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Alzheimer’s disease (AD) is the most common form of neurodegeneration and cognitive dysfunction in the elderly. Identifying molecular signals that mitigate and reverse neurodegeneration in AD may be exploited therapeutically. Transgenic AD mice (PSAPP) exhibit learning and memory deficits at 9 and 11 months, respectively, with associated decreased expression of caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein necessary for synaptic and neuroplasticity. Neuronal-targeted gene therapy using synapsin-Cav-1 cDNA (SynCav1) was delivered to the hippocampus of PSAPP mice at 3 months using adeno-associated virus serotype 9 (AAV9). Bilateral SynCav1 gene therapy was able to preserve MLRs profile, learning and memory, hippocampal dendritic arbor, synaptic ultrastructure, and axonal myelin content in 9- and 11-month PSAPP mice, independent of reducing toxic amyloid deposits and astrogliosis. Our data indicate that SynCav1 gene therapy may be an option for AD and potentially in other forms of neurodegeneration of unknown etiology., Graphical abstract, The findings demonstrate that regardless of the etiology of the neuropathology, SynCav1 may be exploited to treat sporadic conditions or to be used in combination with already existing drugs or biologics designed to target known monogenic candidates linked to other neurodegenerative conditions (AD, ALS, MS).

Background. Recent data show evidence that lipid rafts (LR) proteins could be involved in the formation of exosomes and the sorting of proteins that make up the exosomal cargo. Such data are available for flotillins, structural and functional components of flatted rafts. The presence of the main component of caveolar rafts, caveolin-1 (Cav-1), has been shown in exosomes produced by some cancer cells; however, its possible participation in the regulation of the protein composition of exosomes has not been studied previously.Materials and methods. Knockdown of Cav-1 by transduction of a lentiviral vector expressing precursors of short hairpin ribonucleic acid to Cav-1; isolation (by ultracentrifugation) and analysis (transmission electron microscopy, nanoparticle tracking analysis) of extracellular vesicles (EVs) from non-small cell lung cancer cells (NSCLC) H1299; analysis of proteins in cells and in EVs by immunoblotting.Results. Analysis of the effect of Cav-1 expression on the composition of EV proteins associated with exosome biogenesis revealed a decrease in the level of Alix and TSG101, an increase in the level of LR proteins and the absence of changes in the level of tetraspanin CD9. Conclusion. The obtained data demonstrate a Cav-1-dependent changes in the composition of EVs, indicating a change in the ratio of vesicles formed by the various molecular mechanisms.

Purpose: Adenosine monophosphate-activated protein kinase (AMPK) is thought to inhibit cell proliferation or promote cell death, but the details remain unclear. In this study, we propose that AMPK inhibits the expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) by relying on the hypoxia-inducible factor 1 alpha (HIF-1α)-induced caveolin-1 (Cav-1) expression pathway in noninvasive human bladder tumor (RT4) cells.Methods: In cells exposed to a hypoxic environment (0.5% oxygen), the levels of expression and phospho-activity of the relevant signaling enzymes were examined via Western blots and reverse transcription-polymerase chain reaction. Cell proliferation was assessed using a Cell Counting Kit-8 assay.Results: The level of expression of Cav-1 was very low or undetectable in RT4 cells. Hypoxia was associated with significantly decreased cell growth, along with marked induction of HIF-1α and Cav-1 expression; additionally, it suppressed the expression of the antiapoptotic marker Bcl-2 while leaving AMPK activity unchanged. Under hypoxic conditions, HIF-1α acts as a transcription factor for Cav-1 mRNA gene expression. The cell growth and Bcl-2 expression suppressed under hypoxia were reversed along with decreases in the induced HIF-1α and Cav-1 levels by AMPK activation with metformin (1mM) or phenformin (0.1mM). In addition, pretreatment with AMPK small interfering RNA not only increased the hypoxia-induced expression of HIF-1α and Cav-1, but also reversed the suppression of Bcl-2 expression. These results suggest that HIF-1α and Cav-1 expression in hypoxic environments is regulated by basal AMPK activity; therefore, the inhibition of Bcl-2 expression cannot be expected when AMPK activity is suppressed, even if Cav-1 expression is elevated.Conclusions: For the first time, we find that AMPK activation can regulate HIF-1α induction as well as HIF-1α-induced Cav1 expression, and the hypoxia-induced inhibitory effect on the antiapoptotic pathway in RT4 cells is due to Cav-1-dependent AMPK activity.

HIV‐1 enters the brain by altering properties of the blood‐brain barrier (BBB). Recent evidence indicates that among cells of the BBB, pericytes are prone to HIV‐1 infection. Occludin (ocln) and caveolin‐1 (cav‐1) are critical determinants of BBB integrity that can regulate barrier properties of the BBB in response to HIV‐1 infection. Additionally, Alix is an early acting endosomal factor involved in HIV‐1 budding from the cells. The aim of the present study was to evaluate the role of cav‐1, ocln, and Alix in HIV‐1 infection of brain pericytes. Our results indicated that cav‐1, ocln, and Alix form a multi‐protein complex in which they cross‐regulate each other's expression. Importantly, the stability of this complex was affected by HIV‐1 infection. Modifications of the complex resulted in diminished HIV‐1 infection and alterations of the cytokine profile produced by brain pericytes. These results identify a novel mechanism involved in HIV‐1 infection contributing to a better understanding of the HIV‐1 pathology and the associated neuroinflammatory responses.

Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma. Electronic supplementary material The online version of this article (10.1007/s12035-020-02057-3) contains supplementary material, which is available to authorized users.

Lung cancer is one of the most prevalent malignancies world-wide with non-small cell lung cancer (NSCLC) comprising nearly 80% of all cases. Unfortunately, many lung cancer patients are diagnosed at advanced stages of the disease with an associated poor prognosis. Recently, the Chinese herb root extract Triptolide/Minnelide (TL) has shown significant promise as a therapeutic agent for NSCLC treatment both in vitro and in vivo. The aim of this study was to investigate the underlying mechanism(s) of action regarding TL-induced cytotoxicity in NSCLC. We demonstrate that triptolide treatment of A549 and H460 NSCLC cells decreases Caveolin-1 (CAV-1) mRNA/protein expression, resulting in activation of the Akt/Bcl-2-mediated mitochondrial apoptosis pathway. CAV-1 down-regulation was triggered by Micro-RNA 204-5p (miR204-5p) up-regulation and could be significantly blocked by pre-treatment with both Sirt-1/Sirt-3 specific siRNA and SIRT-1/SIRT-3 enzyme inhibitors, EX-527 and nicotinamide. Overall, our results provide evidence for a novel mechanism by which TL exerts its cytotoxic effects on NSCLC via CAV-1 down-regulation. Furthermore, these findings demonstrate a pivotal role for TL induction of the Akt/Bax pathway in apoptosis of human lung cancer.

Background Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Recently, it is defined that cancer cells can attain a hybrid epithelial/mesenchymal (hybrid E/M) phenotype. Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and also more capable of initiating metastatic lesions. However, the mechanisms regulating hybrid E/M in HCC are not well described yet. In this study, we investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC. Methods Expression of c-Met and lncRNA HOTAIR were defined in HCC cell lines and patient tissues through HCC progression. lncRNA HOTAIR was overexpressed in SNU-449 cells and its effects on c-Met signaling were analyzed. c-Met was overexpressed in SNU-398 cells and its effect on HOTAIR expression was analyzed. Biological significance of HOTAIR/c-Met interplay was defined in means of adhesion, proliferation, motility behavior, invasion, spheroid formation and metastatic ability. Effect of ectopic lncRNA HOTAIR expression on phenotype was defined with investigation of molecular epithelial and mesenchymal traits. Results In vitro and in vivo experiments verified the pivotal role of lncRNA HOTAIR in acquisition of hybrid E/M phenotype through modulating expression and activation of c-Met and its membrane co-localizing partner Caveolin-1, and membrane organization to cope with the rate limiting steps of metastasis such as survival in adhesion independent microenvironment, escaping from anoikis and resisting to fluidic shear stress (FSS) in HCC. Conclusions Our work provides the first evidence suggesting a role for lncRNA HOTAIR in the modulation of c-Met to promote hybrid E/M phenotype. The balance between lncRNA HOTAIR and c-Met might be critical for cell fate decision and metastatic potential of HCC cells.

