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1.
Anticancer Res ; 41(10): 4753-4759, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593424

RESUMO

BACKGROUND/AIM: De-differentiation is a key step for the progression of cancer cells. This study investigated the anti-tumor effect of kartogenin (KGN), which has the ability to differentiate cells, on prostate cancer (PC) cells. MATERIALS AND METHODS: The effects of KGN on androgen receptor (AR) nuclear localization, prostate-specific antigen (PSA) expression, and Smad2 activation as well as the growth of PC cell lines (LNCaP, 22Rv1 and PC-3) were analyzed. RESULTS: KGN significantly inhibited growth of AR-expressing LNCaP and 22Rv1 cells but not of AR-lacking PC-3 cells. KGN decreased AR nuclear localization and PSA expression, but did not enhance the anti-tumor effect of bicalutamide in LNCaP cells. KGN activated Smad2 both in the absence and presence of TGF-ß1. KGN also inhibited growth of docetaxel-resistant PC cells, 22Rv1DR, and re-sensitized them to the agent. CONCLUSION: KGN has a potential as a novel therapeutic for PC patients after treatment failure.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Núcleo Celular/metabolismo , Ácidos Ftálicos/farmacologia , Receptores Androgênicos/metabolismo , Proteína Smad2/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Fator de Crescimento Transformador beta1/farmacologia
2.
BMC Musculoskelet Disord ; 22(1): 843, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34592976

RESUMO

BACKGROUND: The injured flexor tendon has poor healing ability, which is easy to cause tendon adhesion. It can affect the recovery of tendon function, which is still a long-term and difficult task for surgeons. Transforming growth factor ß (TGF-ß) has been widely considered to play an important role in flexor tendon repair in recent years. AIM: This work was to investigate the anti-adhesion and anti-inflammatory effects of TGF-ß3 on flexor digitorum longus (FDL) tendon repair rats. METHOD: Anastomosis models of tendon laceration in the flexion toes of rats were delivered with no treatment, vehicle, or TGF-ß3 -overexpressed adenovirus vector (ad-TGF-ß3) locally to the injured tendon area from day 3 to 8. Subsequently, the expression of TGF-ß3, TGF-ß1/2, Smad3, Smad7, JNK, phosphorylation (p)-JNK, c-Jun, and phosphorylation (p)-c-Jun were detected by western blot, the expression of Mmp9 and Mmp2 by RT-qPCR, the Range of motion (ROM) and gliding resistance by adhesion formation testing, the mechanical strength of tendon healing by biomechanical testing, the pathologic changes of flexor tendon tissues by HE staining, the expression of collagen type III by immunohistochemical staining, and the levels of IL-6, TNF-α, COX2 and IL-1ß in serum by ELISA, respectively. RESULTS: Rat models treated with no treatment showed a lower elevation of TGF-ß3 and Smad7 expression, and a higher elevation of TGF-ß1/2 and Smad3 expression, during day 14 to day 28. Besides, under the treatment of ad-TGF-ß3, a significantly increase was reflected in the expression of TGF-ß3 and Smad7, ROM, as well as mechanical strength of flexor tendon, whereas significantly reduction was shown in gliding resistance, the content of inflammatory cytokines, the ratio of p-JNK/JNK, p-c-Jun/c-Jun, as well as the expression of TGF-ß1/2, Smad3, Mmp9, and Mmp2 genes, as compared to those from vehicle treatment. Meanwhile, TGF-ß3 demonstrated a better pathologic recovery process with no obvious necrosis or fracture of collagen fibers. Besides, TGF-ß3 revealed a significant reduction of collagen type-III expression in the flexor tendon healing tissues. CONCLUSION: These findings suggested that TGF-ß3 effectively protected against flexor tendon injury via regulating adhesion formation.


Assuntos
Traumatismos dos Tendões , Fator de Crescimento Transformador beta3 , Animais , Ratos , Traumatismos dos Tendões/patologia , Tendões/patologia , Aderências Teciduais/patologia , Fator de Crescimento Transformador beta1 , Cicatrização
3.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 33(4): 353-358, 2021 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-34505441

