Caveolin-1 Levels Research Articles

The Biomarker Potential of Caveolin-1 in Penile Cancer.

Various types of human cancers were characterized by an altered expression of epithelial or stromal caveolin-1 (CAV1). However, the clinical significance of CAV1 expression in penile cancer remains largely unknown. Here the expression patterns of CAV1 were analyzed in a retrospective cohort (n=43) of penile squamous cell carcinomas (SCC). Upon penile cancer progression, significantly increased CAV1-levels were determined within the malignant epithelium, whereas within the tumor stroma, namely the fibroblastic tumor compartment harboring activated and/or cancer associated fibroblasts, CAV1 levels significantly decline. Concerning the clinicopathological significance of CAV1 expression in penile cancer as well as respective epithelial-stromal CAV1 distributions, high expression within the tumor cells as well as low expression of CAV1 within the stromal compartment were correlated with decreased overall survival of penile cancer patients. Herein, CAV1 expressions and distributions at advanced penile cancer stages were independent of the immunohistochemically proven tumor protein p53 status. In contrast, less differentiated p16-positive tumor epithelia (indicative for human papilloma virus infection) were characterized by significantly decreased CAV1 levels. Conclusively, we provide further and new evidence that the characteristic shift in stromal‐epithelial CAV1 being functionally relevant to tumor progression even occurs in penile SCC.

DHCR24 Knockdown Lead to Hyperphosphorylation of Tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites by Membrane Lipid-Raft Dependent PP2A Signaling in SH-SY5Y Cells.

Accumulating data suggest that the downregulation of DHCR24 is linked to the pathological risk factors of AD, denoting a potential role of DHCR24 in AD pathogenesis. However, it remains unclear whether the downregulation of DHCR24 affects the abnormal heper-phosphorylation of tau protein, which is involved in tauopathy. In present papers, immunofluorescence and Filipin III fluorescence results showed that DHCR24 knockdown significantly lowered the level of plasma membrane cholesterol and expression level of membrane lipid-raft structural protein caveolin-1; and overexpression of DHCR24 could increase the plasma membrane cholesterol levels and facilitating caveolae structure through increase the expression of caveolin-1. PP2A is the key phosphatase involving in tau phosphorylation, which is localized in cholesterol-dependent caveola/raft lipid domains. Here, the PP2A activity was detected by western blot assay. Interestingly, the level of p-PP2Ac at Y307 (inactive) and p-GSK3β at Y216 (active) in the downstream of the PP2A signal pathway were both significantly increased in silencing DHCR24 SH-SY5Y cells, which denoted an inhibition of the PP2A and activation of GSK3β signaling. Conversely, overexpression of DHCR24 blunted the inhibition effect of PP2A and activation of GSK3β. Besides, in the SH-SY5Y cell lines we demonstrated that DHCR24 knockdown obviously induced hyperphosphorylation of tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites. In contrast, DHCR24 overexpression protects neuronal SH-SY5Y cells against the hyperphosphorylation of tau at Thr181, Thr231, Ser262, Ser396, and Ser422 Sites. Furthermore, PP2A activator D-erythro-Sphingosine (DES) also obviously inhibited the hyperphosphorylation of tau induced by DHCR24 knockdown. Collectively, our findings firstly confirmed that DHCR24 knockdown obviously induced abnormal hyperphosphorylation of tau by a novel lipid raft-dependent PP2A signaling. We propose that DHCR24 downregulation led to altered cholesterol synthesis as a potential mechanism in the progression of tau hyperphosphorylation involving in AD and other tauopathies.