Supplemental Digital Content is available in the text., Objective: Endothelial Cav-1 (caveolin-1) expression plays a relevant role during atherogenesis by controlling NO production, vascular inflammation, LDL (low-density lipoprotein) transcytosis, and extracellular matrix remodeling. Additional studies have identified cholesterol-rich membrane domains as important regulators of autophagy by recruiting ATGs (autophagy-related proteins) to the plasma membrane. Here, we investigate how the expression of Cav-1 in the aortic endothelium influences autophagy and whether enhanced autophagy contributes to the atheroprotective phenotype observed in Cav-1–deficient mice. Approach and Results: To analyze the impact of Cav-1 deficiency on regulation of autophagy in the aortic endothelium during the progression of atherosclerosis, we fed Ldlr−/− and Cav-1−/−Ldlr−/− mice a Western diet and assessed autophagy in the vasculature. We observe that the absence of Cav-1 promotes autophagy activation in athero-prone areas of the aortic endothelium by enhancing autophagic flux. Mechanistically, we found that Cav-1 interacts with the ATG5-ATG12 complex and influences the cellular localization of autophagosome components in lipid rafts, which controls the autophagosome formation and autophagic flux. Pharmacological inhibition of autophagy attenuates the atheroprotection observed in Cav-1−/− mice by increasing endothelial inflammation and macrophage recruitment, identifying a novel molecular mechanism by which Cav-1 deficiency protects against the progression of atherosclerosis. Conclusions: These results identify Cav-1 as a relevant regulator of autophagy in the aortic endothelium and demonstrate that pharmacological suppression of autophagic flux in Cav-1–deficient mice attenuates the atheroprotection observed in Cav-1−/− mice. Additionally, these findings suggest that activation of endothelial autophagy by blocking Cav-1 might provide a potential therapeutic strategy for cardiovascular diseases including atherosclerosis.

Caveolin-1 (CAV1) is commonly considered to function as a cell surface protein, for instance in the genesis of caveolae. Nonetheless, it is also present in many intracellular organelles and compartments. The contributions of these intracellular pools to CAV1 function are generally less well understood, and this is also the case in the context of cancer. This review will summarize literature available on the role of CAV1 in cancer, highlighting particularly our understanding of the canonical (CAV1 in the plasma membrane) and non-canonical pathways (CAV1 in organelles and exosomes) linked to the dual role of the protein as a tumor suppressor and promoter of metastasis. With this in mind, we will focus on recently emerging concepts linking CAV1 function to the regulation of intracellular organelle communication within the same cell where CAV1 is expressed. However, we now know that CAV1 can be released from cells in exosomes and generate systemic effects. Thus, we will also elaborate on how CAV1 participates in intracellular communication between organelles as well as signaling between cells (non-canonical pathways) in cancer.

Muscle fibers are generally formed as multinucleated fibers that are differentiated from myoblasts. Several reports have identified transcription factors and proteins involved in the process of muscle differentiation, but the roles of microRNAs (miRNAs) in myogenesis remain unclear. Here, comparative analysis of the miRNA expression profiles in mouse myoblasts and gastrocnemius (GA) muscle uncovered miR-3074-3p as a novel miRNA showing markedly reduced expression in fully differentiated adult skeletal muscle. Interestingly, elevating miR-3074-3p promoted myogenesis in C2C12 cells, primary myoblasts, and HSMMs, resulting in increased mRNA expression of myogenic makers such as Myog and MyHC. Using a target prediction program, we identified Caveolin-1 (Cav1) as a target mRNA of miR-3074-3p and verified that miR-3074-3p directly interacts with the 3' untranslated region (UTR) of Cav1 mRNA. Consistent with the findings in miR-3074-3p-overexpressing myoblasts, knockdown of Cav1 promoted myogenesis in C2C12 cells and HSMMs. Taken together, our results suggest that miR-3074-3p acts a positive regulator of myogenic differentiation by targeting Cav1. [BMB Reports 2020; 53(5): 278-283].

The tissue factor/coagulation factor VIIa (TF/FVIIa) complex induces transactivation of the IGF-1 receptor (IGF-1R) in a number of different cell types. The mechanism is largely unknown. The transactivation leads to protection from apoptosis and nuclear translocation of the IGF-1R. The aim of this study was to clarify the signaling pathway between TF and IGF-1R after FVIIa treatment with PC3 and DU145 prostate or MDA-MB-231 breast cancer cells as model systems. Protein interactions, levels, and phosphorylations were assessed by proximity ligation assay or flow cytometry in intact cells and by western blot on cell lysates. The transactivation of the IGF-1R was found dependent on TF/FVIIa-induced activation of β1-integrins. A series of experiments led to the conclusion that the caveolae protein caveolin-1 prevented IGF-1R activation in resting cells via its scaffolding domain. TF/FVIIa/β1-integrins terminated this inhibition by activation of Src family kinases and subsequent phosphorylation of caveolin-1 on tyrosine 14. This phosphorylation was not seen after treatment with PAR1 or PAR2 agonists. Consequently, the protective effect of FVIIa against apoptosis induced by the death receptor agonist TRAIL and the de novo synthesis of cyclin D1 induced by nuclear IGF-1R accumulation were both significantly reduced by down-regulation of β1-integrins or overexpression of the caveolin-1 scaffolding domain. In conclusion, we present a plausible mechanism for the interplay between TF and IGF-1R involving FVIIa, β1-integrins, Src family proteins, and caveolin-1. Our results increase the knowledge of diseases associated with TF and IGF-1R overexpression in general but specifically of TF-mediated signaling with focus on cell survival. Electronic supplementary material The online version of this article (10.1007/s10495-020-01611-7) contains supplementary material, which is available to authorized users.

Chronic lung diseases represent a largely global burden whose pathogenesis remains largely unknown. Research increasingly suggests that epigenetic modifications, especially DNA methylation, play a mechanistic role in chronic lung diseases. DNA methylation can affect gene expression and induce various diseases. Of the caveolae in plasma membrane of cell, caveolin‐1 (Cav‐1) is a crucial structural constituent involved in many important life activities. With the increasingly advanced progress of genome‐wide methylation sequencing technologies, the important impact of Cav‐1 DNA methylation has been discovered. The present review overviews the biological characters, functions, and structure of Cav‐1; epigenetic modifications of Cav‐1 in health and disease; expression and regulation of Cav‐1 DNA methylation in the respiratory system and its significance; as well as clinical potential as disease‐specific biomarker and targets for early diagnosis and therapy.

Caveolae are flask‐shaped invaginations of the cell membrane rich in cholesterol and sphingomyelin, with caveolin proteins acting as their primary structural components that allow compartmentalization and orchestration of various signalling molecules. In this review, we discuss how pleiotropic functions of caveolin‐1 (Cav1) and its intricate roles in numerous cellular functions including lipid trafficking, signalling, cell migration and proliferation, as well as cellular senescence, infection and inflammation, are integral for normal development and functioning of skin and its appendages. We then examine how disruption of the homeostatic levels of Cav1 can lead to development of various cutaneous pathophysiologies including skin cancers, cutaneous fibroses, psoriasis, alopecia, age‐related changes in skin and aberrant wound healing and propose how levels of Cav1 may have theragnostic value in skin physiology/pathophysiology.

