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Caveolin-1 (Cav-1), a structural and functional component in the caveolae, plays a critical role in transcytosis, endocytosis, and signal transduction. Cav-1 has been implicated in the mediation of cellular processes by interacting with a variety of signaling molecules. Cav-1 is widely expressed in the endothelial cells, smooth muscle cells, and fibroblasts in the various organs, including the lungs. The Cav-1-mediated internalization and regulation of signaling molecules participate in the physiological and pathological processes. Particularly, the MAPK, NF-κB, TGFβ/Smad, and eNOS/NO signaling pathways have been involved in the regulatory effects of Cav-1 in lung diseases. The important effects of Cav-1 on the lungs indicate that Cav-1 can be a potential target for the treatment of lung diseases. A Cav-1 scaffolding domain peptide CSP7 targeting Cav-1 has been developed. In this article, we mainly discuss the structure of Cav-1 and its critical roles in lung diseases, such as pneumonia, acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary fibrosis, and lung cancer. [ABSTRACT FROM AUTHOR]

Caveolin-1 (Cav-1), a structural and functional component in the caveolae, plays a critical role in transcytosis, endocytosis, and signal transduction. Cav-1 has been implicated in the mediation of cellular processes by interacting with a variety of signaling molecules. Cav-1 is widely expressed in the endothelial cells, smooth muscle cells, and fibroblasts in the various organs, including the lungs. The Cav-1-mediated internalization and regulation of signaling molecules participate in the physiological and pathological processes. Particularly, the MAPK, NF-κB, TGFβ/Smad, and eNOS/NO signaling pathways have been involved in the regulatory effects of Cav-1 in lung diseases. The important effects of Cav-1 on the lungs indicate that Cav-1 can be a potential target for the treatment of lung diseases. A Cav-1 scaffolding domain peptide CSP7 targeting Cav-1 has been developed. In this article, we mainly discuss the structure of Cav-1 and its critical roles in lung diseases, such as pneumonia, acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary fibrosis, and lung cancer. [ABSTRACT FROM AUTHOR]

Introduction: In the US, despite the recent decline in breast cancer deaths, a persistent mortality disparity exists between black and white women with breast cancer, with black women having a 41% higher death rate. Several studies are now reporting that racial disparities can exist independent of socioeconomic and standard of care issues, suggesting that biological factors may be involved. Caveolin-1 (Cav1) loss in the tumor stromal compartment is a novel clinical biomarker for predicting poor outcome in breast cancer including triple negative subtype, however themechanismof Cav1 loss is unknown. We previously identified miR-510-5p as a novel oncomir and propose here that the high levels observed in patients is a novel mechanism leading to stromal Cav1 loss and worse outcomes. Methods: Cav1 was identified as a direct target of miR-510-5p through luciferase, western blot and qPCR assays. Stromal cross talk between epithelial cells and fibroblasts was assessed in vitro using transwell co-culture assays and in vivo using xenograft assays. Results: We found that Cav1 is a direct target of miR-510-5p and that expression in fibroblasts results in an 'activated' phenotype. We propose that this could be important in the context of cancer disparities as we also observed increased levels of circulating miR-510-5p and reduced levels of stromal Cav1 in black women compared to white women with breast cancer. Finally, we observed a significant increase in tumor growth when tumor cells were co-injected with miR-510-5p expressing cancer associated fibroblasts in vivo. Conclusion: We propose that miR-510-5p mediated negative regulation of Cav1 in fibroblasts is a novel mechanism of aggressive tumor growth and may be a driver of breast cancer disparity. [ABSTRACT FROM AUTHOR]

Introduction: Mitochondrial quality control (MQC) is an important mechanism of neural repair after cerebral ischemia (CI). Recent studies have shown that caveolin-1 (Cav-1) is an important signaling molecule in the process of CI injury, but its mechanism of regulating MQC after CI is still unclear. Buyang Huanwu Decoction (BHD) is a classic traditional Chinese medicine formula that is often used to treat CI. Unfortunately, its mechanism of action is still obscure. Methods: In this study, we tested the hypothesis that BHD can regulate MQC through Cav-1 and exert an anti-cerebral ischemia injury effect. We used Cav-1 knockout mice and their homologous wild-type mice, replicated middle cerebral artery occlusion (MCAO) model and BHD intervention. Neurobehavioral scores and pathological detection were used to evaluate neurological function and neuron damage, transmission electron microscopy and enzymology detection of mitochondrial damage. Finally, western blot and RT-qPCR expression of MQCrelated molecules were tested. Results: After CI, mice showed neurologic impairment, neuronal damage, and significant destruction of mitochondrial morphology and function, and MQC was imbalanced. Cav-1 deletion aggravated the damage to neurological function, neurons, mitochondrial morphology and mitochondrial function after CI, aggravated the imbalance of mitochondrial dynamics, and inhibited mitophagy and biosynthesis. BHD can maintain MQC homeostasis after CI through Cav-1 and improve CI injury. Discussion: Cav-1 can affect CI injury by regulating MQC, and this mechanism may be another target of BHD for anti-cerebral ischemia injury. [ABSTRACT FROM AUTHOR]

IntroductionIn the US, despite the recent decline in breast cancer deaths, a persistent mortality disparity exists between black and white women with breast cancer, with black women having a 41% higher death rate. Several studies are now reporting that racial disparities can exist independent of socioeconomic and standard of care issues, suggesting that biological factors may be involved. Caveolin-1 (Cav1) loss in the tumor stromal compartment is a novel clinical biomarker for predicting poor outcome in breast cancer including triple negative subtype, however the mechanism of Cav1 loss is unknown. We previously identified miR-510-5p as a novel oncomir and propose here that the high levels observed in patients is a novel mechanism leading to stromal Cav1 loss and worse outcomes.MethodsCav1 was identified as a direct target of miR-510-5p through luciferase, western blot and qPCR assays. Stromal cross talk between epithelial cells and fibroblasts was assessed in vitro using transwell co-culture assays and in vivo using xenograft assays.ResultsWe found that Cav1 is a direct target of miR-510-5p and that expression in fibroblasts results in an ‘activated’ phenotype. We propose that this could be important in the context of cancer disparities as we also observed increased levels of circulating miR-510-5p and reduced levels of stromal Cav1 in black women compared to white women with breast cancer. Finally, we observed a significant increase in tumor growth when tumor cells were co-injected with miR-510-5p expressing cancer associated fibroblasts in vivo.ConclusionWe propose that miR-510-5p mediated negative regulation of Cav1 in fibroblasts is a novel mechanism of aggressive tumor growth and may be a driver of breast cancer disparity.