Dexmedetomidine attenuates lipopolysaccharide-induced acute liver injury in rats by inhibiting caveolin-1 downstream signaling pathway

Objective: The aim of the present study is to investigate the anti-injury and anti-inflammatory effects of dexmedetomidine (Dex) in acute liver injury induced by lipopolysaccharide (LPS) in Sprague–Dawley rats and its possible mechanism.Methods: The acute liver injury model of male rats was established by injecting LPS into tail vein. The mean arterial pressure (MAP) of rats was recorded at 0–7 h, and lactic acid was detected at different time points. Wet/dry weight ratio (W/D) was calculated. Pathological changes of rat liver were observed by HE staining. ALT and AST levels in serum were detected. The activities of myeloperoxidase (MPO) and superoxide dismutase (SOD) in liver tissue homogenate and the levels of IL-1β and IL-18 in serum were detected by ELISA. Protein levels of Caveolin-1 (Cav-1), TLR-4 and NLRP3 in liver tissue were tested by immunohistochemistry method. The expression of Cav-1, TLR-4 and NLRP3 mRNA in liver tissue was detected by quantitative polymerase chain reaction (qPCR) to explore its related mechanism.Results: Compared with NS group, serum lactic acid, W/D of liver tissue, MPO, SOD, IL-1β and IL-18 were significantly increased and MAP decreased significantly in LPS group and D+L group. However, compared with NS group, D group showed no significant difference in various indicators. Compared with LPS group, MPO, SOD, IL-1β and IL-18 were significantly decreased and MAP was significantly increased in D+L group. D+L group could significantly increase the level of Cav-1 protein and decrease the level of TLR-4 and NLRP3 protein in liver tissue caused by sepsis. The expression of Cav-1 mRNA was significantly up-regulated and the expression of TLR-4 and NLRP3 mRNA was inhibited in D+L group.Conclusion: Dex pretreatment protects against LPS-induced actue liver injury via inhibiting the activation of the NLRP3 signaling pathway by up-regulating the expression of Cav-1 by sepsis.

Small extracellular vesicles containing miR-192/215 mediate hypoxia-induced cancer-associated fibroblast development in head and neck squamous cell carcinoma.

The mechanisms underlying the hypoxic cancer cell-mediated differentiation of cancer-associated fibroblasts (CAFs) have not been elucidated yet. The present study showed that the hypoxic head and neck squamous cell carcinoma (HNSCC) cells promoted CAF-like differentiation through secreting TGF-β and small extracellular vesicles (sEVs) that contain enhanced levels of miR-192/215 family miRNAs. Caveolin-1 (CAV1), which is a target gene of miR-192/215, inhibited the TGF-β/SMAD signaling and promoted CAF-like differentiation of the fibroblasts. Restoring the levels of CAV1 inhibited the hypoxic sEV- and TGF-β-induced CAF-like differentiation. The enhanced levels of miR-192/215 encapsulated in the HNSCC tissue-derived sEVs (but not serum-derived sEVs) indicated hypoxic and aggressive cancer stroma. miR-215 in the tumor tissue-derived sEVs (but not circulating sEVs) was correlated with poor overall survival of patients with HNSCC. This study demonstrated that sEVs function as a "courier" to deliver miRNAs from the cancer cells to the fibroblasts, which promotes the remodeling of the hypoxic tumor microenvironment, and that cancer tissue-derived sEV could potentially serve as a source of biomarker.

Dasatinib, paclitaxel, and carboplatin in women with advanced-stage or recurrent endometrial cancer: A pilot clinical and translational study

PurposeTo evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. Patients and methodsWe performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. ResultsEighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%–77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). ConclusionsCaveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.

Plasma exosomal caveolin-1 predicts Poor Prognosis in Ovarian Cancer

Objective: In this study, we aimed to evaluate the levels of plasma exosomal caveolin-1(CAV1) and determine its prognostic value in ovarian cancer patients.Patients and Methods: Exosome-rich fractions were isolated from the plasma of 155 patients with ovarian cancer. TEM, NTA and western blot analysis were used to confirm the exosome integrity and purification.Results: Compared with healthy controls, plasma exosomal CAV1 levels in ovarian cancer patient were significantly down-regulated (P < 0.001). The low plasma levels of exosomal CAV1 in ovarian cancer patient plasma were related to FIGO stages, grades and lymph node metastasis (all P < 0.01). Among all ovarian cancer patients, DFS was worse in patients who had low plasma exosomal CAV1 levels compared with that in patients with high plasma exosomal CAV1 levels (P < 0.001). The OS of patients with low plasma exosomal CAV1 levels was shorter than that in patients with high plasma exosomal CAV1 levels (P < 0.001). The AUROC of plasma exosomal CAV1 was 0.76 (95% CI: 0.68-0.82) for DFS prediction in ovarian cancer patients, with a sensitivity 52.9 (95% CI: 42.8-62.9) and a specificity 88.7 (95% CI: 77.0-95.7). For OS prediction in ovarian cancer patients, the AUROC of plasma exosomal CAV1 was 0.78 (95% CI: 0.70-0.84), with a sensitivity 65.1 (95% CI: 49.1-79.0) and a specificity 81.2 (95% CI: 72.8-88.0).Conclusions: Low exosomal CAV1 levels were closely related to the FIGO stages I/II, low grade, lymph node metastasis and prognosis of ovarian cancer patients. Plasma exosomal CAV1 may be a potential biomarker for the prognosis in ovarian cancer patients.