In the study here, the potential applicability of KMRC011 - an agonist of toll-like receptor-5 – as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose = 7 Gy) of Co60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 μg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.

Background Airway mucus hypersecretion is an important pathophysiological feature in asthma. Mucins are glycoproteins that are mainly responsible for the viscoelastic property of mucus, and MUC5AC is a major mucin glycoprotein that is overproduced in asthma. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodeling in asthmatics. Therefore, we sought to investigate the effect of VEGF on MUC5AC expression and study the underlying mechanisms. Methods In order to elucidate the precise mechanism underlying the effect of VEGF on MUC5AC expression, we tested the effects of VEGF on RhoA activation and the association of caveolin-1 and VEGFR2 in Primary Bronchial Epithelial Cells. Results VEGF up-regulated MUC5AC mRNA and protein levels in a dose- and time-dependent manner, and activated RhoA. Additionally, VEGF-induced MUC5AC expression and RhoA activation were enhanced by disrupting caveolae with cholesterol depletion and reversed by cholesterol repletion, and inhibited by a selective VEGF receptor 2 (VEGFR2) inhibitor SU1498. Furthermore, phospho-VEGFR2 expression was decreased via overexpression of caveolin-1. VEGF treatment reduced the association of caveolin-1 and VEGFR2. Conclusion Collectively, our findings suggest that VEGF up-regulates MUC5AC expression and RhoA activation by interaction with VEGFR2, and this phenomenon was related with the association of caveolin-1 and VEGFR2. Further studies on these mechanisms are needed to facilitate the development of treatments for asthma.

Caveolin-1 is a transmembrane protein with both tumor promoter and suppressor functions that remain poorly understood. Cav1 phosphorylation by Src kinase on tyrosine 14 is closely associated with focal adhesion dynamics and tumor cell migration, however the role of pCav1 in vivo in tumor progression remains poorly characterized. Herein, we expressed phosphomimetic Y14D, wild type, and non-phosphorylatable Y14F forms of Cav1 in MDA-MB-435 cancer cells. Expression of Cav1Y14D reduced cell proliferation and induced the TP53 tumor suppressor. Ectopic expression in MDA-MB-435 cells of Y14 phosphorylatable Cav1 was required for induction of TP53 in response to oxidative stress. Cav1Y14D promotes an apparent reversal of the Warburg effect and markedly inhibited tumor growth in vivo. However, Cav1 induced pseudopodial recruitment of glycolytic enzymes, and time-lapse intravital imaging showed increased invadopodia protrusion and extravasation into blood vessels for Cav1WT and Y14D but not for Y14F. Our results suggest that Cav1 Y14 phosphorylation levels play a role in the conflicting demands on metabolic resources associated with cancer cell proliferation versus motility.

Caveolin-1 (Cav-1), an integral membrane protein, is a principal component of caveolae and has been reported to play a promoting or inhibiting role in cancer progression. Gynecologic tumor is a group of tumors that affect the tissue and organs of the female reproductive system, especially cervical cancer. Cervical cancer, as one of the most common cancers, severely affects female health in developing countries in particular because of its high morbidity and mortality. This review summarizes some mechanisms of Cav-1 in the development and progression of gynecological tumors. The role of Cav-1 in tumorigenesis, including dysregulation of cell cycle, apoptosis and autophagy, adhesion, invasion, and metastasis, such as the formation of invadopodia and matrix metalloproteinase degradation are presented in detail. In addition, Cav-1 modulates autophagy and the formation of invadopodia and target regulated by miRNAs to affect tumor progress. Taken together, we find that, no matter Cav-1 expression in the tumor or stromal cells , Cav-1 has paradoxical role in different types of gynecological tumors in vivo or in vitro and even in the same tumor from the same organ.

The dialogue between cancer cells and the surrounding fibroblasts, tumor‐associated macrophages (TAM), and immune cells can create a tumor microenvironment (TME) able to promote tumor progression and metastasis and induce resistance to anticancer therapies. Cancer cells, by producing growth factors and cytokines, can recruit and activate fibroblasts in the TME inducing their transdifferention in cancer‐associated fibroblasts (CAFs). Then, CAFs, in a reciprocal cross‐talk with cancer cells, sustain cancer growth and survival and support malignancy and tumor resistance to therapies. Therefore, the identification of the molecular mechanisms regulating the interplay between cancer cells and fibroblasts can offer an intriguing opportunity for novel diagnostic and therapeutic anticancer purpose. HIPK2 is a multifunctional tumor suppressor protein that modulates cancer cell growth and apoptosis in response to anticancer drugs and negatively regulates pathways involved in tumor progression and chemoresistance. HIPK2 protein downregulation is induced by hypoxia and hyperglycemia and HIPK2 knockdown favors tumor progression and resistance to therapy other than a pseudohypoxic, inflammatory, and angiogenic cancer phenotype. Therefore, we hypothesized that HIPK2 modulation in cancer cells could contribute to modify the tumor–host interaction. In support of our hypothesis, here we provide evidence that culturing human fibroblasts (hFB) with conditioned media derived from cancer cells undergoing HIPK2 knockdown (CMsiHIPK2) triggered their transdifferentiation CAF‐like, compared to hFB cultured with CM‐derived from HIPK2‐carrying control cancer cells. CAF transdifferentiation was identified by expression of several markers including α‐smooth muscle actin (α‐SMA) and collagen I and correlated with autophagy–mediated caveolin‐1 degradation. Although the molecular mechanisms dictating CAF‐transdifferentiation need to be elucidated, these results open the way to further study the role of HIPK2 in TME remodeling for prognostic and therapeutic purpose.

There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factors. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveolin-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.

Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for acute liver injury caused by overuse of acetaminophen (APAP). Caveolin-1 (CAV1), a regulator of hepatic energy metabolism and oxidative stress, was found to have a protective effect against NAFLD in our previous study. However, it remains unclear whether CAV1 has a protective effect against APAP-induced hepatotoxicity in NAFLD. The aim of this study was to determine whether CAV1 inhibits oxidative stress through the AMPK/Nrf2/HO-1 pathway to protect the liver from fat accumulation exacerbated by APAP in NAFLD. In this study, seven-week-old C57BL/6 male mice (18–20 g) were raised under similar conditions for in vivo experiment. In vitro, L02 cells were treated with A/O (alcohol and oleic acid mixture) for 48 h, and APAP was added at 24 h for further incubation. The results showed that the protein expression of the AMPK/Nrf2 pathway was enhanced after CAV1 upregulation. The effects of CAV1 on fat accumulation, ROS, and the AMPK/Nrf2 anti-oxidative pathway were reduced after the application of CAV1-siRNA. Finally, treatment with compound C (an AMPK inhibitor) prevented CAV1 plasmid-mediated alleviation of oxidative stress and fat accumulation and reduced the protein level of Nrf2 in the nucleus, demonstrating that the AMPK/Nrf2/HO-1 pathway was involved in the protective effect of CAV1. These results indicate that CAV1 exerted a protective effect against APAP-aggravated lipid deposition and hepatic injury in NAFLD by inhibiting oxidative stress. Therefore, the upregulation of CAV1 might have clinical benefits in reducing APAP-aggravated hepatotoxicity in NAFLD.