RESUMO

OBJECTIVE: To detect the expression of transforming growth factor-ß1 (TGF-ß1), p38MAPK and bone morphogenetic protein-7 (BMP-7) protein in the liver specimens of patients with hepatic alveolar echinococcosis, and to investigate the potential role of TGF-ß1, p38MAPK and BMP-7 protein in hepatic fibrosis caused by hepatic alveolar echinococcosis. METHODS: A total of 20 patients with hepatic alveolar echinococcosis were enrolled as study subjects, and hepatic specimens were sampled from the sites within 0.5 cm (Group A) and 0.5 to 1.5 cm from hepatic alveolar echinococcosis lesions (Group B), while normal liver specimens sampled from the sites 2 cm and greater from hepatic alveolar echinococcosis lesions served as controls (Group C). The fibrosis of liver specimens was pathological examined using HE and Masson staining, and the expression of TGF-ß1, p38MAPK and BMP-7 protein was quantified in liver tissues using Western blotting. The associations of TGF-ß1, p38MAPK and BMP-7 protein expression with hepatic fibrosis were assessed. RESULTS: HE staining showed the malaligned structure of hepatocytes and destruction of the structure of hepatic lobules at various degrees in liver specimens in groups A and B, with hepatocyte degeneration, atrophy and necrosis, hyperplasia of fibrous tissues and eosinophilic granulocyte infiltration seen, while no abnormal pathological alterations of liver tissues, normal hepatocyte structure and morphology and uniform size, no malaligned structure of hepatocytes, clear structure of hepatic lobules, no or mild hepatocyte degeneration or necrosis, and no eosinophilic granulocyte infiltration were seen in Group C. Masson staining showed that there was hyperplasia of multiple fibrous connective tissues in the liver portal areas in groups A and B, with fibrosis seen in hepatic lobules, while no obvious pathological changes were seen in Group C. There were significant differences seen in TGF-ß1 (P < 0.001), p38MAPK (P < 0.01) and BMP-7 protein (P < 0.05) expression in liver tissues in groups A, B and C, and higher TGF-ß1, p38MAPK and BMP-7 protein expression was quantified in groups A and B than in Group C (all P values < 0.05), while greater TGF-ß1, p38MAPK and BMP-7 protein expression was detected in Group B than in Group C (all P values < 0.05). The expression of TGF-ß1, p38MAPK and BMP-7 protein correlated positively with the severity of hepatic fibrosis (r = 0.866, 0.702 and 0.801, all P values < 0.05), and there were significant differences in TGF-ß1 (F = 72.580, P < 0.01), p38MAPK (χ2 = 31.705, P < 0.01) and BMP-7 protein expression (χ2 = 48.388, P < 0.01) among liver tissues with different degrees of fibrosis. The TGF-ß1 protein expression correlated positively with p38MAPK and BMP-7 protein expression (r = 0.607 and 0.702, both P values < 0.001), and the BMP-7 protein expression also correlated positively with p38MAPK protein expression (r = 0.456, P < 0.001). CONCLUSIONS: The interaction among TGF-ß1, p38MAPK and BMP-7 jointly participates in the development of hepatic fibrosis induced hepatic alveolar echinococcosis.


Assuntos
Equinococose Hepática , Fator de Crescimento Transformador beta1 , Proteína Morfogenética Óssea 7/genética , Equinococose Hepática/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Proteínas Quinases p38 Ativadas por Mitógeno
4.
BMC Cancer ; 21(1): 1017, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34511060

RESUMO

BACKGROUND: Neutrophils are important for immune surveillance of tumour cells. Neutrophils may also be epigenetically programmed in the tumour microenvironment to promote tumour progression. In addition to the commonly known high-density neutrophils (HDN) based on their separation on density gradient, recent studies have reported the presence of high levels of low-density neutrophils (LDN) in tumour-bearing mice and cancer patients. We reported previously that estrogen promotes the growth of estrogen receptor α-negative mammary tumours in mice undergoing mammary involution through stimulating pro-tumoral activities of neutrophils in the mammary tissue. METHODS: Female BALB/cAnNTac mice at 7-8 weeks old were mated and bilateral ovariectomy was performed 2 days post-partum. At 24 h after forced-weaning of pups to induce mammary involution, post-partum female mice were injected with either E2V, or vehicle control on alternative days for 2-weeks. On 48 h post-weaning, treated female mice were inoculated subcutaneously with 4 T1-Luc2 cells into the 9th abdominal mammary gland. Age-matched nulliparous female was treated similarly. Animals were euthanized on day 14 post-tumour inoculation for analysis. To evaluate the short-term effect of estrogen, post-partum females were treated with only one dose of E2V on day 12 post-tumour inoculation. RESULTS: Estrogen treatment for 2-weeks reduces the number of blood LDN by more than 10-fold in tumour-bearing nulliparous and involuting mice, whilst it had no significant effect on blood HDN. The effect on tumour-bearing mice is associated with reduced number of mitotic neutrophils in the bone marrow and increased apoptosis in blood neutrophils. Since estrogen enhanced tumour growth in involuting mice, but not in nulliparous mice, we assessed the effect of estrogen on the gene expression associated with pro-tumoral activities of neutrophils. Whilst 48 h treatment with estrogen had no effect, 2-weeks treatment significantly increased the expression of Arg1, Il1b and Tgfb1 in both HDN and LDN of involuting mice. In contrast, estrogen increased the expression of Arg1 and Ccl5 in HDN and LDN of nulliparous mice. CONCLUSIONS: Prolonged estrogenic stimulation in tumour-bearing mice markedly hampered tumour-associated increase of LDN plausibly by inhibiting their output from the bone marrow and by shortening their life span. Estrogen also alters the gene expression in neutrophils that is not seen in tumour-free mice. The results imply that estrogen may significantly influence the tumour-modulating activity of blood neutrophils.


Assuntos
Estrogênios/farmacologia , Neoplasias Mamárias Animais/sangue , Neutrófilos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Arginase/genética , Arginase/metabolismo , Biomarcadores Tumorais/metabolismo , Células da Medula Óssea/citologia , Centrifugação com Gradiente de Concentração , Estrogênios/administração & dosagem , Feminino , Citometria de Fluxo , Expressão Gênica/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Glândulas Mamárias Animais , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neutrófilos/citologia , Neutrófilos/metabolismo , Ovariectomia/métodos , Paridade , Período Pós-Parto , Fatores de Tempo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
5.
Comput Biol Med ; 137: 104823, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34492519

