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1.
Chem Biol Interact ; 315: 108897, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726037

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1ß, MDA, and TGF-ß contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.


Assuntos
Fibrose/tratamento farmacológico , Interleucina-33/metabolismo , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Interleucina-1/metabolismo , Animais , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
2.
Phytomedicine ; 66: 153111, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790902

RESUMO

BACKGROUND: Hyperuricemia (HUA) is an important risk factor for renal diseases and contributes to renal fibrosis. It has been proved that phloretin has antioxidant and anti-inflammatory properties and could inhibit uric acid (UA) uptake in vitro. However, whether phloretin has a renal protective role in vivo remains unknown. PURPOSE: This study aims to evaluate the therapeutic effect of phloretin on HUA-induced renal injury in mice and to reveal its underlying mechanism. METHODS: Mice were induced hyperuricemic by oral gavage of adenine/potassium oxonate. The effects of phloretin on renal function, fibrosis, oxidative stress, inflammation, and UA metabolism in HUA mice were evaluated. The effect of phloretin on NLRP3 pathway was analyzed in human renal tubular cell lines (HK-2). RESULTS: HUA mice showed renal dysfunction with increased renal fibrosis, inflammation and mitochondrial stress. By contrast, phloretin reduced the level of serum blood urea nitrogen (BUN), urinary albumin to creatinine ratio (UACR), tubular necrosis, extracellular matrix (ECM) deposition and interstitial fibroblasts in HUA mice. The renal infiltration of inflammatory cells, cytokines such as NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1ß (IL-1ß) release, mitochondrial reactive oxygen species (ROS) and morphological lesions in HUA mice also decreased. Furthermore, phloretin partly inhibited renal glucose transporter 9 (GLUT9) and promoted urinary UA excretion in HUA mice. In vitro, phloretin suppressed the NLPR3 pathway under LPS or UA stimulation in HK-2 cells. CONCLUSIONS: Phloretin could effectively attenuate UA-induced renal injury via co-inhibiting NLRP3 and UA reabsorption, and thus it might be a potential therapy to hyperuricemia-related renal diseases.


Assuntos
Fibrose/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Floretina/farmacologia , Ácido Úrico/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Humanos , Inflamassomos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Biosci Biotechnol Biochem ; 84(1): 171-177, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31476130

RESUMO

We tested the hypothesis that α-lactalbumin inhibits the disruption of intestinal barrier function and liver cirrhosis by restoring gut-liver axis function in thioacetamide (TAA) -treated rats. Rat diets were supplemented with α-lactalbumin replacing 50% of dietary protein. After consuming α-lactalbumin for one week, rats were intraperitoneally injected with TAA twice a week for 14 weeks. The α-lactalbumin-enriched diet significantly inhibited the elevation of plasma alanine aminotransferase, aspartate aminotransferase, and hyaluronic acids. The supplement significantly reduced plasma lipopolysaccharide levels and increased occludin mRNA level. Hepatic fibrosis and regenerative nodules was developed and intestinal villi were shortened by TAA; α-Lactalbumin attenuated these histopathological changes. These results indicated that α-lactalbumin improved intestinal barrier function, suppressing endotoxin levels. These data also suggested that α-lactalbumin ameliorated the impairment of the gut-liver axis by TAA, inhibiting the development of liver cirrhosis.


Assuntos
Suplementos Nutricionais , Trato Gastrointestinal/efeitos dos fármacos , Lactalbumina/uso terapêutico , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/dietoterapia , Fígado/efeitos dos fármacos , Substâncias Protetoras/uso terapêutico , Tioacetamida/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Fibrose/tratamento farmacológico , Trato Gastrointestinal/metabolismo , Expressão Gênica/efeitos dos fármacos , Ácido Hialurônico/sangue , Injeções Intraperitoneais , Lipopolissacarídeos/sangue , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/prevenção & controle , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Tioacetamida/administração & dosagem , Proteínas de Junções Íntimas/genética
4.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(11): 801-805, 2019 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-31826541

