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1.
Adv Exp Med Biol ; 1185: 169-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884607

RESUMO

Although the retina resides within the immune-protected ocular environment, inflammatory processes mounted in the eye can lead to retinal damage. Unchecked chronic ocular inflammation leads to retinal damage. Thus, retinal degenerative diseases that result in chronic inflammation accelerate retinal tissue destruction and vision loss. Treatments for chronic retinal inflammation involve corticosteroid administration, which has been associated with glaucoma and cataract formation. Therefore, we must consider novel, alternative treatments. Here, we provide a brief review of our current understanding of chronic innate inflammatory processes in retinal degeneration and the complex role of a putative inflammatory regulator, Caveolin-1 (Cav1). Furthermore, we suggest that the complex role of Cav1 in retinal inflammatory modulation is likely dictated by cell type-specific subcellular localization.


Assuntos
Caveolina 1/metabolismo , Inflamação/patologia , Retina/patologia , Humanos , Degeneração Retiniana/patologia
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 845-851, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694095

RESUMO

Objective: To explore the role of S100A8, the receptor for advanced glycation endproducts (RAGE) and Caveolin-1 in neutrophilic asthmatic rats, and to further study the intervention of roxithromycin and the possible mechanisms. Methods: Male Brown Norway rats were randomly assigned to a control group, an asthma group and a Roxithromycin group. The asthmatic rat model was established by intraperitoneal injection of ovalbumin (OVA) and Freund's complete adjuvant (FCA) mixture, and aerosol inhalation of OVA. Rats in the Roxithromycin group were given roxithromycin injection 30 mg/kg 30 minutes before each challenge. Rats in the control and the asthma groups were replaced with equal volumes of saline, respectively. Bronchoalveolar lavage fluid (BALF) neutrophil percentage (Neu%) and pathological changes of pulmonary tissue (hematoxylin-eosin, HE staining) were measured to confirm the establishment of asthmatic models. The concentration of inflammatory cytokines and S100A8 were quantified by enzyme-linked immunosorbent assay (ELISA), and the expression of Caveolin-1 and RAGE at protein levels were detected by immunohistochemistry and Western blot. Results: Neu% in BALF of the asthma group was significantly higher than those of the control group, and Neu% in the Roxithromycin group was lower than the asthma group (all P<0.01). Pulmonary histology revealed that there were a large number of inflammatory cells infiltrated in the bronchial and perivascular, pulmonary interstitial and alveolar spaces, and the bronchial wall and smooth muscles were thickened obviously in the asthma group. Rats in the Roxithromycin group showed milder inflammation and airway remodeling change than the asthma group. There was no obvious pathological damage in the control group. The concentration of IL-6 and IL-17 in BALF and serum of rats in the asthma group were significantly higher than those in the control group (P<0.01), and Roxithromycin inhibited the high expression of these cytokines (P<0.05). The expression of S100A8 and RAGE in the asthma group were significantly higher than those in the control group [(20.6±4.4) vs (7.1±2.0) ng/L; (885±118) vs (462±102) ng/L; (14.2±1.7) vs (7.6±1.8) ng/L; (774±166) vs (406±69) ng/L, all P<0.05], and Roxithromycin inhibited the high expression of these proteins [(14.3±3.7) vs (20.6±4.4) ng/L; (650±53) vs (885±118) ng/L; (10.4±1.2) vs (14.2±1.7) ng/L; (560±64) vs (728±72) ng/L] (all P<0.05). Meanwhile, the expression of Caveolin-1 in the asthma group was significantly lower than that in the control group (P<0.01), and Roxithromycin up-regulated its expression (P<0.01). Correlation analysis showed that there was a significantly positive correlation between the expression of S100A8 and RAGE (r=0.706, P<0.01), while there was a significantly negative correlation between the expression of S100A8 and Caveolin-1 (r=-0.775, P<0.01), and between the expression of Caveolin-1 and RAGE (r=-0.919, P<0.01). Conclusion: S100A8 and Caveolin-1 may play an important role in neutrophilic asthma via RAGE, and Roxithromycin may exerts anti-inflammatory effects and inhibition of airway remodeling partly through this signaling pathway.