RESUMO

BACKGROUND: Transforming growth factor-beta1 (TGF-ß1) acts as a most effective growth inhibitor for normal epithelial cells. Loss of this anti-proliferative factor in breast tissues favors invasion and development of osteolytic metastases, aided by a master transcription factor, runt-related transcription factor 2 (Runx2). Several reports identified Runx2 regulation with the help of non-coding RNAs such as microRNAs (miRNAs) under physiological and pathological conditions. METHODS: Using bioinformatics tools such as miRDB, STarMir, Venny, TarBase, a unique list of miRNAs that putatively target the 3' UTR Runx2 was identified. Further, the expression patterns of those miRNAs at the precursor and mature levels were studied by RT-qPCR analyses. Following this, computational analyses using software like TransmiR and bc-GenExMiner v4.6 were done to speculate the miRNA's other target genes that indirectly regulate Runx2 activity in breast cancer. RESULTS: There were 13 miRNAs that putatively target Runx2 identified using bioinformatics tools. Among these miRNAs, miR-5703 expression was significantly downregulated at both precursor and mature levels upon TGF-ß1-treatment in human breast cancer cells. Computational analyses speculated an indirect targeting of Runx2 by miR-5703 by influencing multiple Runx2 regulatory signaling pathways including Jak/Stat, MAPK, Wnt/ß-Catenin, Notch, BMP, and PKA pathways. Furthermore, a correlation of the expression profiles of the speculated genes and Runx2 with miR-5703 was depicted in triple-negative breast cancer patients. CONCLUSION: Identification of miR-5703 and its network for Runx2 regulation directly or indirectly in breast cancer cells could significantly advance our understanding of breast cancer-mediated bone metastasis. In addition, it would potentially pave the way for miRNAs to be used as biomarkers and therapeutic agents in cancer research.


Assuntos
Neoplasias da Mama , MicroRNAs , Neoplasias da Mama/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Feminino , Humanos , MicroRNAs/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética
6.
BMC Musculoskelet Disord ; 22(1): 818, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556093

RESUMO

BACKGROUND: Fibrosis is an important factor and process of ligamentum flavum hypertrophy. The expression of phosphodiesterase family (PDE) is related to inflammation and fibrosis. This article studied the expression of PDE in hypertrophic ligamentum flavum fibroblasts and investigated whether inhibition of PDE4 activity can play an anti-fibrotic effect. METHODS: Samples of clinical hypertrophic ligamentum flavum were collected and patients with lumbar disc herniations as a control group. The collagenase digestion method is used to separate fibroblasts. qPCR is used to detect the expression of PDE subtypes, type I collagen (Col I), type III collagen (Col III), fibronectin (FN1) and transforming growth factor ß1 (TGF-ß1). Recombinant TGF-ß1 was used to stimulate fibroblasts to make a fibrotic cell model and treated with Rolipram. The morphology of the cells treated with drugs was observed by Sirius Red staining. Scratch the cells to observe their migration and proliferation. WB detects the expression of the above-mentioned multiple fibrotic proteins after drug treatment. Finally, combined with a variety of signaling pathway drugs, the signaling mechanism was studied. RESULTS: Multiple PDE subtypes were expressed in ligamentum flavum fibroblasts. The expression of PDE4A and 4B was significantly up-regulated in the hypertrophic group. Using Rolipram to inhibit PDE4 activity, the expression of Col I and TGF-ß1 in the hypertrophic group was inhibited. Col I recovered to the level of the control group. TGF-ß1 was significantly inhibited, which was lower than the control group. Recombinant TGF-ß1 stimulated fibroblasts to increase the expression of Col I/III, FN1 and TGF-ß1, which was blocked by Rolipram. Rolipram restored the increased expression of p-ERK1/2 stimulated by TGF-ß1. CONCLUSION: The expressions of PDE4A and 4B in the hypertrophic ligamentum flavum are increased, suggesting that it is related to the hypertrophy of the ligamentum flavum. Rolipram has a good anti-fibrosis effect after inhibiting the activity of PDE4. This is related to blocking the function of TGF-ß1, specifically by restoring normal ERK1/2 signal.


Assuntos
Ligamento Amarelo , Fibroblastos/metabolismo , Fibrose , Humanos , Ligamento Amarelo/patologia , Sistema de Sinalização das MAP Quinases , Rolipram/metabolismo , Rolipram/farmacologia , Fator de Crescimento Transformador beta1/metabolismo
7.
Artigo em Russo | MEDLINE | ID: mdl-34460152

RESUMO

OBJECTIVE: To study clinical/laboratory signs of primary vasculitis (PV) of the internal carotid artery (ICA) and vertebral artery (VA). MATERIAL AND METHODS: We examined 31 patients (23 men, 74%, mean age - 36.2±5.7 years) with ICA/VA PV verified by vessel wall contrast enhancement on black blood MRI (T1-weighted fat and blood suppressed sequences with- and without contrast injection) at the Research Center of Neurology (Moscow) from January 2012 to September 2019. Systemic vasculitis was excluded in all cases. Interleukins (IL-1ß, IL-2, IL-6, IL-17), TNF-a, transforming growth factor beta 1 (TGF-ß1) and basic fibroblast growth factor (bFGF) were analyzed by ELISA in 25 patients. Control group consisted of 21 healthy volunteers (12 men, 57%; mean age - 35.3±10.2 years). RESULTS: Clinical manifestations of ICA/VA PV included: ischemic stroke (IS) (94%), which combined with transient ischemic attacks (TIA) in 35%; isolated TIA (3%); Tolosa-Hunt syndrome (3%). Recurrent strokes were observed in 41% of patients on average in 5.3±2.1 months. Carotid artery was involved in 77%, VA - in 16%, both arteries - in 7%. Concomitant involvement of ICA/VA branches was in 19% patients. The level of arterial damage was follows: Intracranial part of arteries involved in 55%, intra-extracranial - in 35%, extracranial - in 10%. Bilateral involvement was found in 26%. Headache/neck pain in the acute IS period was observed in 21%. IS severity (NIHSS) was as follows: moderate (59%), mild (34%), moderately severe (7%). Disability after 3 months according to mRankin scale was as follows: mild (72%) moderate (21%), none (7%). The laboratory study revealed an increased levels of IL-6 (8.19±3.89 pg/ml vs 4.7±1.48 in control, p=0.000), IL-2 (5.64±1.82 pg/ml vs 4.30±1.65, p=0.013), TNF-a (36.9±33.66 pg/ml vs 12.68±5.93, p=0.000), TGF ß1 (2.77±1.60 pg/ml vs 1.63±0.64, p=0.006) and bFGF (417.67±132.68 pg/ml vs 335.71±105.08, p=0.018). The levels of IL-1ß and IL-17 did not differ significantly from the control. CONCLUSION: ICA/VA PV has a number of clinical peculiarities. Proinflammatory cytokines produced by Th17 and Th1 CD4+ lymphocytes as well as bFGF and TGR-ß1 play a role in its pathogenesis. Normal levels of IL-1ß and IL-17 suggest that they are not significant in the development of isolated inflammation in ICA/PA, in contrast to systemic inflammation in giant cell arteritis, in which, according to literature data, their level increases. Isolated ICA/PA inflammation seems to be caused by transaxonal (trigeminal nerve, upper-cervical roots, autonomic nerves) spread of pathogens that initiate immune inflammation in the ICA/PA wall.