MicroRNA-629-5p promotes osteosarcoma proliferation and migration by targeting caveolin 1

Osteosarcoma is a highly malignant tumor that occurs in the bone. Previous studies have shown that multiple microRNAs (miRNAs) regulate the development of osteosarcoma. This study aimed to explore the role of miR-629-5p and its target gene, caveolin 1 (CAV1), in osteosarcoma development. To analyze the expression of miR-629-5p and CAV1 mRNA in osteosarcoma tissues and cell lines, qRT-PCR analysis was performed. Dual-luciferase reporter experiments were subsequently performed to validate the relationship between CAV1 and miR-629-5p. CCK8 assay was used to measure osteosarcoma cell proliferation, and wound-healing assay was performed to study their migratory phenotype. Our findings revealed that miR-629-5p was overexpressed in osteosarcoma tissues and cells, and thereby enhanced cell proliferation and migration. Further, we validated that miR-629-5p targets CAV1 mRNA directly. CAV1 expression, which was negatively correlated with miR-629-5p expression, was found to be downregulated in osteosarcoma tissue samples. Moreover, our data showed that an increase in CAV1 level led to a decline in osteosarcoma cell proliferation and migration, which could be rescued by miR-629-5p upregulation. Overall, our study confirmed that miR-629-5p promoted osteosarcoma proliferation and migration by directly inhibiting CAV1.

Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma

A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders.

Caveolin-1 regulates the expression of miR-183 and inhibits the invasion and migration of invasive pituitary adenomas by affecting early growth response 1 (EGR1)/Krueppel-like factor 5 (KLF5) interaction

This study aims to investigate the mechanism through which Caveolin-1 (CAV-1) regulates the expression of micro ribonucleic acid (miR)-183 in invasive pituitary adenoma (IPA) tissues and GH3 cells, and explore the effects of CAV-1 and miR-183 on the invasion and migration ability of GH3 cells. Western blotting was used to detect the expression level of CAV-1, early growth response 1 (EGR1) and Krueppel-like factor 5 (KLF5). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-183. The mechanisms of interaction between CAV-1, EGR1, and KLF5 were studied by immunoprecipitation experiments. Transwell and cell scratch tests were used to determine the invasion and migration ability of GH3 cells. The dual-luciferase reporter gene experiment was used to detect the effects of EGR1 and KLF5 on miR-183 luciferase activity and verify the targeting relationship between miR-183 and ezrin. The expression of CAV-1 was up-regulated. However, following the knockdown of CAV-1, the invasion and migration ability of GH3 cells was significantly inhibited (P<0.05). The expression of miR-183 was down-regulated, but the expression level of miR-183 was markedly increased following the knockdown of CAV-1 (P<0.05). The knockdown of CAV-1 inhibited the nuclear ectopic of the EGR1 protein in GH3 cells. At the same time, the interaction between EGR1 and KLF5 in GH3 cells was significantly inhibited (P<0.05). The luciferase activity of miR-183 increased significantly after overexpression of KLF5 while overexpression of EGR1 and KLF5 had no significant effect on intracellular luciferase activity. Overexpression of miR-183 markedly inhibited the luciferase activity of wild-type EZR and the expression of the EZR protein in GH3 cells. Furthermore, the overexpression of miR-183 or the inhibition of EZR can reduce the invasion and migration ability of GH3 cells. The simultaneous overexpression or inhibition of miR-183 and EZR expression has no obvious effect on the invasion and migration ability of GH3 cells. CAV-1 up-regulates the expression of miR-183 by inhibiting the nuclear ectopic of EGR1 and the interaction between EGR1 and KLF5 in GH3 cells. Also, miR-183 negatively regulates the expression of EZR and inhibits the invasion and migration of GH3 cells.

