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1.
J Ethnopharmacol ; 300: 115751, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36162550

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial fibrosis leads to cardiac remodeling and dysfunction. Curcumae Rhizoma has been utilized in clinical trials to treat a variety of cardiovascular illnesses, although its role in myocardial fibrosis is unknown. AIM OF THE STUDY: The purpose of current study was to explore the potential mechanism action and anti-myocardial fibrosis effects of treatment with Curcumae Rhizoma. MATERIALS AND METHODS: The chemical components in the aqueous extract from Curcumae Rhizoma were identified using GC-MS analysis. A prediction network describing the relationship between Curcumae Rhizoma and MF was established based on information collected from multiple databases. Functional enrichment analysis was performed to investigate the specific functions and pathways involved in the candidate Curcumae Rhizoma targets acting on MF, which were further validated by vivo experiments. RESULTS: There were 444 targets obtained from the 39 active ingredients in Curcumae Rhizoma, and 5691 disease targets related to MF were identified. Then, 41 key targets were determined with the PPI interaction network, which was structured from 324 overlapping gene targets. GO and KEGG analyses revealed that the p38 MAPK/NF-κB and TGF-ß1/Smad2/3 signaling pathways might play crucial roles in the therapeutic mechanism of MF. According to the results of molecular docking, the binding activity between core components and targets was marvelous (affinity < -6 kcal/mol). Take it a step further, the experimental validation data affirmed that Curcumae Rhizoma substantially decreased myocardial fibrosis and recovered cardiac function in the ISO-induced rats. The associated proteins expression data implied that the p38 MAPK/NF-κB and TGF-ß1/Smad2/3 pathways might be vital in the anti-fibrosis effect of Curcumae Rhizoma. CONCLUSION: The findings suggested that Curcumae Rhizoma diminished myocardial fibrosis by suppressing fibrosis multiplication and collagen deposition through inhibiting p38 MAPK/NF-κB and TGF-ß1/Smad2/3 pathways, which might be a promising therapeutic medicament for alleviating myocardial fibrosis.


Assuntos
Medicamentos de Ervas Chinesas , Fator de Crescimento Transformador beta1 , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fibrose , Simulação de Acoplamento Molecular , NF-kappa B , Farmacologia em Rede , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno
2.
J Biomed Mater Res A ; 111(1): 132-151, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36205298

RESUMO

Previously, we demonstrated that magnesium oxide (MgO)-incorporated electrospun membranes show powerful antibacterial activity and promote wound healing, but the underlying mechanisms have not been entirely understood. Herein, we investigated the relationship between structure and function of MgO-incorporated membranes and interrogated critical bioactive cues that contribute to accelerated wound healing and functional restoration. Our results show that MgO-incorporated membranes exhibit good flexibility and improved water vapor transmission rates (WVTRs) and sustained Mg2+ release in a simulated model of wounds. MgO-incorporated membranes modulate macrophage phenotype to downregulate inflammatory response, contributing to alleviated inflammation and creating a favorable microenvironment for wound healing. Specifically, MgO-incorporated membranes stimulate macrophages to shift to a pro-healing M2 phenotype and upregulate pro-healing cytokine of transforming growth factor-beta 1 (TGF-ß1) and downregulate pro-inflammatory cytokines under lipopolysaccharide (LPS) challenge conditions. Together with increased TGF-ß1 by macrophages, MgO-incorporated membranes significantly boost the proliferation of fibroblasts and upregulate collagen production, thus driving granulation tissue formation and wound closure. MgO-incorporated membranes promote angiogenesis by promoting tube formation and upregulating vascular endothelial growth factor (VEGF) production of endothelial cells. Rapid epithelialization of regenerated skin tissue is attributed to the balanced phenotype of keratinocytes between proliferative and terminally differentiated populations. In addition to coordinating keratinocyte phenotype, MgO-incorporated membranes reduce the expression of inflammatory cytokine interleukin 1-alpha (IL-1α) therefore promoting hair follicle regeneration. These data provide mechanisms of MgO-incorporated membranes that inhibit bacterial infection, alleviate inflammation, facilitate extracellular matrix production and epithelialization, and potentiate hair follicle regeneration.


Assuntos
Óxido de Magnésio , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/metabolismo , Células Endoteliais/metabolismo , Fator A de Crescimento do Endotélio Vascular , Cicatrização , Inflamação
3.
J Steroid Biochem Mol Biol ; 225: 106193, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36162632

