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1.
Exp Eye Res ; 241: 109859, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38467175

RESUMO

It is known that the actin cytoskeleton and its associated cellular interactions in the trabecular meshwork (TM) and juxtacanalicular tissues mainly contribute to the formation of resistance to aqueous outflow of the eye. Fibulin-3, encoded by EFEMP1 gene, has a role in extracellular matrix (ECM) modulation, and interacts with enzymatic ECM regulators, but the effects of fibulin-3 on TM cells has not been explored. Here, we report a stop codon variant (c.T1480C, p.X494Q) of EFEMP1 that co-segregates with primary open angle glaucoma (POAG) in a Chinese pedigree. In the human TM cells, overexpression of wild-type fibulin-3 reduced intracellular actin stress fibers formation and the extracellular fibronectin levels by inhibiting Rho/ROCK signaling. TGFß1 up-regulated fibulin-3 protein levels in human TM cells by activating Rho/ROCK signaling. In rat eyes, overexpression of wild-type fibulin-3 decreased the intraocular pressure and the fibronectin expression of TM, however, overexpression of mutant fibulin-3 (c.T1480C, p.X494Q) showed opposite effects in cells and rat eyes. Taken together, the EFEMP1 variant may impair the regulatory capacity of fibulin-3 which has a role for modulating the cell contractile activity and ECM synthesis in TM cells, and in turn may maintain normal resistance of aqueous humor outflow. This study contributes to the understanding of the important role of fibulin-3 in TM pathophysiology and provides a new possible POAG therapeutic approach.


Assuntos
Humor Aquoso , Glaucoma de Ângulo Aberto , Humanos , Humor Aquoso/metabolismo , Fibronectinas/metabolismo , Glaucoma de Ângulo Aberto/metabolismo , Códon de Terminação/metabolismo , Malha Trabecular/metabolismo , Pressão Intraocular , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo
2.
Front Immunol ; 15: 1344761, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487529

RESUMO

Background: The importance of CD11b/CD18 expression in neutrophil effector functions is well known. Beyond KINDLIN3 and TALIN1, which are involved in the induction of the high-affinity binding CD11b/CD18 conformation, the signaling pathways that orchestrate this response remain incompletely understood. Method: We performed an unbiased screening method for protein selection by biotin identification (BioID) and investigated the KINDLIN3 interactome. We used liquid chromatography with tandem mass spectrometry as a powerful analytical tool. Generation of NB4 CD18, KINDLIN3, or SKAP2 knockout neutrophils was achieved using CRISPR-Cas9 technology, and the cells were examined for their effector function using flow cytometry, live cell imaging, microscopy, adhesion, or antibody-dependent cellular cytotoxicity (ADCC). Results: Among the 325 proteins significantly enriched, we identified Src kinase-associated phosphoprotein 2 (SKAP2), a protein involved in actin polymerization and integrin-mediated outside-in signaling. CD18 immunoprecipitation in primary or NB4 neutrophils demonstrated the presence of SKAP2 in the CD11b/CD18 complex at a steady state. Under this condition, adhesion to plastic, ICAM-1, or fibronectin was observed in the absence of SKAP2, which could be abrogated by blocking the actin rearrangements with latrunculin B. Upon stimulation of NB4 SKAP2-deficient neutrophils, adhesion to fibronectin was enhanced whereas CD18 clustering was strongly reduced. This response corresponded with significantly impaired CD11b/CD18-dependent NADPH oxidase activity, phagocytosis, and cytotoxicity against tumor cells. Conclusion: Our results suggest that SKAP2 has a dual role. It may restrict CD11b/CD18-mediated adhesion only under resting conditions, but its major contribution lies in the regulation of dynamic CD11b/CD18-mediated actin rearrangements and clustering as required for cellular effector functions of human neutrophils.