Environmentally relevant concentrations of carbamazepine induced lipid metabolism disorder of Chinese rare minnow (Gobiocypris rarus) in a gender-specific pattern

Carbamazepine (CBZ), an anticonvulsant and mood stabilizer, is ubiquitous distributed in aquatic environment. Though the toxicity and endocrine disrupting effect of CBZ on non-target organisms have been studied, its lipotoxity are scarcely known. To assess the lipotoxicity of CBZ, 2-month-old Chinese rare minnow were exposed to 0, 1, 10, and 100 μg/L CBZ for 90 d. Obvious dyslipidemia was observed after 30 d and 90 d exposure, whereas overt hyperlipidemia was observed in males at 100 μg/L treatments. Severe lipid droplet accumulation in livers was observed at 10 and 100 μg/L treatments for 30 d and in females, whereas those was observed at all treatments in males. In addition, serious mitochondria damage was observed in males at 100 μg/L treatments. After 90 d exposure, the enzyme activities of FAS and ACCα were significantly increased at 10 and 100 μg/L treatments, whereas HMGCR were markedly increased at 100 μg/L treatments (p < 0.05). However, ACCβ were markedly decreased in females at 10 and 100 μg/L treatments and in males at all treatments (p < 0.05). The transcription levels of fasn, accα, hmgcrα, fdft1, idi1, plin1, plin2, caveolin1, and caveolin2 were significantly increased at 100 μg/L treatments (p < 0.05). Moreover, the body weight was obviously increased at 10 and 100 μg/L treatments in males (p < 0.05). Our results confirmed that environmental relevant concentrations CBZ induced lipid metabolism disorder and mitochondria damage of Chinese rare minnow in a gender-specific pattern, which provided a new insight into the lipotoxicity mechanism of CBZ.

Targeting Caveolin-1 and Claudin-5 with AY9944, Improve Blood-Brain Barrier Permeability; Computational Simulation and Experimental Study.

The current study aimed to determine the protective effect of AY9944 related to Caveolin-1 and Claudin-5 role in lipid raft, which can rescue the blood-brain barrier from enhanced permeability. Therefore, in vivo analyses were performed following ischemia in normal, ischemic, and AY9944-treated animal groups. The results revealed that AY9944 reduced the infarct size, edema, and brain water content. The extravasation of Alb-Alexa 594 and biocytin-TMR was minimum in the AY9944-treated animals. The results showed a significant decrease in the expression level of Caveolin-1 over 8h and 48h and a remarkable increase in the level of Claudin-5 over 48h following ischemia in AY9944-treated animals. Molecular docking simulation demonstrated that AY9944 exerts a possible protective role via attenuating the interaction of the Caveolin-1 and cholesterol in lipid raft. These findings point out that AY9944 plays a protective role in stroke by means of blood-brain barrier preservation. Proper neural function essentially needs a constant homeostatic brain environment which is provided by the blood-brain barrier. Rescuing blood-brain barrier from enhanced permeability via inducing the protective effect of AY9944 related to caveolin-1 and claudin-5 role in lipid raft was the aim of the current study.

Redistribution of Membrane Raft Microdomains by Apolipoprotein A-I In Mouse Aortic Endothelial Cells.

