RESUMEN
The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.
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Caveolina 1 , Citocinas , Imiquimod , Neovascularización Patológica , Psoriasis , Factor de Transcripción STAT3 , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Psoriasis/metabolismo , Caveolina 1/metabolismo , Animales , Ratones , Citocinas/metabolismo , Humanos , Factor de Transcripción STAT3/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Péptidos/farmacología , Péptidos/química , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Modelos Animales de Enfermedad , Agua/química , Solubilidad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , AngiogénesisRESUMEN
Purpose: Castration Resistant Prostate Cancer (CRPC) is characterized by poor prognosis and limited therapeutic options. AgNPs functionalized with glucose (G-AgNPs) were observed cytotoxic to CRPC cell lines (PC-3 and Du-145) and not LNCaP. This study aims to evaluate AgNPs and G-AgNPs' uptake mechanisms in these cells and understand their role in the selective effect against CRPC cells. Methods: Uptake of AgNPs and G-AgNPs was assessed through transmission electron microscopy (TEM). A microRNA (miRNAs) analysis approach was used to uncover the main molecular differences responsible for the endocytic mechanisms' regulation. Caveolin (Cav) 1 and 2 mRNA and protein levels were assessed in the three cell lines. Caveolae-dependent endocytosis was inhibited with genistein or siCav1- and siCav2- in PC-3 and Du-145 and resazurin assay was used to evaluate viability after AgNPs and G-AgNPs administration. Caveolae-dependent endocytosis was induced with Cav1+ and Cav2+ plasmids in LNCaP, resazurin assay was used to evaluate viability after AgNPs and G-AgNPs administration and TEM to assess their location. Results: AgNPs and G-AgNPs were not uptaked by LNCaP. miRNA analysis revealed 37 upregulated and 90 downregulated miRNAs. Functional enrichment analysis of miRNAs' targets resulted in enrichment of terms related to endocytosis and caveolae. We observed that Cav1 and Cav2 are not expressed in LNCaP. Inhibiting caveolae-dependent endocytosis in Du-145 and PC-3 led to a significative reduction of cytotoxic capacity of AgNPs and G-AgNPs and induction of caveolae-dependent endocytosis in LNCaP lead to a significative increase as well as their uptake by cells. Conclusion: This study shows the potential of these AgNPs as a new therapeutic approach directed to CRPC patients, uncovers caveolae-dependent endocytosis as the uptake mechanism of these AgNPs and highlights deregulation of Cav1 and Cav2 expression as a key difference in hormone sensitive and resistant PCa cells which may be responsible for drug resistance.
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Caveolas , Caveolina 1 , Endocitosis , Nanopartículas del Metal , MicroARNs , Neoplasias de la Próstata Resistentes a la Castración , Plata , Masculino , Humanos , Endocitosis/efectos de los fármacos , Endocitosis/fisiología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Caveolas/metabolismo , Caveolas/efectos de los fármacos , Plata/química , Plata/farmacología , Plata/farmacocinética , Caveolina 1/metabolismo , Caveolina 1/genética , Nanopartículas del Metal/química , Línea Celular Tumoral , MicroARNs/metabolismo , MicroARNs/genética , Supervivencia Celular/efectos de los fármacos , Caveolina 2/metabolismo , Caveolina 2/genética , Antineoplásicos/farmacología , Células PC-3RESUMEN
This study aimed to decipher the interaction between CD26 and caveolin-1, key proteins involved in cell signaling and linked to various diseases. Using computational methods, we predicted their binding conformations and assessed stability through 100 ns molecular dynamics (MD) simulations. We identified two distinct binding conformations (con1 and con4), with con1 exhibiting superior stability. In con1, specific amino acids in CD26, namely GLU237, TYR241, TYR248, and ARG147, were observed to engage in interactions with the F-J chain of Caveolin-1, establishing hydrogen bonds and cation or π-π interactions. Meanwhile, in con4, CD26 amino acids ARG253, LYS250, and TYR248 interacted with the J chain of Caveolin-1 via hydrogen bonds, cation-π interactions, and π-π interactions. Virtual screening also revealed potential small-molecule modulators, including Crocin, Poliumoside, and Canagliflozin, that could impact this interaction. Additionally, predictive analyses were conducted on the potential bioactivity, drug-likeness, and ADMET properties of these three compounds. These findings offer valuable insights into the binding mechanism, paving the way for new therapeutic strategies. However, further validation is required before clinical application. In summary, we provide a detailed understanding of the CD26 and caveolin-1 interaction, identifying key amino acids and potential modulators, essential for developing targeted therapies.