Assuntos
Antibacterianos/farmacologia , Asma/tratamento farmacológico , Calgranulina A/efeitos dos fármacos , Caveolina 1/efeitos dos fármacos , Roxitromicina/farmacologia , Remodelação das Vias Aéreas , Animais , Antibacterianos/administração & dosagem , Western Blotting , Líquido da Lavagem Broncoalveolar , Calgranulina A/metabolismo , Caveolina 1/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Pulmão/fisiopatologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ovalbumina , Ratos , Receptor para Produtos Finais de Glicação Avançada , Roxitromicina/administração & dosagem
3.
Exp Mol Pathol ; 111: 104319, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31676327

RESUMO

INTRODUCTION: Cirrhosis primes the liver for hepatocellular carcinoma (HCC) development. However, biomarkers that predict HCC in cirrhosis patients are lacking. Thus, we aimed to identify a biomarker directly from protein analysis and relate it with transcriptomic data to validate in larger cohorts. MATERIAL AND METHOD: Forty-six patients who underwent hepatectomy for HCC that arose from cirrhotic liver were enrolled. Reverse-phase protein array and microarray data of these patients were analyzed. Clinical validation was performed in two independent cohorts and functional validation using cell and tissue microarray (TMA). RESULTS: Systematic analysis performed after selecting 20 proteins from 201 proteins with AUROC >70 effectively categorized patients into high (n = 20) or low (n = 26) risk HCC groups. Proteome-derived late recurrence (PDLR)-gene signature comprising 298 genes that significantly differed between high and low risk groups predicted HCC well in a cohort of 216 cirrhosis patients and also de novo HCC recurrence in a cohort of 259 patients who underwent hepatectomy. Among 20 proteins that were selected for analysis, caveolin-1 (CAV1) was the most dominant protein that categorized the patients into high and low risk groups (P < .001). In a multivariate analysis, compared with other clinical variables, the PDLR-gene signature remained as a significant predictor of HCC (HR 1.904, P = .01). In vitro experiments revealed that compared with mock-transduced immortalized liver cells, CAV1-transduced cells showed significantly increased proliferation (P < .001) and colony formation in soft agar (P < .033). TMA with immunohistochemistry showed that tissues with CAV1 expression were more likely to develop HCC than tissues without CAV1 expression (P = .047). CONCLUSION: CAV1 expression predicts HCC development, making it a potential biomarker and target for preventive therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Caveolina 1/metabolismo , Proliferação de Células , Cirrose Hepática/complicações , Neoplasias Hepáticas/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Caveolina 1/genética , Perfilação da Expressão Gênica , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Análise Serial de Proteínas , Estudos Retrospectivos , Células Tumorais Cultivadas
4.
Int J Nanomedicine ; 14: 6779-6797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692534

RESUMO

Background: Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Macrophages, which recognize microbial infections through identification of bacterial markers such as lipopolysaccharide (LPS), are crucial to the pathogenesis of sepsis-associated liver injury. However, the understanding of the SPIONs-mediated modulation of macrophage responses in LPS-induced sepsis and liver injury is limited. Materials and methods: Superparamagnetic iron oxide nanoparticles (SPIONs) of γ-Fe2O3 nanoparticles were prepared, and their morphology and magnetic properties were characterized. Results: Using a murine model of LPS-induced sepsis and liver injury, we found that SPIONs alleviated LPS-induced sepsis, preventing infiltration of inflammatory cells into the liver. SPIONs also increased the level of interleukin-10 (IL-10) in liver macrophages, while SPIONs's effect on LPS-induced sepsis was abrogated in IL-10-/- mice, indicating that the protective effect of SPIONs is dependent on IL-10+ macrophages. Moreover, SPIONs activated macrophage autophagy to increase IL-10 production, which was markedly attenuated by autophagy inhibition. Furthermore, SPIONs upregulated the expression of Caveolin-1 (Cav1) in macrophages, which plays a role in cellular uptake of metallic nanoparticles. Interestingly, activation of Cav1 and Notch1/HES1 signaling was involved in SPIONs-induced autophagy in both RAW 264.7 cells and bone marrow-derived macrophages (BMDMs). Our data reveal a novel mechanism for SPIONs -induced autophagy in macrophages, which occurs through activation of the Cav1-Notch1/HES1 signaling pathway, which promotes the production of IL-10 in macrophages, leading to inhibition of inflammation in LPS-induced sepsis and liver injury. Conclusion: Our results suggest that SPIONs may represent a potential therapeutic agent for the treatment of sepsis and sepsis-induced liver injury.