Apolipoprotein A-I (apoAI) upregulates ATP-binding cassette transport A1 (ABCA1) in various cell types. ABCA1 has been shown to induce the redistribution of raft-associated proteins and lipids to the non-raft membrane. This report investigated the effect of apoAI on ABCA1 expression and raft cholesterol and protein distribution, as well as the effect of ABCA1 knockdown on apoAI-induced changes in mouse aortic endothelial cells (MAECs). Our data demonstrated that ABCA1 was distributed in both the lipid raft and non-raft membranes and was coimmunoprecipitated with caveolin-1 (CAV1). ApoAI treatment significantly increased the mRNA and protein levels of ABCA1 and reduced the percentage of ABCA1 in the raft membrane. Our data also showed that free cholesterol (FC) and CAV1 were concentrated in the raft-like detergent-resistant membranes (DRMs) under the control conditions. ApoAI treatment did not alter the cellular level of FC and CAV1 significantly but reduced the percentage of FC and CAV1 in the DRMs. Knockdown of ABCA1 attenuated apoAI-induced redistribution of FC and CAV1. The percentage of FC and CAV1 in the DRMs was correlated inversely with the cellular level of ABCA1, suggesting that apoAI induces relocation of CAV1 and FC from the raft to the non-rail membrane via a mechanism involving upregulation of ABCA1.

LncRNA IMFlnc1 promotes porcine intramuscular adipocyte adipogenesis by sponging miR-199a-5p to up-regulate CAV-1

BackgroundLocal Chinese local pig breeds have thinner muscle fiber and higher intramuscular-fat (IMF) content. But its regulation mechanism has not been discussed in-depth. Studies indicated that long non coding RNAs (lncRNAs) play important role in muscle and fat development.ResultsThe lncRNAs expressional differences in the longissimus dorsi (LD) muscle were identified between Huainan pigs (local Chinese pigs, fat-type, HN) and Large White pigs (lean-type, LW) at 38, 58, and 78 days post conception (dpc). In total, 2131 novel lncRNAs were identified in 18 samples, and 291, 305, and 683 differentially expressed lncRNAs (DELs) were found between these two breeds at three stages, respectively. The mRNAs that co-expressed with these DELs were used for GO and KEGG analysis, and the results showed that muscle development and energy metabolism were more active at 58 dpc in HN, but at 78 dpc in LW pigs. Muscle cell differentiation and myofibril assembly might associated with earlier myogenesis and primary-muscle-fiber assembly in HN, and cell proliferation, insulin, and the MAPK pathway might be contribute to longer proliferation and elevated energy metabolism in LW pigs at 78 dpc. The PI3K/Akt and cAMP pathways were associated with higher IMF deposition in HN. Intramuscular fat deposition-associated long noncoding RNA 1 (IMFlnc1) was selected for functional verification, and results indicated that it regulated the expressional level of caveolin-1 (CAV-1) by acting as competing endogenous RNA (ceRNA) to sponge miR-199a-5p.ConclusionsOur data contributed to understanding the role of lncRNAs in porcine-muscle development and IMF deposition, and provided valuable information for improving pig-meat quality.

Predictive Factors of Hemorrhage After Thrombolysis in Patients With Acute Ischemic Stroke.

Background: Ischemic stroke has a poor prognosis and brings a ponderous burden on families and society. Hemorrhagic transformation (HT) after intravenous thrombolysis can increase the mortality of patients with ischemic stroke. Thus, finding new HT biomarkers to be applicable in clinical practice is of great importance.Methods: The related risk factors were recruited for analysis, including smoking, drinking, hyperlipidemia, diabetes, anamnesis, and pathological indicators. Moreover, the relationship between serum levels of caveolin-1, caveolin-2, and HT after rt-PA treatment were also studied.Results: We studied 306 patients with acute ischemic stroke treated with recombinant tissue type plasminogen activator (rt-PA) within 4.5 h of symptom onset. The results showed that Age ≥68 years, smoking, Atrial fibrillation, NIHSS score before thrombolysis ≥17, and systolic pressure 2 h after thrombolysis (mmHg) ≥149 increased the risks of HT after rt-PA administration. Remarkably, the concentration of caveolin-1 (ng/mL) ≤ 0.12 and caveolin-2 (ng/mL) ≤ 0.43 in serum increased the risks of HT after rt-PA administration.Conclusion: Knowledge on the risk factors associated with HT after rt-PA treatment may help develop treatment strategies and reduce the risk of HT. Caveolin-1 and caveolin-2 can be predictors of HT after rt-PA administration. These findings provide evidence for future further investigations aimed to validate these biomarkers.