RESUMO

The effect of long intergenic non-protein coding RNAs (lncRNAs) was verified in prostate cancer (PCa), but the mechanism of LINC01146 in PCa is unclear. Bioinformatics was applied to analyze LINC01146 expression in PCa and predict target genes of LINC01146, followed by the verification of qRT-PCR, RNA pull-down and co-immunoprecipitation (Co-IP). The correlation between LINC01146 expression and clinicopathological characteristics was investigated. The location of LINC01146 in PCa cells was detected by fluorescence in situ hybridization (FISH). After interference with LINC01146 or/and F11 receptor (F11R) or treated with transforming growth factor beta 1 (TGF-ß1), the function of LINC01146 in PCa in vitro or in vivo was determined by CCK-8, colony formation, flow cytometry, scratch test, transwell assay, xenograft experiment and western blot. LINC01146 and F11R were over-expressed in PCa and positively correlated with poor prognosis. LINC01146 located in the cytoplasm and combined with F11R. LINC01146 overexpression impeded apoptosis, facilitated viability, proliferation, migration and invasion in PCa cells in vitro, promoted tumor growth in vivo, downregulated E-cadherin, Bax and Cleaved caspase-3, and upregulated N-cadherin, Vimentin and PCNA, but LINC01146 silencing did the opposite. F11R was positively regulated by LINC01146 and F11R depletion negated the effect of LINC01146 overexpression on malignant phenotypes of PCa cells. The expression of LINC01146 and F11R was regulated by TGF-ß1. The promoting role of TGF-ß1 in migration, invasion and F11R in PCa cells was reversed by LINC01146 silencing. LINC01146 upregulated F11R to facilitate malignant phenotypes of PCa cells, which was regulated by TGF-ß.


Assuntos
Molécula A de Adesão Juncional , MicroRNAs , Neoplasias da Próstata , RNA Longo não Codificante , Masculino , Humanos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/genética , Molécula A de Adesão Juncional/genética , Molécula A de Adesão Juncional/metabolismo , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Hibridização in Situ Fluorescente , Linhagem Celular Tumoral , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante/genética , Proliferação de Células/genética , MicroRNAs/genética , Receptores de Superfície Celular/genética , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo
4.
Phytomedicine ; 108: 154246, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36274411

RESUMO

BACKGROUND: Most chronic kidney diseases (CKDs) develop to end-stage renal disease (ESRD), which is characterized by fibrosis and permanent tissue and function loss. As a result, better and more effective remedies are essential. Kaempferol (KAE) is a common flavonoid extracted from plants. It can control the progression of kidney fibrosis and the epithelial-to-mesenchymal transition (EMT) of the renal tubular system. PURPOSE: We aim to investigate the effect of KAE therapy on extracellular matrix deposition and stimulation of EMT in vitro and in vivo to elucidate the treatment mechanisms regulating these effects. STUDY DESIGN: Chronic hypertension-induced kidney fibrosis was studied in spontaneously hypertensive rats with chronic kidney disease. Biochemical analysis, histological staining, and the expression level of relative proteins were used to assess the effect of KAE on renal function and fibrosis. The direct impact of KAE on proliferation and migration was evaluated using human renal tubular epithelial cells (HK-2) induced by transforming growth factor-ß1 (TGF-ß1), which can then induce EMT. The molecular mechanism of KAE was verified using co-IP assay and immunofluorescence. RESULTS: KAE could reduce blood pressure and decrease the extracellular matrix (ECM) components (including collagen I and collagen Ш), TGF-ß1, and α-SMA in the kidneys of hypertension-induced rats with chronic kidney disease. Moreover, in HK-2 cell treated with TGF-ß1, KAE administration significantly suppressed proliferation, migration, and EMT via increasing the expression of E-cadherin, while reducing the N-cadherin and α-SMA. Sufu was exceedingly repressed in HK-2 cells treated with TGF-ß1. KAE inhibited the activation of Shh and Gli through increasing the expression of Sufu, thereby blocking the nuclear translocation of Gli1 in vitro. CONCLUSION: KAE ameliorated kidney fibrosis and EMT by inhibiting the sonic hedgehog signaling pathway, thereby to attenuate the pathological progression of hypertensive kidney fibrosis.


Assuntos
Hipertensão , Insuficiência Renal Crônica , Ratos , Humanos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Hedgehog/metabolismo , Quempferóis/farmacologia , Fibrose , Transição Epitelial-Mesenquimal , Colágeno , Hipertensão/tratamento farmacológico
5.
Curr Probl Cardiol ; 48(1): 101414, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36155200

RESUMO

Atrial fibrillation (AF) is associated with profound structural and functional changes in the atrium. Inflammation mediated atrial fibrosis is one of the key mechanisms in the pathogenesis of AF. The collagen deposition in extracellular matrix (ECM) is mainly mediated by transforming growth factor ß1 (TGF-ß1) which promotes AF via controlling smads mediated-collagen gene transcription and regulating the balance of metalloproteinases (MMPs)/ tissue inhibitor of metalloproteinases (TIMPs). Although many processes can alter atrial properties and promote AF, animal models and clinical studies have provided insights into 2 major forms of atrial remodeling: Atrial tachycardia remodeling (ATR), which occurs with rapid atrial tachyarrhythmia's such as AF and atrial flutter, and atrial structural remodeling (ASR), which is associated with CHF and other fibrosis-promoting conditions. The mechanism of atrial remodeling such as atrial enlargement, ultra-structural changes of atrial muscle tissue and myocardial interstitial fibrosis in AF is still unclear. At present, many studies focus on calcium overload, renin angiotensin aldosterone system and transforming growth factor ß1, that effect on atrial structural remodeling. Recent experimental studies and clinical investigations have provided structural remodeling is important contributor to the AF. This paper reviews the current understanding of the progresses about mechanism of atrial structural remodeling, and highlights the potential therapeutic approaches aimed at attenuating structural remodeling to prevent AF. Now some recent advancements of this area are reviewed in this paper.


