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1.
Braz. j. biol ; 84: e253616, 2024. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1355880

RESUMO

Abstract This study evaluated the effect of the volatile oil of Alpinia zerumbet (VOAz) on caveolin-1 gene expression and muscular fibrosis. The rats were immobilized to induce fibrosis of the gastrocnemius muscle, and they were treated with VOAz. Collagen quality was assessed by histology and the expression of the caveolin-1 (CAV-1) gene was evaluated using qPCR. Histomorphological analysis indicated a significant reduction in the perimeter, width, and intensity of collagen in the treated groups, thus showing that the oil was effective in regulating the quality of collagen at the three concentrations. The results of expression levels suggested a decrease in the lesioned group and in two treatment groups (0.0115 µg/g and 0.009 µg/g). However, with the lowest concentration (0.0065 µg/g), no significant difference was observed, with levels similar to those found in healthy tissue. Therefore, the results showed that VOAz has the potential to be a non-invasive and low-cost alternative to aid in the treatment of muscular fibrosis.


Resumo Este estudo avaliou o efeito do óleo volátil de Alpinia zerumbet (OVAz) na expressão do gene da caveolina-1 e na fibrose muscular. Os ratos foram imobilizados para induzir a fibrose do músculo gastrocnêmio, e foram tratados com OVAz. A qualidade do colágeno foi avaliada com histologia e à expressão do gene caveolina-1 (CAV-1) foi avaliada usando qPCR. A análise histomorfológica indicou uma redução significativa no perímetro, largura e intensidade do colágeno nos grupos tratados. Os resultados dos níveis de expressão sugeriram diminuição nos grupos de lesão e em dois grupos de tratamento (0,0115 µg/g e 0,009 µg/g). No entanto, com a menor concentração (0,0065 µg/g), não foi observada diferença significativa, apresentando níveis semelhantes aos encontrados em tecido saudável. O uso do OVAz foi eficaz para reverter as alterações do colágeno causadas pela fibrose, e sua menor concentração apresentou uma possível tendência de aumento na expressão do CAV-1. Portanto, os resultados mostraram que o OVAz tem potencial para ser uma alternativa não invasiva e de baixo custo para auxiliar no tratamento da fibrose muscular.


Assuntos
Animais , Ratos , Óleos Voláteis/farmacologia , Colágeno/metabolismo , Alpinia/química , Caveolina 1/metabolismo , Músculos/efeitos dos fármacos , Fibrose , Óleos Vegetais/farmacologia , Brasil , Ratos Wistar , Modelos Animais de Doenças , Músculos/patologia
2.
Int J Oral Sci ; 15(1): 3, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36631446

RESUMO

Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer's disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.


Assuntos
Barreira Hematoencefálica , Caveolina 1 , Ratos , Animais , Barreira Hematoencefálica/metabolismo , Caveolina 1/metabolismo , Porphyromonas gingivalis , Cisteína Endopeptidases Gingipaínas/metabolismo , Transcitose , Permeabilidade , Fatores de Virulência/metabolismo
3.
Free Radic Biol Med ; 195: 245-257, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36596386

RESUMO

Acetaminophen (APAP) is one of the most widely used drugs in the world. The literature shows that excessive or long-term use of APAP can lead to increased cardiovascular dysfunction. An acute increase in angiotensin Ⅱ (Ang Ⅱ) caused by APAP use in fatty liver disease may increase the risk and severity of vascular injury. However, the underlying mechanism remains unclear. Caveolin-1 (CAV1) is a broad-spectrum kinase inhibitor that significantly determines endothelial function. This study aimed to observe the effects of APAP on the vasculature in non-alcoholic fatty liver disease (NAFLD) and to determine whether CAV1 could alleviate vascular oxidative stress and inflammation by targeting Ang Ⅱ or its downstream pathways. In this study, 7-week-old C57BL/6 male mice (18-20 g) were administered APAP by gavage after eight weeks of a high-fat diet. Any resulting vascular oxidative stress and inflammation were assessed. Levels of Ang Ⅱ, CAV1, and other related proteins were measured using ELISA and western blotting. In APAP-treated NAFLD mice, CAV1 expression was downregulated and Ang Ⅱ expression was upregulated compared to normal APAP-treated mice. In vitro, HUVECs were incubated with Ang Ⅱ (300 nM) for 48 h. Overexpression of CAV1 in HUVECs attenuated Ang Ⅱ-induced oxidative stress and inflammation and downregulated the expression of Protein kinase C (PKC) and p-P38/P38. After intervention with CAV1-siRNA, immunofluorescence results showed that the fluorescence intensity of PKC on mitochondria was further increased, and flow cytometry results showed that the mitochondrial membrane potential increased. PKC inhibitors alleviated Ang Ⅱ-induced endothelial injury. In conclusion, our findings confirmed that CAV1 exerts a protective effect against vascular injury by inhibiting oxidative stress and inflammation through the PKC/MAPK pathway. Therefore, restoration of CAV1 may have clinical benefits in reducing APAP-induced vascular damage in NAFLD patients.