Assuntos
Autofagia/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas de Magnetita/uso terapêutico , Sepse/tratamento farmacológico , Animais , Autofagia/fisiologia , Caveolina 1/genética , Caveolina 1/metabolismo , Compostos Férricos/química , Compostos Férricos/farmacologia , Interleucina-10/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Nanopartículas de Magnetita/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Receptor Notch1/metabolismo , Sepse/metabolismo , Sepse/patologia , Fatores de Transcrição HES-1/metabolismo
5.
J Diabetes Res ; 2019: 2354274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534971

RESUMO

Sphingolipids, modified by dietary fatty acids, are integral components of plasma membrane and caveolae that are also vasoactive compounds. We hypothesized that dietary fatty acid saturation affects vasoconstriction to sphingosine-1-phosphate (S1P) through caveolar regulation of rho kinase. Wild type (WT) and caveolin-1-deficient (cav-1 KO) mice which lack vascular caveolae were fed a low-fat diet (LF), 60% high-saturated fat diet (lard, HF), or 60% fat diet with equal amounts of lard and n-3 polyunsaturated menhaden oil (MO). Weight gain of WT on HF and MO diets was similar while markedly blunted in cav-1 KO. Neither high-fat diet affected the expression of cav-1, rho, or rho kinase in arteries from WT. In cav-1 KO, MO increased the vascular expression of rho but had no effect on rho kinase. HF had no effect on rho or rho kinase expression in cav-1 KO. S1P produced a concentration-dependent constriction of gracilis arteries from WT on LF that was reduced with HF and restored to normal with MO. Constriction to S1P was reduced in cav-1 KO and no longer affected by a high-saturated fat diet. Inhibition of rho kinase which reduced constriction to PE independent of diet in arteries from WT and cav-1 KO only reduced constriction to S1P in arteries from WT fed MO. The data suggest that dietary fatty acids modify vascular responses to S1P by a caveolar-dependent mechanism which is enhanced by dietary n-3 polyunsaturated fats.


Assuntos
Artérias/metabolismo , Caveolina 1/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Caveolina 1/genética , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Camundongos , Camundongos Knockout , Esfingosina/metabolismo , Quinases Associadas a rho/metabolismo
6.
Nat Commun ; 10(1): 4185, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519914

RESUMO

Cell migration during the invasion-metastasis cascade requires cancer cells to navigate a spatially complex microenvironment that presents directional choices to migrating cells. Here, we investigate cellular energetics during migration decision-making in confined spaces. Theoretical and experimental data show that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance as well as the degree of spatial confinement to direct decision-making. Energetic costs, driven by the cellular work needed to generate force for matrix displacement, increase with increasing cell stiffness, matrix stiffness, and degree of spatial confinement, limiting migration. By assessing energetic costs between possible migration paths, we can predict the probability of migration choice. Our findings indicate that motility in confined spaces imposes high energetic demands on migrating cells, and cells migrate in the direction of least confinement to minimize energetic costs. Therefore, therapeutically targeting metabolism may limit cancer cell migration and metastasis.


Assuntos
Movimento Celular/fisiologia , Tomada de Decisões , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Engenharia Biomédica , Caveolina 1/genética , Caveolina 1/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Glucose/metabolismo , Humanos , Microscopia de Força Atômica , Microscopia Confocal , Microscopia de Contraste de Fase , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
7.
Biomed Pharmacother ; 118: 109314, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545263