Assuntos
Fator 2 de Crescimento de Fibroblastos , Ataque Isquêmico Transitório , Fator de Crescimento Transformador beta1/metabolismo , Vasculite , Adulto , Artéria Carótida Interna/diagnóstico por imagem , Citocinas , Humanos , Masculino , Artéria Vertebral/diagnóstico por imagem
8.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360888

RESUMO

Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-ß (TGF-ß) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-ß signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1ß and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-ß signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1ß was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.


Assuntos
Condrócitos/metabolismo , Condrócitos/patologia , Osteoartrite/metabolismo , Transdução de Sinais/genética , Proteína Smad2/química , Proteína Smad2/metabolismo , Proteína Smad3/química , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Animais , Bovinos , Linhagem Celular Tumoral , Humanos , Hipertrofia/metabolismo , Inflamação/metabolismo , Interleucina-1beta/farmacologia , Osteoartrite/genética , Osteoartrite/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Domínios Proteicos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad3/genética , Membrana Sinovial/metabolismo , Transfecção , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/farmacologia
9.
Am J Sports Med ; 49(11): 3102-3112, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34351815

RESUMO

BACKGROUND: The increasing use of platelet-rich plasma (PRP) to treat muscle injuries raises concerns because transforming growth factor-beta (TGF-ß) in PRP may promote fibrosis in the injured muscle and thus impair muscle regeneration. PURPOSE: To investigate whether suramin (a TGF-ß inhibitor) can reduce muscle fibrosis to improve healing of the injured muscle after PRP treatment and identify the underlying molecular mechanism. STUDY DESIGN: Controlled laboratory study. METHODS: Myoblasts isolated from the gastrocnemius muscle of Sprague Dawley rats were treated with PRP or PRP plus suramin. MTT assays were performed to evaluate cell viability. The expression of fibrosis-associated proteins (such as type I collagen and fibronectin), Smad2, and phosphorylated Smad2 was determined using Western blot analysis and immunofluorescent staining. An anti-TGF-ß antibody was employed to verify the role of TGF-ß in fibronectin expression. Gastrocnemius muscles were injured through a partial transverse incision and then treated using PRP or PRP plus suramin. Hematoxylin and eosin staining was conducted to evaluate the healing process 7 days after the injury. Immunofluorescent staining was performed to evaluate fibronectin expression. Muscle contractile properties-fast-twitch and tetanic strength-were evaluated through electric stimulation. RESULTS: PRP plus 25 µg/mL of suramin promoted myoblast proliferation. PRP induced fibronectin expression in myoblasts, but suramin reduced this upregulation. The anti-TGF-ß antibody also reduced the upregulation of fibronectin expression in the presence of PRP. The upregulation of phosphorylated Smad2 by PRP was reduced by either the anti-TGF-ß antibody or suramin. In the animal study, no significant difference was discovered in muscle healing between the PRP versus PRP plus suramin groups. However, the PRP plus suramin group had reduced fibronectin expression at the injury site. Fast-twitch strength and tetanic strength were significantly higher in the injured muscle treated using PRP or PRP plus suramin. CONCLUSION: Simultaneous PRP and suramin use reduced fibrosis in the injured muscle and promoted healing without negatively affecting the muscle's contractile properties. The underlying molecular mechanism may be associated with the phosphorylated Smad2 pathway. CLINICAL RELEVANCE: Simultaneous PRP and suramin use may reduce muscle fibrosis without compromising muscle contractile properties and thus improve muscle healing.


Assuntos
Músculo Esquelético/lesões , Plasma Rico em Plaquetas , Suramina , Cicatrização , Animais , Ratos , Ratos Sprague-Dawley , Suramina/farmacologia , Suramina/uso terapêutico , Fator de Crescimento Transformador beta1/antagonistas & inibidores
10.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445365

RESUMO

In this study, we aimed to investigate the influence of N-acetylcysteine (NAC) on the gene expression profile, neoangiogenesis, neutrophils and macrophages in a rat model of incisional wounds. Before creating wounds on the backs of 24 Sprague-Dawley rats, intradermal injections were made. Lidocaine-epinephrin solutions were supplemented with 0.015%, 0.03% or 0.045% solutions of NAC, or nothing (control group). Scars were harvested on the 3rd, 7th, 14th and 60th day post-surgery. We performed immunohistochemical staining in order to visualize macrophages (anti-CD68), neutrophils (anti-MPO) and newly formed blood vessels (anti-CD31). Additionally, RT-qPCR was used to measure the relative expression of 88 genes involved in the wound healing process. On the 14th day, the number of cells stained with anti-CD68 and anti-CD31 antibodies was significantly larger in the tissues treated with 0.03% NAC compared with the control. Among the selected genes, 52 were upregulated and six were downregulated at different time points. Interestingly, NAC exerted a significant effect on the expression of 45 genes 60 days after its administration. In summation, a 0.03% NAC addition to the pre-incisional anesthetic solution improves neovasculature and increases the macrophages' concentration at the wound site on the 14th day, as well as altering the expression of numerous genes that are responsible for the regenerative processes.