Association between caveolin-1 and stroke: a systematic review and meta-analysis.

Caveolin-1 plays critical roles in regulating signal transduction and cholesterol trafficking in cells. However, the relationship between caveolin-1 and stroke remains less reported. In this study, we reviewed information from seventeen studies to get the qualitative evidence of the influence of the caveolin-1 on stroke and collected data from three of the seventeen studies to conduct meta-analysis. The original studies classified participants into two groups with stroke group and control group, respectively. The random-effect model was used in the meta-analysis with the standardized mean difference (SMD) as the measure indicator. Our data showed that the SMD (95% confidence intervals, CIs) between the control group and the stroke group was -0.5449 [-2.3344, 1.0000]. For the subgroup analysis, The SMD (95% confidence intervals, CIs) between the control group and the ischemic stroke group was -1.4589 [-5.0129, 2.0951], and between the control group and the hemorrhagic stroke group was 0.3438 [-0.4140, 1.1017]. Although the differences are not statistically significant between the two groups, the high level of caveolin-1 are associated with the stroke, which may remedy the stroke. Besides, an opposite result was observed for the association of the caveolin-1 on the ischemic stroke and hemorrhagic stroke. To confirm this association, further studies are necessary.

Serum Visinin-Like Protein 1 Is a Better Biomarker Than Neuron-Specific Enolase for Seizure-Induced Neuronal Injury: A Prospective and Observational Study.

Introduction: Visinin-like protein 1 (VILIP-1) is an established biomarker of neuronal injury. The levels of serum VILIP-1, neuron-specific enolase (NSE) and caveolin-1 (CAV-1) were measured to investigate potential of VILIP-1 as a biomarker for seizure-induced neuronal injury, and the correlation of VILIP-1 with severity of epilepsy and blood-brain barrier dysfunction were investigated.Materials and Methods: Patient with epilepsy from 14 to 70 years of age and age-, sex-matched healthy subjects were involved in this study. All blood sample of patients were collected within 3–72 h after the seizure. The severity of epilepsy and levels of serum VILIP-1, NSE and CAV-1 were measured. Accuracy of VILIP-1 and NSE was obtained from receiver operating curve analyses. Associations between VILIP-1 and severity of epilepsy, VILIP-1 and CAV-1 were investigated.Results: A total of 58 patients and 29 healthy control subjects were included in our study. The levels of serum VILIP-1, NSE, and CAV-1 in the patient group were significantly higher than those in the control group. VILIP-1 has higher and significant accuracy for assessing seizure-induced neuronal injury compared with NSE. VILIP-1 levels were positively associated with severity of epilepsy and CAV-1 in patients with epilepsy.Conclusions: VILIP-1 may be a better serum biomarker than NSE for assessing seizure-induced neuronal injury and even brain injury caused by various pathological condition. Further studies are required to explore the clinical contribution of VILIP-1 in diagnosis, treatment strategies and outcome assessments of epilepsy.

Stomatin is highly expressed in exosomes of different origin and is a promising candidate as an exosomal marker.

Proteins involved in the organizing of lipid rafts can be found in exosomes, as shown for caveolin-1, and they could contribute to exosomal cargo sorting, as shown for flotillins. Stomatin belongs to the same stomatin/prohibitin/flotillin/HflK/C family of lipid rafts proteins, but it has never been studied in exosomes except for extracellular vesicles (EVs) originating from blood cells. Here we first show the presence of stomatin in exosomes produced by epithelial cancer cells (non-small cell lung cancer, breast, and ovarian cancer cells) as well as in EVs from biological fluids, including blood plasma, ascitic fluids, and uterine flushings. A high abundance of stomatin in EVs of various origins and its enrichment in exosomes make stomatin a promising exosomal marker. Comparison with other lipid raft proteins and exosomal markers showed that the level of stomatin protein in exosomes from different sources corresponds well to that of CD9, while it differs essentially from flotillin-1 and flotillin-2 homologs, which in turn are present in exosomes in nearly equal proportions. In contrast, the level of vesicular caveolin-1 as well as its EV-to-cellular ratio vary drastically depending on cell type.