Assuntos
Neutrófilos , Quinases da Família src , Humanos , Neutrófilos/metabolismo , Quinases da Família src/metabolismo , Fibronectinas/metabolismo , Antígenos CD18/metabolismo , Adesão Celular , Actinas/metabolismo , Fosfoproteínas/metabolismo , Antígeno de Macrófago 1/metabolismo
3.
Tissue Cell ; 87: 102342, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430848

RESUMO

BACKGROUND: T2DM is a chronic disorder with progressive neuromuscular alterations. L-arginine (ARG) is the most common semi-essential amino acid having several metabolic functions. AIM: to investigate the impact of L-arginine in combating diabetic-induced neuromyopathy and its possible mechanisms. MATERIALS & METHODS: 24 rats were divided into CON, CON+ARG, DC, DC+ARG. Behavioral tests, Body weight (BW), fasting blood glucose (FBG), insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), plasminogen activator inhibitor-1 (PAI-1), and irisin were done. Creatine kinase-MM (CK-MM), interleukin 4 (IL-4), interleukin 6 (IL-6), TAC, MDA, expression of microRNA-29a mRNA & light chain 3 protein were determined in muscle. Histological and NF-κß immunohistochemical expression in muscle and nerve were assessed. RESULTS: ARG supplementation to diabetic rats improved altered behavior, significantly increased BW, insulin, TAC, irisin and Il-4, decreased levels of glucose, microRNA-29a, NF-κß and LC3 expression, PAI-1, CK-MM and restored the normal histological appearance. CONCLUSIONS: ARG supplementation potently alleviated diabetic-induced neuromuscular alterations.


Assuntos
Diabetes Mellitus Experimental , MicroRNAs , Doenças Musculares , Animais , Ratos , Fibronectinas/genética , Interleucina-4 , Inibidor 1 de Ativador de Plasminogênio/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Estresse Oxidativo , Arginina , Antioxidantes , Insulina , Autofagia , MicroRNAs/genética
4.
J Orthop Surg Res ; 19(1): 190, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500202

RESUMO

PURPOSE: To study the effect of miR-150-5p on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), and further explore the relationship between its regulatory mechanism and irisin. METHODS: We isolated mouse BMSCs, and induced osteogenic differentiation by osteogenic induction medium. Using qPCR to detect the expression of osteogenic differentiation-related genes, western blot to detect the expression of osteogenic differentiation-related proteins, and luciferase reporter system to verify that FNDC5 is the target of miR-150-5p. Irisin intraperitoneal injection to treat osteoporosis in mice constructed by subcutaneous injection of dexamethasone. RESULTS: Up-regulation of miR-150-5p inhibited the proliferation of BMSCs, and decreased the content of osteocalcin, ALP activity, calcium deposition, the expression of osteogenic differentiation genes (Runx2, OSX, OCN, OPN, ALP and BMP2) and protein (BMP2, OCN, and Runx2). And down-regulation of miR-150-5p plays the opposite role of up-regulation of miR-150-5p on osteogenic differentiation of BMSCs. Results of luciferase reporter gene assay showed that FNDC5 gene was the target gene of miR-150-5p, and miR-150-5p inhibited the expression of FNDC5 in mouse BMSCs. The expression of osteogenic differentiation genes and protein, the content of osteocalcin, ALP activity and calcium deposition in BMSCs co-overexpressed by miR-150-5p and FNDC5 was significantly higher than that of miR-150-5p overexpressed alone. In addition, the overexpression of FNDC5 reversed the blocked of p38/MAPK pathway by the overexpression of miR-150-5p in BMSCs. Irisin, a protein encoded by FNDC5 gene, improved symptoms in osteoporosis mice through intraperitoneal injection, while the inhibitor of p38/MAPK pathway weakened this function of irisin. CONCLUSION: miR-150-5p inhibits the osteogenic differentiation of BMSCs by targeting irisin to regulate the/p38/MAPK signaling pathway, and miR-150-5p/irisin/p38 pathway is a potential target for treating osteoporosis.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Osteoporose , Animais , Camundongos , Medula Óssea , Cálcio/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibronectinas/farmacologia , Luciferases/metabolismo , Luciferases/farmacologia , Sistema de Sinalização das MAP Quinases/genética , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Osteocalcina/metabolismo , Osteogênese/genética , Osteoporose/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fatores de Transcrição/metabolismo
5.
Nanoscale ; 16(12): 6199-6214, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38446101