Assuntos
Fibrilação Atrial , Remodelamento Atrial , Cardiomiopatias , Animais , Humanos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Átrios do Coração/patologia , Fibrilação Atrial/patologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Inibidores Teciduais de Metaloproteinases/farmacologia , Fibrose , Cardiomiopatias/complicações , Colágeno/metabolismo , Colágeno/farmacologia
6.
J Nutr Biochem ; 111: 109177, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36223833

RESUMO

Increasing evidence has demonstrated that vitamin D deficiency is associated with prostate cancer progression, but its mechanism remains unclear. This study investigated effects of vitamin D deficiency on growth and metastasis of prostate cancer. Nude mice and Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed with vitamin D-deficient (VDD) diets. Prostate cancer growth was aggravated in VDD diet-fed nude mice and TRAMP mice. Invasion and metastasis of prostate cancer were exacerbated in VDD diet-fed TRAMP mice. In vitro experiments showed that calcitriol, an active vitamin D3, inhibited migration and invasion in transforming growth factor (TGF)-ß1 -stimulated and -unstimulated PC-3 and DU145 cells. Mechanistically, calcitriol inhibited epithelial-mesenchymal transition (EMT) in TGF-ß1 -stimulated and -unstimulated DU145 cells. Unexpectedly, calcitriol did not inhibit Smad2/3 phosphorylation in TGF-ß1-stimulated DU145 cells. Instead, calcitriol downregulated expression of proliferation-, metastasis- and EMT-related genes, includes Cyclin D1, MMP7, and Zeb1, by inhibiting interaction between TCF4 and ß-catenin. In addition, calcitriol promoted interaction between cytoplasmic VDR and ß-catenin, reduced ß-catenin phosphorylation and elevated ß-catenin/E-cadherin adherens junction complex formation. We provide novel evidence that vitamin D deficiency aggravates growth and metastasis of prostate cancer possibly through promoting EMT in two ß-catenin-related mechanisms.


Assuntos
Neoplasias da Próstata , Deficiência de Vitamina D , Humanos , Masculino , Camundongos , Animais , Transição Epitelial-Mesenquimal , beta Catenina/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Camundongos Nus , Calcitriol/farmacologia , Neoplasias da Próstata/patologia , Movimento Celular
7.
Acta Cir Bras ; 37(7): e370705, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36327404

RESUMO

PURPOSE: To explore the mechanism of jatrorrhizine on apoptosis and fibrosis induced by myocardial infarction (MI) in an animal model. METHODS: The left anterior descending branch of coronary artery was surgically ligated to duplicate the mouse model of MI. The sham and infarcted mice were treated with normal saline once a day, while mice in experimental groups received low-dose (LD) and high-dose (HD) jatrorrhizine once a day respectively. Two weeks later, cardiac function was detected by echocardiography, and histopathological examination was performed using hematoxylin and eosin (H&E) and Masson staining. The expressions of p53, TGF-ß1, Smad/2/3, Bax, Bcl-2, collagen I and collagen III were quantified using qRT-PCR and western blot assays. RESULTS: Jatrorrhizine significantly improved left ventricular ejection fraction (LVEF) and left ventricle end-systolic (LVES) in mice. Histopathological, administration of jatrorrhizine weakened infiltration of inflammatory cells and cardiac fibrosis in myocardium of mice caused by MI. Additionally, jatrorrhizine suppressed cardiomyocyte apoptosis exhibited as its capability to reverse changes of Bax and Bcl-2 levels in myocardium caused by MI. Jatrorrhizine statistically significantly downregulated expression of collagen I and collagen III, as well as TGF-ß1, Smad2/3 and p53. CONCLUSIONS: Jatrorrhizine reduce cardiomyocyte apoptosis and fibrosis through inhibiting p53/Bax/Bcl-2 and TGF-ß1/Smad2/3 signaling pathways.


