The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.

Glaucoma is a degenerative disease characterized by retinal ganglion cell (RGC) death and visual impairment caused by elevated intraocular pressure (IOP). Elevated IOP can activate microglia, which participate in ganglion cell injury. Based on the study of caveolin-1 (Cav-1) in glaucoma, we aimed to explore the effect and mechanism of Cav-1 on RGC apoptosis in mice with acute ocular hypertension (AOH). AOH mice were established, and Cav-1 was intravitreally injected. Retinal microglia and RGCs were isolated from neonatal mice. TUNEL staining, hematoxylin-eosin staining, immunohistochemistry, flow cytometry, PCR and western blotting were used to observe the effect of Cav-1 on RGCs and mouse retinas. The thickness of the whole retina and the inner retinal sublayer decreased significantly, retinal cell apoptosis increased after AOH injury, and Cav-1 treatment reversed the effect of AOH injury. In addition, Cav-1 treatment promoted the conversion of proinflammatory M1 microglia to anti-inflammatory M2 microglia. Microglia and RGCs were isolated from neonatal mice. Cav-1 protects RGCs from OGD/R-induced injury by changing the polarization status of retinal microglia in vitro. Further studies revealed that Cav-1 activated the Akt/PTEN signaling pathway and inhibited TLR4. Our study provides evidence that Cav-1 may be a promising therapeutic target for glaucoma.

Jiang et al. show that zinc finger FYVE-type containing 21, a Rab5 effector in glomerular endothelial cells is involved in the maintenance of glomerular filtration barrier homeostasis through the stabilization of activated endothelial nitric oxide synthase on subcellular vesicles. The study demonstrates that zinc finger FYVE-type containing 21 could modulate the levels of caveolin-1 in glomerular endothelial cells using vesicle-based trafficking, thereby supporting endothelial nitric oxide synthase activity. The authors provide evidence that decreased zinc finger FYVE-type containing 21 expression in glomerular endothelial cells could play a role in aging-related glomerular filtration barrier dysfunction.

Peritoneal metastasis is one of the most common risk factors contributing to the poor prognosis of gastric cancer. We previously reported that extracellular vesicles from gastric cancer cells could facilitate peritoneal metastasis. However, their impact on gastric cancer-induced peritoneal metastasis under hypoxic conditions remains unclear. This study aims to elucidate how hypoxia-resistant gastric cancer cell-derived extracellular vesicles affect the peritoneal metastasis of normoxic gastric cancer cells. Proteomic analysis revealed elevated levels of Caveolin1 and Laminin β2 in hypoxia-resistant gastric cancer cells and their corresponding extracellular vesicles. Importantly, Caveolin1 was found to play a central role in mediating Laminin β2 sorting into extracellular vesicles derived from hypoxia-resistant gastric cancer cells, and subsequently, extracellular vesicle-associated Laminin β2 promoted peritoneal metastasis in normoxic gastric cancer cells by activating the AKT pathway. Further investigation confirmed that Caveolin1 activation by Rho-related Coiled-coil kinase 1-mediated phosphorylation of Y14 residue is a key factor facilitating Laminin β2 sorting into extracellular vesicles. Moreover, Y14 phosphorylated- Caveolin1 enhanced Laminin β2 sorting by activating Rab11. Finally, our study demonstrated that a combined assessment of plasma extracellular vesicle-associated Caveolin1 and extracellular vesicle-associated Laminin β2 could provide an accurate predictive tool for peritoneal metastasis occurrence in gastric cancer.

OBJECTIVE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored.
METHODS: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism.
RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism.
CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.

Our study examines the immunoexpression patterns of Megalin, Cubilin, Caveolin-1, Gipc1 and Dab2IP in the embryonic development (E) and postnatal (P) mouse kidney, with a focus on differentiating patterns between wild-type (wt) and yotari, Dab1-/- (yot) mice. Immunofluorescence revealed raised immunoexpression of receptors Megalin and Cubilin at the ampulla/collecting ducts and convoluted tubules across all developmental stages, with the most prominent immunoexpression observed in the convoluted tubules and the parietal epithelium of the Bowman\'s capsule. Quantitative analysis showed a higher percentage of Megalin and Cubilin in wt compared to yot mice at E13.5. Co-expression of Megalin and Cubilin was observed at the apical membrane of convoluted tubules and the parietal layer of the Bowman\'s capsule. The staining intensity of Megalin varied across developmental stages, with the strongest reactivity observed at the ampulla and collecting ducts at embryonic day (E) 13.5 in wt mice. In contrast, Caveolin-1 exhibited high immunoexpression in the metanephric mesenchyme, blood vessels, and the border area between the metanephric mesenchyme and renal vesicle, with a decrease in immunoexpression as development progressed. Gipc1 showed diffuse cytoplasmic staining in metanephric mesenchyme, convoluted tubules and collecting ducts, with significant differences in immunoexpression between wild-type and yot mice at both investigated embryonic time points. Dab2IP immunofluorescent staining was most prominent in renal vesicle/glomeruli and ampulla/collecting ducts at E13.5, with mild staining intensity observed in the distal convoluted tubules postnatally. Our findings elucidate distinct immunoexpression of patterns and potential parts of these proteins in the development and function of the kidney, highlighting the importance of further investigation into their regulatory mechanisms.

