mobility group box 1 protein (HMGB1) fragment enhances bone marrow-derived mesenchymal stem cell (BM-MSC) recruitment to damaged tissue to promote tissue regeneration. This study aimed to evaluate whether systemic injection of HMGB1 fragment could promote tissue repair in a rat model of myocardial infarction (MI). METHODS: HMGB1 (n = 14) or phosphate buffered saline (n = 12, control) was administered to MI rats for 4 days. Cardiac performance and left ventricular remodeling were evaluated using ultrasonography and immunostaining. BM-MSC recruitment to damaged tissue in green fluorescent protein-bone marrow transplantation (GFP-BMT) models was evaluated using immunostaining. RESULTS: At four weeks post-treatment, the left ventricular ejection fraction was significantly improved in the HMGB1 group compared to that in the control. Interstitial fibrosis and cardiomyocyte hypertrophy were also significantly attenuated in the HMGB1 group compared to the control. In the peri-infarction area, VEGF-A mRNA expression was significantly higher and TGFß expression was significantly attenuated in the HMGB1 group than in the control. In GFP-BMT rats, GFP+/PDGFRα+ cells were significantly mobilized to the peri-infarction area in the HMGB1 group compared to that in the control, leading to the formation of new vasculature. In addition, intravital imaging revealed that more GFP+/PDGFRα+ cells were recruited to the peri-infarction area in the HMGB1 group than in the control 12 h after treatment. CONCLUSIONS: Systemic administration of HMGB1 induced angiogenesis and reduced fibrosis by recruiting PDGFRα+ mesenchymal cells from the bone marrow, suggesting that HMGB1 administration might be a new therapeutic approach for heart failure after MI.


Assuntos
Proteína HMGB1/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Indutores da Angiogênese/farmacologia , Animais , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Coração/fisiopatologia , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Regeneração/efeitos dos fármacos
14.
Oxid Med Cell Longev ; 2020: 8061246, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32148657

RESUMO

Liver cirrhosis is an outcome of a wide range of liver chronic diseases. It is attributed to oxidative stress; therefore, antioxidant usage could be a promising treatment of that. So, exploring the impact of effective free radical scavenger pristine C60 fullerenes on liver fibrosis and cirrhosis and their ability to interact with main growth factor receptors involved in liver fibrogenesis was aimed to be discovered. We used N-diethylnitrosamine/carbon tetrachloride-induced simulations of rat liver fibrosis (10 weeks) and cirrhosis (15 weeks). Pristine C60 fullerene aqueous colloid solution (C60FAS) was injected daily at a dose of 0.25 mg/kg throughout the experiment. Liver morphology and functional and redox states were assessed. C60 fullerenes' ability to interact with epidermal, vasoendothelial, platelet-derived, and fibroblast growth factor receptors (EGFR, VEGFR, PDGFR, and FGFR, respectively) was estimated by computational modeling. We observed that C60FAS reduced the severity of fibrosis in fibrotic rats (0.75 vs. 3.0 points according to Ishak score), attenuated the hepatocyte injury, normalized elevated blood serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and mitigated oxidative stress manifestation in liver tissue restoring its redox balance. When applied to cirrhotic animals, C60FAS reduced connective tissue deposition as well (2.4 vs. 5.4 points according to Ishak score), diminished ALP and LDH (by 16% and 61%), and normalized conjugated and nonconjugated bilirubin, restoring the liver function. Altered liver lipid and protein peroxides and glutathione peroxidase activity were also leveled. Within a computer simulation, it was shown that C60 fullerenes can block hinge prohibiting ATP binding for EGFR and FGFR and thus blocking associated signal pathways. This ability in addition to their antioxidant properties may contribute to C60 fullerene's antifibrotic action. Thus, C60FAS may have a substantial therapeutic potential as an inhibitor of liver fibrosis and cirrhosis.


Assuntos
Fibrose/tratamento farmacológico , Fulerenos/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Animais , Fulerenos/farmacologia , Humanos , Fígado/fisiopatologia , Masculino , Ratos , Ratos Wistar
15.
Pharmacol Rev ; 72(2): 486-526, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32198236