Assuntos
Infarto do Miocárdio , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Apoptose , Proteína X Associada a bcl-2/metabolismo , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibrose , Infarto do Miocárdio/patologia , Miocárdio/patologia , Volume Sistólico , Fator de Crescimento Transformador beta1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/uso terapêutico , Função Ventricular Esquerda
8.
Sci Rep ; 12(1): 18593, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36329196

RESUMO

This study aims to determine the effects of rosmarinic acid which involved the mechanisms to decrease the postoperative peritoneal adhesion formation in rats. Various incisions and removing a 1 × 1 cm piece of peritoneum was used to induce the peritoneal adhesions. Experimental groups were as follows: 1-Sham group. 2-Control group: Peritoneal adhesions were induced and no treatments were performed. 3-Treatment groups: Following inducing peritoneal adhesions, animals received rosmarinic acid with 50 and 70 mg/kg dosage, respectively. Macroscopic examination of adhesions indicated that adhesion bands were reduced in both treatment groups compared to the control group. Moreover, the adhesion score was decreased in both treatment groups on day 14. Inflammation and fibroblast proliferation were both reduced in the treatment groups on day 14. TGF-ß1, TNF-α, and VEGF were all evaluated by western blot and immunohistochemistry on days 3 and 14. Treatment groups reduced inflammatory cytokines on days 3 and 14. The treatment group with a 70 mg/kg dosage decreased TGF-ß1 and TNF-α levels more than the other treatment group. The administration of rosmarinic acid significantly reduced MDA and increased CAT levels. In conclusion, the rosmarinic acid was effective to reduce the adhesion bands, inflammatory cytokines, angiogenesis, and oxidative stress.


Assuntos
Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa , Ratos , Animais , Modelos Animais de Doenças , Aderências Teciduais/prevenção & controle , Aderências Teciduais/patologia , Peritônio/patologia , Citocinas , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/patologia
9.
FASEB J ; 36(12): e22625, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36331546

RESUMO

Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney disease (CKD), ultimately predisposes patients to end-stage renal disease. However, there is no effective therapy for renal fibrosis. Our earlier studies proved that RIP3-mediated necroptosis might be an important mode of renal tubular cell death in rats with chronic renal injury. Under transmission electron microscopy (TEM), we found morphological changes in the necrosis of human renal tissue, and the percentage of necrotic cells increased significantly in patients with stages 2 and 3a CKD. Immunofluorescence analyses showed that the percentages of TUNEL+ /RIP3+ double-positive and TUNEL+ /MLKL+ double-positive tubular epithelial cells in renal tubules of patients with stages 2 and 3a CKD were significantly increased compared to those in control patients without renal disease. Immunohistochemistry analyses of renal biopsy specimens from patients with CKD revealed RIP3, MLKL, and p-MLKL upregulation in patients with stages 2 and 3a CKD, suggesting that necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. We showed that profibrotic factor proteins (TGF-ß1, Smad2 and Smad3) and fibroblast activation markers (α-SMA and Vimentin) were specifically upregulated in stage 2 and 3a CKD patients. In addition, Pearson correlation analysis showed that the percentage of necroptotic renal tubular epithelial cells was positively correlated with TGF-ß1 and collagen-I. We also showed that RIP1/3 or MLKL inhibitors decreased the expression of RIP3, MLKL, TGF-ß1, and Smad3 in HK-2 cells treated with TNF-α. FGF-2, α-SMA, Vimentin and FN were overexpressed in the hRIFs cultured with the supernatant of necroptotic HK-2 cells, whereas necroptosis blockers (Nec-1s, GSK'872 and NSA) and TGF-ß1/Smad3 pathway antagonists (LY364947 and SIS3) reduced FGF-2, α-SMA, Vimentin and FN levels. Collectively, necroptosis of renal tubular epithelial cells in CKD patients occurs, and the peak of necroptosis was in stages 2 and 3a CKD. Renal tubular epithelial cell necroptosis mediates renal tubulointerstitial fibrosis in patients with chronic kidney disease, which is related to the TGF-ß1/Smad3 signaling pathway.


Assuntos
Insuficiência Renal Crônica , Fator de Crescimento Transformador beta1 , Humanos , Ratos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Necroptose , Vimentina/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fibrose , Células Epiteliais/metabolismo , Insuficiência Renal Crônica/metabolismo , Rim/metabolismo , Necrose/patologia
10.
J Pharmacol Sci ; 150(4): 289-300, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36344052

RESUMO

The purpose of this experiment was to investigate the anti-hepatic fibrosis effect of Aronia melanocarpa polysaccharide (AMP) on TAA-induced liver fibrosis mice and its mechanism, as well as the changes in intestinal flora in vivo. This was established with a dose of 200 mg/kg TAA (i.p) once every three days, lasting for eight weeks. Colchicine with 0.4 mg/kg, and AMP (200 and 400 mg/kg) were given by intragastric administration (i.g) after 28 days of intraperitoneal injection of TAA. AMP treatment significantly inhibited the activities of liver injury markers ALT and AST in serum. Histopathological staining demonstrated that AMP significantly reversed TAA-induced hepatocyte necrosis and collagen deposition. In addition, AMP treatment block TGF- ß1/Smads pathway inhibited the production of ECM and alleviates liver fibrosis. Furthermore, AMP treatment enhanced the phosphorylation of PI3K/AKT and decreased the expression of its downstream apoptosis-related proteins in liver, thus effectively alleviating TAA-induced liver fibrosis. In addition, 16S rDNA gene sequencing analysis showed that AMP treatment helped restore the imbalanced ecosystem of gut microbes, increased the proportion of Bacteroidetes and Proteobacteria, and increased species richness. Above findings clearly show that AMP is an effective method for treating liver fibrosis, possibly by improving the gut microbiota.