Assuntos
Caveolina 1 , Doença Hepática Induzida por Substâncias e Drogas , Hepatopatia Gordurosa não Alcoólica , Lesões do Sistema Vascular , Animais , Masculino , Camundongos , Acetaminofen/efeitos adversos , Caveolina 1/genética , Caveolina 1/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Estresse Oxidativo , Proteína Quinase C/metabolismo , Lesões do Sistema Vascular/metabolismo
4.
DNA Cell Biol ; 42(1): 27-42, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36638349

RESUMO

Caveolin-1 (CAV1) is one of the members of the caveolae, and the role of CAV1 in esophageal cancer (ESCA) is not completely clear. In this study, we found that expression of CAV1 was downregulated in ESCA in The Cancer Genome Atlas and the Genotype-Tissue Expression (GTEx) database and we also use immunohistochemistry of tissue microarray for verification. Then, we used bioinformatics methods to investigate the prognostic value of CAV1, influence on immune cell infiltration in tumor microenvironment (TME) and responding to immunotherapy in ESCA. Our result indicated that CAV1 designs an inflamed TME in ESCA based on the evidence that CAV1 positively correlated with immunomodulators, immune score, stomal score, cancer immunity cycles, tumor-infiltrating immune cells, T cell inflamed score, and immune checkpoints. Immunophenoscore, Tumor Immune Dysfunction and Exclusion algorithms, and the mutation analysis show that the downregulated CAV1 expression indicated higher tumor mutation burden and higher rate of response to immune checkpoint inhibitors (ICIs) in the low-expression group. In a word, our study demonstrated the impact of CAV1 to the TME in ESCA and it may be a new target for ESCA immunotherapy. In addition, the expression of CAV1 can predict the clinical response to ICIs, which may provide clinical treatment guidance.


Assuntos
Caveolina 1 , Neoplasias Esofágicas , Imunoterapia , Humanos , Adjuvantes Imunológicos , Caveolina 1/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/terapia , Microambiente Tumoral
5.
Physiol Rep ; 11(1): e15544, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36635975

RESUMO

Notch is important to vessel homeostasis. We investigated the mechanistic role of caveolin-1 (Cav-1) in mediating the effects of alcohol (Ethanol/EtOH) on the γ-secretase proteolytic activity necessary for Notch signaling in vascular cells. Human coronary artery endothelial cells (HCAEC) were treated with EtOH (0-50 mM), Notch ligand delta-like ligand 4 (Dll4), and the γ-secretase inhibitor DAPT. EtOH stimulated Notch signaling in HCAEC as evidenced by increased Notch receptor (N1, N4) and target gene (hrt2, hrt3) mRNA levels with the most robust response achieved at 25 mM EtOH. Ethanol (25 mM) stimulated γ-secretase proteolytic activity, to the same extent as Dll4, in HCAEC membranes. Ethanol inhibited Cav-1 mRNA and protein levels in HCAEC. Caveolin-1 negatively regulated γ-secretase activity in HCAEC as Cav-1 knockdown stimulated it, while Cav-1 overexpression inhibited it. Moreover, Cav-1 overexpression blocked the stimulatory effect of EtOH on γ-secretase activity in HCAEC. Although EtOH also inhibited Cav-1 expression in human coronary artery smooth muscle cells (HCASMC), EtOH inhibited γ-secretase activity in HCASMC in contrast to its effect in HCAEC. The inhibitory effect of EtOH on γ-secretase in HCASMC was mimicked by Cav-1 knockdown and prevented by Cav-1 overexpression, suggesting that in these cells Cav-1 positively regulates γ-secretase activity. In conclusion, EtOH differentially regulates γ-secretase activity in arterial EC and SMC, being stimulatory and inhibitory, respectively. These effects are both mediated by caveolin-1 inhibition which itself has opposite effects on γ-secretase in the two cell types. This mechanism may underlie, in part, the effects of moderate drinking on atherosclerosis.