RESUMO

Objective: To investigate the intervention effect of SB431542, which inhibits the TGF-ß/Smad3 signaling pathway, on silicotic fibrosis in rats. Methods: A total of 40 specific pathogen-free Sprague-Dawley rats were divided into normal saline control group, model group, SB431542 inhibitor group, and SB431542 inhibitor control group using a random number table, with 10 rats in each group. All rats except those in the normal saline control group were given non-exposed single intratracheal instillation of free silicon dioxide dust suspension 1 mL (50 mg/mL) ; the rats in the SB431542 inhibitor group were given intraperitoneal injection of SB431542 (5 mg/kg) on days 7 and 30 after dust exposure, those in the SB431542 inhibitor control group were given intraperitoneal injection of SB431542 cosolvent (5 mg/kg) on days 7 and 30 after dust exposure, and those in the normal saline control group were given intratracheal instillation of an equal volume of normal saline (5 mg/kg). On day 60 after dust exposure, the paraffin-embedded section of the right upper lobe of lung was collected for HE staining; the left upper lobe of lung was collected to measure the mRNA levels of fibronectin (FN) , collagen type I (COL-I) , and collagen type III (COL-III) by quantitative real-time PCR; the right inferior lobe of lung was collected to measure the protein levels of FN, COL-I, COL-III, phosphorylated Smad3 (p-Smad3) , and Smad3. Results: Compared with the normal saline control group, the model group had nodules with various sizes in lung tissue, with rupture of some alveolar septa, emphysema changes, and pulmonary interstitial fibrosis, as well as significant increases in the mRNA expression of FN, COL-I, and COL-III and the protein expression of FN, COL-I, COL-III, p-Smad3, and Smad3 in lung tissue (P<0.05) . Compared with the SB431542 inhibitor control group, the SB431542 inhibitor group had a relatively complete structure of lung tissue without marked nodules and with a small amount of exudate in alveolar space and the lumen of bronchioles, as well as significant reductions in the mRNA expression of FN, COL-I, and COL-III and the protein expression of FN, COL-I, COL-III, p-Smad3, and Smad3 in lung tissue (P<0.05) . There were no significant differences in the mRNA expression of FN, COL-I, and COL-III and the protein expression of FN, COL-I, COL-III, p-Smad3, and Smad3 between the model group and the SB431542 inhibitor control group (P>0.05) . Conclusion: SB431542 exerts an intervention effect on silicotic fibrosis by blocking the TGF-ß/Smad3 signaling pathway and reducing the expression of the downstream fibrosis factors FN, COL-I, and COL-III.


Assuntos
Benzamidas/uso terapêutico , Dioxóis/uso terapêutico , Fibrose/tratamento farmacológico , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , Benzamidas/farmacologia , Dioxóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética
5.
Invest Ophthalmol Vis Sci ; 60(14): 4784-4791, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31743935

RESUMO

Purpose: To investigate the antifibrotic effects of sakuraso-saponin on a primary culture of human pterygium fibroblasts (HPFs) and normal human Tenon fibroblasts (HTFs) as compared to the effects of mitomycin C (MMC). Methods: Samples of HPFs and HTFs were acquired during primary pterygium surgery. Cell toxicity, cell migration, and expression of α-smooth muscle actin (α-SMA) and transforming growth factor-ß (TGF-ß) were evaluated in HPFs and HTFs after treatment with sakuraso-saponin and MMC. To determine the possible mechanisms underlying the antifibrotic effects of sakuraso-saponin, the expression of phosphorylated Smad2/3 was evaluated after treatment with sakuraso-saponin and MMC. Results: MMC (≥200 µg/mL) significantly reduced cell viability in both HPFs and HTFs, whereas sakuraso-saponin (1.0 µg/mL) decreased cell viability in HPFs only. Both sakuraso-saponin (1.0 µg/mL) and MMC (200 µg/mL) treatment significantly reduced the expression of α-SMA and TGF-ß in HPFs (P < 0.05). It is interesting that the expression of α-SMA and TGF-ß after treatment with sakuraso-saponin was significantly lower than that after treatment with MMC (P < 0.05). The expression of phosphorylated Smad2/3 protein was decreased by sakuraso-saponin and MMC in HPFs. Both sakuraso-saponin and MMC inhibited TGF-ß1-induced cell migration as compared to the control in HPFs. Conclusions: Sakuraso-saponin could be more effective than MMC for the reduction of fibrosis in HPFs. Our results might present the basis for its use as a promising candidate drug for adjuvant therapy to prevent recurrent pterygium after surgery.


