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Acute lung injury (ALI) is an intractable medical problem linked with to high morbidity and mortality all over the worldglobally. The prognosis of advanced acute lung injury remains persistently poor due to its underlying mechanisms remain unclear.Despite advancements in medical research, the its prognosis of advanced ALI remains persistently poor due to unclear underlying mechanisms. We aimed to investigate the protective effects of silencing information regulator 1 (SIRT1) on lipopolysaccharide (LPS)-induced acute lung injuryALI and to reveal its underlying molecular mechanism. Male Sprague-–Dawley rats were divided grouped into 4 groupsfour: normal saline group (group NS), lipopolysaccharide group (group L), SIRT1 activator SRT1720-pretreated group (group S), and SIRT1 inhibitor EX527- pretreated group (group E). Rats They were intranasally dripped with LPS to establish the model of ALI modelsacute lung injury respectively. We investigated the effect of SIRT1 on acute lung injury by analysing We analyzed the CT images of the rat lungs and used, HE staining, lung wet-to-dry ratio, inflammatory factor expression, lung injury marker expression, immunohistochemistry, and related mRNA expression to determine the effect of SIRT1 on ALI. Our results show that LPS induction produced resulted in acute lung injury, ALI and disrupting disrupted normal SIRT1 expression, which led to the overexpression of STAT3, TLR4, TNF-ɑ, and IL-6 and suppression of Cav-1 expression. Upregulation The upregulation of Cav-1 protein and mRNA following the administration of an SIRT1 agonist resulted in reduced lung injury. SRT1720 pretreatment was closely associated with reduced expressions of STAT3,TLR4, TNF-ɑ, and IL-6. ALI lung injury was more severeworsened after administration of SIRT1 inhibitors, and the changes in the above indicators were reversed. These results suggest that SIRT1 may protect against LPS-induced acute lung injuryALI via by counteracting inflammatory remissionion, and this protective effect might may be mediated by suppressing STAT3 to activate the expression ofinduce Cav-1 expression. • Provide a method for alleviating acute lung injury. • SIRT1 may protect against LPS-induced acute lung injury by counteracting inflammation. • The LPS model in rats has important implications for the study of lung injury. [ABSTRACT FROM AUTHOR]

Abstract Objective The aim of this study was to investigate the effects of hyperbaric oxygen on the permeability of the blood-brain barrier in rats with global cerebral ischemia/reperfusion injury and explore possible mechanisms. Methods A rat model of global cerebral ischemia/reperfusion injury established via Pulsinelli four-vessel occlusion method and a total of 162 Wistar rats were randomly divided into three groups, including sham group, global cerebral ischemia/reperfusion group (IR group) and hyperbaric oxygen treated group (HBO group). Permeability of the blood-brain barrier of these rats were evaluated by Evans Blue staining. The expression of caveolin-1 and tight junction protein ZO-1 was examined by Immunohistochemistry staining and western-blotting. Results Successfully establishment of the rat model was verified by W:D ratio, and significantly increased Evans Blue level was found in IR group compared to control group, whereas hyperbaric treatment could result in decreased Evans Blue level in HBO group. Increased expression of caveolin-1 and tight junction protein ZO-1 were found in rats with hyperbaric oxygen exposure compared to those in IS group. Conclusions Hyperbaric oxygen exposure improved the permeability of the blood-brain barrier in rats with global cerebral ischemia/reperfusion injury, and increased expression of caveolin-1 and tight junction protein ZO-1 were involved in the mechanisms. [ABSTRACT FROM AUTHOR]