RESUMO

OBJECTIVE: Toll-like receptor 4(TLR-4)/nuclear factor-kappa B(NF-κB) pathway plays an important role in inducing acute lung injury (ALI). Studies have proved Dexmedetomidine (Dex) inhibits inflammatory response to mitigate lipopolysaccharide (LPS)-induced ALI and protect against multiorgan injury in various scenarios via restraining TLR-4/NF-κB signaling pathway. Many of the known downstream molecules have been orientated with a protein caveolin-1(Cav-1), which is supposed to take part in regulating TLR4-mediated inflammatory responses. However, its mechanisms have not been confirmed. The aim of this study is to evaluate the protective effects and potential mechanisms of Dex against LPS-induced ALI in male rats. METHODS: Male rats received tail-vein injection of LPS to form ALI model. Rats were administrated with intraperitoneal injection Dex0.5 h before ALI. At 6 h after LPS injection, bronchoalveolar lavage fluid (BALF) and lung tissue were harvested. We stained the lung tissue sections with hematoxylin eosin (HE) staining to observe the histopathological damage and measure the ALI pathology score. We also measured the wet-to-dry(W/D) weight ratio of lung tissue. Lung myeloperoxidase (MPO) and inflammatory cytokines in the BALF were detected by Enzyme-linked immunosorbent assay(ELISA). Protein levels of Cav-1, TLR-4 and NF-κB in lung tissue were tested by immunohistochemistry method. The mRNA expression of Cav-1, TLR4 and the NF-κB in lung tissue were measured to determine the related mechanisms by quantitative real-time polymerase chain reaction(RT-PCR). RESULTS: It was indicated that Dex pretreatment markedly mitigated pathomorphologic changes and pathological lung injury scores. Besides, Dex pretreatment obviously decreased the W/D weight ratio of lung tissue, attenuated MPO activity significantly, along with LPS-stimulated augment of lung inflammatory cells infiltration in BALF. Moreover, compared with LPS model group, Dex pretreatment apparently increased the protein levels of Cav-1 downregulated by sepsis and decreased the protein levels of TLR-4 and NF-κB in lung tissue. Furthermore, Dex pretreatment apparently upregulated the expression of Cav-1 mRNA, restrained TLR4 and NF-κB mRNA. CONCLUSION: Dex pretreatment protects against LPS-induced ALI via inhibiting the activation of the TLR-4/NF-kB signaling pathway by upregulating the expression of Cav-1 downregulated by sepsis.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Caveolina 1/metabolismo , Dexmedetomidina/uso terapêutico , Transdução de Sinais , Animais , Líquido da Lavagem Broncoalveolar , Caveolina 1/genética , Citocinas/metabolismo , Dexmedetomidina/farmacologia , Lipopolissacarídeos , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Tamanho do Órgão , Peroxidase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
8.
Arch Esp Urol ; 72(7): 690-696, 2019 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31475680

RESUMO

OBJECTIVE: To compare c-kit-positive interstitial Cajal-like cells (ICC) and Caveolin-1 protein levels as a pacemaker and signaling molecules, on ureteropelvic junction (UPJ) specimens, between two groups of pediatric patients with and without ureteropelvic junction obstruction (UPJO). METHODS: We evaluated the UPJ specimens of 45 pediatric patients operated between 2005- 2012 retrospectively. Group 1 included 37 patients who underwent dismembered pyeloplasty due to UPJO. Eight patients underwent nephrectomy by the other reasons (renal tumor, trauma etc) and had normal UPJ were accepted as Group 2. The specimens were examined immunohistochemically with CD117 and Caveolin-1 antibody. According to the total number of ICC; 0-5 cells were accepted as a few (1), 610 cells as moderate (2), and > 10 as many (3). According to the staining intensity of Caveolin-1 at muscle tissue, a subjective evaluation was performed as; mild staining (1), moderate staining (2) and strong staining (3). RESULTS: The mean value of ICC distribution was calculated 1.37 ± 0.54 in Group 1 and 2.13 ± 0.64 in Group 2 (p = 0.003), and the median value of ICC distribution was found 1 [1-3] in Group 1 and 2 [1-3] in Group 2 (p = 0.008). Median values for the intensity of staining with Caveolin-1 were found 2 [1-3] in the Group 1, and 2.5 [2-3] in the Group 2 (p = 0.025). CONCLUSIONS: A decrease in ICC and Caveolin-1 levels support that there may be a relationship between ICC and Caveolin-1 for UPJO associated with signal transduction and peristalsis in urinary system.


Assuntos
Caveolina 1/metabolismo , Obstrução Ureteral , Criança , Humanos , Pelve Renal , Estudos Retrospectivos , Telócitos , Ureter
9.
Invest Ophthalmol Vis Sci ; 60(12): 4002-4007, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31560766