Assuntos
Alquilantes/farmacologia , Fibroblastos/efeitos dos fármacos , Mitomicina/farmacologia , Pterígio/tratamento farmacológico , Pterígio/patologia , Saponinas/farmacologia , Actinas/metabolismo , Western Blotting , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/metabolismo , Fibrose/tratamento farmacológico , Humanos , Fosforilação , Pterígio/cirurgia , Proteína Smad2/metabolismo , Proteína Smad4/metabolismo , Cápsula de Tenon/citologia , Fator de Crescimento Transformador beta/metabolismo
6.
Bratisl Lek Listy ; 120(11): 813-818, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31747760

RESUMO

OBJECTIVE: Spinal epidural fibrosis is commonly seen after laminectomy. There is not yet proven any agent preventing fibrosis in clinical usage. We used diclofenac sodium and diltiazem, which are fibrosis inhibitors. METHODS AND MATERIALS: 40 rats were divided into four groups of equal numbers: control, diclofenac sodium, diltiazem, and diclofenac sodium + diltiazem. Laminectomies were performed at L5 and L6. After a 4 week period, the rats were decapitated and the vertebral column blocks were removed for histopathologic examination. Fibrosis percentage, spread of fibrous regions, and fibroblast numbers were evaluated in each group and compared between the groups. RESULTS: The distribution of epidural fibrosis density, percentage of fibrosis, and distribution of fibroblasts in the diclofenac sodium + diltiazem group were significantly lower than in the other groups. The fibroblast numbers of the diltiazem, and diclofenac sodium + diltiazem groups were significantly lower than in the other groups. CONCLUSION: Diclofenac sodium + diltiazem used together provided better outcomes because each of them prevented fibrosis via different ways, probably through synergistic action (Tab. 5, Fig. 3, Ref. 43).


Assuntos
Diclofenaco/farmacologia , Diltiazem/farmacologia , Espaço Epidural/patologia , Fibrose/tratamento farmacológico , Laminectomia/efeitos adversos , Animais , Ratos
7.
Eur. j. anat ; 23(6): 412-420, nov. 2019. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-185084

RESUMO

Bisphenol A is a chemical used in the production of the plastic lining of food and beverage containers. As plastics are used extensively in modern life, bisphenol A is liberated into the surrounding environment. The goal of this study was to illustrate the histopathological effects of bisphenol A on the renal cortex with referral to the possible ameliorative effect of green tea extract and to throw more light on some underlying mechanisms, for the first time up to our knowledge, by which green tea extract exerted its effects against bisphenol A-induced nephrotoxicity. Forty adult male Sprague-Dawley rats were classified into four groups: Group I (control group); Group II (bisphenol A-treated group), received bisphenol by gavage 125 μg/kg once daily for 35 days; Group III (bisphenol A and green tea extract treated group), received bisphenol by gavage 125 μg/kg simultaneously with 200 mg/kg/day green tea extract once daily for 35 days; and Group IV (green tea extract treated group), received 200 mg/kg/day green tea extract for 35 days by gavage. At the end of the study, rats were anesthetized and the kidney from all groups were extracted and examined histologically and immunohistochemically. Deterioration of kidney structure was greatest in group II as compa-red to control group. Some of the renal corpuscles showed widening of the Bowman's capsule, shrunken degenerated glomerular tuft and dilated congested glomerular capillaries. Interstitial and intra-tubular hemorrhage was also observed. Moreover, there was a significant increase in the collagen deposition in bisphenol A-treated group in addition to up-regulation of inducible nitric oxide synthase (iNOS), Fas Ligand (Fas L), alpha smooth muscle actin (alfa-SMA) and desmin immunoreaction. The co-administration of green tea extract greatly reduced these nephrotoxic effects of bisphenol A exposure through its antioxidant


No disponible


Assuntos
Animais , Ratos , Chá/metabolismo , Córtex Renal/anatomia & histologia , Córtex Renal/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Fenóis/toxicidade , Imuno-Histoquímica , Estresse Oxidativo/efeitos dos fármacos , Fibrose/tratamento farmacológico , Apoptose/efeitos dos fármacos , Projetos de Pesquisa
8.
J Biomed Sci ; 26(1): 72, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597574