Caveolin-1 (Cav-1), as a membrane protein involved in the formation of caveolae, binds steroid receptors and endothelial nitric oxide synthase, limiting its translocation and activation. In the present study, we investigated the role of Cav-1 in the progression of hepatic fibrosis induced by carbon tetrachloride (CCl 4 ) in murine animals. Therefore, the wild type (WT) and Cav-1-knockout (Cav-1 −/− ) mice were used in our study and subjected to CCl 4 . The results indicated that CCl 4 induced the decrease of Cav-1 expression in liver tissue samples. And Cav-1 −/− intensified CCl 4 -triggered hepatic injury, evidenced by the stronger hepatic histological alterations, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. CCl 4 led to oxidative stress, supported by the reduced superoxide dismutase (SOD) activity and glutathione (GSH) levels, as well as enhanced malondialdehyde (MDA) and O 2 − levels in liver samples. And the process was intensified by Cav-1 −/− . Additionally, CCl 4 -caused hepatic inflammation was aggregated by Cav-1 −/− via further increasing the secretion of pro-inflammatory cytokines. Moreover, CCl 4 -caused fibrosis was strengthened by Cav-1 −/− , which was evidenced by the up-regulation of α-smooth muscle actin (α-SMA), collagen alpha 1 type 1 (Col1A1), lysyl oxidase (Lox) and transforming growth factor-β1 (TGF-β1) in liver tissues. Similar results were observed in TGF-β1-stimulated hepatic stellate cells (HSCs) and LX-2 cells without Cav-1 expressions that in vitro, suppressing Cav-1 further accelerated TGF-β1-induced oxidative stress, inflammation and fibrosis development. In conclusion, our results indicated that Cav-1 played an important role in CCl 4 -induced hepatic injury, which may be used as potential therapeutic target for hepatic fibrosis treatment. [ABSTRACT FROM AUTHOR]

Insufficient sialylation can result in rapid clearance of therapeutic glycoproteins by intracellular degradation, which is mainly mediated by asialoglycoprotein receptors (ASGPRs) on hepatic cells. In contrast, for glycoproteins, a long half-life is often related to high level of terminal sialic acid. These could be extremely important for insufficient sialylated biomedicines in clinic, and development of therapeutic glycoproteins in laboratory. However, how the desialylated glycoproteins are removed and how to evaluate the ASGPRs mediated endocytosis in vitro needs further investigate. Herein we described an integrative characterization of ASGPRs in vitro to elucidate its endocytosis properties. The endocytosis was determined by a fluorescence-based quantization method. The results showed that the ASGPRs could bind to poorly sialylated glycoproteins including asialofetuin and low sialylated recombinant Factor VIIa with a relatively higher ASGPRs binding affinity, and induce a more rapid endocytosis in vitro . Moreover, the mechanism under the internalization of ASGPRs was also investigated, which was found to depend on clathrin and caveolin. Utilizing the relative fluorescence quantification can be suitable for measurement of insufficient sialylated glycoprotein endocytosis and quality control of therapeutic glycoproteins, which could be useful for the understanding of the development of therapeutic glycoproteins. [ABSTRACT FROM AUTHOR]

Aim This study was undertaken to verify if two-weeks treatment of lipoic acid (LA) influence colon damage and pro-inflammatory cytokine synthesis during DSS-induced acute colitis. Moreover, as LA has anti-oxidative properties, we analyzed its influence on the level of antioxidative enzymes, HO-1 and eNOS, and their regulator- caveolin-1. Methods LA was administrated to male C57/BALBc mice at a dose of 25 or 50 mg/kg/day ( i.p. ) for 21 days. Acute colitis was induced by administration of 4% DSS (w/v) in drinking water for 5 days, followed by 2 days of normal drinking water. Mice in LA + DSS groups were treated with LA (25 or 50 mg/kg/day; i.p. ) starting 14 days prior to 4% DSS. Control group received saline for 21 days. In the colon tissue we measured myeloperoxidase activity (MPO), IL-1β, IL-6, IL-17A, IL-23 (ELISA method), and tissue level of cav-1, phospho-eNOS, total eNOS and HO-1 (Western blot). Results Administration of DSS significantly increased total colon damage (p < 0.001), myeloperoxidase (MPO) activity (p < 0.05) and pro-inflammatory IL-6 (p < 0.05). There was also a tendency towards higher IL-1β, IL-17A, and IL-23 in the colon. LA alone did not influence total colon damage, MPO activity, and pro-inflammatory cytokines concentration compared to control (p < 0.05). Notably, mice treated with LA and DSS had significantly decreased total colon damage score (p < 0.001), despite augmented colon MPO activity (p < 0.01), but similar (IL-17A) or even significantly higher level (IL-1β, IL-23) as compared to the DSS group (p < 0.05). IL-6 was insignificantly decreased after LA treatment at a dose of 50 mg/kg. In acute colitis there was a tendency towards an increase in cav-1 and HO-1 and a decrease p-eNOS/total eNOS ratio. Moreover, the LA + DSS groups had higher expression of HO-1 and p-eNOS/total eNOS (p < 0.05) compared to the DSS group, and a tendency towards higher cav-1 level. The changes did not depend on LA dose. Conclusion Our study indicated that LA, at lower doses, may influence cav-1-regulated antioxidative enzyme levels (HO-1 and p-eNOS/total eNOS) despite an increase in colon pro-inflammatory cytokine levels during acute colitis. Hence, LA treatment may be – to some extent – beneficial in attenuation of acute colitis. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common type of carcinoma and the 5th leading cause of cancer-related death in males. Triptolide, is a main and effective component of Tripterygium wilfordii Hook F, which exerts an broad-spectrum anti-malignant tumor function. However, the effect of triptolide on migration and invasion of human prostate cancer cells is still poorly understood. In this study, we demonstrated that triptolide significantly inhibited the proliferation, migration and invasion of prostate cancer cells in a time- and dose-dependent manner. Caveolin-1 (Cav-1) is regarded as a major structural protein of caveolae and participated in lipid transport, signal transduction and tumor progression. Triptolide treatment inhibited the expression of tumor promoter Cav-1 and reduced CD147 and MMPs activities at both mRNA and protein levels. Meanwhile, triptolide treatment combined with Cav-1 knockdown in PCa cells enhanced the effects of anti-migration and anti-invasion, and those effects were restored following Cav-1-rescued. Together, our research indicates that triptolide represses the migration and invasion through Cav-1/CD147/MMPs pathway in PCa cells, which gives a better understanding of triptolide in clinical aggressive prostate cancer therapy. [ABSTRACT FROM AUTHOR]