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Aminoácidos , Caveolina 1 , Dipeptidil Peptidasa 4 , Simulación de Dinámica Molecular , Humanos , Aminoácidos/metabolismo , Caveolina 1/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Enlace de Hidrógeno , Unión Proteica , Conformación ProteicaRESUMEN
Glaucoma is a degenerative disease characterized by retinal ganglion cell (RGC) death and visual impairment caused by elevated intraocular pressure (IOP). Elevated IOP can activate microglia, which participate in ganglion cell injury. Based on the study of caveolin-1 (Cav-1) in glaucoma, we aimed to explore the effect and mechanism of Cav-1 on RGC apoptosis in mice with acute ocular hypertension (AOH). AOH mice were established, and Cav-1 was intravitreally injected. Retinal microglia and RGCs were isolated from neonatal mice. TUNEL staining, hematoxylin-eosin staining, immunohistochemistry, flow cytometry, PCR and western blotting were used to observe the effect of Cav-1 on RGCs and mouse retinas. The thickness of the whole retina and the inner retinal sublayer decreased significantly, retinal cell apoptosis increased after AOH injury, and Cav-1 treatment reversed the effect of AOH injury. In addition, Cav-1 treatment promoted the conversion of proinflammatory M1 microglia to anti-inflammatory M2 microglia. Microglia and RGCs were isolated from neonatal mice. Cav-1 protects RGCs from OGD/R-induced injury by changing the polarization status of retinal microglia in vitro. Further studies revealed that Cav-1 activated the Akt/PTEN signaling pathway and inhibited TLR4. Our study provides evidence that Cav-1 may be a promising therapeutic target for glaucoma.
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Caveolina 1 , Glaucoma , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt , Células Ganglionares de la Retina , Transducción de Señal , Receptor Toll-Like 4 , Animales , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/efectos de los fármacos , Caveolina 1/metabolismo , Transducción de Señal/fisiología , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratones , Glaucoma/metabolismo , Glaucoma/patología , Receptor Toll-Like 4/metabolismo , Ratones Endogámicos C57BL , Apoptosis/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Modelos Animales de EnfermedadRESUMEN
AIM: To observe changes in the serum levels of visinin-like protein-1 (VILIP-1), caveolin-1 (Cav-1) and neuron-specific enolase (NSE) after glioma resection. MATERIAL AND METHODS: Consecutive 14 glioma patients with different histologic grade and 14 age and gender-matched healthy subjects were included in this pilot study. From the patients serum samples were taken in preoperative and on day 2 and 10 of postoperative periods. Healthy subjects provided serum sample once. The serum changes of three proteins were evaluated by ELISA. The results were compared between preoperative and postoperative periods and between patients and controls. RESULTS: Preoperative serum levels of VILIP-1 (p=0.008) and Cav-1 (p=0.012) were significantly higher in the patients. Mean serum levels of VILIP-1 (p=0.002) and Cav-1 (p=0.013) again were significantly higher than those of the controls. NSE did not show significant changes compared to controls in none of the periods. There was a steady decline regarding all three molecules from preoperative to postoperative day 10. However, statistical comparisons did not reveal any significant difference with respect the decline in any molecule. Significant positive correlation was detected between preoperative serum levels of VILIP-1 and Cav-1 (p=0.00001) in the patients and the controls (p=0.0000). CONCLUSION: This pilot study suggested that Cav-1 and particularly VILIP-1 may be used as a valuable serum biomarker for follow-up and for early detection of recurrence in high-grade gliomas. Future studies including larger cohort of patients with homogeneous group of glioma is required.