RESUMO

BACKGROUND: Transforming growth factor (TGF) family members play important roles in the regulation of corneal integrity, and the pathogenesis of corneal fibrosis. Currently, there are no effective agents targeting TGF-ß signaling to diminish corneal fibrosis. Glucosamine (GlcN), which is widely used in the treatment of osteoarthritis, abrogates the morphologic effects of TGF-ß2 on retinal pigmented epithelial cells in a mouse disease model. Here, we sought to determine whether GlcN would exert beneficial effects against TGF-ß1-induced corneal fibrosis. METHODS: In human corneal fibroblasts (HCFs) treated with GlcN, the expression of Krüppel-like factor 4 (KLF4) and its downstream signaling effects were determined in the presence and absence of TGF-ß1 using immunoblot analysis. We further explored GlcN inhibition of fibroblast-to-myofibroblast differentiation via KLF4 siRNA. The effect of cycloheximide on KLF4 protein levels with or without GlcN administration was assessed to determine whether GlcN affects the stability of the KLF4 protein. RESULTS: In HCFs, GlcN induced the expression of KLF4, which regulated the maturation and maintenance of the ocular surface. GlcN partially suppressed the TGF-ß1-induced expression of alpha-smooth muscle actin (α-SMA) and reduced the collagen contraction capacity in HCFs, suggesting a decrease in fibroblast-to-myofibroblast differentiation. This effect appeared to be mediated through suppression of Smad2 phosphorylation and ERK-dependent signaling. The levels of KLF4 mRNA were increased by GlcN and decreased by TGF-ß1 and the TGF-ß1-induced α-SMA mRNA expression was upregulated when the KLF4 gene was silenced. GlcN also appeared to stabilize the KLF4 protein, reducing its turnover in corneal fibroblasts. CONCLUSION: These findings shed light on a novel mechanism by which GlcN suppresses TGF-ß1-induced fibroblast-to-myofibroblast differentiation through the upregulation of KLF4 expression. Current strategies for treating corneal fibrosis were not effective. Elevating KLF4 levels through the use of GlcN might provide an effective alternative to alleviate the development and progression of corneal fibrosis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Doenças da Córnea/tratamento farmacológico , Fibrose/tratamento farmacológico , Glucosamina/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Fator de Crescimento Transformador beta1/genética , Doenças da Córnea/etiologia , Doenças da Córnea/genética , Cicloeximida/administração & dosagem , Fibroblastos/efeitos dos fármacos , Fibrose/etiologia , Fibrose/genética , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Miofibroblastos/fisiologia , Substâncias Protetoras/farmacologia , Inibidores da Síntese de Proteínas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo
9.
J Diabetes Res ; 2019: 2697672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534972

RESUMO

Diabetic kidney disease (DKD) is the most common microvascular complication of diabetes and is one of the main causes of end-stage renal disease (ESRD) in many countries. The pathological features of DKD are the hypertrophy of mesangial cells, apoptosis of podocytes, glomerular basement membrane (GBM) thickening, accumulation of extracellular matrix (ECM), glomerular sclerosis, and tubulointerstitial fibrosis. The etiology of DKD is very complicated and many factors are involved, such as genetic factors, hyperglycemia, hypertension, hyperlipidemia, abnormalities of renal hemodynamics, and metabolism of vasoactive substances. Although some achievements have been made in the exploration of the pathogenesis of DKD, the currently available clinical treatment methods are still not completely effective in preventing the progress of DKD to ESRD. CHM composed of natural products has traditionally been used for symptom relief, which may offer new insights into therapeutic development of DKD. We will summarize the progress of Chinese herbal medicine (CHM) in the treatment of DKD from two aspects. In clinical trials, the Chinese herbal formulas were efficacy and safety confirmed by the randomized controlled trials. In terms of experimental research, studies provided evidence for the efficacy of CHM from the perspectives of balancing metabolic disorders, reducing inflammatory response and oxidative stress, antifibrosis, protecting renal innate cells, and regulating microRNA and metabolism. CHM consisting of different ingredients may play a role in synergistic interactions and multiple target points in the treatment of DKD.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose/tratamento farmacológico , Rim/efeitos dos fármacos , Nefropatias Diabéticas/patologia , Medicamentos de Ervas Chinesas/farmacologia , Fibrose/patologia , Humanos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Podócitos/patologia , Resultado do Tratamento
10.
Adv Exp Med Biol ; 1178: 103-112, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31493224

RESUMO

Coenzyme Q10 (CoQ10) is a vitamin-like substance which functions as an electron carrier within the mitochondrial respiratory chain, as well as serving as an important intracellular antioxidant. Most of the body's CoQ10 requirements are met by endogenous synthesis, although the capacity for CoQ10 production decreases substantially with increasing age. In this article we have reviewed the potential role of CoQ10 supplementation in the treatment of tissue fibrosis, which has been implicated in the age-related loss of function of various organs including the heart. Clinical studies have indicated that CoQ10 supplementation may decrease the level of cardiovascular fibrosis to which older individuals are subjected, and thereby improve cardiovascular function and reduce the risk of cardiovascular associated mortality. Although the factors responsible for the anti-fibrotic action of CoQ10 have yet to be fully elucidated, its antioxidant and anti-inflammatory functions are thought to be major contributors to its clinical efficacy in the treatment of this age-related disorder.