Assuntos
Microbioma Gastrointestinal , Photinia , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Células Estreladas do Fígado/metabolismo , Photinia/metabolismo , Ecossistema , Transdução de Sinais , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fígado/metabolismo , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(10): 1511-1516, 2022 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-36329585

RESUMO

OBJECTIVE: To investigate the effect of hydronidone on CCl4-induced liver fibrosis in rats and explore the possible mechanism. METHODS: Sixty-six male SD rats were randomized into 5 groups, including a control group (n=10), a liver fibrosis model group (n=20), 2 hydronidone dose groups (100 and 250 mg/kg; n=12), and a pirfenidone (250 mg/kg) treatment group (n= 12). Rat models of liver fibrosis were established by subcutaneous injection of CCl4 in all but the control group. Hydronidone and pirfenidone were given daily at the indicated doses by intragastric administration for 6 weeks. After the treatments, serum samples were collected from the rats for detecting liver function parameters, and hydroxyproline content in the liver tissue was determined. Inflammation and fibrosis in the liver tissue were observed using HE staining and Sirius Red staining. In the cell experiment, human hepatic stellate cell line LX-2 was stimulated with TGF-ß1 and treated with hydronidone or pirfenidone, and the expression levels of α-SMA, collagen type I and phosphorylated Smad3, phosphorylated p38, phosphorylated ERK1/2 and phosphorylated Akt were detected with Western blotting. RESULTS: In the rat models of liver fibrosis, treatment with hydronidone obviously improved the liver functions, reduced the content of hydroxyproline in the liver tissue, and significantly alleviated liver fibrosis (P < 0.05). In LX-2 cells, hydronidone dose-dependently decreased the expression levels of α-SMA and collagen type I. In TGF- ß1-stimulated cells, the phosphorylation levels of Smad3, P38, ERK, and Akt increased progressively with the extension of the treatment time, but this effect was significantly attenuated by treatment with hydronidone (P < 0.05). CONCLUSION: Hydronidone can inhibit the phosphorylation of the proteins in the TGF-ß signaling pathway, thereby preventing TGF-ß1-mediated activation of hepatic stellate cells, which may be a possible mechanism by which hydronidone alleviates CCl4-induced liver fibrosis in rats.


Assuntos
Células Estreladas do Fígado , Fator de Crescimento Transformador beta1 , Animais , Masculino , Ratos , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismo , Colágeno Tipo I , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hidroxiprolina/metabolismo , Hidroxiprolina/farmacologia , Hidroxiprolina/uso terapêutico , Cirrose Hepática , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Cells ; 11(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36359733

RESUMO

Liver fibrosis can develop on the background of hyperglycemia in diabetes mellitus. However, xenobiotic-related factors may accelerate diabetes-associated liver fibrosis. In this study, we aimed to assess the antfibrotic effect of ADSC and HGF therapy and to establish the cellular and molecular mechanisms through in vitro and in vivo experiments. In vitro, TGF-ß1-activated hepatic stellate cells (HSCs) were cocultured with ADSCs or HGF, and the expression of several fibrosis markers was investigated. The antifibrotic effect of the ADSCs, HGF, and ADSCs supplemented with HGF was further assessed in vivo on diabetic mice with liver fibrosis experimentally induced. In vitro results showed the inhibition of HSC proliferation and decrease in fibrogenesis markers. Coadministration of ADSCs and HGF on diabetic mice with liver fibrosis enhanced antifibrotic effects confirmed by the downregulation of Col I, α-SMA, TGF-ß1, and Smad2, while Smad7 was upregulated. Moreover, stem cell therapy supplemented with HGF considerably attenuated inflammation and microvesicular steatosis, decreased collagen deposits, and alleviated liver fibrosis. In conclusion, the HGF-based ADSC therapy might be of interest for the treatment of liver fibrosis in diabetic patients, consecutive aggression exerts by different environmental factors.


Assuntos
Diabetes Mellitus Experimental , Células Estreladas do Fígado , Cirrose Hepática , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/metabolismo , Células Estreladas do Fígado/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/terapia , Cirrose Hepática/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células-Tronco Mesenquimais
13.
ACS Appl Mater Interfaces ; 14(46): 51669-51682, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36367478