RESUMO

Before it was molecularly cloned in 1994, acute-phase response factor or signal transducer and activator of transcription (STAT)3 was the focus of intense research into understanding the mammalian response to injury, particularly the acute-phase response. Although known to be essential for liver production of acute-phase reactant proteins, many of which augment innate immune responses, molecular cloning of acute-phase response factor or STAT3 and the research this enabled helped establish the central function of Janus kinase (JAK) family members in cytokine signaling and identified a multitude of cytokines and peptide hormones, beyond interleukin-6 and its family members, that activate JAKs and STAT3, as well as numerous new programs that their activation drives. Many, like the acute-phase response, are adaptive, whereas several are maladaptive and lead to chronic inflammation and adverse consequences, such as cachexia, fibrosis, organ dysfunction, and cancer. Molecular cloning of STAT3 also enabled the identification of other noncanonical roles for STAT3 in normal physiology, including its contribution to the function of the electron transport chain and oxidative phosphorylation, its basal and stress-related adaptive functions in mitochondria, its function as a scaffold in inflammation-enhanced platelet activation, and its contributions to endothelial permeability and calcium efflux from endoplasmic reticulum. In this review, we will summarize the molecular and cellular biology of JAK/STAT3 signaling and its functions under basal and stress conditions, which are adaptive, and then review maladaptive JAK/STAT3 signaling in animals and humans that lead to disease, as well as recent attempts to modulate them to treat these diseases. In addition, we will discuss how consideration of the noncanonical and stress-related functions of STAT3 cannot be ignored in efforts to target the canonical functions of STAT3, if the goal is to develop drugs that are not only effective but safe. SIGNIFICANCE STATEMENT: Key biological functions of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 signaling can be delineated into two broad categories: those essential for normal cell and organ development and those activated in response to stress that are adaptive. Persistent or dysregulated JAK/STAT3 signaling, however, is maladaptive and contributes to many diseases, including diseases characterized by chronic inflammation and fibrosis, and cancer. A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.


Assuntos
Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Fibrose/metabolismo , Humanos , Inflamação/metabolismo , Janus Quinases/genética , Terapia de Alvo Molecular , Neoplasias/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fator de Transcrição STAT3/genética
16.
Clin Sci (Lond) ; 134(6): 609-628, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32175563

RESUMO

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Retinoid X receptor (RXR) plays an important role in cardiac development and has been implicated in cardiovascular diseases. In the present study, we investigated the effects of RXR agonist treatment on streptozotocin (STZ)-induced diabetic cardiomyopathy (DCM) and the underlying mechanism. Sprague-Dawley (SD) rats induced by STZ injection were treated with either RXR agonist bexarotene (Bex) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Cardiac fibroblasts (CFs) were treated with high glucose (HG) with or without the indicated concentration of Bex or the RXR ligand 9-cis-retinoic acid (9-cis-RA). The protein abundance levels were measured along with collagen, body weight (BW), blood biochemical indexes and transforming growth factor-ß (TGF-ß) levels. The effects of RXRα down-regulation by RXRα small interfering RNA (siRNA) were examined. The results showed that bexarotene treatment resulted in amelioration of left ventricular dysfunction by inhibiting cardiomyocyte apoptosis and myocardial fibrosis. Immunoblot with heart tissue homogenates from diabetic rats revealed that bexarotene activated liver kinase B1 (LKB1) signaling and inhibited p70 ribosomal protein S6 kinase (p70S6K). The increased collagen levels in the heart tissues of DCM rats were reduced by bexarotene treatment. Treatment of CFs with HG resulted in significantly reduced LKB1 activity and increased p70S6K activity. RXRα mediated the antagonism of 9-cis-RA on HG-induced LKB1/p70S6K activation changes in vitro. Our findings suggest that RXR agonist ameliorates STZ-induced DCM by inhibiting myocardial fibrosis via modulation of the LKB1/p70S6K signaling pathway. RXR agonists may serve as novel therapeutic agents for the treatment of DCM.


Assuntos
Bexaroteno/administração & dosagem , Cardiomiopatias/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Proteínas Serina-Treonina Quinases/metabolismo , Receptores X Retinoide/agonistas , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Estreptozocina
17.
Ars pharm ; 61(1): 45-47, ene.-mar. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-188574

RESUMO

OBJETIVOS: Determinar la efectividad del tratamiento de la hepatitis C crónica definida como la respuesta viral sostenida a las 12 semanas (RVS12) tras la finalización del tratamiento con fármacos antivirales de acción directa (AAD) (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir y grazoprevir/elbasvir) en pacientes atendidos en la consulta de farmacia ambulatoria. MÉTODOS: estudio retrospectivo que incluye los pacientes atendidos por farmacia que iniciaron tratamiento con AAD entre el 1 de diciembre de 2017 y el 31 de mayo de 2018. Se registraron datos demográficos, de la enfermedad, grado de adherencia y consultas sobre el tratamiento (interacciones, efectos adversos y otras). RESULTADOS: Se incluyeron 205 pacientes con diferentes genotipos de hepatitis C, estados de fibrosis y grados de morbilidad. La efectividad fue del 99,5%, similar a la reportada en los ensayos clínicos. CONCLUSIONES: Estos resultados se asemejan a los obtenidos en las consultas de farmacia en Estados Unidos, funcionando desde hace más de diez años


OBJECTIVE: To determine the effectiveness of the treatment of chronic hepatitis C determined as the sustained viral response at 12 weeks (SVR12) after the end of treatment with direct-acting antiviral drugs (DAA) (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir and grazoprevir/elbasvir) in attended patients from the outpatient pharmacy consultation. METHOD: a retrospective study that includes patients attended by pharmacists who started treatment between December 1, 2017 and May 31, 2018. Demographic data, disease, adherence and treatment consultations were recorded (interactions, adverse effects and others). RESULTS: Two hundred and five patients were included, with different hepatitis C genotypes, fibrosis states and morbidity levels. Effectiveness was 99.5%, similar to that of clinical trials. CONCLUSIONS: These results resemble those obtained in pharmacy consultations in the United States, operating for more than ten years


Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Hepatite C/tratamento farmacológico , Resultado do Tratamento , Assistência Farmacêutica , Antivirais/uso terapêutico , Estudos Retrospectivos , Fibrose/complicações , Fibrose/tratamento farmacológico , Cooperação e Adesão ao Tratamento
18.
Int J Mol Sci ; 21(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033294

RESUMO

Biological factors such as TGF-ß3 are possible supporters of the healing process in chronic rotator cuff tears. In the present study, electrospun chitosan coated polycaprolacton (CS-g-PCL) fibre scaffolds were loaded with TGF-ß3 and their effect on tendon healing was compared biomechanically and histologically to unloaded fibre scaffolds in a chronic tendon defect rat model. The biomechanical analysis revealed that tendon-bone constructs with unloaded scaffolds had significantly lower values for maximum force compared to native tendons. Tendon-bone constructs with TGF-ß3-loaded fibre scaffolds showed only slightly lower values. In histological evaluation minor differences could be observed. Both groups showed advanced fibre scaffold degradation driven partly by foreign body giant cell accumulation and high cellular numbers in the reconstructed area. Normal levels of neutrophils indicate that present mast cells mediated rather phagocytosis than inflammation. Fibrosis as sign of foreign body encapsulation and scar formation was only minorly present. In conclusion, TGF-ß3-loading of electrospun PCL fibre scaffolds resulted in more robust constructs without causing significant advantages on a cellular level. A deeper investigation with special focus on macrophages and foreign body giant cells interactions is one of the major foci in further investigations.


Assuntos
Poliésteres/química , Lesões do Manguito Rotador/terapia , Fator de Crescimento Transformador beta3/administração & dosagem , Cicatrização/efeitos dos fármacos , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Quitosana/química , Cicatriz/tratamento farmacológico , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Ratos , Manguito Rotador , Traumatismos dos Tendões/tratamento farmacológico , Tendões/efeitos dos fármacos , Tecidos Suporte
19.
Mol Med Rep ; 21(3): 1097-1106, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016456

RESUMO

The aim of the present study was to investigate the effect of urantide on collagen metabolism in the hearts of rats with atherosclerosis (AS) by evaluating the expression of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway constituents. Urantide was delivered to rats with AS via tail vein injection for 3, 7 and 14 days. Serological indicators were identified by an automated biochemical analyzer. Histomorphological changes in the cardiac tissue of rats were observed by pathological staining techniques. The expression of genes and proteins was assessed using reverse transcription­quantitative PCR and western blot analysis, respectively. Localization of proteins was detected by immunofluorescence. Overexpression of urotensin II (UII) and its receptor, G protein­coupled receptor 14 (GPR14), was observed in the hearts of rats with AS and the expression of both proteins significantly declined after urantide administration. Triglyceride, total cholesterol, low­density lipoprotein, high­density lipoprotein and calcium levels were improved in rats with AS following treatment with urantide. Notably, urantide was able to antagonize the UII/GPR14 system. Urantide treatment resulted in markedly decreased expression levels of matrix metalloproteinase 2 (MMP­2), collagen type I/III, and genes and proteins in the JAK2/STAT3 pathway. By contrast, TIMP metallopeptidase inhibitor 2 (TIMP­2) levels were increased. In addition, the MMP­2/TIMP­2 protein ratio was significantly decreased in rats treated with urantide compared with AS rats with no urantide treatment. Constituents of the JAK2/STAT3 pathway and collagen type I/III were found to be localized in the diseased tissue and blood vessels of the hearts of rats with AS. In conclusion, urantide was able to effectively block the UII/GPR14 system by regulating the JAK2/STAT3 pathway and collagen metabolism. Inhibition of the UII/GPR14 system may prevent and potentially treat atherosclerotic myocardial fibrosis. Based on the current results, it was hypothesized that collagen metabolism may be associated with the JAK2/STAT3 pathway.


Assuntos
Aterosclerose/metabolismo , Colágeno/metabolismo , Fibrose/metabolismo , Cardiopatias/metabolismo , Janus Quinase 2/metabolismo , Fragmentos de Peptídeos/farmacologia , Fator de Transcrição STAT3/metabolismo , Urotensinas/farmacologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Modelos Animais de Doenças , Fibrose/tratamento farmacológico , Fibrose/patologia , Cardiopatias/tratamento farmacológico , Cardiopatias/patologia , Janus Quinase 2/genética , Lipoproteínas LDL/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Urotensinas/genética , Urotensinas/metabolismo
20.
Sci Rep ; 10(1): 1782, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024850

RESUMO

Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.


Assuntos
Peso Corporal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Obstrução Ureteral/complicações , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Inflamação/etiologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
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