Macrophages (MФ), the primary cell of the innate immune system, serves as the first line of defense. During bacterial infection, Gram-negative (G-) bacteria release nanosized outer membrane vesicles (OMVs), facilitating the crosstalk between the microbe and the host. The underlying mechanisms by which OMVs induced proinflammatory (M1) activation are still unknown. Our study shows that OMVs caused M1 activation via modulating various toll-like receptor (TLR) expressions as they contain LPS, LTA, bacterial DNAs, and flagellins. Also, we found that caveolin-1 (cav-1), a 21-kDa scaffolding protein of caveolae and lipid rafts, plays a significant role in OMV-induced pro-inflammatory response in regulating various TLR signaling pathways. Specifically, cav-1 deletion increased the expression of OMV-induced TLRs, pro-inflammatory cytokine secretions (TNF-a and IL-1b), and the reactive oxygen species (ROS) production in MФs. Further, we examined the interaction between Cav-1 and TLR4 by immunoprecipitation, colocalization, and computational models, providing future direction to explore the role of cav-1 in OMV-induced other TLR signaling. Altogether, Cav-1 is a key regulator in OMVinduced multiple TLRs response. This study promotes future research to develop drugs by targeting the specific motif of cav-1 or TLRs against bacterial infection and macrophage-mediated inflammation. [ABSTRACT FROM AUTHOR]

Macrophages (MФ), the primary cell of the innate immune system, serves as the first line of defense. During bacterial infection, Gram-negative (G-) bacteria release nanosized outer membrane vesicles (OMVs), facilitating the crosstalk between the microbe and the host. The underlying mechanisms by which OMVs induced pro-inflammatory (M1) activation are still unknown. Our study shows that OMVs caused M1 activation via modulating various toll-like receptor (TLR) expressions as they contain LPS, LTA, bacterial DNAs, and flagellins. Also, we found that caveolin-1 (cav-1), a 21-kDa scaffolding protein of caveolae and lipid rafts, plays a significant role in OMV-induced pro-inflammatory response in regulating various TLR signaling pathways. Specifically, cav-1 deletion increased the expression of OMV-induced TLRs, pro-inflammatory cytokine secretions (TNF-α and IL-1β), and the reactive oxygen species (ROS) production in MФs. Further, we examined the interaction between Cav-1 and TLR4 by immunoprecipitation, colocalization, and computational models, providing future direction to explore the role of cav-1 in OMV-induced other TLR signaling. Altogether, Cav-1 is a key regulator in OMV-induced multiple TLRs response. This study promotes future research to develop drugs by targeting the specific motif of cav-1 or TLRs against bacterial infection and macrophage-mediated inflammation.

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

Background: Animal and cell model studies have implicated CAV1 in the pathophysiology of metabolic disorders. Our previous studies demonstrated a potential association of CAV1 rs1997623 C/A variant with pediatric metabolic syndrome (MetS) in Arab children. In the present study, we evaluate whether the CAV1 variant associates with MetS Arab adults as well. The association signal is further examined for ancestry-specific variation by considering cohorts of other ethnicities. Method: The CAV1 rs1997623 was genotyped in three cohorts of Arab (n = 479), South Asian (n = 660), and South East Asian (n = 362) ethnic adults from Kuwait. MetS status of the individuals was diagnosed using the IDF criteria (presence of central obesity and at least two abnormalities out of: elevated TG, low HDL, hypertension, or T2D). The quantitative measure of MetS was calculated as siMS = 2 × WC/Height + FBG/5.6 + TG/1.7 + SBP/130–HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous MetS traits were assessed using linear and logistic regression models adjusted for age and sex. In addition, empirical p-values (Pemp) were generated using max(T) permutation procedure based on 10,000 permutations. Results: The CAV1 variant was significantly associated with MetS status (OR = 1.811 [1.25–2.61]; p-value = 0.0015; Pemp = 0.0013) and with siMS (Effect size = 0.206; p-value = 0.0035; Pemp = 0.0028) in the cohort of Arab individuals. The association was weak and insignificant in the South Asian and South East Asian cohorts (OR = 1.19 and 1.11; p-values = 0.25 and 0.67, respectively). Conclusion: The reported association of CAV1 rs1997623 C/A with MetS in Arab pediatric population is now demonstrated in an adult Arab cohort as well. The weak association signal seen in the Asian cohorts lead us to propose a certain extent of ethnic-specificity in CAV1 rs1997623 association with MetS. [ABSTRACT FROM AUTHOR]

Background: Animal and cell model studies have implicated CAV1 in the pathophysiology of metabolic disorders. Our previous studies demonstrated a potential association of CAV1 rs1997623 C/A variant with pediatric metabolic syndrome (MetS) in Arab children. In the present study, we evaluate whether the CAV1 variant associates with MetS Arab adults as well. The association signal is further examined for ancestry-specific variation by considering cohorts of other ethnicities.Method: The CAV1 rs1997623 was genotyped in three cohorts of Arab (n = 479), South Asian (n = 660), and South East Asian (n = 362) ethnic adults from Kuwait. MetS status of the individuals was diagnosed using the IDF criteria (presence of central obesity and at least two abnormalities out of: elevated TG, low HDL, hypertension, or T2D). The quantitative measure of MetS was calculated as siMS = 2 × WC/Height + FBG/5.6 + TG/1.7 + SBP/130–HDL/1.02 for males or HDL/1.28 for females. Allelic associations with quantitative and dichotomous MetS traits were assessed using linear and logistic regression models adjusted for age and sex. In addition, empirical p-values (Pemp) were generated using max(T) permutation procedure based on 10,000 permutations.Results: The CAV1 variant was significantly associated with MetS status (OR = 1.811 [1.25–2.61]; p-value = 0.0015; Pemp = 0.0013) and with siMS (Effect size = 0.206; p-value = 0.0035; Pemp = 0.0028) in the cohort of Arab individuals. The association was weak and insignificant in the South Asian and South East Asian cohorts (OR = 1.19 and 1.11; p-values = 0.25 and 0.67, respectively).Conclusion: The reported association of CAV1 rs1997623 C/A with MetS in Arab pediatric population is now demonstrated in an adult Arab cohort as well. The weak association signal seen in the Asian cohorts lead us to propose a certain extent of ethnic-specificity in CAV1 rs1997623 association with MetS.

Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of Streptococcus pneumonia, a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca2+ levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol. We hypothesized that the abundance of cholesterol-rich domains in EC plasma membranes confers cellular susceptibility to PLY. Contrary to this hypothesis, we found increased PLY-induced IC Ca2+ following membrane cholesterol depletion. Caveolin-1 (Cav-1) is an essential structural protein of caveolae and its regulation by cholesterol levels suggested a possible role in EC barrier function. Indeed, Cav-1 and its scaffolding domain peptide protected the endothelial barrier from PLY-induced disruption. In loss of function experiments, Cav-1 was knocked-out using CRISPR-Cas9 or silenced in human lung microvascular ECs. Loss of Cav-1 significantly enhanced the ability of PLY to disrupt endothelial barrier integrity. Rescue experiments with re-expression of Cav-1 or its scaffolding domain peptide protected the EC barrier against PLY-induced barrier disruption. Dynamin-2 (DNM2) is known to regulate caveolar membrane endocytosis. Inhibition of endocytosis, with dynamin inhibitors or siDNM2 amplified PLY induced EC barrier dysfunction. These results suggest that Cav-1 protects the endothelial barrier against PLY by promoting endocytosis of damaged membrane, thus reducing calcium entry and PLY-dependent signaling. [ABSTRACT FROM AUTHOR]

Pneumolysin (PLY) is a bacterial pore forming toxin and primary virulence factor of Streptococcus pneumonia, a major cause of pneumonia. PLY binds cholesterol-rich domains of the endothelial cell (EC) plasma membrane resulting in pore assembly and increased intracellular (IC) Ca2+ levels that compromise endothelial barrier integrity. Caveolae are specialized plasmalemma microdomains of ECs enriched in cholesterol. We hypothesized that the abundance of cholesterol-rich domains in EC plasma membranes confers cellular susceptibility to PLY. Contrary to this hypothesis, we found increased PLY-induced IC Ca2+ following membrane cholesterol depletion. Caveolin-1 (Cav-1) is an essential structural protein of caveolae and its regulation by cholesterol levels suggested a possible role in EC barrier function. Indeed, Cav-1 and its scaffolding domain peptide protected the endothelial barrier from PLY-induced disruption. In loss of function experiments, Cav-1 was knocked-out using CRISPR-Cas9 or silenced in human lung microvascular ECs. Loss of Cav-1 significantly enhanced the ability of PLY to disrupt endothelial barrier integrity. Rescue experiments with re-expression of Cav-1 or its scaffolding domain peptide protected the EC barrier against PLY-induced barrier disruption. Dynamin-2 (DNM2) is known to regulate caveolar membrane endocytosis. Inhibition of endocytosis, with dynamin inhibitors or siDNM2 amplified PLY induced EC barrier dysfunction. These results suggest that Cav-1 protects the endothelial barrier against PLY by promoting endocytosis of damaged membrane, thus reducing calcium entry and PLY-dependent signaling.

The blood-brain barrier (BBB) comprises a single layer of endothelial cells and maintains a safe and homeostatic environment for proper neuronal function and synaptic transmission. BBB is not a discrete physical barrier, but a complex, dynamic, and adaptable interface. BBB continues to mature under the influence of the neural environment within a short period of time after birth. However, the basic mechanism of BBB formation and maintenance remains a mystery. Early studies have identified two structural characteristics of microvascular endothelium: special tight junctions (TJs) and a very low transcellular vesicle transport rate. Previous studies believed that BBB damage was mainly due to the destruction of tight junctions, and the role of vesicle transcytosis was neglected, so there was a lack of research on its impact on blood-brain barrier. It is urgent to get a better clarification of the unique structural and functional characteristics of the BBB endothelium to explain the role of BBB injury in neurological diseases. RNA sequencing was used to study the molecular characterization of cerebral cortex vascular endothelium by isolating them from neonatal, adolescent and adult rats. For investigation the maintenance mechanism of the BBB, we focused on the cellular and molecular regulation of barrier formation and the two characteristics of microvascular endothelial cells. Interestingly, we found that during the development of the blood-brain barrier, although the tight junctions gradually mature, endothelial cell transcytosis is gradually enhanced, resulting in an increase in the permeability of the blood-brain barrier. This study suggested that under physiological conditions, low vesicle transport is playing an important role in maintaining the integrity of the blood-brain barrier. This study not only summarized the unique characteristics of microvascular endothelial cells, but also illustrated a clarified mechanism of the development and maintenance of BBB which can provide new therapeutic opportunities for central nervous system drug delivery. Raw data of RNA sequencing were deposited in NCBI Sequence Read Archive database (PRJNA790676). Graphical representation of the proposed molecular pathway. During BBB development, cav-1 is gradually upregulated, vesicle transcytosis is gradually increased. Although tight junctions are gradually matured, BBB permeability is still increased, revealing the important role of low vesicle transcytosis in maintaining BBB permeability. [ABSTRACT FROM AUTHOR]

Background: Caveolin-1 (Cav-1) plays pivotal roles in the endothelial function and angiogenesis postischemia. Moyamoya disease (MMD) is characterized by progressive artery stenosis with unknown etiology. We aim to determine whether serum Cav-1 levels of patients with MMD were associated with collateral vessel formation after bypass surgery. Methods: We studied serum Cav-1 levels of 130 patients with MMD (16 with RNF213 p.R4810K mutation and 114 without RNF213 p.R4810K mutation), 15 patients with acute stroke, and 33 healthy controls. Cerebral perfusion and collateral circulation were evaluated preoperation and at 6 months after operation using pseudocontinuous arterial spin labeling MRI (pCASL-MRI) and digital subtraction angiography (DSA), respectively. Endothelial expression of Cav-1 was verified in the superficial temporal artery (STA) wall of patients with MMD by immunofluorescence double staining. We also investigated whether overexpression of Cav-1 affects cell migration and tube formation using human microvascular endothelial cells (HMECs). Results: The serum Cav-1 level of patients with MMD intermediated between the stroke group and healthy controls and it was enhanced after the bypass surgery (681.87 ± 311.63 vs. 832.91 ± 464.41 pg/ml, p = 0.049). By 6 months after bypass surgery, patients with MMD with better collateral compensation manifested higher postoperative/preoperative Cav-1 ratio (rCav-1) than bad compensation patients. Consistently, cerebral blood flow (CBF) determined by pCASL-MRI (nCBFMCA ratio) was positively in line with rCav-1 ratio (r = 0.8615, p < 0.0001). Cav-1 was expressed in the endothelial cells of the STA vessels of patients with MMD. Overexpression of Cav-1 by plasmid transfection in HMECs promoted tube formation and cell migration. Conclusion: This study indicated that Cav-1 may be a potential driver to promote angiogenesis and collateral formation after bypass surgery in patients with MMD, providing a better understanding of MMD pathophysiology and potential non-surgical targets of MMD. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) comprises a single layer of endothelial cells and maintains a safe and homeostatic environment for proper neuronal function and synaptic transmission. BBB is not a discrete physical barrier, but a complex, dynamic, and adaptable interface. BBB continues to mature under the influence of the neural environment within a short period of time after birth. However, the basic mechanism of BBB formation and maintenance remains a mystery. Early studies have identified two structural characteristics of microvascular endothelium: special tight junctions (TJs) and a very low transcellular vesicle transport rate. Previous studies believed that BBB damage was mainly due to the destruction of tight junctions, and the role of vesicle transcytosis was neglected, so there was a lack of research on its impact on blood-brain barrier. It is urgent to get a better clarification of the unique structural and functional characteristics of the BBB endothelium to explain the role of BBB injury in neurological diseases. RNA sequencing was used to study the molecular characterization of cerebral cortex vascular endothelium by isolating them from neonatal, adolescent and adult rats. For investigation the maintenance mechanism of the BBB, we focused on the cellular and molecular regulation of barrier formation and the two characteristics of microvascular endothelial cells. Interestingly, we found that during the development of the blood-brain barrier, although the tight junctions gradually mature, endothelial cell transcytosis is gradually enhanced, resulting in an increase in the permeability of the blood-brain barrier. This study suggested that under physiological conditions, low vesicle transport is playing an important role in maintaining the integrity of the blood-brain barrier. This study not only summarized the unique characteristics of microvascular endothelial cells, but also illustrated a clarified mechanism of the development and maintenance of BBB which can provide new therapeutic opportunities for central nervous system drug delivery. Raw data of RNA sequencing were deposited in NCBI Sequence Read Archive database (PRJNA790676).