RESUMO

While the filtering and accumulation effects of the extracellular matrix (ECM) on nanoparticles (NPs) have been experimentally observed, the detailed interactions between NPs and specific biomolecules within the ECM remain poorly understood and pose challenges for in vivo molecular-level investigations. Herein, we adopt molecular dynamics simulations to elucidate the impacts of methyl-, hydroxy-, amine-, and carboxyl-modified gold NPs on the cell-binding domains of fibronectin (Fn), an indispensable component of the ECM for cell attachment and signaling. Simulation results show that NPs can specifically bind to distinct Fn domains, and the strength of these interactions depends on the physicochemical properties of NPs. NP-NH3+ exhibits the highest affinity to domains rich in acidic residues, leading to strong electrostatic interactions that induce severe deformation, potentially disrupting the normal functioning of Fn. NP-CH3 and NP-COO- selectively occupy the RGD/PHSRN motifs, which may hinder their recognition by integrins on the cell surface. Additionally, NPs can disrupt the dimerization of Fn through competing for residues at the dimer interface or by diminishing the shape complementarity between dimerized proteins. The mechanical stretching of Fn, crucial for ECM fibrillogenesis, is suppressed by NPs due to their local rigidifying effect. These results provide valuable molecular-level insights into the impacts of various NPs on the ECM, holding significant implications for advancing nanomedicine and nanosafety evaluation.


Assuntos
Fibronectinas , Nanopartículas , Fibronectinas/química , Integrinas/metabolismo , Matriz Extracelular/metabolismo , Transdução de Sinais
6.
PLoS One ; 19(3): e0300888, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512830

RESUMO

Neuronal death could be responsible for the cognitive impairments found in astronauts exposed to spaceflight, highlighting the need to identify potential countermeasures to ensure neuronal health in microgravity conditions. Therefore, differentiated HT22 cells were exposed to simulated microgravity by random positioning machine (RPM) for 48 h, treating them with a single administration of Trolox, recombinant irisin (r-Irisin) or both. Particularly, we investigated cell viability by MTS assay, Trypan Blue staining and western blotting analysis for Akt and B-cell lymphoma 2 (Bcl-2), the intracellular increase of reactive oxygen species (ROS) by fluorescent probe and NADPH oxidase 4 (NOX4) expression, as well as the expression of brain-derived neurotrophic factor (BDNF), a major neurotrophin responsible for neurogenesis and synaptic plasticity. Although both Trolox and r-Irisin manifested a protective effect on neuronal health, the combined treatment produced the best results, with significant improvement in all parameters examined. In conclusion, further studies are needed to evaluate the potential of such combination treatment in counteracting weightlessness-induced neuronal death, as well as to identify other potential strategies to safeguard the health of astronauts exposed to spaceflight.


Assuntos
Cromanos , Fibronectinas , Ausência de Peso , Fibronectinas/farmacologia , Fibronectinas/metabolismo , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Diferenciação Celular
7.
Cells ; 13(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474393

RESUMO

CD40 induces pro-inflammatory responses in endothelial and Müller cells and is required for the development of diabetic retinopathy (DR). CD40 is upregulated in these cells in patients with DR. CD40 upregulation is a central feature of CD40-driven inflammatory disorders. What drives CD40 upregulation in the diabetic retina remains unknown. We examined the role of advanced glycation end products (AGEs) in CD40 upregulation in endothelial cells and Müller cells. Human endothelial cells and Müller cells were incubated with unmodified or methylglyoxal (MGO)-modified fibronectin. CD40 expression was assessed by flow cytometry. The expression of ICAM-1 and CCL2 was examined by flow cytometry or ELISA after stimulation with CD154 (CD40 ligand). The expression of carboxymethyl lysine (CML), fibronectin, and laminin as well as CD40 in endothelial and Müller cells from patients with DR was examined by confocal microscopy. Fibronectin modified by MGO upregulated CD40 in endothelial and Müller cells. CD40 upregulation was functionally relevant. MGO-modified fibronectin enhanced CD154-driven upregulation of ICAM-1 and CCL2 in endothelial and Müller cells. Increased CD40 expression in endothelial and Müller cells from patients with DR was associated with increased CML expression in fibronectin and laminin. These findings identify AGEs as inducers of CD40 upregulation in endothelial and Müller cells and enhancers of CD40-dependent pro-inflammatory responses. CD40 upregulation in these cells is associated with higher CML expression in fibronectin and laminin in patients with DR. This study revealed that CD40 and AGEs, two important drivers of DR, are interconnected.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Humanos , Retinopatia Diabética/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Fibronectinas/metabolismo , Células Ependimogliais/metabolismo , Células Endoteliais/metabolismo , Óxido de Magnésio/metabolismo , Retina/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Laminina/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Diabetes Mellitus/metabolismo
8.
Int J Mol Sci ; 25(5)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38474169