RESUMO

Purpose: This study aims to investigate the pharmacologic consequence of genetic deletion of nitric oxide synthase 3 (NOS3) in caveolin 1 (Cav1)-/- mice (double knockout [DKO]) in response to a nitric oxide (NO) donor and two NOS inhibitors. Methods: NO donor sodium nitroprusside (SNP; 10-40 mg/mL), NOS inhibitor L-NG-nitroarginine methyl ester (L-NAME; 10-200 µM), and cavtratin (10-75 µM ) was administered topically to the eye while the contralateral eyes were vehicle controls. Intraocular pressure (IOP) was measured in both eyes by tonometry. Cyclic guanosine monophosphate (cGMP) level in outflow tissue was measured by ELISA assay. Protein expression were analyzed by western blot. Results: Inducible NOS (iNOS) expression significantly increased in the DKO mice compared with the wild type (WT), Cav1 knockout (Cav1 KO), and NOS3 KO mice. In contrast to WT, Cav1 KO and NOS3 KO mice, SNP concentration of up to 30 mg/mL did not significantly affect IOP in DKO mice. However, higher concentration (40 mg/mL) SNP significantly reduced IOP by 14% (n = 8, P < 0.01). Similarly, only 200 µM L-NAME produced a significant increase in IOP (n = 10, P < 0.05). Cavtratin did not significantly change IOP in DKO and NOS3 KO mice. cGMP activity in DKO mice was significantly lower than Cav1 KO mice (n = 4, P < 0.05). Conclusions: In conclusion, our results demonstrated that genetic deletion of NOS3 in Cav1 deficient mice resulted in reduced sensitivity to the NO donor SNP and the two NOS inhibitors possibly due to compromised NOS and cGMP activity.


Assuntos
Caveolina 1/deficiência , Inibidores Enzimáticos/farmacologia , Deleção de Genes , Pressão Intraocular/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/genética , Administração Oftálmica , Animais , Western Blotting , Caveolina 1/metabolismo , Caveolina 1/farmacologia , GMP Cíclico/metabolismo , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroprussiato/farmacologia , Fragmentos de Peptídeos/farmacologia , Tonometria Ocular
10.
Indian J Pharmacol ; 51(3): 173-180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31391685

RESUMO

OBJECTIVE: The present study aims to investigate the role of caveolin-1 in dementia of Alzheimer's type using intracerebroventricular streptozotocin (ICV-STZ)-induced neurodegeneration model in rats. MATERIALS AND METHODS: Male Wistar rats (220-260 g) were employed. STZ 3 mg/kg via ICV route was given once to cause neuronal injury. Daidzein - a caveolin inhibitor at 0.2, 0.4, and 0.6 mg/kg s.c. were given daily whereas minoxidil - a caveolin activator was given at 0.45 mg/kg, i.p. on alternate days for 28 days. STZ was also given at its submaximal dose 1.5 mg/kg to minoxidil group only. RESULTS: ICV-STZ control animals exhibited cognitive and neurological deficits on the Morris water maze, elevated plus maze, and balance beam tests (P < 0.0001). Treatment with daidzein significantly restored memory impairments and decreased oxidative damage whereas minoxidil potentiates the effect of STZ causing significant impairment in memory. Significant oxidative stress such as lipid peroxidation and glutathione (P < 0.0001) were also observed due to ICV-STZ administration resulting in neuronal damage which was significantly prevented by treatment with daidzein in brain tissues. CONCLUSION: The findings from the present investigation may conclude that the caveolin-1 from caveolae at the cell membrane induces memory deficits and oxidative stress phenotype that resemble the neurological phenotype of Alzheimer's disease. Further studies are warranted to gauge the effect of caveolin dyshomeostasis on the amyloidogenic cascade.


Assuntos
Caveolina 1/metabolismo , Cognição , Demência/metabolismo , Memória , Doenças Neurodegenerativas/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Caveolina 1/antagonistas & inibidores , Membrana Celular/metabolismo , Demência/induzido quimicamente , Demência/tratamento farmacológico , Modelos Animais de Doenças , Glutationa/metabolismo , Isoflavonas/uso terapêutico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/tratamento farmacológico , Estresse Oxidativo , Ratos Wistar , Estreptozocina
11.
Endocrinology ; 160(11): 2692-2708, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433456

RESUMO

Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERß and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERß to the cell membrane with caveolin-1 interactions. Exposure to 17ß-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2-dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERß in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERß selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERß, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERß membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Próstata/metabolismo , Caveolina 1/metabolismo , Células Cultivadas , Histona Metiltransferases/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Fosforilação , Fosfotransferases/metabolismo , Próstata/citologia
12.
Exp Neurol ; 322: 113044, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31454490