Background Pulmonary arterial hypertension (PAH) is associated with sustained vasoconstriction, inflammation and suppressed apoptosis of smooth muscle cells. Our previous studies have found that rat bone marrow-derived mesenchymal stem cells (rBMSCs) transduced with a mutant caveolin-1(F92A-Cav1) could enhance endothelial nitric oxide synthase (eNOS) activity and improve pulmonary vascular remodeling, but the potential mechanism is not yet fully explored. The present study was to investigate the gene expression profile upon rBMSCs/F92A-Cav1delivered to PAH rat to evaluate the role of F92A-Cav1 in its regulation. Methods PAH was induced with monocrotaline (MCT, 60 mg/kg) prior to delivery of lentiviral vector transduced rBMSCs expressing Cav1 or F92A-Cav1. Gene expression profiling was performed using Rat Signal Transduction PathwayFinder array. The expression changes of 84 key genes representing 10 signal transduction pathways in rat following rBMSCs/F92A-Cav1 treatment was examined. Results Screening with the Rat Signal Transduction PathwayFinder R 2 PCR Array system and subsequent western blot, immunohistochemistry or real time PCR analysis revealed that F92A-Cav1 modified rBMSCs can inhibit the inflammation factors (TNF-alpha, Icam1 and C/EBPdelta), pro-proliferation genes (c-Myc, Bcl2a1d, Notch1and Hey2), oxidative stress gene (Hmox1) and activate cell cycle arrested gene Cdkn1a, ameliorating inflammation and inhibiting cell proliferation in PAH rat. Conclusion rBMSCs/F92A-Cav1 inhibits inflammation and cell proliferation by regulating signaling pathways that related to inflammation, proliferation, cell cycle and oxidative stress. [ABSTRACT FROM AUTHOR]

Multiple pathophysiological pathways are activated during the process of myocardial injury. Various cardioprotective strategies protect the myocardium from ischemia, infarction, and ischemia/reperfusion (I/R) injury through different targets, yet the clinical translation remains limited. Caveolae and its structure protein, caveolins, have been suggested as a bridge to transmit damage-preventing signals and mediate the protection of ultrastructure in cardiomyocytes under pathological conditions. In this review, we first briefly introduce caveolae and caveolins. Then we review the cardioprotective strategies mediated by caveolins through various pathophysiological pathways. Finally, some possible research directions are proposed to provide future experiments and clinical translation perspectives targeting caveolin based on the investigative evidence. [Display omitted] • Novel observation on caveolins act as bridge of protection effect in cardiomyocytes. • Various pathophysiological aspects mediated by caveolins been potential targets. • Caveolin can be involved in intercellular signal transduction as a mediator. • Therapy with caveolin-CSD peptide may be a treatment modality for myocardial injury. [ABSTRACT FROM AUTHOR]