RESUMO

Irisin is a myokine with potential effects on glucose metabolism and the development of diabetes in humans. We analysed irisin serum levels (ISL) in 47 patients without diabetes before and 1, 2, 3, 4 and 5 weeks after kidney transplantation (KTx). All measurements of irisin before KTx levels were lower than 25 ng/mL (median 8.4 ng/mL). We found an outstanding increase in ISL measured after KTx, reaching more than 1000 times in 44% of patients (HIL-high irisin level group). The increase appeared at the first measurement (one week after KTx). Factors connected to the large growth of ISL were, i.e., BMI > 30 (p = 0.04) and subsequent KTx-second and third (p < 0.001). The global mean blood glucose level during the first two weeks after KTx was significantly lower in the HIL group (p = 0.002), the same as the day-by-day analysed mean fasting and postprandial serum glucose in the first days after KTx. In 12 months of observation, diabetes requiring insulin therapy occurred in the HIL group at a rate of 19%, while in the rest of the patients, the rate was 27%, p = 0.526. Irisin levels increase significantly in some patients after kidney transplantation, accompanied by lower blood glucose levels in the early post-transplant period. Whether an increase in irisin levels results in better glycaemic control remains questionable and requires further research, as well as the relationship between irisin levels and the occurrence of PTDM.


Assuntos
Diabetes Mellitus , Transplante de Rim , Humanos , Fibronectinas , Glicemia/metabolismo , Controle Glicêmico
9.
Exp Dermatol ; 33(3): e15021, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429832

RESUMO

Langerhans cells (LCs) are mainly present in the epidermis and mucosa, and have important roles during skin infection. Migration of LCs to lymph nodes is essential for antigen presentation. However, due to the difficulties in isolating and culturing human LCs, it is not fully understood how LCs move and interact with the extracellular matrix (ECM) through their adhesion molecules such as integrin, during the immune responses. In this study, we aimed to investigate LC motility, cell shape and the role of integrin under inflammatory conditions using monocyte-derived Langerhans cells (moLCs) as a model. As a result, lipopolysaccharide (LPS) stimulation increased adhesion on fibronectin coated substrate and integrin α5 expression in moLCs. Time-lapse imaging of moLCs revealed that stimulation with LPS elongated cell shape, whilst decreasing their motility. Additionally, this decrease in motility was not observed when pre-treated with a neutralising antibody targeting integrin α5. Together, our data suggested that activation of LCs decreases their motility by promoting integrin α5 expression to enhance their affinity to the fibronectin, which may contribute to their migration during inflammation.


Assuntos
Integrina alfa5 , Células de Langerhans , Humanos , Fibronectinas/metabolismo , Imunidade , Integrina alfa5/metabolismo , Integrinas/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos
10.
J Mater Sci Mater Med ; 35(1): 23, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38526676