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Caveolina 1 , Glioma , Neurocalcina , Fosfopiruvato Hidratasa , Neoplasias Supratentoriales , Humanos , Caveolina 1/sangre , Fosfopiruvato Hidratasa/sangre , Proyectos Piloto , Masculino , Glioma/cirugía , Glioma/sangre , Femenino , Persona de Mediana Edad , Adulto , Neoplasias Supratentoriales/cirugía , Neoplasias Supratentoriales/sangre , Neurocalcina/sangre , Biomarcadores de Tumor/sangre , Anciano , Periodo PosoperatorioRESUMEN
Peritoneal metastasis is one of the most common risk factors contributing to the poor prognosis of gastric cancer. We previously reported that extracellular vesicles from gastric cancer cells could facilitate peritoneal metastasis. However, their impact on gastric cancer-induced peritoneal metastasis under hypoxic conditions remains unclear. This study aims to elucidate how hypoxia-resistant gastric cancer cell-derived extracellular vesicles affect the peritoneal metastasis of normoxic gastric cancer cells. Proteomic analysis revealed elevated levels of Caveolin1 and Laminin ß2 in hypoxia-resistant gastric cancer cells and their corresponding extracellular vesicles. Importantly, Caveolin1 was found to play a central role in mediating Laminin ß2 sorting into extracellular vesicles derived from hypoxia-resistant gastric cancer cells, and subsequently, extracellular vesicle-associated Laminin ß2 promoted peritoneal metastasis in normoxic gastric cancer cells by activating the AKT pathway. Further investigation confirmed that Caveolin1 activation by Rho-related Coiled-coil kinase 1-mediated phosphorylation of Y14 residue is a key factor facilitating Laminin ß2 sorting into extracellular vesicles. Moreover, Y14 phosphorylated- Caveolin1 enhanced Laminin ß2 sorting by activating Rab11. Finally, our study demonstrated that a combined assessment of plasma extracellular vesicle-associated Caveolin1 and extracellular vesicle-associated Laminin ß2 could provide an accurate predictive tool for peritoneal metastasis occurrence in gastric cancer.
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Caveolina 1 , Vesículas Extracelulares , Neoplasias Peritoneales , Neoplasias Gástricas , Proteínas de Unión al GTP rab , Quinasas Asociadas a rho , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Humanos , Caveolina 1/metabolismo , Caveolina 1/genética , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/metabolismo , Animales , Quinasas Asociadas a rho/metabolismo , Vesículas Extracelulares/metabolismo , Ratones , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab/genética , Línea Celular Tumoral , Transducción de Señal , Masculino , FemeninoRESUMEN
Jiang et al. show that zinc finger FYVE-type containing 21, a Rab5 effector in glomerular endothelial cells is involved in the maintenance of glomerular filtration barrier homeostasis through the stabilization of activated endothelial nitric oxide synthase on subcellular vesicles. The study demonstrates that zinc finger FYVE-type containing 21 could modulate the levels of caveolin-1 in glomerular endothelial cells using vesicle-based trafficking, thereby supporting endothelial nitric oxide synthase activity. The authors provide evidence that decreased zinc finger FYVE-type containing 21 expression in glomerular endothelial cells could play a role in aging-related glomerular filtration barrier dysfunction.
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Envejecimiento , Caveolina 1 , Células Endoteliales , Óxido Nítrico Sintasa de Tipo III , Envejecimiento/metabolismo , Envejecimiento/fisiología , Humanos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Caveolina 1/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Animales , Barrera de Filtración Glomerular/metabolismo , Glomérulos Renales/patología , Glomérulos Renales/fisiopatología , Glomérulos Renales/metabolismo , Riñón/fisiopatología , Riñón/metabolismo , Endotelio Vascular/fisiopatología , Endotelio Vascular/metabolismoRESUMEN
PURPOSE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored. EXPERIMENTAL DESIGN: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism. RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism. CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.
