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Gestational diabetes mellitus (GDM) is a common disorder in the clinic, which may lead to severe detrimental outcomes both for mothers and infants. However, the underlying mechanisms for GDM are still not clear. In the present study, we performed label-free proteomics using placentas from GDM patients and normal controls. Vitronectin caused our attention among differentially expressed proteins due to its potential role in the pathological progression of GDM. Vitronectin was increased in the placentas of GDM patients, which was confirmed by Western blot analysis. Vitronectin represses insulin signal transduction in trophoblast cells, whereas the knockdown of vitronectin further potentiates insulin-evoked events. Neutralization of CD51/61 abolishes the repressed insulin signal transduction in vitronectin-treated trophoblast cells. Moreover, vitronectin activates JNK in a CD51/61-depedent manner. Inhibition of JNK rescues impaired insulin signal transduction induced by vitronectin. Overall, our data indicate that vitronectin binds CD51/61 in trophoblast cells to activate JNK, and thus induces insulin resistance. In this regard, increased expression of vitronectin is likely a risk factor for the pathological progression of GDM. Moreover, blockade of vitronectin production or its receptors (CD51/61) may have therapeutic potential for dealing with GDM.

Chronic renal failure (CRF) causes a reduction in glomerular filtration rate and damage to renal parenchyma. Fushengong decoction (FSGD) showed improvement in renal function in CRF rats. This study aims to analyze the differentially expressed proteins in CRF patients treated with Western medicine alone or in combination with FSGD. Sixty patients with CRF recruited from Yongchuan Traditional Chinese Medicine Hospital affiliated to Chongqing Medical University were randomly assigned into control (treated with Western medicine alone) and observation groups (received additional FSGD treatment thrice daily for 8 weeks). The clinical efficacy and changes in serum Bun, serum creatinine, Cystatin C, and transforming growth factor beta 1 (TGF-β1) before and after treatment were observed. We employed isotope relative labeling absolute quantification labeling and liquid chromatography-mass spectrometry to identify differentially expressed proteins and carried out bioinformatics Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Patients in the observation group showed greater clinical improvement and lower levels of serum Bun, serum creatinine, Cyc-c, and TGF-β1 than the control group. We identified 32 differentially up-regulated and 52 down-regulated proteins in the observation group. These proteins are involved in the blood coagulation system, protein serine/threonine kinase activity, and TGF-β, which are closely related to the pathogenesis of CRF. Protein-protein-interaction network analysis indicated that candidate proteins fibronectin 1, fibrinogen alpha chain, vitronectin, and Serpin Family C Member 1 were in the key nodes. This study provided an experimental basis suggesting that FSGD combined with Western medicine could significantly improve renal function and renal fibrosis of CRF patients, which may be through the regulation of fibronectin 1, fibrinogen alpha chain, vitronectin, Serpin Family C Member 1, TGF-β, and the complement coagulation pathway (see Graphical abstract S1, Supplemental Digital Content, http://links.lww.com/MD/L947).

Schlemm\'s canal (SC) functions to maintain proper intraocular pressure (IOP) by draining aqueous humor and has emerged as a promising therapeutic target for glaucoma, the second-leading cause of irreversible blindness worldwide. However, our current understanding of the mechanisms governing SC development and functionality remains limited. Here, we show that vitronectin (VTN) produced by limbal macrophages promotes SC formation and prevents intraocular hypertension by activating integrin αvβ3 signaling. Genetic inactivation of this signaling system inhibited the phosphorylation of AKT and FOXO1 and reduced β-catenin activity and FOXC2 expression, thereby causing impaired Prox1 expression and deteriorated SC morphogenesis. This ultimately led to increased IOP and glaucomatous optic neuropathy. Intriguingly, we found that aged SC displayed downregulated integrin β3 in association with dampened Prox1 expression. Conversely, FOXO1 inhibition rejuvenated the aged SC by inducing Prox1 expression and SC regrowth, highlighting a possible strategy by targeting VTN/integrin αvβ3 signaling to improve SC functionality.