An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis in uremic patients, yet its dysfunction poses a significant clinical challenge. Venous stenosis, primarily caused by venous neointimal hyperplasia, is a key factor in the failure of vascular access. During vascular access dysfunction, endothelial cells (ECs) transform mechanical stimuli into intracellular signals and interact with vascular smooth muscle cells. Tanshinone IIA, an important compound derived from Salvia miltiorrhiza, has been widely used to treat cardiovascular diseases. However, its role in modulating ECs under uremic conditions remains incompletely understood. In this research, ECs were exposed to sodium tanshinone IIA sulfonate (STS) and subjected to shear stress and uremic conditions. The results indicate that STS can reduce the suppressive effects on the expression of NF-κB p65, JNK and Collagen I in uremia-induced ECs. Moreover, the downregulation of NF-κB p65, JNK and Collagen I can be enhanced through the inhibition of ERK1/2 and the upregulation of Caveolin-1. These findings suggest that tanshinone IIA may improve EC function under uremic conditions by targeting the Caveolin-1/ERK1/2 pathway, presenting tanshinone IIA as a potential therapeutic agent against AVF immaturity caused by EC dysfunction.

BACKGROUND: The roles of Caveolin-1 (Cav-1) and the Wnt/β-catenin signaling pathways in cerebral ischemia-reperfusion (I/R) injury are well established. The translocation of β-catenin into the nucleus is critical for regulating neuronal apoptosis, repair, and neurogenesis within the ischemic brain. It has been reported that the scaffold domain of Caveolin-1 (Cav-1) (residues 95-98) interacts with β-catenin (residues 330-337). However, the specific contribution of the Cav-1/β-catenin complex to I/R injury remains unknown.
RESULTS: To investigate the mechanism underlying the involvement of the Cav-1/β-catenin complex in the subcellular translocation of β-catenin and its subsequent effects on cerebral I/R injury, we treated ischemic brains with ASON (Cav-1 antisense oligodeoxynucleotides) or FTVT (a competitive peptide antagonist of the Cav-1 and β-catenin interaction). Our study demonstrated that the binding of Cav-1 to β-catenin following I/R injury prevented the nuclear accumulation of β-catenin. Treatment with ASON or FTVT after I/R injury significantly increased the levels of nuclear β-catenin. Furthermore, ASON reduced the phosphorylation of β-catenin at Ser33, Ser37, and Thr41, which contributes to its proteasomal degradation, while FTVT increased phosphorylation at Tyr333, which is associated with its nuclear translocation.
CONCLUSIONS: The above results indicate that the formation of the Cav-1/β-catenin complex anchors β-catenin in the cytoplasm following I/R injury. Additionally, both ASON and FTVT treatments attenuated neuronal death in ischemic brains. Our study suggests that targeting the interaction between Cav-1 and β-catenin serve as a novel therapeutic strategy to protect against neuronal damage during cerebral injury.

The rise of gene therapy has solved many diseases that cannot be effectively treated by conventional methods. Gene vectors is very important to protect and deliver the therapeutic genes to the target site. Polyethyleneimine (PEI) modified with mannitol could enhance the gene transfection efficiency reported by our group previously. In order to further control and improve the effective gene release to action site, disulfide bonds were introduced into mannitol-modified PEI to construct new non-viral gene vectors PeiSM. The degrees of mannitol linking with disulfide bonds were screened. Among them, moderate mannitol-modified PEI with disulfide bonds showed the best transfection efficiency, and significantly enhanced long-term systemic transgene expression for 72 hin vivoeven at a single dose administration, and could promote caveolae-mediated uptake through up-regulating the phosphorylation of caveolin-1 and increase the loaded gene release from the nanocomplexes in high glutathione intracellular environment. This functionalized gene delivery system can be used as an potential and safe non-viral nanovector for further gene therapy.

Migrasomes, vesicular organelles generated on the retraction fibers of migrating cells, play a crucial role in migracytosis, mediating intercellular communication. The cargoes determine the functional specificity of migrasomes. Migrasomes harbor numerous intraluminal vesicles, a pivotal component of their cargoes. The mechanism underlying the transportation of these intraluminal vesicles to the migrasomes remains enigmatic. In this study, we identified that Rab10 and Caveolin-1 (CAV1) mark the intraluminal vesicles in migrasomes. Transport of Rab10-CAV1 vesicles to migrasomes required the motor protein Myosin Va and adaptor proteins RILPL2. Notably, the phosphorylation of Rab10 by the kinase LRRK2 regulated this process. Moreover, CSF-1 can be transported to migrasomes through this mechanism, subsequently fostering monocyte-macrophage differentiation in skin wound healing, which served as a proof of the physiological importance of this transporting mechanism.