Background Nitric oxide (NO) is generated in endothelial cells by endothelial nitric oxide synthase (eNOS). Caveolin-1 (Cav1) inhibits eNOS function and NO production. Modifying Cav1 scaffold domain, in particular Phenylalanine at position 92 (F92) is critical for the inhibitory actions of Cav1 toward eNOS. The aims of this study were to investigate the effect of enhanced NO production in term of in vitro angiogenesis on rat bone marrow derived mesenchymal stem cells (BMSCs) transduced with a novel bicistronic lentiviral vector co-expressing eNOS and mutant Cav1 (F92A). Methods A bicistronic eNOS/F92-Cav1 lentiviral vector was constructed, and used to transduce rat BMSCs. The expression of eNOS and VEGF protein were confirmed by western-blot. NO production was detected by the greiss assay and in vitro angiogenesis was assessed by matrigel assisted capillary tube formation. The cell viability was evaluated using a Cell Counting Kit (CCK)-8. Results The bicistronic eNOS/F92A-Cav1 lentiviral vector increased eNOS and VEGF protein expression, NO production compared to controls. In vitro capillary formation was increased in eNOS-F92A transduced cells and cell viability was not affected by transduction. Conclusion Transduction of rat BMSCs with an eNOS-F92A-Cav1 lentiviral vector can increase NO production by enhancing eNOS protein expression. The increased NO production did not reduce cell viability. This study demonstrates that genetic modification of BMSCs to enhance NO producton could be applied in stem cell based therapeutic approaches to treat diseases such as pulmonary arterial hypertension (PAH) which is characterized by decreased endothelial NO release. [ABSTRACT FROM AUTHOR]

Previous work done in our laboratory showed that water restriction during 24 and 72 h induced changes in cardiovascular NOS activity without altering NOS protein levels in young and adult animals. These findings indicate that the involvement of NO in the regulatory mechanisms during dehydration depends on the magnitude of the water restriction and on age. Our aim was to study whether a controlled water restriction of 1 month affects cardiac function, NO synthase (NOS) activity and NOS, and cav-1 and -3 protein levels in rats during aging. Male Sprague-Dawley rats aged 2 and 16 months were divided into 2 groups: (CR) control restriction (WR) water restriction. Measurements of arterial blood pressure, heart rate, oxidative stress, NOS activity and NOS/cav-1 and -3 protein levels were performed. Cardiac function was evaluated by echocardiography. The results showed that adult rats have greater ESV, EDV and SV than young rats with similar SBP. Decreased atria NOS activity was caused by a reduction in NOS protein levels. Adult animals showed increased cav-1. Water restriction decreased NOS activity in young and adult rats associated to an increased cav-1. TBARS levels increased in adult animals. Higher ventricular NOS activity in adulthood would be caused by a reduction in both cav. Water restriction reduced NOS activity and increased cav in both age groups. In conclusion, our results indicated that dehydration modifies cardiac NO system activity and its regulatory proteins cav in order to maintain physiological cardiac function. Functional alterations are induced by the aging process as well as hypovolemic state. [ABSTRACT FROM AUTHOR]

Abstract: Caveolin-1 (CAV-1), one component of caveolae, involves in multiple cellular processes and signal transductions. We previously showed that the expression of CAV-1 gene in NCI-H446 cells inhibited cell proliferation and promoted cell metastasis. Here we explore the function of CAV-1 on tumor growth and metastasis by using NCI-H460 in vitro. First, we established NCI-H460 cell line, which CAV-1 was stably knockdown. Then we investigated the effects of CAV-1 on the morphology, proliferation, cell cycle and metastasis potential for NCI-H460 cell by crystal violet stains, CCK-8, colony formation, flow cytometry, scratch-wound assay and transwell assay. Western blot was used to examine the expression changes of cyclin D1, PCNA, E-cadherin and β-catenin. Our results showed stable knockdown of CAV-1 inhibited the proliferation of NCI-H460 cells. Cell cycle of the transfected cells was arrested in G1/S phase and the expressions of cyclin D1 and PCNA protein were downregulated. Downregulation of CAV-1 promoted the migration and invasion abilities of NCI-H460 cells in vitro. The expression of β-catenin increased and the level of E-cadherin decreased. In summary, our findings provide experimental evidence that CAV-1 may function as a proproliferative and antimetastatic gene in NCI-H460 cell line. [Copyright &y& Elsevier]