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Carcinoma Ductal Pancreático , Proliferación Celular , Colesterol , Homeostasis , Neoplasias Pancreáticas , Humanos , Colesterol/metabolismo , Colesterol/biosíntesis , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Animales , Línea Celular Tumoral , Ratones , Regulación Neoplásica de la Expresión Génica , Progresión de la Enfermedad , Pronóstico , Caveolina 1/genética , Caveolina 1/metabolismo , Ratones Desnudos , MasculinoRESUMEN
BACKGROUND: The roles of Caveolin-1 (Cav-1) and the Wnt/ß-catenin signaling pathways in cerebral ischemia-reperfusion (I/R) injury are well established. The translocation of ß-catenin into the nucleus is critical for regulating neuronal apoptosis, repair, and neurogenesis within the ischemic brain. It has been reported that the scaffold domain of Caveolin-1 (Cav-1) (residues 95-98) interacts with ß-catenin (residues 330-337). However, the specific contribution of the Cav-1/ß-catenin complex to I/R injury remains unknown. METHODS AND RESULTS: To investigate the mechanism underlying the involvement of the Cav-1/ß-catenin complex in the subcellular translocation of ß-catenin and its subsequent effects on cerebral I/R injury, we treated ischemic brains with ASON (Cav-1 antisense oligodeoxynucleotides) or FTVT (a competitive peptide antagonist of the Cav-1 and ß-catenin interaction). Our study demonstrated that the binding of Cav-1 to ß-catenin following I/R injury prevented the nuclear accumulation of ß-catenin. Treatment with ASON or FTVT after I/R injury significantly increased the levels of nuclear ß-catenin. Furthermore, ASON reduced the phosphorylation of ß-catenin at Ser33, Ser37, and Thr41, which contributes to its proteasomal degradation, while FTVT increased phosphorylation at Tyr333, which is associated with its nuclear translocation. CONCLUSIONS: The above results indicate that the formation of the Cav-1/ß-catenin complex anchors ß-catenin in the cytoplasm following I/R injury. Additionally, both ASON and FTVT treatments attenuated neuronal death in ischemic brains. Our study suggests that targeting the interaction between Cav-1 and ß-catenin serve as a novel therapeutic strategy to protect against neuronal damage during cerebral injury.
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Caveolina 1 , Núcleo Celular , Neuronas , Daño por Reperfusión , beta Catenina , beta Catenina/metabolismo , Animales , Daño por Reperfusión/metabolismo , Caveolina 1/metabolismo , Caveolina 1/genética , Neuronas/metabolismo , Neuronas/patología , Núcleo Celular/metabolismo , Masculino , Ratas , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Apoptosis , Vía de Señalización Wnt , Ratas Sprague-Dawley , Unión Proteica , Transporte de Proteínas , Muerte CelularRESUMEN
BACKGROUND: In early atherosclerosis, circulating LDLs (low-density lipoproteins) traverse individual endothelial cells by an active process termed transcytosis. The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) treated advanced atherosclerosis using a blocking antibody for IL-1ß (interleukin-1ß); this significantly reduced cardiovascular events. However, whether IL-1ß regulates early disease, particularly LDL transcytosis, remains unknown. METHODS: We used total internal reflection fluorescence microscopy to quantify transcytosis by human coronary artery endothelial cells exposed to IL-1ß. To investigate transcytosis in vivo, we injected wild-type and knockout mice with IL-1ß and LDL to visualize acute LDL deposition in the aortic arch. RESULTS: Exposure to picomolar concentrations of IL-1ß induced transcytosis of LDL but not of albumin by human coronary artery endothelial cells. Surprisingly, expression of the 2 known receptors for LDL transcytosis, ALK-1 (activin receptor-like kinase-1) and SR-BI (scavenger receptor BI), was unchanged or decreased. Instead, IL-1ß increased the