Diabetes is a metabolic disorder induced by the modulation of insulin on glucose metabolism, and the dysfunction and decreased number of islets β-cells are the main causes of T2DM (type 2 diabetes mellitus). Among multiple factors that might participate in T2DM pathogenesis, the critical roles of miRNAs in T2DM and β-cell dysfunction have been reported. Through bioinformatics analyses and literature review, we found that miR-344 might play a role in the occurrence and progression of diabetes in rats. The expression levels of miR-344-5p were dramatically decreased within cholesterol-stimulated and palmitic acid (PA)-induced rats’ islet β-cells. In cholesterol-stimulated and PA-induced diabetic β-cell model, cholesterol-caused and PA-caused suppression on cell viability, increase in intracellular cholesterol level, decrease in GSIS, and increase in lip droplet deposition were dramatically attenuated via the overexpression of miR-344-5p, whereas aggravated via the inhibition of miR-344-5p. miR-344-5p also inhibited cholesterol-induced β-cell death via affecting the apoptotic caspase 3/Bax signaling. Insulin receptor downstream MPAK/ERK signaling was involved in the protection of miR-344-5p against cholesterol-induced pancreatic β-cell dysfunction. Moreover, miR-344-5p directly targeted Cav1; Cav1 silencing could partially reverse the functions of miR-344-5p inhibition upon cholesterol-induced β-cell dysfunction, β-cell apoptosis, the apoptotic caspase 3/Bax signaling, and insulin receptor downstream MPAK/ERK signaling. In conclusion, the miR-344-5p/Cav1 axis modulates cholesterol-induced β-cell apoptosis and dysfunction. The apoptotic caspase 3/Bax signaling and MAPK/ERK signaling might be involved.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, with aging being considered the greatest risk factor for developing PD. Caveolin-1 (Cav-1) is known to participate in the aging process. Recent evidence indicates that prion-like propagation of misfolded α-synuclein (α-syn) released from neurons to neighboring neurons plays an important role in PD progression. In the present study, we explored the association between cav-1 and cell-to-cell transmission of α-syn.Methods: Using SH-SY5Y cells and primary neurons overexpressing WT and Y14A cav-1, we investigated the effect of cav-1 expression on the uptake of α-syn using a dual chamber system. Additionally, we investigated the effect of cav-1 expression on the formation of Lewy body-like inclusions using co-culture assay and microfluidic chamber assay.Results: We demonstrated that cav-1 expression in the brain increased with age, and considerably increased in the brain of A53T α-syn transgenic mice. Cav-1 overexpression facilitated the uptake of α-syn into neurons and formation of additional Lewy body-like inclusion bodies, phosphorylation of cav-1 at tyrosine 14 was found to be crucial for this process. Conclusions: This study demonstrates the relationship between age and α-syn spread and will facilitate our understanding of the molecular mechanism of the cell-to-cell transmission of α-syn.

Background Caveolin-1 (CAV-1) is a cholesterol-dependent essential component located in caveolae. Several studies have been CAV-1 related to cardio-metabolic parameters in animal models, however, there are few studies in humans. Importantly, there is no study has investigated the interaction between CAV-1 rs3807992 gene and dietary patterns (DPs) on cardio-metabolic risk factors. Methods The current cross-sectional study was conducted on 404 overweight and obese women. Dietary intake was obtained from FFQ with 147 items. The CAV-1 genotype was measured by the PCR-RFLP method. The anthropometric measurements, serum lipid profile, and inflammatory markers were measured by standard protocols. Results There was a significant interaction between CAV-1 rs3807992 and healthy DP on high-density cholesterol (HDL) (P-interaction = 0.03), TC/HDL (P-interaction = 0.03) and high sensitivity C-reactive protein (hs-CRP) (P-interaction = 0.04); in A-allele carriers, higher following a healthy DP was related to a higher level of HDL and lower TC/HDL and hs-CRP. As well as, the significant interactions were observed between CAV-1 rs3807992 and unhealthy DP in relation to triglyceride (TG) (P-interaction = 0.001), aspartate aminotransferase (AST) (P-interaction = 0.01) and monocyte chemoattractant protein-1(MCP-1) (P-interaction = 0.01); A-allele carriers were more following the unhealthy DP had lower levels of TG, AST and MCP-1. Conclusions Our study revealed a significant gene-diet interaction between rs3807992 SNPs and DPs in relation to cardio-metabolic risk factors; A-allele carriers might be more sensitive to dietary composition compared to GG homozygotes. Following a healthy DP in A-allele-carriers may be improved their genetic association with cardio-metabolic risk factors.

Intestinal ischaemia‐reperfusion (I/R) injury can result in acute lung injury due to ischaemia and hypoxia. Dexmedetomidine (Dex), a highly selective alpha2‐noradrenergic receptor (α2AR) agonist used in anaesthesia, is reported to regulate inflammation in organs. This study aimed to investigate the role and mechanism of Dex in lung injury caused by intestinal I/R. After establishing a rat model of intestinal I/R, we measured the wet‐to‐dry specific gravity of rat lungs upon treatments with Dex, SB239063 and the α2AR antagonist Atipamezole. Moreover, injury scoring and histopathological studies of lung tissues were performed, followed by ELISA detection on tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐1β and IL‐6 expression. Correlation of Caveolin‐1 (Cav‐1) protein expression with p38, p‐p38, p‐p65 and p65 in rat lung tissues was analysed, and the degree of cell apoptosis in lung tissues after intestinal I/R injury was detected by TUNEL assay. The lung injury induced by intestinal I/R was a dynamic process. Moreover, Dex had protective effects against lung injury by mediating the expression of Cal‐1 and α2A‐AR. Specifically, Dex promoted Cav‐1 expression via α2A‐AR activation and mitigated intestinal I/R‐induced lung injury, even in the presence of Atipamezole. The protective effect of Dex on intestinal I/R‐induced lung injury was also closely related to α2A‐AR/p38 mitogen‐activated protein kinases/nuclear factor‐kappaB (MAPK/NF‐κB) pathway. Dex can alleviate pulmonary inflammation after in intestinal I/R by promoting Cav‐1 to inhibit the activation of p38 and NF‐κB. In conclusion, Dex can reduce pulmonary inflammatory response even after receiving threats from both intestinal I/R injury and Atipamezole.

© 2021 Ramírez, Torrecilla-Parra, Pardo-Marqués, de-Frutos, Pérez-García, Tabraue, de la Rosa, Martín-Rodriguez, Díaz-Sarmiento, Nuñez, Orizaola, Través, Camps, Boscá and Castrillo., Macrophages are immune cells that play crucial roles in host defense against pathogens by triggering their exceptional phagocytic and inflammatory functions. Macrophages that reside in healthy tissues also accomplish important tasks to preserve organ homeostasis, including lipid uptake/efflux or apoptotic-cell clearance. Both homeostatic and inflammatory functions of macrophages require the precise stability of lipid-rich microdomains located at the cell membrane for the initiation of downstream signaling cascades. Caveolin-1 (Cav-1) is the main protein responsible for the biogenesis of caveolae and plays an important role in vascular inflammation and atherosclerosis. The Liver X receptors (LXRs) are key transcription factors for cholesterol efflux and inflammatory gene responses in macrophages. Although the role of Cav-1 in cellular cholesterol homeostasis and vascular inflammation has been reported, the connection between LXR transcriptional activity and Cav-1 expression and function in macrophages has not been investigated. Here, using gain and loss of function approaches, we demonstrate that LXR-dependent transcriptional pathways modulate Cav-1 expression and compartmentation within the membrane during macrophage activation. As a result, Cav-1 participates in LXR-dependent cholesterol efflux and the control of inflammatory responses. Together, our data show modulation of the LXR-Cav-1 axis could be exploited to control exacerbated inflammation and cholesterol overload in the macrophage during the pathogenesis of lipid and immune disorders, such as atherosclerosis., We thank MINECO FPI predoctoral fellowship granted to MCO (BES-2015-075339). Experimental work was supported by grants from Ministerio de Ciencia, Investigación y Universidades, y Fondo Europeo de Desarrollo Regional (FEDER) Grant REF: PID2019-104284RB-I00/AEI/10.13039/501100011033 (to AC) and support from Networks of Excellence from MINECO (Nuclear Receptors in Cancer, Metabolism and Inflammation [NuRCaMeIn] SAF2017-90604-REDT to AC. Ministerio de Economía, Industria y Competitividad, Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación (SAF2017-82436-R, RTC2017-6283-1), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional (to LB). Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación Proyectos de I+D+i Retos Investigación 2018 (RTI2018-095061-B-I00); TALENTO Grant from Madrid Government, Spain (2017-T1/BMD-5333); Consejería de Ciencia, Universidades e Innovación Comunidad de Madrid, Spain (PEJD-2018-POST/BMD-8900 and PEDJ-2018-AI/BDM-9724) to CMR.