Assuntos
Secretases da Proteína Precursora do Amiloide , Caveolina 1 , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Células Cultivadas , Vasos Coronários/metabolismo , Células Endoteliais/metabolismo , Etanol/farmacologia , Miócitos de Músculo Liso/metabolismo , RNA Mensageiro/metabolismo
6.
Int Immunopharmacol ; 114: 109558, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36700765

RESUMO

The overuse of acetaminophen (APAP) may cause more severe hepatotoxicity in patients with non-alcoholic fatty liver disease (NAFLD). Caveolin-1 (CAV1), is an essential regulator of metabolic function, which can alleviate liver damage by scavenging reactive oxygen species (ROS). Evidence suggests that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated pyroptosis is involved in the development of NAFLD. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linking ROS to NLRP3 inflammasome. However, whether CAV1 alleviates APAP-aggravated hepatotoxicity in NAFLD via the ROS/TXNIP/NLRP3 pathway remains unclear. An in vivo fatty liver model was established by feeding mice a high-fat diet for 56 days. Additionally, using in vitro approach, AML-12 cells were incubated with free fatty acids for 48 h and APAP was added during the last 24 h. We found that the overuse of APAP in NAFLD not only induced oxidative stress, but also increased TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition. In addition to inhibiting ROS generation and lipid deposition, overexpression of CAV1 reduced the elevated levels of TXNIP expression and NLRP3-mediated pyroptosis. However, the effect of CAV1 on TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition was reversed by CAV1 small interfering RNA (siRNA) intervention. Finally, N-acetyl cysteine (NAC) treatment reduced CAV1 siRNA-mediated changes in TXNIP expression and NLRP3-mediated pyroptosis levels. These results demonstrate that the inhibitory effect of CAV1 on NLRP3-mediated pyroptosis may be mediated through the ROS/TXNIP axis. Moreover, the current study provides novel mechanistic insights into the protective effects of CAV1 on APAP-aggravated hepatotoxicity in NAFLD.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Acetaminofen , Espécies Reativas de Oxigênio/metabolismo , Caveolina 1/metabolismo , Inflamassomos/metabolismo , Piroptose , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , RNA Interferente Pequeno , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Lipídeos , Proteínas de Transporte/genética
7.
Traffic ; 24(2): 76-94, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36519961

RESUMO

Caveolin-1 (Cav-1) is a fundamental constituent of caveolae, whose functionality and structure are strictly dependent on cholesterol. In this work the U18666A inhibitor was used to study the role of cholesterol transport in the endosomal degradative-secretory system in a metastatic human melanoma cell line (WM266-4). We found that U18666A induces a shift of Cav-1 from the plasma membrane to the endolysosomal compartment, which is involved, through Multi Vesicular Bodies (MVBs), in the formation and release of small extracellular vesicles (sEVs). Moreover, this inhibitor induces an increase in the production of sEVs with chemical-physical characteristics similar to control sEVs but with a different protein composition (lower expression of Cav-1 and increase of LC3II) and reduced transfer capacity on target cells. Furthermore, we determined that U18666A affects mitochondrial function and also cancer cell aggressive features, such as migration and invasion. Taken together, these results indicate that the blockage of cholesterol transport, determining the internalization of Cav-1, may modify sEVs secretory pathways through an increased fusion between autophagosomes and MVBs to form amphisome, which in turn fuses with the plasma membrane releasing a heterogeneous population of sEVs to maintain homeostasis and ensure correct cellular functionality.