expression of the LDLR (LDL receptor); this was unexpected because LDLR is not required for LDL transcytosis. Overexpression of LDLR had no effect on basal LDL transcytosis. However, knockdown of LDLR abrogated the effect of IL-1ß on transcytosis rates while the depletion of Cav-1 (caveolin-1) did not. Since LDLR was necessary but overexpression had no effect, we reasoned that another player must be involved. Using public RNA sequencing data to curate a list of Rab (Ras-associated binding) GTPases affected by IL-1ß, we identified Rab27a. Overexpression of Rab27a alone had no effect on basal transcytosis, but its knockdown prevented induction by IL-1ß. This was phenocopied by depletion of the Rab27a effector JFC1 (synaptotagmin-like protein 1). In vivo, IL-1ß increased LDL transcytosis in the aortic arch of wild-type but not Ldlr-/- or Rab27a-deficient mice. The JFC1 inhibitor nexinhib20 also blocked IL-1ß-induced LDL accumulation in the aorta. CONCLUSIONS: IL-1ß induces LDL transcytosis by a distinct pathway requiring LDLR and Rab27a; this route differs from basal transcytosis. We speculate that induction of transcytosis by IL-1ß may contribute to the acceleration of early disease.
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Vasos Coronarios , Células Endoteliales , Interleucina-1beta , Lipoproteínas LDL , Ratones Noqueados , Receptores de LDL , Transducción de Señal , Transcitosis , Proteínas de Unión al GTP rab , Interleucina-1beta/metabolismo , Animales , Humanos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab/genética , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Vasos Coronarios/metabolismo , Vasos Coronarios/efectos de los fármacos , Células Cultivadas , Ratones Endogámicos C57BL , Caveolina 1/metabolismo , Caveolina 1/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Modelos Animales de Enfermedad , Aorta Torácica/metabolismo , Aorta Torácica/efectos de los fármacos , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Masculino , RatonesRESUMEN
As the uncontrolled entry of calcium ions (Ca2+) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca2+ entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca2+ ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca2+ entry through a single channel may not be capable of preventing the Ca2+ flood of cells by the uncontrolled Ca2+ entry. Furthermore, as Ca2+ signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca2+ entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca2+ entry into microglia; (ii) to decrease the Ca2+-dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca2+ entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs.
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Proteína ORAI1 , Receptores Purinérgicos P2X7 , Humanos , Animales , Proteína ORAI1/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Calcio/metabolismo , Neuroprotección/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Caveolina 1/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/patología , Canales de Calcio/metabolismoRESUMEN
Caveolins are a family of transmembrane proteins located in caveolae, small lipid raft invaginations of the plasma membrane. The roles of caveolin-enriched lipid rafts are diverse, and include mechano-protection, lipid homeostasis, metabolism, transport, and cell signaling. Caveolin-1 (Cav-1) and other caveolins were described in endothelial cells and later in other cell types of the central nervous system (CNS), including neurons, astrocytes, oligodendrocytes, microglia, and pericytes. This pancellular presence of caveolins demands a better understanding of their functional roles in each cell type. In this review we describe the various functions of Cav-1 in the cells of normal and pathological brains. Several emerging preclinical findings suggest that Cav-1 could represent a potential therapeutic target in brain disorders.