Glucagon-like peptide-1 (GLP-1) is a gut hormone mainly produced in the intestinal epithelial endocrine L cells, involved in maintaining glucose homeostasis. The use of GLP-1 analogous and dipeptidyl peptidase-IV (DPP-IV) inhibitors is well-established in Type 2 Diabetes. The efficacy of these therapies is related to the activation of GLP-1 receptor (GLP-1R), which is widely expressed in several tissues. Therefore, GLP-1 is of great clinical interest not only for its actions at the level of the beta cells, but also for the extra-pancreatic effects. Activation of GLP-1R results in intracellular signaling that is regulated by availability of downstream molecules and receptor internalization. It has been shown that GLP-1R co-localizes with caveolin-1, the main component of caveolae, small invagination of the plasma membrane, which are involved in controlling receptor activity by assembling signaling complexes and regulating receptor trafficking. The aim of this review is to outline the important role of caveolin-1 in mediating biological effects of GLP-1 and its analogous.

In addition to providing structural support, caveolin-1 (Cav1), a component of lipid rafts, including caveolae, in the plasma membrane, is involved in various cellular mechanisms, including signal transduction. Although pre-synaptic membrane dynamics and trafficking are essential cellular processes during synaptic vesicle exocytosis/synaptic transmission and synaptic vesicle endocytosis/synaptic retrieval, little is known about the involvement of Cav1 in synaptic vesicle dynamics. Here we demonstrate that synaptic vesicle exocytosis is significantly impaired in Cav1–knockdown (Cav1–KD) neurons. Specifically, the size of the synaptic recycled vesicle pool is modestly decreased in Cav1–KD synapses and the kinetics of synaptic vesicle endocytosis are somewhat slowed. Notably, neurons rescued by triple mutants of Cav1 lacking palmitoylation sites mutants show impairments in both synaptic transmission and retrieval. Collectively, our findings implicate Cav1 in activity-driven synaptic vesicle dynamics—both exocytosis and endocytosis—and demonstrate that palmitoylation of Cav1 is important for this activity. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00764-z.

Background Encephalomyocarditis virus, member of Cardiovirus genus within Picornaviridae family, is an important pathogen that infects different domestic and wild animals. However, the molecular mechanism of its entry remains unclear. In this study, we investigated the mechanism of EMCV infectivity in relation to endocytic pathway using BHK-21 cells. Methods The function of numerous cellular key factors implicated in the various endocytic mechanisms were systematically explored using chemical inhibitors. Furthermore, RNA interference (RNAi) as well as the overexpression of dominant protein combined to virus infectivity assays, and confocal microscopy was used to examine EMCV infection in details. Results The results indicated that the EMCV entry into BHK-21 cells depends on caveolin, dynamin, and actin but not clathrin nor macropinocytosis pathways. The effects of overexpression and knockdown of caveolin-1, one components of the caveolae, was examined on EMCV infection. The results showed that EMCV infection was positive correlation with caveolin-1 expression. Confocal microscopy analysis and internalization assay showed that caveolin-1 is required at the early stage of EMCV infection. Conclusions Caveolin-1, dynamin, and actin-dependent endocytosis pathways are necessary for EMCV infection in vitro.

The extent of cellular heterogeneity involved in neuronal regeneration after spinal cord injury (SCI) remains unclear. Therefore, we established stress-responsive transgenic zebrafish embryos with SCI. As a result, we found an SCI-induced cell population, termed SCI stress-responsive regenerating cells (SrRCs), essential for neuronal regeneration post-SCI. SrRCs were mostly composed of subtypes of radial glia (RGs-SrRCs) and neuron stem/progenitor cells (NSPCs-SrRCs) that are able to differentiate into neurons, and they formed a bridge across the lesion and connected with neighbouring undamaged motor neurons post-SCI. Compared to SrRCs at the caudal side of the SCI site (caudal-SrRCs), rostral-SrRCs participated more actively in neuronal regeneration. After RNA-seq analysis, we discovered that caveolin 1 ( cav1 ) was significantly upregulated in rostral-SrRCs and that cav1 was responsible for the axonal regrowth and regenerative capability of rostral-SrRCs. Collectively, we define a specific SCI-induced cell population, SrRCs, involved in neuronal regeneration, demonstrate that rostral-SrRCs exhibit higher neuronal differentiation capability and prove that cav1 is predominantly expressed in rostral-SrRCs, playing a major role in neuronal regeneration after SCI.

PurposeThe prognostic value of caveolin-1 in prostate cancer remains uncertain. Hence, this meta-analysis was performed to evaluate the prognostic value of caveolin-1 in prostate cancer, as well as ascertain the relationship between caveolin-1 expression and clinicopathological characteristics of prostate cancer patients.MethodsThe PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Biology Medicine databases were electronically searched to retrieve published studies on caveolin-1 expression in prostate cancer. After study selection and data extraction, the meta-analysis was conducted using Review manager 5.3 software. Odds ratio (OR) with 95% confidence interval (CI) was used to estimate the pooled effect. Funnel plot was used to assess publication bias.ResultsA total of ten studies were enrolled, which included 3976 cases of prostate cancer, 72 cases of high-grade intraepithelial neoplasia (HGPIN), and 157 normal controls. Results of the meta-analysis showed that the positive rate of caveolin-1 expression in prostate cancer was 18.28 times higher than that in normal control (OR= 18.28, 95% CI: 9.02–37.04, p10 vs. ≤ 10 (OR=2.09, 95% CI: 1.35–3.22, pConclusionCaveolin-1 is overexpressed in prostate cancer, which can serve as a risk factor and adverse clinicopathological feature of prostate cancer. Caveolin-1 can also predict poor survival in prostate cancer patients after radical prostatectomy.

ObjectivesObesity and insulin resistance (IR) are interrelated in a range of ways. The IR-obesity relationship is not a cause-and-effect association. Molecular biology research has made tremendous strides in discovering contributors to find this association. Genes that control adipocyte function such as caveolin-1 (CAV1);probably interact in the pathogenesis of human IR in this context. The involvement ofCAV1in glucose/lipid homeostasis is revealed and could modify the signaling of the insulin receptor. We examined the association betweenCAV1and insulin signaling in modifying dyslipidemia and fat composition in overweight and obese women with a prevalent variant in theCAV1gene.ResultsMinor allele carriers were slightly older and had higher BMI (p = 0.02), FMI (p = 0.006), and VLF (p = 0.01) values; and tended to have lower total cholesterol TC (p = 0.04), low-density lipoprotein cholesterol (LDL-C) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). HOMA-IR levels predicted fat mass index (FMI) 0.47 (0.08, 0.87), visceral fat level (VFL) 0.65 (0.23, 1.07), TC 6.82 (1.76, 11.88) and HDL-C − 1.663 (− 3.11, − 0.214) only between minor allele carriers in adjusted models. (β, CI). Our results cast a new light on the IR mechanism and future studies will elucidate the clinical relevance ofCAV1-IR in patients with dyslipidemia and high fat composition.