Assuntos
Vesículas Extracelulares , Melanoma , Humanos , Caveolina 1/metabolismo , Autofagossomos/metabolismo , Vesículas Extracelulares/metabolismo , Colesterol/metabolismo
8.
Nat Cell Biol ; 25(1): 120-133, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36543981

RESUMO

In response to different types and intensities of mechanical force, cells modulate their physical properties and adapt their plasma membrane (PM). Caveolae are PM nano-invaginations that contribute to mechanoadaptation, buffering tension changes. However, whether core caveolar proteins contribute to PM tension accommodation independently from the caveolar assembly is unknown. Here we provide experimental and computational evidence supporting that caveolin-1 confers deformability and mechanoprotection independently from caveolae, through modulation of PM curvature. Freeze-fracture electron microscopy reveals that caveolin-1 stabilizes non-caveolar invaginations-dolines-capable of responding to low-medium mechanical forces, impacting downstream mechanotransduction and conferring mechanoprotection to cells devoid of caveolae. Upon cavin-1/PTRF binding, doline size is restricted and membrane buffering is limited to relatively high forces, capable of flattening caveolae. Thus, caveolae and dolines constitute two distinct albeit complementary components of a buffering system that allows cells to adapt efficiently to a broad range of mechanical stimuli.


Assuntos
Cavéolas , Caveolina 1 , Cavéolas/metabolismo , Caveolina 1/metabolismo , Mecanotransdução Celular , Membrana Celular/metabolismo , Proteínas/metabolismo
9.
Clin Immunol ; 246: 109215, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36581222

RESUMO

Although the use of IVIg has increased in various immune-driven diseases and even in pregnancy, the exact action mechanisms of IVIg are not fully understood. Dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) is a known receptor for α-2,6-sialylated IgG (sIVIg), which is responsible for the anti-inflammatory effect of IVIg. DC-SIGN is expressed on Hofbauer cells (HBCs) of the fetal villi of the placenta which act as an innate immune modulator at the maternal-fetal interface. Preeclampsia is a major complication in pregnancy and is related to IL-10, a cytokine with an important role in immune tolerance. DC-SIGN interaction with sIVIg in HBCs promoted IL-10 secretion through the activation of the caveolin-1/NF-κB pathway, especially in plasma lipid rafts. Consistent results were obtained for HBCs from patients with preeclampsia. Collectively, the stimulation of DC-SIGN+ HBCs with sIVIg enhanced immune tolerance in the feto-maternal environment, suggesting the therapeutic application of sIVIg to prevent preeclampsia.


Assuntos
Imunoglobulinas Intravenosas , Pré-Eclâmpsia , Gravidez , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , NF-kappa B/metabolismo , Interleucina-10/metabolismo , Caveolina 1/metabolismo , Lectinas Tipo C/metabolismo , Tolerância Imunológica , Células Dendríticas
10.
Cells ; 11(23)2022 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-36497195

RESUMO

Caveolin-1 (CAV1) is implicated in the pathophysiology of diabetes and obesity. Previously, we demonstrated an association between the CAV1 rs1997623 C > A variant and metabolic syndrome (MetS). Here, we decipher the functional role of rs1997623 in CAV1 gene regulation. A cohort of 38 patients participated in this study. The quantitative MetS scores (siMS) of the participants were computed. CAV1 transcript and protein expression were tested in subcutaneous adipose tissue using RT-PCR and immunohistochemistry. Chromatin immunoprecipitation assays were performed using primary preadipocytes isolated from individuals with different CAV1 rs1997623 genotypes (AA, AC, and CC). The regulatory region flanking the variant was cloned into a luciferase reporter plasmid and expressed in human preadipocytes. Additional knockdown and overexpression assays were carried out. We show a significant correlation between siMS and CAV1 transcript levels and protein levels in human adipose tissue collected from an Arab cohort. We found that the CAV1 rs1997623 A allele generates a transcriptionally active locus and a new transcription factor binding site for early B-cell factor 1 (EBF1), which enhanced CAV1 expression. Our in vivo and in vitro combined study implicates, for the first time, EBF1 in regulating CAV1 expression in individuals harboring the rs1997623 C > A variant.