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Caveolinas , Sistema Nervioso Central , Humanos , Animales , Caveolinas/metabolismo , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiología , Caveolina 1/metabolismo , Neuronas/metabolismo , Neuronas/fisiologíaRESUMEN
An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis in uremic patients, yet its dysfunction poses a significant clinical challenge. Venous stenosis, primarily caused by venous neointimal hyperplasia, is a key factor in the failure of vascular access. During vascular access dysfunction, endothelial cells (ECs) transform mechanical stimuli into intracellular signals and interact with vascular smooth muscle cells. Tanshinone IIA, an important compound derived from Salvia miltiorrhiza, has been widely used to treat cardiovascular diseases. However, its role in modulating ECs under uremic conditions remains incompletely understood. In this research, ECs were exposed to sodium tanshinone IIA sulfonate (STS) and subjected to shear stress and uremic conditions. The results indicate that STS can reduce the suppressive effects on the expression of NF-κB p65, JNK and Collagen I in uremia-induced ECs. Moreover, the downregulation of NF-κB p65, JNK and Collagen I can be enhanced through the inhibition of ERK1/2 and the upregulation of Caveolin-1. These findings suggest that tanshinone IIA may improve EC function under uremic conditions by targeting the Caveolin-1/ERK1/2 pathway, presenting tanshinone IIA as a potential therapeutic agent against AVF immaturity caused by EC dysfunction.
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Abietanos , Caveolina 1 , Uremia , Uremia/metabolismo , Uremia/tratamiento farmacológico , Uremia/patología , Humanos , Abietanos/farmacología , Abietanos/uso terapéutico , Caveolina 1/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Colágeno Tipo I/metabolismo , Factor de Transcripción ReIA/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , FenantrenosRESUMEN
BACKGROUND: Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC. METHODS: CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells. RESULTS: In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12-2.81) and 2.20 (95% CI 1.39-3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression. CONCLUSION: CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target.
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Caveolina 1 , Resistencia a Antineoplásicos , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Humanos , Caveolina 1/genética , Caveolina 1/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral/genética , Femenino , Resistencia a Antineoplásicos/genética , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Transición Epitelial-Mesenquimal/genética , AncianoRESUMEN
Migrasomes, vesicular organelles generated on the retraction fibers of migrating cells, play a crucial role in migracytosis, mediating intercellular communication. The cargoes determine the functional specificity of migrasomes. Migrasomes harbor numerous intraluminal vesicles, a pivotal component of their cargoes. The mechanism underlying the transportation of these intraluminal vesicles to the migrasomes remains enigmatic. In this study, we identified that Rab10 and Caveolin-1 (CAV1) mark the intraluminal vesicles in migrasomes. Transport of Rab10-CAV1 vesicles to migrasomes required the motor protein Myosin Va and adaptor proteins RILPL2. Notably, the phosphorylation of Rab10 by the kinase LRRK2 regulated this process. Moreover, CSF-1 can be transported to migrasomes through this mechanism, subsequently fostering monocyte-macrophage differentiation in skin wound healing, which served as a proof of the physiological importance of this transporting mechanism.
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Caveolina 1 , Movimiento Celular , Proteínas de Unión al GTP rab , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión al GTP rab/genética , Humanos , Caveolina 1/metabolismo , Caveolina 1/genética , Macrófagos/metabolismo , Fosforilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Miosina Tipo V/metabolismo , Miosina Tipo V/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Ratones , Cadenas Pesadas de Miosina/metabolismo , Cadenas Pesadas de Miosina/genética , Transporte Biológico , Cicatrización de Heridas/fisiología , Orgánulos/metabolismoRESUMEN
The rise of gene therapy has solved many diseases that cannot be effectively treated by conventional methods. Gene vectors is very important to protect and deliver the therapeutic genes to the target site. Polyethyleneimine (PEI) modified with mannitol could enhance the gene transfection efficiency reported by our group previously. In order to further control and improve the effective gene release to action site, disulfide bonds were introduced into mannitol-modified PEI to construct new non-viral gene vectors PeiSM. The degrees of mannitol linking with disulfide bonds were screened. Among them, moderate mannitol-modified PEI with disulfide bonds showed the best transfection efficiency, and significantly enhanced long-term systemic transgene expression for 72 hin vivoeven at a single dose administration, and could promote caveolae-mediated uptake through up-regulating the phosphorylation of caveolin-1 and increase the loaded gene release from the nanocomplexes in high glutathione intracellular environment. This functionalized gene delivery system can be used as an potential and safe non-viral nanovector for further gene therapy.