Emerging evidence suggests that extracellular vesicles (EVs) play an essential role in mediating intercellular communication and inter-organ crosstalk both at normal physiological conditions and in the pathogenesis of human diseases. EV cargos are made up of a broad spectrum of molecules including lipids, proteins, and nucleic acids such as DNA, RNA, and microRNAs. The complex EV cargo composition is cell type-specific. A dynamic change in EV cargos occurs along with extracellular stimuli and a change in the pathophysiological status of the host. Currently, the underlying mechanisms by which EVs are formed and EV cargos are selected in the absence and presence of noxious stimuli and pathogens remain incompletely explored. The term EVs refers to a heterogeneous group of vesicles generated via different mechanisms. Some EVs are formed via direct membrane budding, while the others are produced through multivesicular bodies (MVBs) or during apoptosis. Despite the complexity of EV formation and EV cargo selection, recent studies suggest that caveolin-1, a well-known structural protein of caveolae, regulates the formation and cargo selection of some EVs, such as microvesicles (MVs). In this article, we will review the current understanding of this emerging and novel role of cav-1.

Hypertension is one of the critical risk factors of cerebrovascular disease. Caveolin-1 (Cav-1) has been suggested to be involved in the development of hypertension; however, the underlying mechanism remains largely unknown. Therefore, the present study aimed to investigate the mechanism underlying Cav-1 in hypertension. In the present study, the hypertension model was induced by infusion of angiotensin II (Ang-II) in rats. Cell Counting Kit-8 assay was used to detect the viability of human umbilical vein endothelial cells (HUVECs). Flow cytometry was used to determine the apoptosis of HUVECs. Transmission electron microscopy was utilized to address the thickness of the vessel walls. Reverse transcription-quantitative PCR, western blotting and immunofluorescence staining were used to assess the mechanism of cav-1/Notch1 involved in hypertensive vascular remodeling. In the present study, an Ang-II-induced hypertension model was successfully established in rats. With this model, it was found that the expression levels of cav-1 and Notch1 were significantly increased in brain tissues in the hypertension group compared with the sham-operated group. In cultured HUVECs, knockdown of cav-1 regulated Ang-II-induced HUVEC viability and apoptosis, and modulated hypertensive vascular remodeling, which was mediated by the Notch pathway. The data of the present study demonstrated that the cav-1/Notch signaling plays an important role in the regulation of Ang-II-induced hypertension and vascular remodeling.

Purpose To determine whether caveolin-1 (i) prevents epithelial-mesenchymal transition in the RPE and laser-induced subretinal fibrosis and (ii) promotes or inhibits cellular senescence in the RPE. Methods We examined laser-induced subretinal fibrosis and RPE cell contraction in wild-type and Caveolin-1 knockout (Cav-1-/-) mice treated with or without cavtratin, a cell-permeable peptide of caveolin-1. The senescence marker p16INK4a was measured in RPE tissues from patients with geographic atrophy and aged mice, laser-induced subretinal fibrosis, and primary human RPE cells. Human RPE was examined by TUNEL staining, reactive oxygen species generation, cell viability, and senescence-associated β-galactosidase staining. Results The volume of subretinal fibrosis was significantly smaller in cavtratin-injected eyes from wild-type mice than in control eyes from wild-type, P = 0.0062, and Cav-1-/- mice, P = 0.0095. Cavtratin treatment produced significant improvements in primary RPE cell contraction in wild-type, P = 0.04, and Cav-1-/- mice, P = 0.01. p16INK4a expression in the RPE was higher in patients with than without geographic atrophy. p16INK4a was expressed in 18-month-old but not 2-month-old wild-type mouse eyes. p16INK4a and collagen type I antibodies showed co-localization in subretinal fibrosis. Cavtratin did not affect RPE cell apoptosis or reactive oxygen species generation, but decreased cell viability and increased senescence-associated β-galactosidase-positive cells. Conclusions Enhanced expression of caveolin-1 successfully blocked epithelial-mesenchymal transition of RPE and the reduction of subretinal fibrosis in mice. Nevertheless, in exchange for blocking subretinal fibrosis, caveolin-1 promotes RPE cellular senescence and might affect the progression of geographic atrophy in AMD.

Purpose Polymorphisms at the caveolin-1/2 locus are associated with glaucoma and IOP risk and deletion of caveolin-1 (Cav1) in mice elevates IOP and reduces outflow facility. However, the specific location/cell type responsible for Cav1-dependent regulation of IOP is unclear. We hypothesized that endothelial Cav1 in the conventional outflow (CO) pathway regulate IOP via endothelial nitric oxide synthase (eNOS) signaling. Methods We created a mouse with targeted deletion of Cav1 in endothelial cells (Cav1ΔEC) and evaluated IOP, outflow facility, outflow pathway distal vascular morphology, eNOS phosphorylation, and tyrosine nitration of iridocorneal angle tissues by Western blotting. Results Endothelial deletion of Cav1 resulted in significantly elevated IOP versus wild-type mice but not a concomitant decrease in outflow facility. Endothelial Cav1 deficiency did not alter the trabecular meshwork or Schlemm's canal morphology, suggesting that the effects observed were not due to developmental deformities. Endothelial Cav1 deletion resulted in eNOS hyperactivity, modestly increased protein nitration, and significant enlargement of the drainage vessels distal to Schlemm's canal. L-Nitro-arginine methyl ester treatment reduced outflow in Cav1ΔEC but not wild-type mice and had no effect on the size of drainage vessels. Endothelin-1 treatment decrease the outflow and drainage vessel size in both wild-type and Cav1ΔEC mice. Conclusions Our results suggest that hyperactive eNOS signaling in the CO pathway of both Cav1ΔEC and global Cav1 knockout mice results in chronic dilation of distal CO vessels and protein nitration, but that Cav1 expression in the trabecular meshwork is sufficient to rescue CO defects reported in global Cav1 knockout mice.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin’s aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1–43.2) lower aldosterone level ( P =0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels ( P =0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant ( P =0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin’s aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

Oxidative stress (OS) has been linked to the aetiology of many diseases including osteoarthritis (OA). Recent studies have shown that caveolin-1&mdash, a structural protein of plasma membrane&rsquo, s caveolae&mdash, is upregulated in response to OS. Here, we explore the function of caveolin-1 in chondrocytes derived from healthy individuals (control) and OA patients that were subjected to exogenous OS. We showed that caveolin-1 was upregulated in response to acute OS in the control, but not in OA chondrocytes. Moreover, OS-induced DNA damage analysis revealed that control cells started repairing the DNA lesions 6 h post-oxidative treatment, while OA cells seemed unable to restore these damages. Importantly, in the control cells, we observed a translocation of caveolin-1 from the membrane/cytoplasm in and out of the nucleus, which coincided with the appearance and restoration of DNA lesions. When caveolin-1 was prevented from translocating to the nucleus, the control cells were unable to repair DNA damage. In OA cells, no such translocation of caveolin-1 was observed, which could account for their inability to repair DNA damage. Taken together, these results provide novel insights considering the role of caveolin-1 in response to OS-induced DNA damage while revealing its implication in the pathophysiology of OA.