Assuntos
Acetilcisteína/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Fator de Crescimento Transformador beta1/genética , Cicatrização/efeitos dos fármacos , Acetilcisteína/farmacologia , Anestesia Local , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Mol Biol (Mosk) ; 55(4): 617-625, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34432779

RESUMO

MUC4 is a predominant membrane-tethered mucin lubricating and protecting the epithelial surface and playing various biological roles in the renewal and differentiation of epithelial cells, cell signaling, cell adhesion, and carcinogenesis. Interestingly, recent studies have demonstrated that MUC4 expression regulates the epithelial-mesenchymal transition (EMT) of cancer cells in ovarian, pancreatic, and lung cancer. However, the effects of MUC4 expression on EMT in human airway epithelial cells are not yet well known. Here, we describe the effects of transforming growth factor beta 1 (TGF-ß1)-induced MUC4 expression on EMT and evaluate its downstream signaling pathway in human airway epithelial cells. In human airway epithelial NCI-H292 cells, exposure to TGF-ß1 induced expression of MUC4, CDH2, VIM and SNAI1 genes and encoded by them proteins, MUC4, N-cadherin, vimentin and Snail, and reduced the level of CDH1 and its product, E-cadherin. In MUC4-knockdown cells, TGF-ß1-induced expression levels of MUC4, CDH2, VIM and SNAI1 and corresponding proteins were suppressed, but CDH1 and E-cadherin levels were not. In addition, TGF-ß1-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) was suppressed, but that of Smad2/3, Akt, and p38 was not. The results of this study suggest that MUC4 silencing inhibits TGF-ß1 -induced EMT via the ERK1/2 pathway, and a possible role of MUC4 in the induction of EMT in human airway epithelial cells.


Assuntos
Transição Epitelial-Mesenquimal , Fator de Crescimento Transformador beta1 , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Humanos , Sistema de Sinalização das MAP Quinases , Proteína Quinase 3 Ativada por Mitógeno/genética , Mucina-4/genética , Mucina-4/metabolismo , Fator de Crescimento Transformador beta1/genética
12.
Zhonghua Shao Shang Za Zhi ; 37(8): 725-730, 2021 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-34404160

RESUMO

Objective: To investigate the expression of microRNA-296 (miR-296) in rabbit hypertrophic scars and its role in human fibroblasts (HFbs). Methods: The experimental method was used. Twelve healthy adult New Zealand long-eared rabbits regardless gender were randomly divided into normal control group and scar group, with 6 rabbits in each group. The rabbit ear hypertrophic scar model was created in scar group according to the literature, and the rabbits in normal control group did not receive any treatment. On 60 days after setting up the models in scar group, hematoxylin-eosin staining was performed to observe the growth and arrangement of fibroblasts (Fbs) in the ear scars and skin tissue of rabbits in the two groups. The mRNA expressions of miR-296 and transforming growth factor-ß1 (TGF-ß1) in ear scars and skin tissue of rabbits in the two groups were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction, and the correlation of mRNA between miR-296 and TGF-ß1 was performed with Pearson regression analysis. Two batches of HFbs were used and transfected respectively with corresponding sequences, with the 1st batch being divided into TGF-ß1 wild type+miR-296 negative control group and TGF-ß1 wild type+miR-296 mimic group and the 2nd batch being divided into TGF-ß1 mutant type+miR-296 negative control group and TGF-ß1 mutant type+miR-296 mimic group. At 48 h after transfection, luciferase reporter gene detection kit was used to detect the luciferase and renal luciferase expression of TGF-ß1 in the cells of each group, with their ratio being used to reflect the gene expression level. Two batches of HFbs were used, and each batch of cells were divided into miR-296 negative control group and miR-296 mimic group, being transfected with the corresponding sequences. At 0 (immediately), 12, 24, 36, and 48 h after transfecting the first batch of cells, the cell proliferation was detected by thiazolyl blue method. At 24 h after transfecting the second batch of cells, the expression of TGF-ß1 and collagen type Ⅰ was detected by Western blotting. The number of samples in cell experiments was 3. Data were statistically analyzed with analysis of variance for factorial design, independent sample t test. Results: On 60 days after setting up the models in scar group, the Fbs of rabbit ear scar tissue in scar group proliferated and arranged disorderly, while the growth and arrangement of Fbs in rabbit ear skin tissue in normal control group were normal. The mRNA expression of miR-296 of rabbit scar tissue in scar group (0.65±0.11) was significantly lower than 1.19±0.12 of rabbit ear skin tissue in normal control group (t=5.175, P<0.01). The mRNA expression of TGF-ß1 of rabbit ear scar tissue in scar group (1.47±0.06) was significantly higher than 1.10±0.03 of rabbit ear skin tissue in normal control group (t=12.410, P<0.01). Pearson regression analysis showed that there was a negative correlation between the mRNA expression of miR-296 and TGF-ß1 in the ear scars and skin tissue of 12 rabbits (F=7.278, P<0.05). At 48 h after transfection, the gene expression of TGF-ß1 of cells in TGF-ß1 wild type+miR-296 mimic group was significantly lower than that in TGF-ß1 wild type+miR-296 negative control group (t=35.190, P<0.01), while the gene expression of TGF-ß1 of cells in the two TGF-ß1 mutant type groups were close (P>0.05). The HFbs proliferation ability in miR-296 mimic group was significantly lower than that in miR-296 negative control group at 12, 24, 36, and 48 h after transfection(t=3.275, 11.980, 10.460, 17.260, P<0.05 or P<0.01). At 24 h after transfection, the protein expressions of TGF-ß1 and type Ⅰ collagen of cells in miR-296 negative control group were significantly higher than those in miR-296 mimic group (t=3.758, 29.390, P<0.05 or P<0.01). Conclusions: The miR-296 expression in rabbit hypertrophic scars is down-regulated; miR-296 can inhibit the proliferation of HFbs and the expression of type Ⅰ collagen by down regulating the expression of TGF-ß1.