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Vectores Genéticos , Glutatión , Polietileneimina , Transfección , Polietileneimina/química , Transfección/métodos , Glutatión/metabolismo , Glutatión/química , Animales , Humanos , Vectores Genéticos/química , Vectores Genéticos/genética , Manitol/química , Ratones , Caveolina 1/metabolismo , Caveolina 1/genética , Terapia Genética/métodos , Técnicas de Transferencia de Gen , Disulfuros/químicaRESUMEN
Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary cicatricial alopecia that cause a major impact on quality of life due to irreversible hair loss and symptoms as itching, burning and pain. They are characterized by permanent loss of hair follicle stem cells (HFSCs) by pathomechanisms still poorly understood, resulting in poor efficacy of currently available treatments. Caveolae are flask-shaped lipid rafts invaginated within the plasma membrane of multiple cell types. Although their role in the HF physiology and pathophysiology is relatively unknown, we have previously demonstrated that the primary structural component of caveolae (caveolin-1 or Cav1) is upregulated in FFA. Thus, we propose to investigate the expression and localization of caveolae-associated structural proteins (Cav1, Cav2, and Cavin-1) and HFSCs (identified by K15) in both LPP and FFA. We analyzed 4 patients with LPP biopsied in affected and non-affected (NA) scalp, 4 patients with FFA biopsied in affected scalp and 4 healthy controls. Affected scalp of LPP and FFA demonstrated increased levels of Cav1 and Cavin-1 compared with HC and LPP-NA. Moreover, Cav1, Cav2 and Cavin1 all exhibit high colocalization with K15 and their expression appears to be negatively correlated, supporting the hypothesis that these proteins are important players in LPP/FFA and may serve as therapeutic targets in future treatments.
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Alopecia , Caveolas , Caveolina 1 , Folículo Piloso , Liquen Plano , Regulación hacia Arriba , Humanos , Alopecia/patología , Alopecia/metabolismo , Folículo Piloso/patología , Folículo Piloso/metabolismo , Liquen Plano/metabolismo , Liquen Plano/patología , Persona de Mediana Edad , Femenino , Caveolina 1/metabolismo , Masculino , Caveolas/metabolismo , Cuero Cabelludo/patología , Adulto , Queratina-15/metabolismo , Anciano , Biopsia , Fibrosis , Células Madre/metabolismo , Células Madre/patología , Proteínas de Unión al ARN/metabolismoRESUMEN
Caveolin-1 is critical for interacting with the TGF-ß receptor (TGFßR) and EGF receptor (EGFR) signaling, often observed in advanced cancers and tissue fibrosis. However, the mechanism underlying caveolin-1-mediated transactivation of TGFßR and EGFR signaling remains unclear. Therefore, we sought to determine whether caveolin-1 is involved in canonical and non-canonical TGFßR and EGFR signaling transactivation in this study. Methyl-ß-cyclodextrin (MßCD) was used to disrupt the cholesterol-containing membranes domains, and the caveolin-1 scaffolding domain (CSD) peptide was used to mimic the CSD of caveolin-1. Additionally, we transfected the Madin-Darby canine kidney cells with wild-type or phosphorylation-defective caveolin-1. We discovered that tyrosine 14 of caveolin-1 was critical for the negative regulation of TGFßR and EGFR canonical signaling. On the contrary, caveolin-1 inhibited TGF-ß1-induced ERK2 activation independent of tyrosine 14 phosphorylation. Although EGF failed to induce Smad3 phosphorylation in caveolin-1 knockdown cells, it activated Smad3 upon MßCD co-treatment, indicating that caveolin-1 indirectly regulated the non-canonical pathway of EGF. In conclusion, caveolin-1 differentially modulates TGFßR and EGFR signaling. Thus, targeting caveolin-1 is a potential strategy for treating diseases involving TGF-ß1 and EGF signaling.