RESUMO

The astrocyte-endothelial cell interaction is crucial for normal brain homeostasis and blood-brain barrier (BBB) disruption in pathological conditions. However, the mechanism by which astrocytes control BBB integrity, especially after traumatic brain injury (TBI), remains unclear. Here, we present evidence that astrocyte-derived fatty acid-binding protein 7 (FABP7), a differentiation- and migration-associated molecule, may function as a modulator of BBB permeability in a rat weight-drop model of TBI. Immunohistochemical analysis revealed that TBI induced increased expression of FABP7 in astrocytes, accompanied by caveolin-1 (Cav-1) upregulation in endothelial cells. Administration of recombinant FABP7 significantly ameliorated TBI-induced neurological deficits, brain edema, and BBB permeability, concomitant with upregulation of endothelial Cav-1 and tight junction protein expression, while FABP7 knockdown resulted in the opposite effects. Furthermore, pretreatment with daidzein, a specific inhibitor of Cav-1, reversed the inhibitory effects of recombinant FABP7 on matrix metalloproteinase (MMP)-2/9 expression and abolished its BBB protection after TBI. Altogether, these findings suggest that astrocyte-derived FABP7 upregulation may represent an endogenous protective response to BBB disruption partly mediated through a Cav-1/MMP signaling pathway following TBI.


Assuntos
Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Proteína 7 de Ligação a Ácidos Graxos/metabolismo , Transdução de Sinais/fisiologia , Animais , Barreira Hematoencefálica/patologia , Lesões Encefálicas Traumáticas/patologia , Caveolina 1/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ratos , Ratos Sprague-Dawley
13.
DNA Cell Biol ; 38(10): 1048-1055, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433200

RESUMO

DNA condensed agents can improve the transfection efficiency of the cationic liposome delivery system. However, various condensed agents have distinct transfection efficiency and cellular cytotoxicity. The object of this study was to screen the optimal agents with the high transfection efficiency and low cytotoxicity from four polymer compressive materials, polyethylenimine (PEI), chitosan, poly-l-lysine (PLL), and spermidine. DNA was precompressed with these four agents and then combined to cationic liposomes. Subsequently, the entrapment and transfection efficiency of the obtained complexes were investigated. Finally, the particle sizes, cytotoxicity, and endocytosis fashion of these copolymers (Lipo-PEI, Lipo-chitosan, Lipo-PLL, and Lipo-spermidine) were examined. It was found that these four copolymers had significantly lower cytotoxicity and higher transfection efficiency (45.5%, 42.4%, 36.8%, and 47.4%, respectively) than those in the control groups. The transfection efficiency of Lipo-PEI and Lipo-spermidine copolymers were better than the other two copolymers. In 293T cells, nystatin significantly inhibited the transfection efficiency of Lipo-PEI-DNA and Lipo-spermidine-DNA (51.88% and 46.05%, respectively), which suggest that the endocytosis pathway of Lipo-spermidine and Lipo-PEI copolymers was probably caveolin dependent. Our study indicated that these dual-degradable copolymers especially liposome-spermidine copolymer could be used as the potential biocompatible gene delivery carriers.


Assuntos
Quitosana/química , Lipossomos/química , Polietilenoimina/química , Polilisina/química , Espermidina/química , Transfecção/métodos , Cátions , Caveolina 1/genética , Caveolina 1/metabolismo , Quitosana/metabolismo , Colesterol/química , Colesterol/metabolismo , Endocitose/efeitos dos fármacos , Endocitose/genética , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/metabolismo , Células HEK293 , Humanos , Lipossomos/metabolismo , Nistatina/farmacologia , Tamanho da Partícula , Plasmídeos/química , Plasmídeos/metabolismo , Polietilenoimina/metabolismo , Polilisina/metabolismo , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/metabolismo , Espermidina/metabolismo
14.
Mediators Inflamm ; 2019: 7162976, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31316302

RESUMO

Background: Oscillatory shear stress (OSS) disrupts endothelial homeostasis and promotes oxidative stress, which can lead to atherosclerosis. In atherosclerotic lesions, Toll-like receptor 4 (TLR4) is highly expressed. However, the molecular mechanism by which TLR4 modulates oxidative changes and the cell signaling transudation upon OSS is yet to be determined. Methods and Results: Carotid artery constriction (CAC) surgery and a parallel-plate flow chamber were used to modulate shear stress. The results showed that OSS significantly increased the oxidative burden, and this was partly due to TLR4 activation. OSS activated NOX2 and had no significant influence to NOX1 or NOX4 in endothelial cells (ECs). OSS phosphorylated caveolin-1, promoted its binding with endothelial nitric oxide synthase (eNOS), and resulted in deactivation of eNOS. TLR4 inhibition restored levels of nitric oxide (NO) and superoxide dismutase (SOD) in OSS-exposed cells. Conclusion: TLR4 modulates OSS-induced oxidative stress by activating NOX2 and suppressing eNOS.