BackgroundCaveolin-1 (Cav-1) plays pivotal roles in the endothelial function and angiogenesis postischemia. Moyamoya disease (MMD) is characterized by progressive artery stenosis with unknown etiology. We aim to determine whether serum Cav-1 levels of patients with MMD were associated with collateral vessel formation after bypass surgery.MethodsWe studied serum Cav-1 levels of 130 patients with MMD (16 with RNF213 p.R4810K mutation and 114 without RNF213 p.R4810K mutation), 15 patients with acute stroke, and 33 healthy controls. Cerebral perfusion and collateral circulation were evaluated preoperation and at 6 months after operation using pseudocontinuous arterial spin labeling MRI (pCASL-MRI) and digital subtraction angiography (DSA), respectively. Endothelial expression of Cav-1 was verified in the superficial temporal artery (STA) wall of patients with MMD by immunofluorescence double staining. We also investigated whether overexpression of Cav-1 affects cell migration and tube formation using human microvascular endothelial cells (HMECs).ResultsThe serum Cav-1 level of patients with MMD intermediated between the stroke group and healthy controls and it was enhanced after the bypass surgery (681.87 ± 311.63 vs. 832.91 ± 464.41 pg/ml, p = 0.049). By 6 months after bypass surgery, patients with MMD with better collateral compensation manifested higher postoperative/preoperative Cav-1 ratio (rCav-1) than bad compensation patients. Consistently, cerebral blood flow (CBF) determined by pCASL-MRI (nCBFMCA ratio) was positively in line with rCav-1 ratio (r = 0.8615, p < 0.0001). Cav-1 was expressed in the endothelial cells of the STA vessels of patients with MMD. Overexpression of Cav-1 by plasmid transfection in HMECs promoted tube formation and cell migration.ConclusionThis study indicated that Cav-1 may be a potential driver to promote angiogenesis and collateral formation after bypass surgery in patients with MMD, providing a better understanding of MMD pathophysiology and potential non-surgical targets of MMD.

In prostate cancer (PCa), a characteristic stromal–epithelial redistribution of the membrane protein caveolin 1 (CAV1) occurs upon tumor progression, where a gain of CAV1 in the malignant epithelial cells is accompanied by a loss of CAV1 in the tumor stroma, both facts that were correlated with higher Gleason scores, poor prognosis, and pronounced resistance to therapy particularly to radiotherapy (RT). However, it needs to be clarified whether inhibiting the CAV1 gain in the malignant prostate epithelium or limiting the loss of stromal CAV1 would be the better choice for improving PCa therapy, particularly for improving the response to RT; or whether ideally both processes need to be targeted. Concerning the first assumption, we investigated the RT response of LNCaP PCa cells following overexpression of different CAV1 mutants. While CAV1 overexpression generally caused an increased epithelial-to-mesenchymal phenotype in respective LNCaP cells, effects that were accompanied by increasing levels of the 5′-AMP-activated protein kinase (AMPK), a master regulator of cellular homeostasis, only wildtype CAV1 was able to increase the three-dimensional growth of LNCaP spheroids, particularly following RT. Both effects could be limited by an additional treatment with the SRC inhibitor dasatinib, finally resulting in radiosensitization. Using co-cultured (CAV1-expressing) fibroblasts as an approximation to the in vivo situation of early PCa it could be revealed that RT itself caused an activated, more tumor-promoting phenotype of stromal fibroblats with an increased an increased metabolic potential, that could not be limited by combined dasatinib treatment. Thus, targeting fibroblasts and/or limiting fibroblast activation, potentially by limiting the loss of stromal CAV1 seems to be absolute for inhibiting the resistance-promoting CAV1-dependent signals of the tumor stroma.

In prostate cancer (PCa), a characteristic stromal–epithelial redistribution of the membrane protein caveolin 1 (CAV1) occurs upon tumor progression, where a gain of CAV1 in the malignant epithelial cells is accompanied by a loss of CAV1 in the tumor stroma, both facts that were correlated with higher Gleason scores, poor prognosis, and pronounced resistance to therapy particularly to radiotherapy (RT). However, it needs to be clarified whether inhibiting the CAV1 gain in the malignant prostate epithelium or limiting the loss of stromal CAV1 would be the better choice for improving PCa therapy, particularly for improving the response to RT; or whether ideally both processes need to be targeted. Concerning the first assumption, we investigated the RT response of LNCaP PCa cells following overexpression of different CAV1 mutants. While CAV1 overexpression generally caused an increased epithelial-to-mesenchymal phenotype in respective LNCaP cells, effects that were accompanied by increasing levels of the 5′-AMP-activated protein kinase (AMPK), a master regulator of cellular homeostasis, only wildtype CAV1 was able to increase the three-dimensional growth of LNCaP spheroids, particularly following RT. Both effects could be limited by an additional treatment with the SRC inhibitor dasatinib, finally resulting in radiosensitization. Using co-cultured (CAV1-expressing) fibroblasts as an approximation to the in vivo situation of early PCa it could be revealed that RT itself caused an activated, more tumor-promoting phenotype of stromal fibroblats with an increased an increased metabolic potential, that could not be limited by combined dasatinib treatment. Thus, targeting fibroblasts and/or limiting fibroblast activation, potentially by limiting the loss of stromal CAV1 seems to be absolute for inhibiting the resistance-promoting CAV1-dependent signals of the tumor stroma. [ABSTRACT FROM AUTHOR]