Role for caveolin-mediated transcytosis in facilitating transport of large cargoes into the brain via ultrasound

The blood-brain barrier (BBB) is a dynamic diffusional barrier regulating the molecular and chemical flux between the blood and brain, thereby preserving cerebral homeostasis. Endothelial cells form the core anatomical component of the BBB based on properties such as specialized junctional complexes between cells, which restricts paracellular transport, and extremely low levels of vesicular transport, restricting transcytosis. In performing its protective function, the BBB also constrains the entry of therapeutics into the brain, hampering the treatment of various neurological disorders. Focused ultrasound is a novel therapeutic modality that has shown efficacy in transiently and non-invasively opening the BBB for the targeted delivery of therapeutics to the brain. Although the ability of ultrasound to disrupt the junctional assembly of endothelial cells has been partially investigated, its effect on the transcellular mode of transport has been largely neglected. In this study, we found that ultrasound induces a pronounced increase in the levels of the vesicle-forming protein caveolin-1. In order to investigate the role of vesicle-mediated transcytoplasmic transport, we compared the leakage of various cargo sizes between a mouse model that lacks caveolin-1 and wild-type mice following sonication of the hippocampus. The absence of caveolin-1 did not lead to overt abnormalities in the cerebral vasculature in the mice. We found that caveolin-1 has a critical role specifically in the transport of large (500 kDa), but not smaller (3 and 70 kDa) cargoes. Our findings indicate differential effects of therapeutic ultrasound on cellular transport mechanisms, with implications for therapeutic interventions.

Elevated Expression of CAV1 is Associated with Unfavorable Prognosis of Patients with Breast Cancer Who Undergo Surgery and Neoadjuvant Chemotherapy.

IntroductionNeoadjuvant chemotherapy (NACT), which is standard treatment for locally advanced breast cancer, improves the resectability of patients with early breast cancer and reduces the extent of breast and axillary surgery. Caveolin-1 (CAV1) is implicated in human cancers, although its utility for cancer prognosis is unknown. Here, we investigated the expression of CAV1 in breast cancer tissues to evaluate its prognostic significance on patients with breast cancer administered NACT.MethodsCAV1 expression in 80 breast cancer tissue samples was evaluated using immunohistochemistry (IHC). The association between CAV1 levels and clinical factors was analyzed using the chi-square test and that between CAV1 and prognosis was evaluated using multivariate Cox regression and Kaplan–Meier analyses.ResultsHigh levels of CAV1 were significantly associated with survival, and patients with overexpression of CAV1 had a poor prognosis. Adjusted multivariate Cox regression analyses revealed that a high level of CAV1 expression was an independent, significant prognostic factor for patients with breast cancer treated with NACT.DiscussionOverexpression of CAV1 in patients with breast cancer administered NACT was associated with shorter disease-free survival and overall survival. Therefore, high levels of CAV1 may serve as a prognostic biomarker for such patients.

LDL receptor-related protein LRP6 senses nutrient levels and regulates Hippo signaling.

Controlled cell growth and proliferation are essential for tissue homeostasis and development. Wnt and Hippo signaling are well known as positive and negative regulators of cell proliferation, respectively. The regulation of Hippo signaling by the Wnt pathway has been shown, but how and which components of Wnt signaling are involved in the activation of Hippo signaling during nutrient starvation are unknown. Here, we report that a reduction in the level of low-density lipoprotein receptor-related protein 6 (LRP6) during nutrient starvation induces phosphorylation and cytoplasmic localization of YAP, inhibiting YAP-dependent transcription. Phosphorylation of YAP via loss of LRP6 is mediated by large tumor suppressor kinases 1/2 (LATS1/2) and Merlin. We found that O-GlcNAcylation of LRP6 was reduced, and the overall amount of LRP6 was decreased via endocytosis-mediated lysosomal degradation during nutrient starvation. Merlin binds to LRP6; when LRP6 is less O-GlcNAcylated, Merlin dissociates from it and becomes capable of interacting with LATS1 to induce phosphorylation of YAP. Our data suggest that LRP6 has unexpected roles as a nutrient sensor and Hippo signaling regulator.