Assuntos
Células Endoteliais/citologia , NADPH Oxidase 2/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Receptor 4 Toll-Like/metabolismo , Animais , Artérias Carótidas/patologia , Caveolina 1/metabolismo , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Homeostase , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , NADPH Oxidase 1/metabolismo , NADPH Oxidase 4/metabolismo , Óxido Nítrico , Ratos , Resistência ao Cisalhamento , Transdução de Sinais , Estresse Mecânico , Superóxido Dismutase-1/metabolismo
15.
J Ovarian Res ; 12(1): 57, 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31228941

RESUMO

BACKGROUND: Ovarian cancer (OC) is the second most common gynaecological malignancy. MicroRNAs (miRNAs) have been found to be aberrantly expressed in OC tissue and have been proposed as biomarkers and therapeutic targets for OC. RESULTS: In this study, we found that miR-96-5p was up-regulated in OC tissues and OC cells compared to normal ovarian tissues and epithelial cell line. And, miR-96-5p was also up-regulated in the serum samples from OC patients compared to health participants. In addition, there was a positive correlation of miR-96-5p levels between OC tissues and serum samples. At the cellular level, overexpression of miR-96-5p promoted cell proliferation and migration in OC cells. Moreover, we further validated Caveolae1 (CAV1) as the direct target of miR-96-5p in OC cells through luciferase activity assays and western blot. CAV1 was obvious low expression in OC tissues. The overexpression of CAV1 abrogated the promotion of miR-96-5p on the OC cells proliferation and migration. Finally, we found that AKT signaling pathway was involved in this process. MiR-96-5p inhibited the phosphorylation of AKT and expression of down-stream proteins Cyclin D1 and P70 by targeting CAV1. CONCLUSIONS: The above findings suggested that targeting miR-96-5p may be a promising strategy for OC treatment.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Caveolina 1/genética , MicroRNAs/metabolismo , Neoplasias Ovarianas/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Caveolina 1/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
16.
Nat Commun ; 10(1): 2692, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217420

RESUMO

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.


Assuntos
Antígenos CD/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nefropatias Diabéticas/patologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Caveolina 1/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Ceramidas/metabolismo , Ceramidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Podócitos/citologia , Podócitos/metabolismo , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Resultado do Tratamento
17.
Oxid Med Cell Longev ; 2019: 4275984, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31178960

RESUMO

Background: Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. The idea of therapeutic angiogenesis in ischemic myocardium is a promising strategy for MI patients. Buyang Huanwu decoction (BHD), a famous Chinese herbal prescription, exerted antioxidant, antiapoptotic, and anti-inflammatory effects, which contribute to cardio-/cerebral protection. Here, we aim to investigate the effects of BHD on angiogenesis through the caveolin-1 (Cav-1)/vascular endothelial growth factor (VEGF) pathway in MI model of mice. Materials and Methods: C57BL/6 mice were randomly divided into 3 groups by the table of random number: (1) sham-operated group (sham, n = 15), (2) AMI group (AMI+sham, n = 20), and (3) BHD-treated group (AMI+BHD, n = 20). 2,3,5-Triphenyltetrazolium chloride solution stain was used to determine myocardial infarct size. Myocardial histopathology was tested using Masson staining and hematoxylin-eosin staining. CD31 immunofluorescence staining was used to analyze the angiogenesis in the infarction border zone. Western blot analysis, immunofluorescence staining, and/or real-time quantitative reverse transcription polymerase chain reaction was applied to test the expression of Cav-1, VEGF, vascular endothelial growth factor receptor 2 (VEGFR2), and/or phosphorylated extracellular signal-regulated kinase (p-ERK). All statistical analyses were performed using the SPSS 20.0 software and GraphPad Prism 6.05. Values of P < 0.05 were considered as statistically significant. Results and Conclusion: Compared with the AMI group, the BHD-treated group showed a significant improvement in the heart weight/body weight ratio, echocardiography images, cardiac function, infarct size, Mason staining of the collagen deposition area, and density of microvessel in the infarction border zone (P < 0.05). Compared with the AMI group, BHD promoted the expression of Cav-1, VEGF, VEGFR2, and p-ERK in the infarction border zone after AMI. BHD could exert cardioprotective effects on the mouse model with AMI through targeting angiogenesis via Cav-1/VEGF signaling pathway.