RESUMO

Repeated mechanical and chemical insults cause an irreversible alteration of extracellular matrix (ECM) composition and properties, giving rise to vocal fold scarring that is refractory to treatment. Although it is well known that fibroblast activation to myofibroblast is the key to the development of the pathology, the lack of a physiologically relevant in vitro model of vocal folds impedes mechanistic investigations on how ECM cues promote myofibroblast differentiation. Herein, we describe a bio-orthogonally cross-linked hydrogel platform that recapitulates the alteration of matrix adhesiveness due to enhanced fibronectin deposition when vocal fold wound healing is initiated. The synthetic ECM (sECM) was established via the cycloaddition reaction of tetrazine (Tz) with slow (norbornene, Nb)- and fast (trans-cyclooctene, TCO)-reacting dienophiles. The relatively slow Tz-Nb ligation allowed the establishment of the covalent hydrogel network for 3D cell encapsulation, while the rapid and efficient Tz-TCO reaction enabled precise conjugation of the cell-adhesive RGDSP peptide in the hydrogel network. To mimic the dynamic changes of ECM composition during wound healing, RGDSP was conjugated to cell-laden hydrogel constructs via a diffusion-controlled bioorthognal ligation method 3 days post encapsulation. At a low RGDSP concentration (0.2 mM), fibroblasts residing in the hydrogel remained quiescent when maintained in transforming growth factor beta 1 (TGF-ß1)-conditioned media. However, at a high concentration (2 mM), RGDSP potentiated TGF-ß1-induced myofibroblast differentiation, as evidenced by the formation of an actin cytoskeleton network, including F-actin and alpha-smooth muscle actin. The RGDSP-driven fibroblast activation to myofibroblast was accompanied with an increase in the expression of wound healing-related genes, the secretion of profibrotic cytokines, and matrix contraction required for tissue remodeling. This work represents the first step toward the establishment of a 3D hydrogel-based cellular model for studying myofibroblast differentiation in a defined niche associated with vocal fold scarring.


Assuntos
Miofibroblastos , Fator de Crescimento Transformador beta1 , Humanos , Fator de Crescimento Transformador beta1/farmacologia , Prega Vocal/metabolismo , Hidrogéis/farmacologia , Hidrogéis/metabolismo , Cicatriz/metabolismo , Adesividade , Fibroblastos
14.
Cell Commun Signal ; 20(1): 183, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411467

RESUMO

BACKGROUND AND PURPOSE: Hyperoxia-induced acute lung injury (HALI) is a critical life-threatening disorder characterized by severe infiltration immune cells and death of type II alveolar epithelial cells (AECII). However, little is known about the relations between immune cells and AECII in HALI. IL-17A is a pro-inflammatory cytokine mainly secreted by Th17 cells, contributing to the pathogenesis of various inflammatory diseases. The present study investigated the role of IL-17A in cell-cell communication between immune cells and AECII in HALI, and explored the therapeutic effect of salidroside (Sal, a natural anti-inflammatory agents) on HALI. METHODS: Mice with HALI were induced by exposure to hyperoxia over 90% for 12 h, 24 h, 48 h or 72 h, and the optimal timing was detected by H&E and Masson staining. Ferroptosis was confirmed by detecting the levels of MDA, Fe2+ and GPX4, and the morphological alterations of AECII under transmission electron microscopy. The expression of pro-inflammatory cytokine, including IL-6, TGF-ß1, IL-17A and IL-17A receptor (IL-17RA) were measured by Western blotting and immunohistochemical stanning. The ferroptosis-related Act1/TRAF6/p38 MAPK pathway was detected by Western blotting. The role of pro-inflammatory cytokine IL-17A for AECII ferroptosis, and the effect of Sal on HALI were investigated by administration of Y-320 (IL-17 inhibitor) and Sal respectively 3 days before mice exposed to hyperoxia. RESULTS: Mice exposed to hyperoxia for 24 h suffered sufficient HALI with inflammatory cell infiltration and collagen deposition, and exhibited features of ferroptosis under TME. Meanwhile, compared with sham mice, mice exposed to hyperoxia showed down-regulation of GPX4, and up-regulation of IL-6, TGF-ß1, IL-17A, IL-17RA, Act1, TRAF6, p38 MAPK and p-p38 MAPK. Moreover, inhibition of IL-17A with Y-320 or administration with Sal could reverse the effect caused by hyperoxia respectively. CONCLUSIONS: IL-17A is associated with immune cells infiltration in HALI, and contributes to ferroptosis of AECII that related to Act1/TRAF6/p38 MAPK pathway. Additionally, Sal protects against HALI throughout the whole pathogenic process. Video Abstract.


Oxygen inhalation has been widely used in the treatment of some diseases caused by hypoxia. This often leads people to mistakenly believe that oxygen inhalation is beneficial without harm. However, long-term high concentration oxygen inhalation will cause serious harm to the human body, sometimes even fatal. Hyperoxia causes lung cells to secrete proinflammatory factors, which promote the differentiation of infiltrated immune cells. The differentiated immune cells in turn act on lung cells and lead to their death. In short, this process is a vicious circle. Our research explores this process and is committed to finding a drug to reduce the damage of hyperoxia to the lungs when oxygen must be inhaled.