The aim of this work was to investigate whether Caveolin-1 (Cav-1), a membrane scaffolding protein widely implicated in cancer, may play a role in radiation response in rhabdomyosarcoma (RMS), a pediatric soft tissue tumor. For this purpose, we employed human RD cells in which Cav-1 expression was stably increased via gene transfection. After radiation treatment, we observed that Cav-1 limited cell cycle arrest in the G2/M phase and enhanced resistance to cell senescence and apoptosis via reduction of p21Cip1/Waf1, p16INK4a and Caspase-3 cleavage. After radiotherapy, Cav-1-mediated cell radioresistance was characterized by low accumulation of H2AX foci, as confirmed by Comet assay, marked neutralization of reactive oxygen species (ROS) and enhanced DNA repair via activation of ATM, Ku70/80 complex and DNA-PK. We found that Cav-1-overexpressing RD cells, already under basal conditions, had higher glutathione (GSH) content and greater catalase expression, which conferred protection against acute treatment with hydrogen peroxide. Furthermore, pre-treatment of Cav-1-overexpressing cells with PP2 or LY294002 compounds restored the sensitivity to radiation treatment, indicating a role for Src-kinases and Akt pathways in Cav-1-mediated radioresistance. These findings were confirmed using radioresistant RD and RH30 lines generated by hypofractionated radiotherapy protocol, which showed marked increase of Cav-1, catalase and Akt, and sensitivity to PP2 and LY294002 treatment. In conclusion, these data suggest that concerted activity of Cav-1 and catalase, in cooperation with activation of Src-kinase and Akt pathways, may represent a network of vital mechanisms that allow irradiated RMS cells to evade cell death induced by oxidative stress and DNA damage.

As one of the most important components of caveolae, caveolin-1 is involved in caveolae-mediated endocytosis and transcytosis pathways, and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction. In recent years, the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored. In addition, the interplay between caveolin-1 and nano-drugs is bidirectional. Caveolin-1 could determine the intracellular biofate of specific nano-drugs, preventing from lysosomal degradation, and facilitate them penetrate into deeper site of tumors by transcytosis; while some nanocarriers could also affect caveolin-1 levels in tumor cells, thereby changing certain biophysical function of cells. This article reviews the role of caveolin-1 in tumor prognosis, chemotherapeutic drug resistance, antibody drug sensitivity, and nano-drug delivery, providing a reference for the further application of caveolin-1 in nano-drug delivery systems.

High fat consumption can enhance metastasis and decrease survival in prostate cancer, but the picture remains incomplete on the epidemiological and cell-biological level, impeding progress toward individualized recommendations in the clinic. Recent work has highlighted the role of exosomes secreted by prostate cancer cells in the progression of the disease, particularly in metastatic invasion, and also the utility of targeting these extracellular vesicles for diagnostics, as carriers of disease progression markers. Here, we investigated the question of a potential impact of the chief nutritional saturated fatty acid on the exosome secretion. Palmitic acid decreased the secretion of exosomes in human prostate cancer cells in vitro in a concentration-dependent manner. At the same time, the content of some prospective metastatic markers in the secreted exosomal fraction was also reduced, as was the ability of the cells to invade across extracellular matrix barriers. While by themselves our in vitro results imply that on the cell level, palmitic acid may be beneficial vis-&agrave, vis the course of the disease, they also suggest that, by virtue of the decreased biomarker secretion, palmitic acid has the potential to cause unjustified deprioritization of treatment in obese and lipidemic men.

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.

Background: Improvement in postoperative risk stratification of upper tract urothelial carcinoma (UTUC) is required to better predict outcomes and counsel patients on adjuvant treatment. Objective: To validate the association between caveolin-1 and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for UTUC. Design, setting, and participants: Caveolin-1 expression was evaluated via immunochemistry on a tissue microarray from 621 patients. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positive. The median follow-up in this retrospective study was 35 mo (interquartile range 16-65). Intervention: Radical nephroureterectomy. Outcome measurements and statistical analysis: Univariate and multivariable Cox proportional hazards regression models were used to assess the association between caveolin-1 expression and recurrence and cancer-specific mortality (CSM). Results and limitations: Caveolin-1 was overexpressed in 150 patients (24%). Overexpression was associated with higher pathological stage (p< 0.001) and grade (p< 0.001). In univariate analyses, overexpression of caveolin-1 was significantly associated with lower recurrence (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.2-2.6; p = 0.004) and CSM (HR 1.8, 95% CI 1.2-2.7; p = 0.005); however, multivariable analyses did not prove its independent association with outcomes. The study is limited by its retrospective nature. Conclusions: Despite overexpression in a quarter of UTUC patients, caveolin-1 was not independently associated with oncological outcomes. Its use could be evaluated to improve clinical staging of biopsy specimens and to help in clinical decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. Patient summary: Development of a panel of prognostic and predictive markers is mandatory for patient consultations in the era of personalized medicine. We evaluated the role of caveolin-1 in a large series of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma (UTUC) and found that it was not independently associated with oncological outcomes. Nevertheless, it was associated with adverse pathological features. Considering caveolin-1 in UTUC biopsy specimens could help in improving clinical staging and decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment. Caveolin-1 is associated with worse oncological features among patients treated with radical nephroureterectomy for upper tract urothelial carcinoma (UTUC), but is not independently associated with oncological outcomes. Its clinical use could be explored in UTUC biopsy specimens for improving clinical staging and helping in decision-making regarding a kidney-sparing approach or neoadjuvant systemic treatment.

Sepsis is a major cause of patient mortality and morbidity from bacterial infections. Although neutrophils are known to be important in the development of sepsis, how distinctive neutrophil subtypes regulate inflammatory processes involved in septicemia remains unclear. Preconditioning protects organisms against subsequent higher-dose exposures to the same, or even different, stimuli. Several studies have reported various effects of preconditioning on immune cells. However, the detailed mechanisms underlying neutrophil-mediated protection through preconditioning in sepsis remain unknown. Methods: Flow cytometry was conducted to sort the mice peritoneal lavage cells and the blood samples from patients with sepsis. Western blotting and ELISA were carried out to elucidate the expression of TLR9 signal transduction pathway proteins. Histological analysis was used to assess the effect of InP on intestine and liver structure in tlr9-/- and cav-1-/- mice. Fluorescence microscopy, Co-IP, and FRET were carried out to determine the association of TLR9 with Cav-1. Results: We show that membrane toll-like receptor-9 positive (mTLR9+) neutrophils exert a protective effect against fatal bacterial infections through the process of inflammatory preconditioning (InP). InP, which occurs in the setting of a low-dose bacterial challenge, active ingredient is Monophosphoryl lipid A (MPLA), triggers the membrane translocation of TLR9 from the neutrophil cytosol, where it binds to Cav-1. Our findings showed that InP enables TLR9 to facilitate MyD88-mediated TRAF3 and IRF3 signal transduction. Depletion of either TLR9 or Cav-1 largely eliminates the neutrophil-mediated InP effect in sepsis models in vitro and in vivo. Further, examination of clinical samples from patients with sepsis showed that clinical outcomes and likelihood of recovery are closely correlated with mTLR9 and Cav-1 expression in circulating neutrophils. Conclusion: These results demonstrate that the TLR9-Cav-1 axis is a critical signaling pathway involved in the regulation of neutrophil-dependent MPLA mediated InP, and the presence of mTLR9+ neutrophils could be an attractive indicator of clinical outcomes in bacterial sepsis that could be further explored as a potential therapeutic target.

Ischemic stroke is a leading cause of morbidity and mortality worldwide. Thrombolytic therapy, the only established treatment to reduce the neurological deficits caused by ischemic stroke, is limited by time window and potential complications. Therefore, it is necessary to develop new therapeutic strategies to improve neuronal growth and neurological function following ischemic stroke. Membrane lipid rafts (MLRs) are crucial structures for neuron survival and growth signaling pathways. Caveolin-1 (Cav-1), the main scaffold protein present in MLRs, targets many neural growth proteins and promotes growth of neurons and dendrites. Targeting Cav-1 may be a promising therapeutic strategy to enhance neuroplasticity after cerebral ischemia. This review addresses the role of Cav-1 and MLRs in neuronal growth after ischemic stroke, with an emphasis on the mechanisms by which Cav-1/MLRs modulate neuroplasticity via related receptors, signaling pathways, and gene expression. We further discuss how Cav-1/MLRs may be exploited as a potential therapeutic target to restore neuroplasticity after ischemic stroke. Finally, several representative pharmacological agents known to enhance neuroplasticity are discussed in this review.