Assuntos
Antioxidantes , Ubiquinona/análogos & derivados , Antioxidantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/patologia , Fibrose/tratamento farmacológico , Humanos , Ubiquinona/uso terapêutico
11.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484417

RESUMO

Skeletal muscle injury presents a challenging traumatological dilemma, and current therapeutic options remain mediocre. This study was designed to delineate if engraftment of mesenchymal stem cells derived from umbilical cord Wharton's jelly (uMSCs) could aid in skeletal muscle healing and persuasive molecular mechanisms. We established a skeletal muscle injury model by injection of myotoxin bupivacaine (BPVC) into quadriceps muscles of C57BL/6 mice. Post BPVC injection, neutrophils, the first host defensive line, rapidly invaded injured muscle and induced acute inflammation. Engrafted uMSCs effectively abolished neutrophil infiltration and activation, and diminished neutrophil chemotaxis, including Complement component 5a (C5a), Keratinocyte chemoattractant (KC), Macrophage inflammatory protein (MIP)-2, LPS-induced CXC chemokine (LIX), Fractalkine, Leukotriene B4 (LTB4), and Interferon-γ, as determined using a Quantibody Mouse Cytokine Array assay. Subsequently, uMSCs noticeably prevented BPVC-accelerated collagen deposition and fibrosis, measured by Masson's trichrome staining. Remarkably, uMSCs attenuated BPVC-induced Transforming growth factor (TGF)-ß1 expression, a master regulator of fibrosis. Engrafted uMSCs attenuated TGF-ß1 transmitting through interrupting the canonical Sma- And Mad-Related Protein (Smad)2/3 dependent pathway and noncanonical Smad-independent Transforming growth factor beta-activated kinase (TAK)-1/p38 mitogen-activated protein kinases signaling. The uMSCs abrogated TGF-ß1-induced fibrosis by reducing extracellular matrix components including fibronectin-1, collagen (COL) 1A1, and COL10A1. Most importantly, uMSCs modestly extricated BPVC-impaired gait functions, determined using CatWalk™ XT gait analysis. This work provides several innovative insights into and molecular bases for employing uMSCs to execute therapeutic potential through the elimination of neutrophil-mediated acute inflammation toward protecting against fibrosis, thereby rescuing functional impairments post injury.


Assuntos
Fibrose/tratamento farmacológico , Fibrose/terapia , Inflamação/metabolismo , Células-Tronco Mesenquimais/fisiologia , Neutrófilos/metabolismo , Animais , Fibrose/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/terapia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Cordão Umbilical/citologia
12.
Med Sci Monit ; 25: 5892-5902, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391414

RESUMO

BACKGROUND Peritoneal dialysis is the most common treatment for end-stage renal disease. However, peritoneal fibrosis resulting from long-term peritoneal dialysis restricts peritoneal ultrafiltration. Previous studies have shown a role for 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) in preventing fibrosis, but the potential mechanisms remain unknown. This study aimed to investigate the role of 1,25(OH)2D3 in epithelial-mesenchymal transition (EMT) and the downstream signaling pathway in HMrSV5 human peritoneal mesothelial cells in vitro. MATERIAL AND METHODS An in vitro cell model of peritoneal fibrosis was established using the HMrSV5 human peritoneal mesothelial cell line. High glucose and lipopolysaccharide (LPS) culture conditions, with or without 1,25(OH)2D3, were used. Wnt agonist 1, a Wnt signaling pathway activator, was applied. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure the vitamin D receptor (VDR) and histone deacetylase 3 (HDAC3) gene and protein expression levels, ß-catenin, and EMT-associated biomarkers. RESULTS High glucose plus LPS culture medium inhibited cell proliferation, induced cell apoptosis and promoted EMT in HMrSV5 cells, which was reversed by 1,25(OH)2D3 by down-regulation of HDAC3 and upregulation of VDR. HDAC3 inhibited VDR gene expression. The expression of EMT-associated biomarkers was increased by Wnt agonist 1 and inhibited by 1,25(OH)2D3. CONCLUSIONS In HMrSV5 human peritoneal mesothelial cells, 1,25(OH)2D3 reversed EMT by inhibiting the expression of HDAC3 and upregulating VDR gene expression via the Wnt/ß-catenin signaling pathway.