Assuntos
Cicatriz Hipertrófica , MicroRNAs , Animais , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/patologia , Colágeno Tipo I , Fibroblastos , Humanos , MicroRNAs/genética , RNA Mensageiro , Coelhos , Fator de Crescimento Transformador beta1/genética
13.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(3): 266-271, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34374239

RESUMO

Objective: To investigate the effect of TGF-ß1/Smad signaling pathway on the apoptosis of HepG2 cells under endoplasmic reticulum stress (ERS). Methods: An ERS model was established firstly. Human hepatocellular carcinoma HepG2 cells were treated with 3 µmol/L tunicamycin (TM) for 24 h to induce ERS. Cells were divided into 6 groups, each with 3 replicate holes, and the experiment was repeated 3 times. The 6 groups included untreated group, TM group (3 µmol/L TM treatment group), TM + NC group(3 µmol/L TM + si-TGF-ß1 negative control group), TM + si-TGF-ß1 group(3 µmol/L TM + si-TGF-ß1 group), TM + pEX-3 group(3 µmol/L TM + plasmid control group), and TM + TGF-ß1 pEX-3 group(3 µmol/L TM + TGF-ß1 overexpressed plasmid group). HepG2 cells were transfected with TGF-ß1 small interfering RNA (TGF-ß1 si-RNA) and TGF-ß1 overexpressed plasmids (TGF-ß1 pEX-3) by Lipofectamine. Twenty-four hours after transfection, RT-qPCR and Western blot were used to detect the expression of TGF-ß1 and p-Smad2 in HepG2 cells of each group. CCK-8 and flow cytometry were used to analyze changes in the proliferation inhibition rate and apoptosis rate of HepG2 cells in each group. Results: Compared with the untreated group, the expressions of TGF-ß1 and p-Smad2 in TM group were significantly reduced (P<0.05). Compared with the TM group, the expressions of TGF-ß1 and p-Smad2, as well as the cell proliferation inhibition rate and apoptosis rate in TM + si-TGF-ß1 group were obviously decreased (P< 0.01), while the expressions of TGF-ß1 and p-Smad2, cell proliferation inhibition rate and apoptosis rate of TM + TGF-ß1 pEX-3 group were significantly increased (P<0.01). Conclusion: The TGF-ß1/Smad signaling pathway was inhibited in hepatocellular carcinoma HepG2 cells under ERS, when this pathway was activated, the apoptosis rate of HepG2 cells under ERS was increased significantly.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptose , Estresse do Retículo Endoplasmático , Células Hep G2 , Humanos , Transdução de Sinais , Fator de Crescimento Transformador beta1
14.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 37(3): 308-312, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34374245

RESUMO

Objective: To investigate the effects of interleukin 11 (IL-11) antagonist on bleomycin (BLM)-induced pulmonary fibrosis in mice. Methods: C57BL/6 mice were randomly divided into the control group, IL-11 antagonist group, BLM group, and BLM + IL-11 antagonist group (30 in each group). Mice in the BLM group and BLM + IL-11 antagonist group were injected with BLM at the dose of 1.5 mg/kg to induce pulmonary fibrosis. The IL-11 antagonist IL-11 Rα FC (2.5 mg/kg) was administered via the tail vein to the mice in the IL-11 antagonist group and BLM + IL-11 antagonist group every 3 days from the BLM injection. The survival status of the mice was observed. On the 21st day after modeling, HE staining, Masson staining, and Ashcroft score were used to evaluate the degree of pulmonary fibrosis. The content of hydroxyproline (HYP) in lung tissue was determined by the alkaline hydrolysis method. The gene and protein expressions of Collagen I, Collagen III, and α-SMA in lung tissues were detected by real-time PCR and Western blot, respectively. TGF-ß1 content in lung tissue was determined by enzyme-linked immunosorbent assay. Results: Compared with the control group, BLM reduced the survival rate, destructed the lung tissue, and increased the gene and protein expressions of Collagen I, Collagen III, α-SMA, and the content of TGF-ß1 in lung tissue. While, IL-11 Rα Fc treatment improved the survival rate of BLM-induced pulmonary mice, reduced pathological changes, and hydroxyproline content in lung tissue. IL-11 Rα Fc also reduced Collagen I, Collagen III, and α-SMA mRNA and protein expression in the lungs of BLM-treated mice, as well as TGF-ß1 content. Conclusion: The IL-11 antagonist alleviates BLM-induced pulmonary fibrosis in mice, which provides a new idea for the clinical treatment of pulmonary fibrosis.