We have investigated the role caveolae/caveolin-1 (Cav-1) plays in endothelial nitric oxide synthase (eNOS) activation and how it impacts pregnancy-induced decreased vascular reactivity in normotensive (Wistar rats) and spontaneously hypertensive rats (SHR). Wistar rats and SHR were divided into non-pregnant (NP) and pregnant (P). Nitrite levels were assessed by the Griess method in the aorta and mesenteric vascular bed. In functional studies, arteries were incubated with methyl-β-cyclodextrin (dextrin, 10mmol/L), which disrupts caveolae by depleting cholesterol, and concentration-response curves to phenylephrine (PE) and acetylcholine (ACh) were constructed. Electronic microscopy was used to determine endothelial caveolae density in the aorta and resistance mesenteric artery in the presence of vehicle or dextrin (10mmol/L). Western blot was performed to evaluate Cav-1, p-Cav-1, calmodulin (CaM), and heat shock protein 90 (Hsp90) expression. Cav-1/eNOS interaction in the aorta and mesenteric vascular bed was assessed by co-immunoprecipitation. Nitric oxide (NO) generation was greater in arteries from P groups compared to NP groups. Dextrin did not change vascular responses in the aorta from P groups or the number of caveolae in P groups compared to NP groups. Compared to NP Wistar rats, NP SHR showed smaller number of caveolae and reduced Cav-1 expression. Pregnancy did not alter Cav-1, CaM, or Hsp90 expression in the aorta or mesenteric vascular bed from Wistar rats or SHR. These results suggest that pregnancy does not alter expression of the main eNOS regulatory proteins, but it decreases Cav-1/eNOS interaction. Reduced Cav-1/eNOS interaction in the aorta and mesenteric vascular bed seems to be an important mechanism to increase eNOS activity and nitric oxide production in pregnant normotensive and hypertensive rats. [ABSTRACT FROM AUTHOR]

Breast cancer remains the most common malignancy and the leading causality of cancer-associated mortality among women worldwide. With proven efficacy, Oldenlandia diffusa has been extensively applied in breast cancer treatment in Traditional Chinese Medicine (TCM) for thousands of years. However, the bioactive compounds of Oldenlandia diffusa accounting for its anti-breast cancer activity and the underlying biological mechanisms remain to be uncovered. Herein, bioactivity-guided fractionation suggested ursolic acid as the strongest anti-breast cancer compound in Oldenlandia diffusa. Ursolic acid treatment dramatically suppressed the proliferation and promoted mitochondrial-mediated apoptosis in breast cancer cells while brought little cytotoxicities in nonmalignant mammary epithelial cells in vitro. Meanwhile, ursolic acid dramatically impaired both the glycolytic metabolism and mitochondrial respiration function of breast cancer cells. Further investigations demonstrated that ursolic acid may impair the glycolytic metabolism of breast cancer cells by activating Caveolin-1 (Cav-1) signaling, as Cav-1 knockdown could partially abrogate the suppressive effect of ursolic acid on that. Mechanistically, ursolic acid could activate SP1-mediated CAV1 transcription by promoting SP1 expression as well as its binding with CAV1 promoter region. More meaningfully, ursolic acid administration could dramatically suppress the growth and metastasis of breast cancer in both the zebrafish and mouse xenotransplantation models of breast cancer in vivo without any detectable hepatotoxicity, nephrotoxicity or hematotoxicity. This study not only provides preclinical evidence supporting the application of ursolic acid as a promising candidate drug for breast cancer treatment but also sheds novel light on Cav-1 as a druggable target for glycolytic modulation of breast cancer.

Polarization of hepatic macrophages plays a crucial role in the injury and repair processes of acute and chronic liver diseases. However, the underlying molecular mechanisms remain elusive. Caveolin-1 (Cav1) is the structural protein of caveolae, the invaginations of the plasma membrane. It has distinct functions in regulating hepatitis, cirrhosis, and hepatocarcinogenesis. Given the increasing number of cases of liver cancer, nonalcoholic steatohepatitis, and non-alcoholic fatty liver disease worldwide, investigations on the role of Cav1 in liver diseases are warranted. In this study, we aimed to investigate the role of Cav1 in the pathogenesis of acute liver injury. Wild-type (WT) and Cav1 knockout (KO) mice (Cav1tm1Mls) were injected with carbon tetrachloride (CCl4). Cav1 KO mice showed significantly reduced degeneration, necrosis, and apoptosis of hepatocytes and decreased level of alanine transaminase (ALT) compared to WT mice. Moreover, Cav1 was required for the recruitment of hepatic macrophages. The analysis of the mRNA levels of CD86, tumor necrosis factor (TNF), and interleukin (IL)-6, as well as the protein expression of inducible nitric oxide synthase (iNOS), indicated that Cav1 deficiency inhibited the polarization of hepatic macrophages towards the M1 phenotype in the injured liver. Consistent with in vivo results, the expressions of CD86, TNF, IL-6, and iNOS were significantly downregulated in Cav1 KO macrophages. Also, fluorescence-activated cell sorting (FACS) analysis showed that the proportion of M1 macrophages was significantly decreased in the liver tissues obtained from Cav1 KO mice following CCl4 treatment. In summary, our results showed that Cav1 deficiency protected mice against CCl4-induced acute liver injury by regulating polarization of hepatic macrophages. We provided direct genetic evidence that Cav1 expressed in hepatic macrophages contributed to the pathogenesis of acute liver injury by regulating the polarization of hepatic macrophages towards the M1 phenotype. These findings suggest that Cav1 expressed in macrophages may represent a potential therapeutic target for acute liver injury.

Glioblastoma (GB) remains an aggressive malignancy with an extremely poor prognosis. Discovering new candidate drug targets for GB remains an unmet medical need. Caveolin-1 (Cav-1) has been shown to act variously as both a tumour suppressor and tumour promoter in many cancers. The implications of Cav-1 expression in GB remains poorly understood. Using clinical and genomic databases we examined the relationship between tumour Cav-1 gene expression (including its spatial distribution) and clinical pathological parameters of the GB tumour and survival probability in a TCGA cohort (n=155) and CGGA cohort (n=220) of GB patients. High expression of Cav-1 represented a significant independent predictor of shortened survival (HR = 2.985, 5.1 vs 14.9 months) with a greater statistically significant impact in female patients and in the Proneural and Mesenchymal GB subtypes. High Cav-1 expression correlated with other factors associated with poor prognosis: IDH w/t status, high histological tumour grade and low KPS score. A total of 4879 differentially expressed genes (DEGs) in the GB tumour were found to correlate with Cav-1 expression (either positively or negatively). Pathway enrichment analysis highlighted an over-representation of these DEGs to certain biological pathways. Focusing on those that lie within a framework of epithelial to mesenchymal transition and tumour cell migration and invasion we identified 27 of these DEGs. We then examined the prognostic value of Cav-1 when used in combination with any of these 27 genes and identified a subset of combinations (with Cav-1) indicative of co-operative synergistic mechanisms of action. Overall, the work has confirmed Cav-1 can serve as an independent prognostic marker in GB, but also augment prognosis when used in combination with a panel of biomarkers or clinicopathologic parameters. Moreover, Cav-1 appears to be linked to many signalling entities within the GB tumour and as such this work begins to substantiate Cav-1 or its associated signalling partners as candidate target for GB new drug discovery.