Assuntos
Calcitriol/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Calcitriol/metabolismo , Linhagem Celular , China , Células Epiteliais/metabolismo , Epitélio , Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Humanos , Peritônio/metabolismo , Peritônio/patologia , Receptores de Calcitriol/genética , Fator de Crescimento Transformador beta1/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
13.
Drug Deliv ; 26(1): 812-819, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31389267

RESUMO

The aim of this study is to investigate the effects and toxicities of poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV)-loading rosiglitazone on preventing scar formation after glaucoma filtration surgery (GFS) in the rabbit model. Rosiglitazone/PHBV drug delivery system was prepared via electrospinning. Release behavior of RSG/PHBV membrane was evaluated by high-performance liquid chromatography. The different concentration membranes were implanted under the conjunctiva of the rabbit's eyes (RSG/PHBV groups). Also, MMC-soaked sponges were placed under the conjunctiva of the eyes (positive group) for 3 min. Intraocular pressures and bleb features were then assessed for 4 weeks postoperative. Bleb sections were stained with HE, Masson's trichrome and α smooth muscle action (αSMA) immunohistochemistry. The protein expression of collagen I, αSMA, and connective tissue growth factor in the bleb area were then quantified. The following results were observed: (1) the concentration of rosiglitazone would not affect the morphology of RSG/PHBV membrane. (2) RSG/PHBV membrane would effective and safety prevent the formation of fibrosis after GFS in the rabbit model. Implantation of RSG/PHBV membrane prevents scar formation after GFS. What's more, it ameliorated toxicity to conjunctiva and cornea compared with the placement of MMC. The RSG/PHBV membrane would be a more effectivity and safer strategy than MMC.


Assuntos
Fibrose/tratamento farmacológico , Glaucoma/tratamento farmacológico , Poliésteres/administração & dosagem , Rosiglitazona/administração & dosagem , Animais , Cicatriz/tratamento farmacológico , Túnica Conjuntiva/efeitos dos fármacos , Córnea/efeitos dos fármacos , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Cirurgia Filtrante/métodos , Pressão Intraocular/efeitos dos fármacos , Coelhos , Cicatrização/efeitos dos fármacos
14.
J Orthop Surg Res ; 14(1): 258, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412883

RESUMO

BACKGROUND: Failed back surgery syndrome (FBSS) is a common complication after the laminectomy. Epidural fibrosis is the major cause of lower back pain and other complications. Numerous studies have shown that apigenin (API) could treat various fibrotic diseases by regulating various signaling pathways, whereas no study has discussed whether API can inhibit fibroblast proliferation and reduce epidural fibrosis after the laminectomy by regulating Wnt3a/ß-catenin signaling pathway. METHODS: Human fibroblasts were cultured and treated with API in different concentrations for 24 h. CCK-8 detection and EdU incorporation assay were performed to detect cell viability and cell proliferation. Western blotting analysis was applied to detect expressions of proliferative proteins, Wnt3a, and its downstream proteins. Moreover, the Wnt3a gene was overexpressed in fibroblasts to define the relationship between Wnt3a/ß-catenin signaling pathway and fibroblast proliferation. Wnt3a overexpressed fibroblasts were treated with API to verify if it could reverse the effects of API treatment. Twenty-four Sprague-Dawley rats were randomly divided into four groups. Laminectomy was performed and the rats were gavaged with different doses of API or 5% sodium carboxyl methyl cellulose (CMC-Na) solution for 1 month. The abilities of API to inhibit fibroblast proliferation and to reduce epidural fibrosis were evaluated using histological and immunohistochemical analysis. RESULTS: CCK-8 detection and EdU incorporation assay demonstrated that API could inhibit the viability and proliferation rate of fibroblasts in a concentration-dependent manner. The Western blotting analysis revealed that API could inhibit the expressions of PCNA, cyclinD1, Wnt3a, and its downstream proteins. The overexpression of Wnt3a in fibroblasts could upregulate the expressions of proliferative proteins such as PCNA and cyclinD1. The inhibitory effect of API on PCNA, Wnt3a, and its downstream proteins was partially reversed by overexpression of Wnt3a. Moreover, the results of the histological and immunohistochemical analysis revealed that API could reduce the epidural fibrosis in rats by inhibiting fibroblast proliferation in a dose-dependent manner. CONCLUSIONS: API can inhibit fibroblast proliferation and reduce epidural fibrosis by suppressing Wnt3a/ß-catenin signaling pathway, which can be adopted as a new option to prevent epidural fibrosis after the laminectomy.