Assuntos
Caveolina 1 , Síndrome Metabólica , Polimorfismo de Nucleotídeo Único , Transativadores , Humanos , Tecido Adiposo/metabolismo , Alelos , Sítios de Ligação , Caveolina 1/genética , Genótipo , Síndrome Metabólica/metabolismo , Transativadores/metabolismo
12.
Int J Mol Sci ; 23(23)2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36499524

RESUMO

Caveolin-2 is a protein suitable for the study of interactions of caveolins with other proteins and lipids present in caveolar lipid rafts. Caveolin-2 has a lower tendency to associate with high molecular weight oligomers than caveolin-1, facilitating the study of its structural modulation upon association with other proteins or lipids. In this paper, we have successfully expressed and purified recombinant human caveolin-2 using E. coli. The structural changes of caveolin-2 upon interaction with a lipid bilayer of liposomes were characterized using bioinformatic prediction models, circular dichroism, differential scanning calorimetry, and fluorescence techniques. Our data support that caveolin-2 binds and alters cholesterol-rich domains in the membranes through a CARC domain, a type of cholesterol-interacting domain in its sequence. The far UV-CD spectra support that the purified protein keeps its folding properties but undergoes a change in its secondary structure in the presence of lipids that correlates with the acquisition of a more stable conformation, as shown by differential scanning calorimetry experiments. Fluorescence experiments using egg yolk lecithin large unilamellar vesicles loaded with 1,6-diphenylhexatriene confirmed that caveolin-2 adsorbs to the membrane but only penetrates the core of the phospholipid bilayer if vesicles are supplemented with 30% of cholesterol. Our study sheds light on the caveolin-2 interaction with lipids. In addition, we propose that purified recombinant caveolin-2 can provide a new tool to study protein-lipid interactions within caveolae.


Assuntos
Caveolina 1 , Escherichia coli , Humanos , Escherichia coli/metabolismo , Caveolina 1/metabolismo , Caveolina 2/metabolismo , Cavéolas/metabolismo , Colesterol/metabolismo , Microdomínios da Membrana/metabolismo , Bicamadas Lipídicas/metabolismo
13.
BMC Med Genomics ; 15(1): 258, 2022 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-36517810

RESUMO

BACKGROUND AND AIMS: Caveolin-1 (CAV-1) in adipocyte tissue and other body parts possesses numerous biological functions. In the present study, we sought to investigate the interaction between CAV-1 polymorphism and dietary fat quality indexes on visceral adiposity index (VAI) and body adiposity index (BAI) among overweight and obese women. METHODS: This study was conducted on 386 women aged 18-48 years old. Biochemical measurements were assessed by standard protocols. We used a food frequency questionnaire (FFQ) to calculate the dietary intake and the indexes of dietary fat quality intake. Anthropometric values and body composition were measured by standard methods. Finally, the CAV-1 genotype was measured using the PCR-RFLP method. RESULTS: We found marginally significant differences between AA and GG genotypes of waist-to-hip ratio (WHR) (P = 0.06) and BAI (P = 0.06) of participants after adjusting for potential confounders. For dietary intakes, after adjusting with the energy intake, mean differences in biotin (P = 0.04) and total fiber (P = 0.06) were significant and marginally significant, respectively. The interaction between two risk alleles (AA) with omega-6 to omega-3 ratio (W6/W3) on BAI, after adjustment for potential confounders (age, physical activity, energy intake, education), was marginally positive (ß = 14.08, 95% CI = - 18.65, 46.81, P = 0.07). In comparison to the reference group (GG), there was a positive interaction between the two risk alleles (AA) with W6/W3 ratio on VAI (ß = 2.81, 95% CI = 1.20, 8.84, P = 0.06) in the adjusted model. CONCLUSIONS: We found that there might be an interaction between CAV-1 genotypes with dietary quality fat indexes on VAI and BAI among overweight and obese women.