Breast cancer remains the most common malignancy and the leading causality of cancer-associated mortality among women worldwide. With proven efficacy, Oldenlandia diffusa has been extensively applied in breast cancer treatment in Traditional Chinese Medicine (TCM) for thousands of years. However, the bioactive compounds of Oldenlandia diffusa accounting for its anti-breast cancer activity and the underlying biological mechanisms remain to be uncovered. Herein, bioactivity-guided fractionation suggested ursolic acid as the strongest anti-breast cancer compound in Oldenlandia diffusa. Ursolic acid treatment dramatically suppressed the proliferation and promoted mitochondrial-mediated apoptosis in breast cancer cells while brought little cytotoxicities in nonmalignant mammary epithelial cells in vitro. Meanwhile, ursolic acid dramatically impaired both the glycolytic metabolism and mitochondrial respiration function of breast cancer cells. Further investigations demonstrated that ursolic acid may impair the glycolytic metabolism of breast cancer cells by activating Caveolin-1 (Cav-1) signaling, as Cav-1 knockdown could partially abrogate the suppressive effect of ursolic acid on that. Mechanistically, ursolic acid could activate SP1-mediated CAV1 transcription by promoting SP1 expression as well as its binding with CAV1 promoter region. More meaningfully, ursolic acid administration could dramatically suppress the growth and metastasis of breast cancer in both the zebrafish and mouse xenotransplantation models of breast cancer in vivo without any detectable hepatotoxicity, nephrotoxicity or hematotoxicity. This study not only provides preclinical evidence supporting the application of ursolic acid as a promising candidate drug for breast cancer treatment but also sheds novel light on Cav-1 as a druggable target for glycolytic modulation of breast cancer. [ABSTRACT FROM AUTHOR]

Glioblastoma (GB) remains an aggressive malignancy with an extremely poor prognosis. Discovering new candidate drug targets for GB remains an unmet medical need. Caveolin-1 (Cav-1) has been shown to act variously as both a tumour suppressor and tumour promoter in many cancers. The implications of Cav-1 expression in GB remains poorly understood. Using clinical and genomic databases we examined the relationship between tumour Cav-1 gene expression (including its spatial distribution) and clinical pathological parameters of the GB tumour and survival probability in a TCGA cohort (n=155) and CGGA cohort (n=220) of GB patients. High expression of Cav-1 represented a significant independent predictor of shortened survival (HR = 2.985, 5.1 vs 14.9 months) with a greater statistically significant impact in female patients and in the Proneural and Mesenchymal GB subtypes. High Cav-1 expression correlated with other factors associated with poor prognosis: IDH w/t status, high histological tumour grade and low KPS score. A total of 4879 differentially expressed genes (DEGs) in the GB tumour were found to correlate with Cav-1 expression (either positively or negatively). Pathway enrichment analysis highlighted an over-representation of these DEGs to certain biological pathways. Focusing on those that lie within a framework of epithelial to mesenchymal transition and tumour cell migration and invasion we identified 27 of these DEGs. We then examined the prognostic value of Cav-1 when used in combination with any of these 27 genes and identified a subset of combinations (with Cav-1) indicative of co-operative synergistic mechanisms of action. Overall, the work has confirmed Cav-1 can serve as an independent prognostic marker in GB, but also augment prognosis when used in combination with a panel of biomarkers or clinicopathologic parameters. Moreover, Cav-1 appears to be linked to many signalling entities within the GB tumour and as such this work begins to substantiate Cav-1 or its associated signalling partners as candidate target for GB new drug discovery. [ABSTRACT FROM AUTHOR]

Polarization of hepatic macrophages plays a crucial role in the injury and repair processes of acute and chronic liver diseases. However, the underlying molecular mechanisms remain elusive. Caveolin-1 (Cav1) is the structural protein of caveolae, the invaginations of the plasma membrane. It has distinct functions in regulating hepatitis, cirrhosis, and hepatocarcinogenesis. Given the increasing number of cases of liver cancer, nonalcoholic steatohepatitis, and non-alcoholic fatty liver disease worldwide, investigations on the role of Cav1 in liver diseases are warranted. In this study, we aimed to investigate the role of Cav1 in the pathogenesis of acute liver injury. Wild-type (WT) and Cav1 knockout (KO) mice (Cav1tm1Mls) were injected with carbon tetrachloride (CCl4). Cav1 KO mice showed significantly reduced degeneration, necrosis, and apoptosis of hepatocytes and decreased level of alanine transaminase (ALT) compared to WT mice. Moreover, Cav1 was required for the recruitment of hepatic macrophages. The analysis of the mRNA levels of CD86, tumor necrosis factor (TNF), and interleukin (IL)-6, as well as the protein expression of inducible nitric oxide synthase (iNOS), indicated that Cav1 deficiency inhibited the polarization of hepatic macrophages towards the M1 phenotype in the injured liver. Consistent with in vivo results, the expressions of CD86, TNF, IL-6, and iNOS were significantly downregulated in Cav1 KO macrophages. Also, fluorescence-activated cell sorting (FACS) analysis showed that the proportion of M1 macrophages was significantly decreased in the liver tissues obtained from Cav1 KO mice following CCl4 treatment. In summary, our results showed that Cav1 deficiency protected mice against CCl4-induced acute liver injury by regulating polarization of hepatic macrophages. We provided direct genetic evidence that Cav1 expressed in hepatic macrophages contributed to the pathogenesis of acute liver injury by regulating the polarization of hepatic macrophages towards the M1 phenotype. These findings suggest that Cav1 expressed in macrophages may represent a potential therapeutic target for acute liver injury. [ABSTRACT FROM AUTHOR]

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.

Compound Phyllanthus urinaria L. (CP) is a traditional Chinese medicine (TCM) formula for cancer treatment in the clinic, particularly during progression of hepatitis B-associated hepatocellular carcinoma (HBV-associated HCC). Nevertheless, its anti-metastatic action and mechanisms are not well elucidated. In this study, CP was found to exert remarkable inhibitory effects on the proliferation, migration and invasion of HBV-associated HCC cells. The following network and biological analyses predicted that CP mainly targeted Caveolin-1 (Cav-1) to induce anti-metastatic effects, and Wnt/β-catenin pathway was one of the core mechanisms of CP action against HBV-associated HCC. Further experimental validation implied that Cav-1 overexpression promoted metastasis of HBV-associated HCC by stabilizing β-catenin, while CP administration induced autophagic degradation of Cav-1, activated the Akt/GSK3β-mediated proteasome degradation of β-catenin via ubiquitination activation, and subsequently attenuated the metastasis-promoting effect of Cav-1. In addition, the anti-cancer and anti-metastatic action of CP was further confirmed by in vivo and ex vivo experiments. It was found that CP inhibited the tumor growth and metastasis of HBV-associated HCC in both mice liver cancer xenograft and zebrafish xenotransplantation models. Taken together, our study not only highlights the novel function of CP formula in suppressing metastasis of HBV-associated HCC, but it also addresses the critical role of Cav-1 in mediating Akt/GSK3β/β-catenin axis to control the late-phase of cancer progression.