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Caveolina 1 , Receptores ErbB , Transducción de Señal , Animales , Perros , Caveolina 1/metabolismo , Caveolina 1/genética , Células de Riñón Canino Madin Darby , Receptores ErbB/metabolismo , Fosforilación , Factor de Crecimiento Epidérmico/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Humanos , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Obesity has become a major global health problem and the effect on bone formation has received increasing attention. However, the interaction between obesity and bone metabolism is complex and still not fully understood. Here, we show that caveolin-1 (Cav1), a membrane scaffold protein involved in regulating a variety of cellular processes, plays a key regulatory role as a bridge connecting obesity and bone metabolism. High-fat diet (HFD)-induced obese C57BL/6J mouse displayed a significant increase in Cav1 expression and lower osteogenic activity; In vitro treatment of osteoblastic MC3T3-E1 cells with 1 mM free fatty acids (FFA) significantly promoted Cav1 expression and PINK1/Parkin regulated mitophagy, but inhibited the expression of osteogenic marker genes. Conversely, reduced expression of the Cav1 gene prevented these effects. Both endogenous oxidative stress and Sirt1 pathway were also significantly reduced after Cav1 knockdown in FFA-treated cells. Finally, Cav1-Sirt1 docking and co-immunoprecipitation results showed that Cav1 interacted with Sirt1 and FFA enhanced the interaction. Taken together, these results suggest that obesity impairs bone development and formation through up-regulation of the Cav1 gene, which lead to inhibition of Sirt1/FOXO1 and Sirt1/PGC-1α signaling pathways through interacting with Sirt1 molecule, and an increase of mitophagy level.
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Caveolina 1 , Ratones Endogámicos C57BL , Mitofagia , Obesidad , Osteogénesis , Transducción de Señal , Sirtuina 1 , Animales , Masculino , Ratones , Caveolina 1/metabolismo , Línea Celular , Dieta Alta en Grasa , Obesidad/metabolismo , Obesidad/patología , Osteogénesis/efectos de los fármacos , Sirtuina 1/metabolismoRESUMEN
BACKGROUND: Radiation-induced fibrosis (RIF) is an important late complication of radiation therapy, and the resulting damaging effects of RIF can significantly impact reconstructive outcomes. There is currently a paucity of effective treatment options available, likely due to the continuing knowledge gap surrounding the cellular mechanisms involved. In this study, detailed analyses of irradiated and non-irradiated human skin samples were performed incorporating histological and single-cell transcriptional analysis to identify novel features guiding development of skin fibrosis following radiation injury. METHODS: Paired irradiated and contralateral non-irradiated skin samples were obtained from six female patients undergoing post-oncologic breast reconstruction. Skin samples underwent histological evaluation, immunohistochemistry, and biomechanical testing. Single-cell RNA sequencing was performed using the 10X single cell platform. Cells were separated into clusters using Seurat in R. The SingleR classifier was applied to ascribe cell type identities to each cluster. Differentially expressed genes characteristic to each cluster were then determined using non-parametric testing. RESULTS: Comparing irradiated and non-irradiated skin, epidermal atrophy, dermal thickening, and evidence of thick, disorganized collagen deposition within the extracellular matrix of irradiated skin were readily appreciated on histology. These histologic features were associated with stiffness that was higher in irradiated skin. Single-cell RNA sequencing revealed six predominant cell types. Focusing on fibroblasts/stromal lineage cells, five distinct transcriptional clusters (Clusters 0-4) were identified. Interestingly, while all clusters were noted to express Cav1, Cluster 2 was the only one to also express Cav2. Immunohistochemistry demonstrated increased expression of Cav2 in irradiated skin, whereas Cav1 was more readily identified in non-irradiated skin, suggesting Cav1 and Cav2 may act antagonistically to modulate fibrotic cellular responses. CONCLUSION: In response to radiation therapy, specific changes to fibroblast subpopulations and enhanced Cav2 expression may contribute to fibrosis. Altogether, this study introduces a novel pathway of caveolin involvement which may contribute to fibrotic development following radiation injury.