Assuntos
Adiposidade , Caveolina 1 , Sobrepeso , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Adiposidade/genética , Índice de Massa Corporal , Caveolina 1/genética , Estudos Transversais , Gorduras na Dieta/efeitos adversos , Obesidade/genética , Obesidade Abdominal/genética , Sobrepeso/genética
14.
Front Immunol ; 13: 1035451, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532050

RESUMO

The skin is the outermost layer and largest organ in the human body. Since the skin interfaces with the environment, it has a variety of roles, including providing a protective barrier against external factors, regulating body temperature, and retaining water in the body. It is also involved in the immune system, interacting with immune cells residing in the dermis. Caveolin-1 (CAV-1) is essential for caveolae formation and has multiple functions including endocytosis, lipid homeostasis, and signal transduction. CAV-1 is known to interact with a variety of signaling molecules and receptors and may influence cell proliferation and migration. Several skin-related disorders, especially those of the inflammatory or hyperproliferative type such as skin cancers, psoriasis, fibrosis, and wound healing, are reported to be associated with aberrant CAV-1 expression. In this review, we have explored CAV-1 involvement in skin physiology and skin diseases.


Assuntos
Psoríase , Dermatopatias , Humanos , Caveolina 1 , Pele/metabolismo , Transdução de Sinais
16.
Front Immunol ; 13: 951381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405687

RESUMO

The diabetic population has been increasing in the past decades and diabetic cardiomyopathy (DCM), a pathology that is defined by the presence of cardiac remodeling and dysfunction without conventional cardiac risk factors such as hypertension and coronary heart diseases, would eventually lead to fatal heart failure in the absence of effective treatment. Impaired insulin signaling, commonly known as insulin resistance, plays an important role in the development of DCM. A family of integral membrane proteins named caveolins (mainly caveolin-1 and caveolin-3 in the myocardium) and a protein hormone adiponectin (APN) have all been shown to be important for maintaining normal insulin signaling. Abnormalities in caveolins and APN have respectively been demonstrated to cause DCM. This review aims to summarize recent research findings of the roles and mechanisms of caveolins and APN in the development of DCM, and also explore the possible interplay between caveolins and APN.


Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Resistência à Insulina , Humanos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/prevenção & controle , Caveolina 1 , Miocárdio/patologia , Insulina/metabolismo , Adiponectina/metabolismo , Diabetes Mellitus/patologia
17.
Microb Cell Fact ; 21(1): 239, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36384643

RESUMO

BACKGROUND: Caveolae are invaginated plasma membrane domains of 50-100 nm in diameter involved in many important physiological functions in eukaryotic cells. They are composed of different proteins, including the membrane-embedded caveolins and the peripheric cavins. Caveolin-1 has already been expressed in various expression systems (E. coli, insect cells, Toxoplasma gondii, cell-free system), generating intracellular caveolin-enriched vesicles in E. coli, insect cells and T. gondii. These systems helped to understand the protein insertion within the membrane and its oligomerization. There is still need for fundamental insights into the formation of specific domains on membrane, the deformation of a biological membrane driven by caveolin-1, the organization of a caveolar coat, and the requirement of specific lipids and proteins during the process. The aim of this study was to test whether the heterologously expressed caveolin-1ß was able to induce the formation of intracellular vesicles within a Gram+ bacterium, Lactococcus lactis, since it displays a specific lipid composition different from E. coli and appears to emerge as a good alternative to E. coli for efficient overexpression of various membrane proteins. RESULTS: Recombinant bacteria transformed with the plasmid pNZ-HTC coding for the canine isoform of caveolin-1ß were shown to produce caveolin-1ß, in its functional oligomeric form, at a high expression level unexpected for an eukaryotic membrane protein. Electron microscopy revealed several intracellular vesicles from 30 to 60 nm, a size comparable to E. coli h-caveolae, beneath the plasma membrane of the overexpressing bacteria, showing that caveolin-1ß is sufficient to induce membrane vesiculation. Immunolabelling studies showed antibodies on such neo-formed intracellular vesicles, but none on plasma membrane. Density gradient fractionation allowed the correlation between detection of oligomers on Western blot and appearance of vesicles measurable by DLS, showing the requirement of caveolin-1ß oligomerization for vesicle formation. CONCLUSIONS: Lactococcus lactis cells can heterologously overexpress caveolin-1ß, generating caveolin-1ß enriched intracellular neo-formed vesicles. These vesicles might be useful for potential co-expression of membrane proteins of pharmaceutical interest for their simplified functional characterization.