Assuntos
Interleucina-11 , Fibrose Pulmonar , Animais , Bleomicina/toxicidade , Pulmão , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fator de Crescimento Transformador beta1
15.
Molecules ; 26(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34361644

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with multiple causes, characterized by excessive myofibrocyte aggregation and extracellular matrix deposition. Related studies have shown that transforming growth factor-ß1 (TGF-ß1) is a key cytokine causing fibrosis, promoting abnormal epithelial-mesenchymal communication and fibroblast-to-myofibroblast transition. Fedratinib (Fed) is a marketed drug for the treatment of primary and secondary myelofibrosis, targeting selective JAK2 tyrosine kinase inhibitors. However, its role in pulmonary fibrosis remains unclear. In this study, we investigated the potential effects and mechanisms of Fed on pulmonary fibrosis in vitro and in vivo. In vitro studies have shown that Fed attenuates TGF-ß1- and IL-6-induced myofibroblast activation and inflammatory response by regulating the JAK2/STAT3 signaling pathway. In vivo studies have shown that Fed can reduce bleomycin-induced inflammation and collagen deposition and improve lung function. In conclusion, Fed inhibited inflammation and fibrosis processes induced by TGF-ß1 and IL-6 by targeting the JAK2 receptor.


Assuntos
Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Janus Quinase 2/metabolismo , Pirrolidinas/farmacologia , Sulfonamidas/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Bleomicina , Movimento Celular/efeitos dos fármacos , Fibroblastos/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3
16.
Heart Lung Circ ; 30(11): 1769-1777, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34389253

RESUMO

BACKGROUND: Lack of blood pressure control leads to a higher incidence of hypertension-mediated target organ damage (HMOD). One of the markers of HMOD is an increased arterial stiffness, an independent predictor of cardiovascular complications. However, abstract numbers showing the level of arterial stiffness do not give patients a clear understanding of the risk of their condition. In order to increase patient compliance, the term "vascular age" (VA) was introduced. Arteriosclerosis plays the main role in increasing VA. The greatest interest, according to the literature, in the study of this issue is in arteriosclerosis caused by transforming growth factor ß1 (TGF-ß1)-the effect of TGF-ß1 on the culture of smooth muscle cells leads to their proliferation and growth; also, TGF-ß1 increases the amount of collagen and accelerates the degradation of elastin. METHODS: We included 140 people in the study: 80 patients with controlled arterial hypertension (CAH), 30 with uncontrolled arterial hypertension (UAH), and 30 patients who formed the control group. All patients underwent a determination of arterial stiffness and VA using the cardio-ankle vascular index (CAVI), a corrected (blood-pressure independent) cardio-ankle vascular index (CAVI0) and the concentration of TGF-ß1 was measured. RESULTS: The TGF-ß1 value in the UAH group was 22.6 (25th percentile=20.6; 75th percentile=25.6) ng/mL, and in the control group it was 17.4 (25th percentile=11.8; 75th percentile=19.3) ng/mL. In the CAH group, an intermediate value was noted-19.2 (25th percentile=17.2; 75th percentile=24.7) ng/mL. The CAVI in the UAH group was 9.2 (25th percentile=8.5; 75th percentile=9.9), in the control group-7 (25th percentile=6.5; 75th percentile=7.5). In the CAH group, the average CAVI was 7.8 (25th percentile=7.0; 75th percentile=8.5). The CAVI 0 in the UAH group was 14.8 (25th percentile=12.0; 75th percentile=15.6), in the control group - 9.7 (25th percentile=8.8; 75th percentile=9.7). In the CAH group, the average CAVI was 11.1 (25th percentile=10.1; 75th percentile=13.6). Vascular age in the UAH group was 71.5 (25th percentile=64; 75th percentile=74) years, in the CAH group 59 (25th percentile=49; 75th percentile=69) years, and in both groups (UAH, CAH), VA was significantly higher than the chronological age (p<0.05). In the control group, the VA did not significantly differ from the chronological age (p>0.05) and it was 54 (25th percentile=44; 75th percentile=59) years. A significant relationship was found between the TGF-ß1 level and CAVI (CAH r=0.777; UAH r=0.753; p<0.05), CAVI 0 (CAH r=0.625; UAH r=0.502; p<0.05) and VA in patients with AH (CAH r=0.649; UAH r=0.753; p<0.05). CONCLUSION: In patients in the UAH group, there was an increase in the concentration of TGF-ß1, an increase in the arterial stiffness and in VA in comparison with patients in the CAH group and the control group. The relationship between TGF-ß1 and the arterial stiffness and VA was revealed in patients with hypertension.


Assuntos
Fatores Etários , Hipertensão , Fator de Crescimento Transformador beta1 , Rigidez Vascular , Pressão Sanguínea , Elastina , Humanos , Hipertensão/epidemiologia , Pessoa de Meia-Idade
17.
Int J Mol Sci ; 22(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34445725

RESUMO

Umbelliferone (UMB), also known as 7-hydroxycoumarin, is a derivative of coumarin, which is widely found in many plants such as carrots, coriander, and garden angelica. Although many studies have already revealed the various pharmacological properties of UMB, its effect on benign prostatic hyperplasia (BPH) remains unclear. Therefore, the present study aimed to elucidate the underlying mechanism of the anti-proliferative effect of UMB in a human benign prostatic hyperplasia cell line (BPH-1), as well as its ameliorative effect on BPH in testosterone propionate (TP)-induced rats. The results showed that UMB exerts an anti-proliferative effect in BPH-1 cells by modulating the signal transducer and activator of transcription 3 (STAT3)/E2F transcription factor 1 (E2F1) axis. UMB treatment not only inhibited androgen/androgen receptor (AR) signaling-related markers, but also downregulated the overexpression of G1/S phase cell cycle-related markers. In TP-induced rats, UMB administration demonstrated an anti-BPH effect by significantly reducing prostate size, weight, and epithelial thickness. In addition, UMB suppressed cell proliferation by reducing the expression of proliferating cell nuclear antigen (PCNA) and p-STAT3 (Tyr 705) in prostate tissue following TP injection. These findings suggest that UMB has pharmacological effects against BPH.