UNASSIGNED: Vitronectin (VTN) has been reported to trigger cell pyroptosis to aggravate inflammation in our previous study. However, the function of VTN in inflammatory bowel disease (IBD) remains to be addressed.
UNASSIGNED: Real-time PCR and western blotting were performed to analyze VTN-regulated intestinal epithelial cell (IEC) differentiation through ferroptosis, and immunofluorescence (IF), luciferase, and chromatin immunoprecipitation were used to identify whether VTN-modulated ferroptosis is dependent on phosphodiesterase 4 (PDE4)/protein kinase A (PKA)/cyclic adenosine monophosphate-response element-binding protein (CREB) cascade pathway. In vivo experiment in mice and a pilot study in patients with IBD were used to confirm inhibition of PDE4-alleviated IECs ferroptosis, leading to cell differentiation during mucosal healing.
UNASSIGNED: Herein, we found that caudal-related homeobox transcription factor 2-mediated IECs differentiation was impaired in response to VTN, which was attributed to enhanced ferroptosis characterized by decreased glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 expression. Inhibition of ferroptosis in IECs rescued the inhibitory effect of VTN on cell differentiation. Further analysis showed that VTN triggered phosphorylation of PDE4, leading to inhibit PKA/CREB activation and CREB nuclear translocation, which further reduced GPX4 transactivation. Endogenous PKA interacted with CREB, and this interaction was destroyed in response to VTN stimulation. What is more, overexpression of CREB in CaCO2 cells overcame the promotion of VTN on ferroptosis. Most importantly, inhibition of PDE4 by roflumilast or dipyridamole could alleviate dextran sulfate sodium-induced colitis in mice and in a pilot clinical study confirmed by IF.
UNASSIGNED: These findings demonstrated that highly expressed VTN disrupted IECs differentiation through PDE4-mediated ferroptosis in IBD, suggesting targeting PDE4 could be a promising therapeutic strategy for patients with IBD.

Background: Renal infiltration of inflammatory cells including macrophages is a crucial event in kidney fibrogenesis. However, how macrophage regulates fibroblast activation in the fibrotic kidney remains elusive. In this study, we show that macrophages promoted fibroblast activation by assembling a vitronectin (Vtn)-enriched, extracellular microenvironment. Methods: We prepared decellularized kidney tissue scaffold (KTS) from normal and fibrotic kidney after unilateral ischemia-reperfusion injury (UIRI) and carried out an unbiased quantitative proteomics analysis. NRK-49F cells were seeded on macrophage-derived extracellular matrix (ECM) scaffold. Genetic Vtn knockout (Vtn-/-) mice and chronic kidney disease (CKD) model with overexpression of Vtn were used to corroborate a role of Vtn/integrin αvβ5/Src in kidney fibrosis. Results: Vtn was identified as one of the most upregulated proteins in the decellularized kidney tissue scaffold from fibrotic kidney by mass spectrometry. Furthermore, Vtn was upregulated in the kidney of mouse models of CKD and primarily expressed and secreted by activated macrophages. Urinary Vtn levels were elevated in CKD patients and inversely correlated with kidney function. Genetic ablation or knockdown of Vtn protected mice from developing kidney fibrosis after injury. Conversely, overexpression of Vtn exacerbated renal fibrotic lesions and aggravated renal insufficiency. We found that macrophage-derived, Vtn-enriched extracellular matrix scaffold promoted fibroblast activation and proliferation. In vitro, Vtn triggered fibroblast activation by stimulating integrin αvβ5 and Src kinase signaling. Either blockade of αvβ5 with neutralizing antibody or pharmacological inhibition of Src by Saracatinib abolished Vtn-induced fibroblast activation. Moreover, Saracatinib dose-dependently ameliorated Vtn-induced kidney fibrosis in vivo. These results demonstrate that macrophage induces fibroblast activation by assembling a Vtn-enriched extracellular microenvironment, which triggers integrin αvβ5 and Src kinase signaling. Conclusion: Our findings uncover a novel mechanism by which macrophages contribute to kidney fibrosis via assembling a Vtn-enriched extracellular niche and suggest that disrupting fibrogenic microenvironment could be a therapeutic strategy for fibrotic CKD.

Riemerella anatipestifer is an important bacterial pathogen in poultry. Pathogenic bacteria recruit host complement factors to resist the bactericidal effect of serum complement. Vitronectin (Vn) is a complementary regulatory protein that inhibits the formation of the membrane attack complex (MAC). Microbes use outer membrane proteins (OMPs) to hijack Vn for complement evasion. However, the mechanism by which R. anatipestifer achieves evasion is unclear. This study aimed to characterise OMPs of R. anatipestifer which interact with duck Vn (dVn) during complement evasion. Far-western assays and comparison of wild-type and mutant strains that were treated with dVn and duck serum demonstrated particularly strong binding of OMP76 to dVn. These data were confirmed with Escherichia coli strains expressing and not expressing OMP76. Combining tertiary structure analysis and homology modelling, truncated and knocked-out fragments of OMP76 showed that a cluster of critical amino acids in an extracellular loop of OMP76 mediate the interaction with dVn. Moreover, binding of dVn to R. anatipestifer inhibited MAC deposition on the bacterial surface thereby enhancing survival in duck serum. Virulence of the mutant strain ΔOMP76 was attenuated significantly relative to the wild-type strain. Furthermore, adhesion and invasion abilities of ΔOMP76 decreased, and histopathological changes showed that ΔOMP76 was less virulent in ducklings. Thus, OMP76 is a key virulence factor of R. anatipestifer. The identification of OMP76-mediated evasion of complement by recruitment of dVn contributes significantly to the understanding of the molecular mechanism by which R. anatipestifer escapes host innate immunity and provides a new target for the development of subunit vaccines.