Assuntos
Caveolina 1 , Lactococcus lactis , Cães , Animais , Caveolina 1/genética , Caveolina 1/metabolismo , Lactococcus lactis/genética , Lactococcus lactis/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Membrana/metabolismo , Membrana Celular/metabolismo
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(10): 1324-1331, 2022 Oct 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36411683

RESUMO

OBJECTIVES: The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily, and LXR-ß is an important receptor for cholesterol content in brain cells. LXR-ß/retinoic X receptor (RXR-α)/ATP binding cassette transporter A1 (ABCA1) cholesterol transmembrane transport system is closely related to the occurrence and development of Alzheimer's disease (AD). LXR agonist TO901317 can affect the accumulation of ß- amyloid protein in the brain tissue of APP/PS1 double transgenic AD mice. However, the molecular mechanism is not clarified in detail. This study aims to evaluate the effects of LXR agonist TO901317 on the cognitive function of AD mice fed with high cholesterol diet, and to explore its possible mechanism from the perspective of cholesterol metabolism. METHODS: Twenty four male 6-month-old APP/PS1 double transgenic AD mice were randomly divided into 4 groups, 6 mice in each group: a control group (fed with normal diet), a cholesterol rich diet (CRD) group, a TO901317 group (fed with CRD combined with TO901317), and a GSK2033 group (fed with CRD combined with TO901317 and LXR antagonist GSK2033). The mice were fed with pellet feed made of high cholesterol feed, mixed with lard, egg yolk powder, and cod liver oil twice a day. TO901317 and GSK2033 were dissolved and diluted to a final concentration at 0.03%. The drugs were given to the mice daily through gastric tube according to their body weight. Meanwhile, the mice in the drug group were fed with high cholesterol diet . After feeding for 3 months, Morris water maze was used to observe the changes of spatial exploration and memory ability of AD mice in each group. The contents of TC, LDL, and HDL in serum of mice in each group were detected by cholesterol enzyme colorimetry, and the differences among the groups were compared. The expression of Aß42 in the brain of AD mice was detected by ELISA. Western blotting was used to detect the protein levels of LXR-ß, RXR-α, ABCA1, and Caveolin-1 in the brain of each group. RESULTS: Morris water maze results showed that the times, distance and the duration of mice crossing the platform in the CRD group were significantly decreased compared with the control group (all P<0.05), while these three figures in TO901317 group were significantly increased compared with the CRD group (all P<0.05). Compared with the TO901317 group, there was a decrease of these figures in the GSK2033 group (all P<0.05). The serum TC and LDL levels in the CRD group were significantly higher than those in the control group, while HDL levels were significantly lower (all P<0.001). The figures of the TC and LDL contents level in the TO901317 group were lower than those in the CRD group, while HDL levels were higher (all P<0.001). Compared with TO901317 group, the contents of the TC and LDL in GSK2033 group were significantly increased, while HDL content was significantly decreased (all P<0.001). ELISA results showed that the production of Aß42 peptides in the brain of CRD group was the highest while the content in the TO901317 group was significantly decreased (P<0.001), which was the lowest among the groups. The figure in the control group was close to the GSK2033 group. Western blotting results showed that the protein levels of LXR-ß, RXR-α, and ABCA1 in the CRD group were significantly decreased compared with the control group, but the protein level of Caveolin-1 was increased (all P<0.01). After TO901317 treatment, the protein levels of LXR-ß, RXR-α and ABCA1 were significantly increased, while the protein level of Caveolin-1 was decreased partially (all P<0.001). In the GSK2033 group, the effect of TO901317 on AD mice was partially reversed by GSK2033. Compared to TO901317 group, the protein levels of LXR-ß, RXR-α, and ABCA1 showed a decrease trend, while the protein level of Caveolin-1 showed an increase state (all P<0.05). CONCLUSIONS: High cholesterol diet leads to severer spatial exploration, learning and memory impairment in transgenic AD mice, while the LXR agonist TO901317 attenuates this effect. The mechanism may be that TO901317 promotes cholesterol efflux by activating LXR-ß/RXR-α/ABCA1 transmembrane transport system, reduces the expression of Caveolin-1, improves the composition of lipid raft, and ultimately reduces the production of Aß42 in the brain.