Assuntos
Apigenina/farmacologia , Espaço Epidural/metabolismo , Fibroblastos/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Animais , Apigenina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Espaço Epidural/efeitos dos fármacos , Espaço Epidural/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Células HEK293 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína Wnt3A/antagonistas & inibidores , beta Catenina/antagonistas & inibidores
15.
Radiat Res ; 192(5): 473-482, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31415221

RESUMO

Radiation therapy is a mainstream strategy in the treatment of several cancer types that are surgically unresectable. Unfortunately, cancer patients often suffer from unintended consequences of radiotherapy, including the development of skin inflammation (dermatitis), which may progress to fibrosis. These morbid complications often require interruption of radiotherapy and threaten the relapse of underlying cancer. Current treatment options for radiation dermatitis are suboptimal and compel the need to develop safer, more effective therapies. In this study, we assessed the biophysical properties of topically-formulated esomeprazole (here referred to as dermaprazole) and performed proof-of-concept studies to evaluate its efficacy in vitro and in vivo. We found that dermaprazole induced nuclear translocation of erythroid 2-related factor 2 (Nrf2) and significantly upregulated heme oxygenase 1 (HO1) gene and protein expression in a 3D human skin model. Our animal study demonstrated that dermaprazole improved macroscopic appearance of the irradiated skin and accelerated healing of the wounds. Histopathology data corroborated the photographic evidence and confirmed that both prophylactically and therapeutically administered dermaprazole conferred potent anti-inflammatory and antifibrotic effects. Gene expression data showed that dermaprazole downregulated several pro-oxidant, pro-inflammatory and profibrotic genes. In conclusion, topical formulation of the FDA-approved drug esomeprazole is highly effective in attenuating dermal inflammation and fibrosis.


Assuntos
Administração Tópica , Esomeprazol/administração & dosagem , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Radiodermatite/tratamento farmacológico , Transporte Ativo do Núcleo Celular , Animais , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Anatômicos , Fator 2 Relacionado a NF-E2/metabolismo , Radioterapia/efeitos adversos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Cicatrização/efeitos dos fármacos
16.
PLoS Negl Trop Dis ; 13(7): e0007602, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31365537

RESUMO

TGF-ß involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-ß signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TßR1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-ß signaling pathway reduced TGF-ß/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-ß inhibitors.


Assuntos
Benzamidas/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Coração/efeitos dos fármacos , Pirazóis/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Tripanossomicidas/uso terapêutico , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Doença Crônica , Conexina 43/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Coração/parasitologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Trypanosoma cruzi/efeitos dos fármacos
17.
Int Urol Nephrol ; 51(11): 2073-2081, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401712

RESUMO

Obstructive nephropathy is a common cause for chronic kidney disease. Surgery, which is adopted to promptly relieve the obstruction, is the most important method to save damaged kidneys. However, earlier studies have shown that renal function will continue to deteriorate until the terminal stage after the obstruction' relief. The aim of this study is to explore the renal fibrosis and investigate the effect of losartan on renal fibrosis after the obstruction' relief using an improved mouse model of relief for unilateral ureteral obstruction (RUUO). Experiments carried out using C57BL/6 mice (n = 30) were randomly divided into RUUO + Losartan group, RUUO group and sham group. Using an improved mouse RUUO model, this study revealed that the mouse kidney for 3- or 7-day unilateral ureteral obstruction undergoing the RUUO surgery was still in a state of injury and fibrosis, while losartan could effectively ameliorate renal fibrosis by upregulating the expression of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) in kidney after the surgery of RUUO.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Rim/patologia , Losartan/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/fisiologia , Regulação para Cima/efeitos dos fármacos , Animais , Fibrose/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Fatores de Tempo , Resultado do Tratamento , Obstrução Ureteral/complicações , Obstrução Ureteral/cirurgia
18.
Eur J Med Chem ; 180: 15-27, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31299584

RESUMO

Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a-d, 19a-d, 22a-d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a-d, 21a-d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC50 value of 0.030 µM in the enzymatic assay. Compound 22c showed four-fold more potent activity against ALK5 kinase than the clinical candidate, compound LY-2157299. The selectivity index of 22c against p38α MAP kinase is 235, which is much higher than that of LY-2157299 (4) and equally selective to that of EW-7197 (218). Compound 22c effectively suppressed protein and mRNA expression of collagen I and α-SMA in TGF-ß-induced LX-2 human hepatic stellate cell (HSC), this result shows that compound 22c has the ability to inhibit the activation of HSC. Compound 22c is expected to be a preclinical candidate for the treatment of hepatic fibrosis.