Assuntos
Lesão Pulmonar Aguda , Ferroptose , Hiperóxia , Camundongos , Animais , Interleucina-17 , Fator 6 Associado a Receptor de TNF/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Células Epiteliais Alveolares/metabolismo , Hiperóxia/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Interleucina-6/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Citocinas/metabolismo , Proteínas de Transporte
15.
J Fr Ophtalmol ; 45(10): 1177-1183, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36357250

RESUMO

PURPOSE: To investigate the relationship between levels of transforming growth factor beta (TGF-beta), matrix metalloproteinase (MMP) and tissue inhibitors of MMP (TIMP) in the aqueous humor (AH) and plasma (PL) of myopic patients. METHODS: Aqueous humor and plasma were collected intraoperatively from 37 myopic patients with various axial lengths (AL) during ICL surgery. The concentrations of TGF-ß1, TGF-ß2, TGF-ß3, MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were measured using Luminex xMAP Technology kits (Milliplex xMAP kits). The association between TGFß and MMP/TIMP levels were analyzed based on the Spearman's correlation test or Pearson's correlation test. RESULTS: There was a negative correlation between TGF-ß1 and MMP-1, TIMP-2, TIMP-3 and TIMP-4 in the AH, and a positive correlation between TGF-ß1 and MMP-1 in the PL. In the AH, levels of TGF-ß2 were positively correlated with levels of TIMP-3 (r=0.441; P < 0.001). In the PL, levels of TGF-ß2 also correlated positively with levels of TIMP-3 (r=0.427; P < 0.001)). CONCLUSION: The level of TGF-ß2 was the highest among TGF-ßs in the AH. A consistent positive correlation between TGF-ß2 and TIMP-3 was found both in the AH and PL, indicating that systemic levels of TGF-ß2 and MMPs/TIMPs may also play a role in myopic progression.


Assuntos
Miopia , Fator de Crescimento Transformador beta2 , Humanos , Humor Aquoso , Inibidor Tecidual de Metaloproteinase-3 , Inibidor Tecidual de Metaloproteinase-2 , Fator de Crescimento Transformador beta1 , Metaloproteinase 1 da Matriz , Fatores de Crescimento Transformadores
16.
Folia Biol (Praha) ; 68(2): 45-49, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36384261

RESUMO

Autologous serum eye drops (ASEDs) are used as a treatment for severe dry eye disease. The concentration and stability of various growth factors in ASEDs is determinative for their efficiency. We therefore assessed the concentrations of transforming growth factor beta 1 (TGF-ß1), epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1) in ASEDs following storage at 4-8, -20, -80 and -156 °C. Twenty % and 100% sera from eight healthy volunteers were analysed by the sandwich enzyme immunoassay at different time intervals up to seven months. The mean levels of TGF-ß1 and EGF in undiluted and 20% serum did not differ significantly from the baseline levels in fresh serum for any storage conditions after 7 days at 4-8 °C, as well as after 4- and 7-month preservation at sub-zero temperatures. In 20% serum, no IGF-1 concentration decrease was found following 7 days of preservation at 4-8 °C. However, a decrease to 78 % and 81 % (P < 0.01) of baseline values was found in 20% serum after 4-month storage at -20 °C and 7-month storage at -156 °C, respectively. A more pronounced decrease in IGF-1 was observed in undiluted serum. All assessed growth factors present in 20% frozen serum remained stable for up to 7 months. The highest stability was achieved at -80 °C. At -20 and -156 °C, some decrease in IGF-1 occurred. Our results indicate that 20% ASEDs can be stored frozen up to 7 months under proper conditions.


Assuntos
Fator de Crescimento Epidérmico , Fator de Crescimento Insulin-Like I , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Transformador beta1 , Temperatura , Soro/metabolismo , Soluções Oftálmicas
17.
Cell Death Dis ; 13(11): 948, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357371

RESUMO

Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined. In this study, we developed a R495Q mutant pig model using cytosine base editing and observed an early-onset MF in these mutant pigs shortly after birth. Unexpectedly, we found that the "cardiac-specific" MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels. CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-ß1) and other pro-inflammatory genes. The upregulation of TGF-ß1 promoted the expression of hypoxia-inducible factor-1 subunit α (HIF-1α) and its downstream targets involved in glycolysis such as GLUT1, PFK, and LDHA. Consequently, the enhanced aerobic glycolysis with higher rate of ATP biosynthesis accelerated the activation of cardiac fibroblasts, contributing to the development of HCM. This work reveals an intrinsic role of MYBPC3 in maintaining cardiac fibroblast homeostasis and disruption of MYBPC3 in these cells contributes to the disease pathogenesis of HCM.