Assuntos
Doença de Alzheimer , Masculino , Animais , Camundongos , Receptores X do Fígado/genética , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Camundongos Transgênicos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Caveolina 1/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Cognição , Peptídeos beta-Amiloides/metabolismo , Colesterol
19.
Nat Commun ; 13(1): 6813, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357389

RESUMO

Oligovascular coupling contributes to white matter vascular homeostasis. However, little is known about the effects of oligovascular interaction on oligodendrocyte precursor cell (OPC) changes in chronic cerebral ischemia. Here, using a mouse of bilateral carotid artery stenosis, we show a gradual accumulation of OPCs on vasculature with impaired oligodendrogenesis. Mechanistically, chronic ischemia induces a substantial loss of endothelial caveolin-1 (Cav-1), leading to vascular secretion of heat shock protein 90α (HSP90α). Endothelial-specific over-expression of Cav-1 or genetic knockdown of vascular HSP90α restores normal vascular-OPC interaction, promotes oligodendrogenesis and attenuates ischemic myelin damage. miR-3074(-1)-3p is identified as a direct inducer of Cav-1 reduction in mice and humans. Endothelial uptake of nanoparticle-antagomir improves myelin damage and cognitive deficits dependent on Cav-1. In summary, our findings demonstrate that vascular abnormality may compromise oligodendrogenesis and myelin regeneration through endothelial Cav-1, which may provide an intercellular mechanism in ischemic demyelination.


Assuntos
Isquemia Encefálica , MicroRNAs , Células Precursoras de Oligodendrócitos , Humanos , Caveolina 1/genética , Caveolina 1/metabolismo , Endotélio Vascular/metabolismo , Isquemia Encefálica/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Bainha de Mielina/metabolismo , Isquemia/metabolismo , Oligodendroglia/metabolismo , MicroRNAs/metabolismo
20.
Biomolecules ; 12(11)2022 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-36421712

RESUMO

Caveolin-1 is a cholesterol-binding scaffold protein, which is localized in detergent-resistant membrane (DRM) rafts and interacts with components of signal transduction systems, including visual cascade. Among these components are neuronal calcium sensors (NCSs), some of which are redox-sensitive proteins that respond to calcium signals by modulating the activity of multiple intracellular targets. Here, we report that the formation of the caveolin-1 complex with recoverin, a photoreceptor NCS serving as the membrane-binding regulator of rhodopsin kinase (GRK1), is a redox-dependent process. Biochemical and biophysical in vitro experiments revealed a two-fold decreased affinity of recoverin to caveolin-1 mutant Y14E mimicking its oxidative stress-induced phosphorylation of the scaffold protein. At the same time, wild-type caveolin-1 demonstrated a 5-10-fold increased affinity to disulfide dimer of recoverin (dRec) or its thiol oxidation mimicking the C39D mutant. The formation of dRec in vitro was not affected by caveolin-1 but was significantly potentiated by zinc, the well-known mediator of redox homeostasis. In the MDCK cell model, oxidative stress indeed triggered Y14 phosphorylation of caveolin-1 and disulfide dimerization of recoverin. Notably, oxidative conditions promoted the accumulation of phosphorylated caveolin-1 in the plasma membrane and the recruitment of recoverin to the same sites. Co-localization of these proteins was preserved upon depletion of intracellular calcium, i.e., under conditions reducing membrane affinity of recoverin but favoring its interaction with caveolin-1. Taken together, these data suggest redox regulation of the signaling complex between recoverin and caveolin-1. During oxidative stress, the high-affinity interaction of thiol-oxidized recoverin with caveolin-1/DRMs may disturb the light-induced translocation of the former within photoreceptors and affect rhodopsin desensitization.


Assuntos
Cálcio , Caveolina 1 , Recoverina/metabolismo , Cálcio/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Oxirredução , Dissulfetos/metabolismo , Visão Ocular , Compostos de Sulfidrila
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