Assuntos
Proliferação de Células/efeitos dos fármacos , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Umbeliferonas/uso terapêutico , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Masculino , Próstata/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos Wistar , Receptores Androgênicos/metabolismo , Fator de Transcrição STAT3/metabolismo , Propionato de Testosterona , Fator de Crescimento Transformador beta1/metabolismo , Umbeliferonas/farmacologia
18.
J Transl Med ; 19(1): 349, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399790

RESUMO

BACKGROUND: Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis. METHODS: The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-ß1)-induced differentiated lung fibroblasts were used for in vitro models. RESULTS: At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2-10 mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-ß1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway. CONCLUSIONS: In this study, we identified that metformin might be a potential drug for silicosis treatment.


Assuntos
Metformina , Fibrose Pulmonar , Proteínas Quinases Ativadas por AMP , Animais , Transição Epitelial-Mesenquimal , Fibroblastos , Humanos , Pulmão , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Dióxido de Silício/toxicidade , Fator de Crescimento Transformador beta1
19.
BMC Musculoskelet Disord ; 22(1): 680, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380439

RESUMO

BACKGROUND: Skeletal muscle atrophy and fibrosis are pathological conditions that contribute to morbidity in numerous conditions including aging, cachexia, and denervation. Muscle atrophy is characterized as reduction of muscle fiber size and loss of muscle mass while muscle fibrosis is due to fibroblasts activation and excessive production of extracellular matrix. Purinergic receptor P2Y2 has been implicated in fibrosis. This study aims to elucidate the roles of P2Y2 in sleketal muscle atrophy and fibrosis. METHODS: Primary muscle fibroblasts were isolated from wild type and P2Y2 knockout (KO) mice and their proliferating and migrating abilities were assessed by CCK-8 and Transwell migration assays respectively. Fibroblasts were activated with TGF-ß1 and assessed by western blot of myofibroblast markers including α-SMA, CTGF, and collagen I. Muscle atrophy and fibrosis were induced by transection of distal sciatic nerve and assessed using Masson staining. RESULTS: P2Y2 KO fibroblasts proliferated and migrated significantly slower than WT fibroblasts with or without TGF-ß1.The proliferation and ECM production were enhanced by P2Y2 agonist PSB-1114 and inhibited by antagonist AR-C118925. TGF-ß1 induced fibrotic activation was abolished by P2Y2 ablation and inhibited by AKT, ERK, and PKC inhibitors. Ablation of P2Y2 reduced denervation induced muscle atrophy and fibrosis. CONCLUSIONS: P2Y2 is a promoter of skeletal muscle atrophy and activation of fibroblasts after muscle injury, which signaling through AKT, ERK and PKC. P2Y2 could be a potential intervention target after muscle injury.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Esquelético/patologia , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptores Purinérgicos P2Y2/metabolismo , Animais , Células Cultivadas , Fibroblastos/patologia , Fibrose , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
20.
Exp Eye Res ; 210: 108725, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34375589

RESUMO

Antiproliferative therapies are crucially important for improving the success rate of the glaucoma filtration surgeries. In this study, we investigated the potential efficacy of Forkhead Domain Inhibitory-6 (FDI-6) in inhibiting post-trabeculectomy subconjunctival fibrosis. In vitro, the effect of FDI-6 (10 µM) on fibrotic response and its underlying mechanism were investigated in rabbit tenon's fibroblasts (RTFs) treated with or without transforming growth factor-ß1 (TGF-ß1, 20 ng/mL). In vivo, FDI-6 (40 µM) was injected subconjunctivally to a rabbit trabeculectomy model. Intraocular pressure (IOP) changes were monitored within the 14-day period post-surgery. Bleb morphology and subepithelial fibrosis at the operating area were evaluated with slit lamp and confocal microscopic examinations and with histologic examinations. The results showed that, in cell culture studies, FDI-6 suppressed the proliferation, migration, collagen gel contraction and the expression levels of fibronectin (FN) and α-smooth muscle actin (α-SMA) in RTFs with TGF-ß treatment by down-regulating the TGF-ß1/Smad2/3 signaling pathway. In animal studies, the IOPs of the FDI-6-treated group were significantly lower than those of the saline-treated group after trabeculectomy. The FDI-6-treated eyes showed a better bleb appearance with fewer blood vessels compared to the saline-treated eyes. The analysis of confocal microscopy in vivo and histopathology revealed that subconjunctival fibrosis after trabeculectomy was significantly attenuated in the FDI-6-treated group compared to the controls. In conclusion, our studies indicate that FDI-6 exerts an inhibitory effect on subconjunctival fibrosis caused by trabeculectomy, holding potentials as a new antiproliferative agent used in anti-glaucoma filtration surgeries in the future.


Assuntos
Túnica Conjuntiva/patologia , Modelos Animais de Doenças , Glaucoma/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Piridinas/uso terapêutico , Tiofenos/uso terapêutico , Trabeculectomia , Actinas/metabolismo , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Fibrose/prevenção & controle , Proteína Forkhead Box M1/genética , Proteína Forkhead Box M1/metabolismo , Marcação In Situ das Extremidades Cortadas , Injeções Intraoculares , Pressão Intraocular/efeitos dos fármacos , Masculino , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Cápsula de Tenon/efeitos dos fármacos , Cápsula de Tenon/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Cicatrização/efeitos dos fármacos
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