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Compound Phyllanthus urinaria L. (CP) is a traditional Chinese medicine (TCM) formula for cancer treatment in the clinic, particularly during progression of hepatitis B-associated hepatocellular carcinoma (HBV-associated HCC). Nevertheless, its anti-metastatic action and mechanisms are not well elucidated. In this study, CP was found to exert remarkable inhibitory effects on the proliferation, migration and invasion of HBV-associated HCC cells. The following network and biological analyses predicted that CP mainly targeted Caveolin-1 (Cav-1) to induce anti-metastatic effects, and Wnt/β-catenin pathway was one of the core mechanisms of CP action against HBV-associated HCC. Further experimental validation implied that Cav-1 overexpression promoted metastasis of HBV-associated HCC by stabilizing β-catenin, while CP administration induced autophagic degradation of Cav-1, activated the Akt/GSK3β-mediated proteasome degradation of β-catenin via ubiquitination activation, and subsequently attenuated the metastasis-promoting effect of Cav-1. In addition, the anti-cancer and anti-metastatic action of CP was further confirmed by in vivo and ex vivo experiments. It was found that CP inhibited the tumor growth and metastasis of HBV-associated HCC in both mice liver cancer xenograft and zebrafish xenotransplantation models. Taken together, our study not only highlights the novel function of CP formula in suppressing metastasis of HBV-associated HCC, but it also addresses the critical role of Cav-1 in mediating Akt/GSK3β/β-catenin axis to control the late-phase of cancer progression. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton and membrane-associated caveolae contribute to active processes, such as cell morphogenesis and motility. How these two systems interact and control directional cell migration is an outstanding question but remains understudied. Here we identified a negative feedback between contractile actin assemblies and phosphorylated caveolin-1 (CAV-1) in migrating cells. Cytoplasmic CAV-1 vesicles display actin-associated motilities by sliding along actin filaments or/and coupling to do retrograde flow with actomyosin bundles. Inhibition of contractile stress fibers, but not Arp2/3-dependent branched actin filaments, diminished the phosphorylation of CAV-1 on site Tyr14, and resulted in substantially increased size and decreased motility of cytoplasmic CAV-1 vesicles. Reciprocally, both the CAV-1 phospho-deficient mutation on site Tyr14 and CAV-1 knockout resulted in dramatic AMPK phosphorylation, further causing reduced active level of RhoA-myosin II and increased active level of Rac1-PAK1-Cofilin, consequently led to disordered contractile stress fibers and prominent lamellipodia. As a result, cells displayed depolarized morphology and compromised directional migration. Collectively, we propose a model in which feedback-driven regulation between actin and CAV-1 instructs persistent cell migration.

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.

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.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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, p

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.

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.

Purpose: The 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. Methods: The 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. Results: A 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, p<0.01), and 4.73 times higher than that in HGPIN (OR= 4.73, 95% CI: 2.38–9.42, p<0.01). The relationship between caveolin-1 and clinicopathological characteristics of prostate cancer showed that the differences in caveolin-1 expression in patients with prostate-specific antigen (PSA) >10 vs. ≤ 10 (OR=2.09, 95% CI: 1.35–3.22, p<0.01), differentiation degree low vs. medium/high (OR=2.74, 95% CI: 1.84–4.08, p<0.01), TNM stage T3+T4 vs. T1+T2 (OR=2.77, 95% CI: 1.78–4.29, p<0.01), and lymph node metastasis present vs. absent (OR=2.61, 95% CI: 1.84–3.69, p<0.01) were statistically significant. The correlation analysis between caveolin-1 and the survival time of patients with prostate cancer demonstrated that caveolin-1 was closely related to the prognosis of prostate cancer patients (HR=1.50, 95% CI: 1.28–1.76, p<0.01). Conclusion: Caveolin-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Caveolin-1 (CAV1) is a membrane protein associated with metabolism in various cell types. The transforming growth factor beta (TGF-β) is a pro-fibrogenic cytokine in the liver, but its metabolic gene signatures remain unclear to date. We have previously shown that CAV1 alters TGF-β signaling and blocks its pro-apoptotic function. Here, we defined TGF-β-induced metabolic gene signatures in hepatocytes and assessed whether CAV1 abundance affects TGF-β control of those metabolic genes. Microarray analyses of primary hepatocytes after TGF-β stimulation (48 h) showed differential expression of 4224 genes, of which 721 are metabolic genes (adjusted p < 0.001). Functional annotation analysis revealed that TGF-β mainly suppresses metabolic gene network, including genes involved in glutathione, cholesterol, fatty acid, and amino acid metabolism. TGF-β also upregulated several genes related to glycan metabolism and ion transport. In contrast to TGF-β effects, CAV1 knockdown triggered the upregulation of metabolic genes. Immortalized mouse hepatocytes (AML12 cells) were used to validate the gene changes induced by TGF-β stimulation and CAV1 knockdown. Noteworthy, of the TGF-β metabolic target genes, CAV1 modulated the expression of 228 (27%). In conclusion, we present several novel metabolic gene signatures of TGF-β in hepatocytes and show that CAV1 abundance alters almost a third of these genes. These findings could enable a better understanding of TGF-β function in normal and diseased liver especially where differential CAV1 level is implicated.

ObjectiveThe purpose of the study was to explore the effect of YangXue QingNao Wan (YXQNW), a compound Chinese medicine, on cerebrovascular hyperpermeability, neuronal injury, and related mechanisms in spontaneously hypertensive rat (SHR).MethodsFourteen-week-old male SHR were used, with Wistar Kyoto (WKY) rats as control. YXQNW (0.5 g/kg/day), enalapril (EN, 8 mg/kg/day), and nifedipine (NF, 7.1 mg/kg/day) were administrated orally for 4 weeks. To assess the effects of the YXQNW on blood pressure, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) were measured. After administering the drugs for 4 weeks, the cerebral blood flow (CBF), albumin leakage from microvessels in middle cerebral artery (MCA)-dominated area, and the number and morphology of microvessels were assessed in the hippocampus area and cortex. Neuronal damage and apoptosis were assessed by Nissl staining and TUNEL staining. To assess the mechanisms of cerebrovascular hyperpermeability, we performed immunofluorescence and Western blot to assess the expression and integrity of cerebral microvascular tight junction (TJ) and caveolin-1 (Cav-1) in cortex. Energy metabolism and Src-MLC-MLCK pathway in cortex were assessed then for elucidating the underlying mechanism of the observed effect of YXQNW.ResultsSpontaneously hypertensive rat exhibited higher blood pressure, Evans blue (EB) extravasation, albumin leakage, increased brain water content, decreased CBF, perivascular edema, and neuronal apoptosis in the hippocampus and cortex, all of which were attenuated by YXQNW treatment. YXQNW inhibited the downregulation of TJ proteins, mitochondrial Complex I, Complex II, and Complex V, and upregulation of caveolin-1, inhibiting Src/MLCK/MLC signaling in SHR. YXQNW combined with EN + NF revealed a better effect for some outcomes compared with either YXQNW or EN + NF alone.ConclusionThe overall result shows the potential of YXQNW to attenuate blood–brain barrier (BBB) breakdown in SHR, which involves regulation of energy metabolism and Src/MLCK/MLC signaling. This result provides evidence supporting the application of YXQNW as an adjuvant management for hypertensive patients to prevent hypertensive encephalopathy.