Abstract: Caveolin-1 (CAV-1) either functions as a tumor suppressor gene or as an oncogene depending on the types of tumor cells and tumors. In current work, we investigated the influences of CAV-1 on the proliferation and cell cycle of small cell lung cancer (SCLC) cell NCI-H446, empty vector transfected NCI-H446 (NCI-H446-neo) and wild-type CAV-1 gene stably transfected NCI-H446 (NCI-H446-CAV-1) cells and explored the potential underlying mechanism. The colony formation capacity of NCI-H446-CAV-1 cell was 58.5% of that for NCI-H446 cell and 57.0% of that for NCI-H446-neo cell. CAV-1 inhibited the cell growth and cell cycle distribution of NCI-H446 cell in vitro. CAV-1 over-expression decreased the population of NCI-H446 cell at S phase and blocked NCI-H446 cell at G2/M phase without apparent effect on G1/G0 cell population. The level of phosphoryalted extracellular signal-regulated kinases (p-ERK1/2) instead of whole ERK1/2 in NCI-H446 cell was dramatically decreased following the stable expression of CAV-1. ERK1/2 phosphorylation might be critical for NCI-H446 cell growth. This work also revealed CAV-1 potentially regulated NCI-H446 growth in a hormone-dependant manner. Estrogen receptor (ER) and progestin receptor (PR) were significantly down-regulated in NCI-H446-CAV-1 cell comparing to NCI-H446 and NCI-H446-neo cells. Taken together, CAV-1 affected cell growth of lung cancer NCI-H446 cell through the interactions with p-ERK1/2, ER and PR. [Copyright &y& Elsevier]

Toll-like receptor 4(TLR-4)/nuclear factor-kappa B(NF-κB) pathway plays an important role in inducing acute lung injury (ALI). Studies have proved Dexmedetomidine (Dex) inhibits inflammatory response to mitigate lipopolysaccharide (LPS)‐induced ALI and protect against multiorgan injury in various scenarios via restraining TLR-4/NF-κB signaling pathway. Many of the known downstream molecules have been orientated with a protein caveolin-1(Cav-1), which is supposed to take part in regulating TLR4-mediated inflammatory responses. However, its mechanisms have not been confirmed. The aim of this study is to evaluate the protective effects and potential mechanisms of Dex against LPS-induced ALI in male rats. Male rats received tail-vein injection of LPS to form ALI model. Rats were administrated with intraperitoneal injection Dex0.5 h before ALI. At 6 h after LPS injection, bronchoalveolar lavage fluid (BALF) and lung tissue were harvested. We stained the lung tissue sections with hematoxylin eosin (HE) staining to observe the histopathological damage and measure the ALI pathology score. We also measured the wet-to-dry(W/D) weight ratio of lung tissue. Lung myeloperoxidase (MPO) and inflammatory cytokines in the BALF were detected by Enzyme‐linked immunosorbent assay(ELISA). Protein levels of Cav-1, TLR-4 and NF-κB in lung tissue were tested by immunohistochemistry method. The mRNA expression of Cav-1, TLR4 and the NF-κB in lung tissue were measured to determine the related mechanisms by quantitative real-time polymerase chain reaction(RT-PCR). It was indicated that Dex pretreatment markedly mitigated pathomorphologic changes and pathological lung injury scores. Besides, Dex pretreatment obviously decreased the W/D weight ratio of lung tissue, attenuated MPO activity significantly, along with LPS-stimulated augment of lung inflammatory cells infiltration in BALF. Moreover, compared with LPS model group, Dex pretreatment apparently increased the protein levels of Cav-1 downregulated by sepsis and decreased the protein levels of TLR-4 and NF-κB in lung tissue. Furthermore, Dex pretreatment apparently upregulated the expression of Cav-1 mRNA, restrained TLR4 and NF-κB mRNA. Dex pretreatment protects against LPS‐induced ALI via inhibiting the activation of the TLR-4/NF-kB signaling pathway by upregulating the expression of Cav-1 downregulated by sepsis. [ABSTRACT FROM AUTHOR]