Assuntos
Cardiomiopatias , Cardiomiopatia Hipertrófica , Camundongos , Suínos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células NIH 3T3 , Cardiomiopatia Hipertrófica/genética , Mutação , Cardiomiopatias/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fibrose
18.
Sci Rep ; 12(1): 19160, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357407

RESUMO

Renal fibrosis (RF) is the common pathway for a variety of chronic kidney diseases that progress to end-stage renal disease. Chitosan oligosaccharide (COS) has been identified as possessing many health functions. However, it is not clear whether COS can prevent RF. The purpose of this paper was to explore the action and mechanism of COS in alleviating RF. First, an acute unilateral ureteral obstruction operation (UUO) in male BALB/c mice was performed to induce RF, and COS or fosinopril (positive control drug) were administered for 7 consecutive days. Data from our experiments indicated that COS treatment can significantly alleviate kidney injury and decrease the levels of blood urea nitrogen (BUN) and serum creatinine (SCr) in the UUO mouse model. More importantly, our results show that COS can reduce collagen deposition and decrease the expression of fibrosis proteins, such as collagen IV, fibronectin, collagen I, α-smooth muscle actin (α-SMA) and E-cadherin, ameliorating experimental renal fibrosis in vivo. In addition, we also found that COS suppressed oxidative stress and inflammation in RF model mice. Further studies indicated that the mechanism by which COS alleviates renal fibrosis is closely related to the regulation of the TGF-ß1/Smad pathway. COS has a therapeutic effect on ameliorating renal fibrosis similar to that of the positive control drug fosinopril. Taken together, COS can alleviate renal fibrosis induced by UUO by reducing oxidative stress damage and regulating the TGF-ß1/Smad pathway.


Assuntos
Quitosana , Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Masculino , Camundongos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Quitosana/metabolismo , Fosinopril/farmacologia , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Nefropatias/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/metabolismo , Rim/metabolismo , Insuficiência Renal Crônica/patologia , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Oligossacarídeos/metabolismo
19.
Cells ; 11(21)2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36359901

RESUMO

Renal fibrosis is a common pathological feature of various kidney diseases, leading to irreversible renal failure and end-stage renal disease. However, there are still no effective treatments to reverse renal fibrosis. This study aimed to explore the potential mechanism of a targeted drug for fibrosis. Here, unilateral ureteral obstruction (UUO)-treated mice and a TGF-ß1-treated human renal tubular epithelial cell line (HK-2 cells) were used as models of renal fibrosis. Based on the changes of mRNA in UUO kidneys detected by transcriptome sequencing, MK-2206, an Akt inhibitor, was predicted as a potential drug to alleviate renal fibrosis through bioinformatics. We dissolved UUO mice with MK-2206 by gastric gavage and cultured TGF-ß-induced HK-2 cells with MK-2206. Histopathological examinations were performed after MK-2206 intervention, and the degree of renal fibrosis, as well as the expression of Akt/mTOR pathway-related proteins, were evaluated by immunohistochemical staining, immunofluorescence staining, and Western blot. The results showed that MK-2206 significantly improved the pathological structure of the kidney. Furthermore, MK-2206 intervention effectively inhibited UUO- and TGF-ß1-induced epithelial-mesenchymal transition, fibroblast activation, and extracellular matrix deposition. Mechanistically, MK-2206 treatment attenuated the activation of the Akt/mTOR signaling pathway. Taken together, our study revealed for the first time that MK-2206 is a promising drug for the improvement of renal fibrosis.


Assuntos
Nefropatias , Obstrução Ureteral , Camundongos , Humanos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Transdução de Sinais , Obstrução Ureteral/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo
20.
Sci Rep ; 12(1): 18910, 2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344553

RESUMO

Overproduction of mucins in the airways donates largely to airway blockage in asthma patients. Glycoprotein MUC7 plays a role in the clearance of bacteria and has anti-candidacidal criteria. Our goal was to investigate the association between the MUC7 variable number of tandem repeats (VNTR) polymorphism and bronchial asthma among Egyptian children. The MUC7 VNTR polymorphism was investigated among 100 children with bronchial asthma and 100 healthy controls using polymerase chain reaction (PCR) method. Serum levels of immunoglobulin E (IgE), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta1 (TGF-ß1) were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The frequencies of 6*5 genotype, 5*5 genotype, (6*5 + 5*5) genotypes, and MUC7*5 allele of the MUC7 VNTR variant were significantly lower among asthmatic patients than controls (p < 0.015, OR = 0.39, 95% CI = 0.19-0.81; p = 0.03, OR = 0.18, 95% CI = 0.04-0.86; p < 0.001, OR = 0.29, 95% CI = 0.15-0.58; p < 0.001, OR = 0.3, 95% CI = 0.17-0.55, respectively). The (6*5 + 5*5) genotypes of the MUC7 VNTR variant were not associated with the clinical manifestations and serum levels of IgE, TNF-α, and TGF-ß1 among asthmatic patients (p ˃ 0.05). In conclusion, the (6*5 + 5*5) genotypes of the MUC7 VNTR variant may have a protective role for bronchial asthma in Egyptian children.


Assuntos
Asma , Polimorfismo Genético , Criança , Humanos , Fator de Crescimento Transformador beta1/genética , Repetições Minissatélites , Fator de Necrose Tumoral alfa/genética , Egito , Asma/genética , Genótipo , Imunoglobulina E/genética , Predisposição Genética para Doença , Mucinas/genética , Proteínas e Peptídeos Salivares/genética
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