Objective: Lipopolysaccharide (LPS) causes microvascular dysfunction, which is a key episode in the pathogenesis of endotoxemia. This work aimed to investigate the effect of Qing-Ying-Tang (QYT), a compound Chinese medicine in cerebral microcirculation disturbance and brain damage induced by LPS.Methods: Male C57/BL6 mice were continuously transfused with LPS (7.5 mg/kg/h) through the left femoral vein for 2 h. QYT (14.3 g/kg) was given orally 2 h after LPS administration. The dynamics of cerebral microcirculation were evaluated by intravital microscopy. Brain tissue edema was assessed by brain water content and Evans Blue leakage. Cytokines in plasma and brain were evaluated by flow cytometry. Confocal microscopy and Western blot were applied to detect the expression of junction and adhesion proteins, and signaling proteins concerned in mouse brain tissue.Results: Post-treatment with QYT significantly ameliorated LPS-induced leukocyte adhesion to microvascular wall and albumin leakage from cerebral venules and brain tissue edema, attenuated the increase of MCP-1, MIP-1α, IL-1α, IL-6, and VCAM-1 in brain tissue and the activation of NF-κB and expression of MMP-9 in brain. QYT ameliorated the downregulation of claudin-5, occludin, JAM-1, ZO-1, collagen IV as well as the expression and phosphorylation of VE-cadherin in mouse brain.Conclusions: This study demonstrated that QYT protected cerebral microvascular barrier from disruption after LPS by acting on the transcellular pathway mediated by caveolae and paracellular pathway mediated by junction proteins. This result suggests QYT as a potential strategy to deal with endotoxemia.

Proper axonal growth and guidance is essential for neuron differentiation and development. Abnormal neuronal development due to genetic or epigenetic influences can contribute to neurological and mental disorders such as Down syndrome, Rett syndrome, and autism. Identification of the molecular targets that promote proper neuronal growth and differentiation may restore structural and functional neuroplasticity, thus improving functional performance in neurodevelopmental disorders. Using differentiated human neuronal progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs), the present study demonstrates that during early stage differentiation of human NPCs, neuron-targeted overexpression constitutively active Rac1 (Rac1CA) and constitutively active Cdc42 (Cdc42CA) enhance expression of P-Cav-1, T-Cav-1, and P-cofilin and increases axonal growth. Similarly, neuron-targeted over-expression of Cav-1 (termed SynCav1) increases axonal development by increasing both axon length and volume. Moreover, inhibition of Cav-1(Y14A) phosphorylation blunts Rac1/Cdc42-mediated both axonal growth and differentiation of human NPCs and SynCav1(Y14A)-treated NPCs exhibited blunted axonal growth. These results suggest that: (1) SynCav1-mediated dendritic and axonal growth in human NPCs is dependent upon P-Cav-1, (2) P-Cav-1 is necessary for proper axonal growth during early stages of neuronal differentiation, and (3) Rac1/Cdc42CA-mediated neuronal growth is in part dependent upon P-Cav-1. In conclusion, Cav-1 phosphorylation is essential for human neuronal axonal growth during early stages of neuronal differentiation.

Caveolin-1 (CAV1) is a membrane protein associated with metabolism in various cell types. The transforming growth factor beta (TGF-β) is a pro-fibrogenic cytokine in the liver, but its metabolic gene signatures remain unclear to date. We have previously shown that CAV1 alters TGF-β signaling and blocks its pro-apoptotic function. Here, we defined TGF-β-induced metabolic gene signatures in hepatocytes and assessed whether CAV1 abundance affects TGF-β control of those metabolic genes. Microarray analyses of primary hepatocytes after TGF-β stimulation (48 h) showed differential expression of 4224 genes, of which 721 are metabolic genes (adjusted p < 0.001). Functional annotation analysis revealed that TGF-β mainly suppresses metabolic gene network, including genes involved in glutathione, cholesterol, fatty acid, and amino acid metabolism. TGF-β also upregulated several genes related to glycan metabolism and ion transport. In contrast to TGF-β effects, CAV1 knockdown triggered the upregulation of metabolic genes. Immortalized mouse hepatocytes (AML12 cells) were used to validate the gene changes induced by TGF-β stimulation and CAV1 knockdown. Noteworthy, of the TGF-β metabolic target genes, CAV1 modulated the expression of 228 (27%). In conclusion, we present several novel metabolic gene signatures of TGF-β in hepatocytes and show that CAV1 abundance alters almost a third of these genes. These findings could enable a better understanding of TGF-β function in normal and diseased liver especially where differential CAV1 level is implicated. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the study was to explore the effect of YangXue QingNao Wan (YXQNW), a compound Chinese medicine, on cerebrovascular hyperpermeability, neuronal injury, and related mechanisms in spontaneously hypertensive rat (SHR). Methods: Fourteen-week-old male SHR were used, with Wistar Kyoto (WKY) rats as control. YXQNW (0.5 g/kg/day), enalapril (EN, 8 mg/kg/day), and nifedipine (NF, 7.1 mg/kg/day) were administrated orally for 4 weeks. To assess the effects of the YXQNW on blood pressure, the systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean blood pressure (MBP) were measured. After administering the drugs for 4 weeks, the cerebral blood flow (CBF), albumin leakage from microvessels in middle cerebral artery (MCA)-dominated area, and the number and morphology of microvessels were assessed in the hippocampus area and cortex. Neuronal damage and apoptosis were assessed by Nissl staining and TUNEL staining. To assess the mechanisms of cerebrovascular hyperpermeability, we performed immunofluorescence and Western blot to assess the expression and integrity of cerebral microvascular tight junction (TJ) and caveolin-1 (Cav-1) in cortex. Energy metabolism and Src-MLC-MLCK pathway in cortex were assessed then for elucidating the underlying mechanism of the observed effect of YXQNW. Results: Spontaneously hypertensive rat exhibited higher blood pressure, Evans blue (EB) extravasation, albumin leakage, increased brain water content, decreased CBF, perivascular edema, and neuronal apoptosis in the hippocampus and cortex, all of which were attenuated by YXQNW treatment. YXQNW inhibited the downregulation of TJ proteins, mitochondrial Complex I, Complex II, and Complex V, and upregulation of caveolin-1, inhibiting Src/MLCK/MLC signaling in SHR. YXQNW combined with EN + NF revealed a better effect for some outcomes compared with either YXQNW or EN + NF alone. Conclusion: The overall result shows the potential of YXQNW to attenuate blood–brain barrier (BBB) breakdown in SHR, which involves regulation of energy metabolism and Src/MLCK/MLC signaling. This result provides evidence supporting the application of YXQNW as an adjuvant management for hypertensive patients to prevent hypertensive encephalopathy. [ABSTRACT FROM AUTHOR]