Idiopathic pulmonary fibrosis (IPF) is a common chronic and progressive lung disease. Fibulin-2 (FBLN2) is upregulated in patients with IPF; however, its exact role in IPF remains unclear. The present study aimed to investigate the role and the regulatory mechanism of FBLN2 in TGF-β1-induced fibrogenesis using human lung fibroblast-derived MRC-5 cells. Cell transfection was performed to regulate FBLN2 expression. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the expression levels of FBLN2 and vitronectin (VTN). Cell viability and migration were determined via the Cell Counting Kit-8 and wound healing assays, respectively. Immunofluorescence was performed to detect α-smooth muscle actin (α-SMA)-positive cells. The STRING database was used to predict the interaction between FBLN2 and VTN, which was verified via the protein immunoprecipitation assay. The results demonstrated that inhibition of FBLN2 notably inhibited TGF-β1-induced proliferation and migration, as well as downregulating the protein expression levels of MMP2 and MMP9 in MRC-5 cells. In addition, inhibition of FBLN2 suppressed the expression levels of α-SMA, collagen type 1 α1 and fibronectin. FBLN2 was demonstrated to bind to VTN and negatively regulate its expression. Furthermore, overexpression of VTN partly abolished the inhibitory effects of FBLN2 knockdown on TGF-β1-induced proliferation, migration and fibrosis, as well as the activity of focal adhesion kinase (FAK) signaling. Taken together, the results of the present study suggest that FBLN2 knockdown can attenuate TGF-β1-induced fibrosis in MRC-5 cells by downregulating VTN expression via FAK signaling. Thus, FBLN2 may be a potential therapeutic target for IPF treatment.

Vitronectin (VTN), a multifunctional glycoprotein with various physiological functions, exists in plasma and the extracellular matrix. It is known to be involved in the cell attachment, spreading and migration through binding to the integrin receptor, mainly via the RGD sequence. VTN is also widely used in the maintenance and expansion of pluripotent stem cells, but its effects go beyond that. Recent evidence shows more functions of VTN in the nervous system as it participates in neural differentiation, neuronutrition and neurogenesis, as well as in regulating axon size, supporting and guiding neurite extension. Furthermore, VTN was proved to play a key role in protecting the brain as it can reduce the permeability of the blood-brain barrier by interacting with integrin receptors in vascular endothelial cells. Moreover, evidence suggests that VTN is associated with neurodegenerative diseases, such as Alzheimer\'s disease, but its function has not been fully understood. This review summarizes the functions of VTN and its receptors in neurons and describes the role of VTN in the blood-brain barrier and neurodegenerative diseases.

Acute organophosphate poisoning kills tens of thousands of people annually around the world. These substances are widely used as insecticides in homes, industry, and agricultural environments. Due to the ease of access, they can cause accidental or intentional risks of exposure through the skin or respiratory contact. This study aimed to evaluate the serum levels of hs-CRP, Vitronectin, and NT-proBNP and their relationship with the extent and severity of cardiac complications in patients with organophosphate pesticide poisoning. In this descriptive-comparative study, 160 patients were studied with acute organophosphate poisoning. Also, for better comparison, 40 healthy individuals participated in this study. Diagnosis of organophosphate poisoning was based on clinical findings of serum butyrylcholinesterase levels. The hs-CRP measurement was performed by an autoanalyzer (Abbott, model Alcyon 300, USA) with the ELISA hs-CRP kit (The apDia Company, Belgium). Vitronectin (VN) measurements were performed by ELISA method and Glory science human VN kit with Catalog No: 11668. NT-ProBNP serum levels were analyzed by ProBNP assay kit (Roche, Germany) by ECLIA method using Elecsys 2010 Analyzer. The most important variables studied in this study were the electrical activity and conduction system of the heart, PR distance, QTC interval, and T-wave changes. In this study, most of the patients were women and girls (60.78%). The highest percentage of organophosphate poisoning was in the age group of 15-24 years (37.25%). In most cases (78.43%), poisoning was intentional or suicidal. Evaluation of electrophysiological abnormalities of the heart showed that 89 patients (55.62%) had long QTC interval (>450 msec), 43 cases (26.87%) had possible long QTC (431-450 msec), and 28 cases (17.5%) had normal QTC (<430 msec). Only 9.37% of cases (n = 15) showed an increase in P-R distance, which is characteristic of the first-degree ventricular atrial block. Sinus bradycardia occurred in 57 cases (35.62%) and sinus tachycardia in 43 cases (26.87%); in 60 cases (37.5%), the pulse rate was normal. Smooth T-wave changes were observed in 9.8% of patients and reverse T-wave was observed in 17.6%. A long T-wave was not reported in any case. In only two cases (1.25%) was grade 1 ventricular atrial block and grade 2 and 3 blocks were not observed. In general, there was a significant difference in the hs-CRP, vitronectin, and NT-proBNP serum levels between the patient and control groups in all studied variables. These parameters were also related to the extent and severity of the disease.