Assuntos
Caveolina 1/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Doença Aguda , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Masculino , Camundongos , Infarto do Miocárdio/patologia , Neovascularização Patológica/patologia , Transdução de Sinais
18.
Mediators Inflamm ; 2019: 8297391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31148948

RESUMO

Multiple organ dysfunction syndrome (MODS) remains a great challenge in critical care because of its common occurrence, high cost of care, and high mortality. Vascular endothelial injury is the initiation step in the development of MODS, and EPCs are essential for the process of organ repair. It is unclear whether and how caveolin-1 (Cav-1) in EPCs contributes to the pathogenesis of MODS. The present study is aimed at investigating the potential role of Cav-1 in EPCs during MODS. We established a MODS model in pigs, isolated and characterized EPCs from the MODS model, and tracked Cav-1 expression and various in vitro behaviors of EPCs from the MODS model. Then, we knockdown Cav-1 expression with siRNA or induce Cav-1 expression with proinflammatory factors to evaluate potential effects on EPCs. Our results suggest that Cav-1 expression correlated with EPC functions during MODS and Cav-1 regulates the function of endothelial progenitor cells via PI3K/Akt/eNOS signaling during MODS. Thus, Cav-1 in EPCs could be an attractive target for the treatment of MODS.


Assuntos
Caveolina 1/metabolismo , Células Progenitoras Endoteliais/metabolismo , Animais , Caveolina 1/genética , Masculino , Insuficiência de Múltiplos Órgãos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Suínos
19.
Int Immunopharmacol ; 73: 424-434, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31152980

RESUMO

Oxidized low density lipoprotein (ox-LDL) can induce the proliferation and differentiation of endothelial cells, which is one of the important mechanisms of ox-LDL atherosclerosis. Adiponectin is an endogenous bioactive polypeptide secreted by adipocytes, it participates in the metabolism of fat and glucose. It has the effect of reducing blood triglyceride and LDL content. Adiponectin also inhibits the abnormal proliferation and migration of endothelial cells, but its molecular mechanism is unclear. In this study, we used cell model of Ox-LDL-induced human aortic endothelial cells (HAECs) proliferation to analyze the molecular mechanism of APN inhibiting HAECs abnormal proliferation. The results showed that APN could inhibit the cell viability and DNA synthesis of HAECs after Ox-LDL treatment, up-regulate the apoptosis level and reduce the proportion of S + G2 phase cells. Further analysis showed that adiponectin could promote the dephosphorylation of Caveolin-1, which could dissociate eNOS and Caveolin-1, promote the phosphorylation of eNOS and enhance the synthesis of NO. NO increased expression levels of cleaved caspase 3 and p21 in the cells and inhibited the abnormal proliferation of HAECs. The regulation of phosphorylation and dephosphorylation of Caveolae-1 plays a key role in this process. Further study of the molecular mechanism of Caveolae-1 in the inhibition of HAECs abnormal proliferation by APN may reveal the potential of APN in the treatment of cardiovascular diseases.


Assuntos
Adiponectina/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Lipoproteínas LDL , Aorta , Caspase 3/metabolismo , Caveolina 1/metabolismo , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Endoteliais/metabolismo , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Regulação para Cima
20.
Int J Oncol ; 54(6): 2054-2068, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081050

RESUMO

The failure of androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to androgen receptor antagonists. Although an aberrant caveolin­1 (Cav­1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration­resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav­1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme­linked immunosorbent assay, which revealed that Cav­1 was overexpressed in CRPC. Furthermore, Kaplan­Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav­1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence­free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav­1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut­off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav­1 induced the invasion and migration of CRPC cells by the activation of the H­Ras/phosphoinositide­specific phospholipase Cε signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of androgen receptor antagonists by downregulating the expression of Cav­1. Collectively, the findings of this study provide evidence that Cav­1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav­1 may prove to be a useful strategy with which to prevent and/or treat CRPC.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Caveolina 1/genética , Caveolina 1/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração/metabolismo , Sinvastatina/farmacologia , Adulto , Idoso , Caveolina 1/sangue , Linhagem Celular Tumoral , Movimento Celular , Colesterol/sangue , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Estudos Retrospectivos , Análise de Sobrevida , Regulação para Cima/efeitos dos fármacos
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