Assuntos
Desenho de Drogas , Fibrose/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Relação Estrutura-Atividade
19.
Ecotoxicol Environ Saf ; 182: 109425, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31295660

RESUMO

BACKGROUND: Inhalation of fine particulate matter (PM2.5) induces the occurrence of lung inflammation and fibrosis, but its molecular mechanism remains unclear. Resveratrol (RES) is known to have anti-inflammatory properties in many pulmonary diseases. Here, we aimed to investigate the effect of long-term "real-world" ambient PM exposure on lung inflammation and fibrosis and further explore the protective effect and mechanism of RES. METHODS AND RESULTS: RES (50 and 100 mg/kg.bw) was administered to C57BL/6J mice that were exposed to ambient PM for 5 months. The control group breathed filtered air without RES, and the PM group was exposed to PM without RES. The inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and lung fibrosis were evaluated by enzyme-linked immune sorbent assay (ELISA) kits and Masson's trichrome staining. The real-time PCR and Western blot analysis were used to determine the signal pathway. In vivo, PM exposure markedly elevated the levels of inflammatory cytokines and TGF-ß1 in BALF, induced lung fibrosis. Meanwhile, PM exposure triggered autophagy process and activated the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in lung. Also, RES treatment abolished PM-induced lung inflammation and fibrosis, and inhibited autophagic process and NLRP3 inflammasome activation. In vitro, PM2.5-induced cytotoxicity in BEAS-2B cells dose-dependently. Besides, RES alleviated PM2.5-induced cytotoxicity, inhibited autophagic process and NLRP3 inflammasome activity and decreased IL-1ß production in BEAS-2B cells. CONCLUSION: Long-term PM exposure induced lung inflammation and fibrosis, and RES intervention alleviated these adverse effects via inhibiting autophagy-related NLRP3 inflammasome activation.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose/tratamento farmacológico , Material Particulado/toxicidade , Pneumonia/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Citocinas/metabolismo , Inibidores Enzimáticos/uso terapêutico , Inflamassomos/metabolismo , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia/induzido quimicamente , Proteínas , Fibrose Pulmonar , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1
20.
Acta Biochim Biophys Sin (Shanghai) ; 51(8): 799-806, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31287495

RESUMO

The epithelial-mesenchymal transition (EMT) process results in fibrosis of renal tubular epithelial cells and is of great importance in the development of acute kidney injury (AKI). Urinary IGF-binding protein-7 (IGFBP7) was obviously increased in AKI and is considered to be a biomarker for AKI. However, whether it has an effect on the inhibition of lipopolysaccharide (LPS)-induced EMT in human HK2 cells and on that of cecal ligation and puncture (CLP)-induced EMT in human HK2 cells and in mice remains to be elucidated. Western blot analysis was performed to examine the phosphorylation of ERK1/2 level and expressions of IGFBP7, ERK1/2, EMT markers, such as E-cadherin, α-SMA, and vimentin, and EMT regulatory factors, such as Snail, transforming growth factor-ß1 (TGF-ß1), and connective tissue growth factor (CTGF). The levels of IGFBP7, TGF-ß1, and CTGF were detected by enzyme linked immunosorbent assay (ELISA). Concentrations of creatinine (Cr), blood urea nitrogen (BUN), and albumin (ALB) were measured by biochemical analysis. Here, we found that LPS promoted EMT and ERK1/2 activation in HK2 cells, which were inhibited by silencing of IGFBP7. Furthermore, IGFBP7 overexpression significantly increased EMT and ERK1/2 activation in HK2 cells, which were inhibited by ERK1/2 signaling inhibitor PD98059. IGFBP7 knockdown effectively attenuated renal fibrosis, concentrations of Cr, BUN and ALB, and activation of ERK1/2 signaling in CLP-induced mice. These results suggest that inhibiting IGFBP7 can effectively protect the renal tubular epithelial cells from EMT induced by LPS or CLP both in vitro and in vivo, which may be associated with inactivation of ERK1/2 signaling.


Assuntos
Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Sepse/metabolismo , Actinas/metabolismo , Lesão Renal Aguda/metabolismo , Albuminas/análise , Animais , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Nitrogênio da Ureia Sanguínea , Caderinas/metabolismo , Linhagem Celular , Creatinina/sangue , Fibrose/tratamento farmacológico , Flavonoides/farmacologia , Inativação Gênica , Humanos , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Transdução de Sinais , Vimentina/metabolismo
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