Reduced functionality of transforming growth factor β (TGF‐β) is a major pathogenetic component of Alzheimer's disease (AD). The reduction is caused by an ≈50% decrease in the AD brain of the TGF‐β receptor, TGFBR, causing a bottleneck effect that reduces the downstream actions of TGF‐β, which is highly disadvantageous for brain function. Degradation of TGFBR occurs in caveolae with participation by caveolin‐1 (Cav‐1) and CD109. Mechanisms for this are discussed. In the cerebral microcirculation, endothelial cells (which are rich in caveolae) carry CD109 as a surface marker that co‐precipitates with Cav‐1. Atorvastatin reduced Cav‐1 by 75% and, because Cav‐1 and CD109 co‐immunoprecipitate reciprocally, atorvastatin would also reduce the level of CD109. Administration of atorvastatin as a component of combination therapy would diminish the degradation of TGFBR and thereby benefit patients with AD.

Objective: The aim of this study was to evaluate the levels of caveolin-1 in thyroid follicular epithelial cells of papillary thyroid cancer, follicular thyroid cancer, and nonmalignant thyroid nodule benign follicular adenoma, as well as to explore the relationship between the levels of caveolin-1 and thyroid function. Methods: Thirty cases of papillary thyroid cancer, 10 cases of follicular thyroid cancer, 32 cases of nonmalignant thyroid nodule benign follicular adenoma, and 30 controls were enrolled in this study. Caveolin-1 expression in tissue specimens obtained from these cases was evaluated by immunohistochemistry and Western blotting. Results: Caveolin-1 expression in thyroid epithelial cells of patients with papillary thyroid cancer, particularly female patients, was significantly higher than that in patients with follicular thyroid cancer and nonmalignant thyroid nodule benign follicular adenoma ( P < .005). Serum thyroid-stimulating hormone (TSH) levels in the caveolin-1-positive expression group were lower than that in the caveolin-1-negative expression group, and the lowest expression of caveolin-1 was detected in tissues of patients with Graves’ disease. The serum TSH level was associated with caveolin-1 expression in thyroid epithelial cells. Conclusion: Caveolin-1 may participate in regulating thyroid function and is a potential biomarker of follicular thyroid cancer.

Virus infection has drawn extensive attention since it causes serious or even deadly diseases, consequently inducing a series of social and public health problems. Caveolin-1 is the most important structural protein of caveolae, a membrane invagination widely known for its role in endocytosis and subsequent cytoplasmic transportation. Caveolae/caveolin-1 is tightly associated with a wide range of biological processes, including cholesterol homeostasis, cell mechano-sensing, tumorigenesis, and signal transduction. Intriguingly, the versatile roles of caveolae/caveolin-1 in virus infections have increasingly been appreciated. Over the past few decades, more and more viruses have been identified to invade host cells via caveolae-mediated endocytosis, although other known pathways have been explored. The subsequent post-entry events, including trafficking, replication, assembly, and egress of a large number of viruses, are caveolae/caveolin-1-dependent. Deprivation of caveolae/caveolin-1 by drug application or gene editing leads to abnormalities in viral uptake, viral protein expression, or virion release, whereas the underlying mechanisms remain elusive and must be explored holistically to provide potential novel antiviral targets and strategies. This review recapitulates our current knowledge on how caveolae/caveolin-1 functions in every step of the viral infection cycle and various relevant signaling pathways, hoping to provide a new perspective for future viral cell biology research.

VEEV, WEEV, and eastern equine encephalitis virus (EEEV) are emerging infectious diseases in the Americas, and they have caused several major outbreaks in the human and horse population during the past few decades. Shortly after infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. Neuroinvasion has been associated with virus entry into the CNS directly from the bloodstream; however, the underlying molecular mechanisms have remained largely unknown. Here, we demonstrate that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPases within brain endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower viral burdens in the brain than in similarly infected wild-type animals. These studies identify a potentially targetable pathway to limit neuroinvasion by alphaviruses., Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative strains also demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit (NVU), differentially rendering brain endothelial cells, pericytes, and astrocytes permissive to viral replication. Transmission and immunoelectron microscopy revealed early events in virus internalization and Cav-1 association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS and that IFN differentially restricts this process at the BBB.

Drug resistance is a major challenge for chemotherapy in treating human gastric cancer (GC), as the underlying molecular mechanism of chemoresistance in GC remains unknown. Caveolin-1 (Cav-1) is a scaffold protein of plasma membrane caveolae that acts as a tumor modulator by interacting with several cell signals. In this research, we showed that the survival rate of GC cells to cisplatin (CDDP) increased in the presence of Cav-1. Moreover, Cav-1 overexpression inhibited cisplatin-induced apoptosis and improved the survival rate of GC cells. Cav-1 overexpression and knock-down experiments indicated that Cav-1 expression stimulated wingless-type MMTV integration site (WNTs) pathway through the phosphorylation of LRP6 and dephosphorylation of β-catenin. Cav-1 was positively associated with the increase of WNT downstream target gene Met, which led to the activation of HER2 signaling. Moreover, our results demonstrated that the expression of Cav-1 and Met were positively associated with the resistance of GC cells to cisplatin. Collectively, Cav-1 enhances the cisplatin-resistance of GC cells by activating the WNT signaling pathway and Met-HER2 crosstalk. Understanding the role of Cav-1 in the chemoresistance of GC would help to develop novel therapies for a better treatment outcome of GC patients.

The aggressive immunological activity elicited by acute viral myocarditis contributes to a large amount of cardiomyocytes loss and poor prognosis of patients in clinic. Low‐intensity pulsed ultrasound (LIPUS), which is an effective treatment modality for osteoarthropathy, has been recently illustrated regulating the overactive inflammatory response in various diseases. Here, we aimed to investigate whether LIPUS could attenuate coxsackievirus B3 (CVB3) infection‐induced injury by coordinating the inflammatory response. Male BALB/c mice were inoculated intraperitoneally with CVB3 to establish the model of acute viral myocarditis. LIPUS treatment was given on Day 1, Day 1, 3 and Day 1, 3, 5 post‐inoculation, respectively. All mice were followed up for 14 days. Day 1, 3, 5 LIPUS treatment significantly improved the survival rate, attenuated the ventricular dysfunction and ameliorated the cardiac histopathological injury of CVB3‐infected mice. Western blotting analysis showed Day 1, 3, 5 LIPUS treatment decreased pro‐inflammatory cytokines, increased the activation of caveolin‐1 and suppressed p38 mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (ERK) signallings in heart tissue. RAW264.7 cells were treated with lipopolysaccharides (LPS) to simulate the augmented inflammatory response in vivo. LIPUS treatment on RAW264.7 inhibited the expression of pro‐inflammatory cytokines, activated caveolin‐1 and suppressed p38 MAPK and ERK signallings. Transfecting RAW264.7 with caveolin‐1 siRNA blunted the suppression of pro‐inflammatory cytokines and MAPK signallings by LIPUS treatment. Taken together, we demonstrated for the first time that LIPUS treatment attenuated the aggressive inflammatory response during acute viral myocarditis. The underlying mechanism may be activating caveolin‐1 and suppressing MAPK signallings.