RESUMO

In the aging society, slow bone regeneration poses a serious hindrance to the quality of life. To deal with this problem, in this study, we have combined irisin with the bioglass regular beads to enhance the bone regeneration process. For this purpose, highly porous bioglass was obtained as spherical beads by using sodium alginate. The bioglass was evaluated by various analytical techniques such as SEM, EDS, XRD, and pore size distribution. The results depicted that porous bioglass was prepared correctly and SEM analysis showed a highly porous bioglass was formulated. On this bioglass, irisin was loaded with the assistance of polyvinyl alcohol (PVA) in three concentrations (50 ng/ml, 100 ng/ml, and 150 ng/ml per 1 g of bioglass). SEM analysis showed that pores are covered with PVA. The irisin release profile showed a sustained release over the time period of 7 days. In vitro, biocompatibility evaluation by the MC3T3E1 cells showed that prepared bioglass and irisin loaded bioglass (BGI50, BGI100, and BG150) are highly biocompatible. Alizarin Red staining analysis showed that after 2 weeks BGI50 samples showed highest calcium nodule formation. In vivo in the rabbit femur model was conducted for 1 and 2 months. BGI150 samples showed highest BV/TV ratio of 37.1 after 2 months. The histological data showed new bone formation surrounding the beads and with beads loaded with irisin. Immunohistochemistry using markers OPN, RUNX, COL, and ALP supported the osteogenic properties of the irisin-loaded bioglass beads. The results indicated that irisin-loaded bioglass displayed remarkable bone regeneration.


Assuntos
Osteogênese , Tecidos Suporte , Animais , Coelhos , Tecidos Suporte/química , Fibronectinas , Qualidade de Vida , Cerâmica/química , Álcool de Polivinil
11.
Front Endocrinol (Lausanne) ; 15: 1337995, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38405155

RESUMO

Vascular calcification is a common accompanying pathological change in many chronic diseases, which is caused by calcium deposition in the blood vessel wall and leads to abnormal blood vessel function. With the progress of medical technology, the diagnosis rate of vascular calcification has explosively increased. However, due to its mechanism's complexity, no effective drug can relieve or even reverse vascular calcification. Irisin is a myogenic cytokine regulating adipose tissue browning, energy metabolism, glucose metabolism, and other physiological processes. Previous studies have shown that irisin could serve as a predictor for vascular calcification, and protect against hypertension, diabetes, chronic kidney disease, and other risk factors for vascular calcification. In terms of mechanism, it improves vascular endothelial dysfunction and phenotypic transformation of vascular smooth muscle cells. All the above evidence suggests that irisin plays a predictive and protective role in vascular calcification. In this review, we summarize the association of irisin to the related risk factors for vascular calcification and mainly explore the role of irisin in vascular calcification.


Assuntos
Hipertensão , Insuficiência Renal Crônica , Calcificação Vascular , Humanos , Fibronectinas , Fatores de Risco
12.
J Transl Med ; 22(1): 137, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317144

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a complex multifactorial vascular pathology characterized by an increased pulmonary arterial pressure, vasoconstriction, remodelling of the pulmonary vasculature, thrombosis in situ and inflammation associated with right-side heart failure. Herein, we explored the potential beneficial effects of treatment with siRNA AP-1 on pulmonary arterial hypertension (PAH), right ventricular dysfunction along with perivascular and interstitial fibrosis in pulmonary artery-PA, right ventricle-RV and lung in an experimental animal model of monocrotaline (MCT)-induced PAH. METHODS: Golden Syrian hamsters were divided into: (1) C group-healthy animals taken as control; (2) MCT group obtained by a single subcutaneous injection of 60 mg/kg MCT at the beginning of the experiment; (3) MCT-siRNA AP-1 group received a one-time subcutaneous dose of MCT and subcutaneous injections containing 100 nM siRNA AP-1, every two weeks. All animal groups received water and standard chow ad libitum for 12 weeks. RESULTS: In comparison with the MCT group, siRNA AP-1 treatment had significant beneficial effects on investigated tissues contributing to: (1) a reduction in TGF-ß1/ET-1/IL-1ß/TNF-α plasma concentrations; (2) a reduced level of cytosolic ROS production in PA, RV and lung and notable improvements regarding the ultrastructure of these tissues; a decrease of inflammatory and fibrotic marker expressions in PA (COL1A/Fibronectin/Vimentin/α-SMA/CTGF/Calponin/MMP-9), RV and lung (COL1A/CTGF/Fibronectin/α-SMA/F-actin/OB-cadherin) and an increase of endothelial marker expressions (CD31/VE-cadherin) in PA; (4) structural and functional recoveries of the PA [reduced Vel, restored vascular reactivity (NA contraction, ACh relaxation)] and RV (enlarged internal cavity diameter in diastole, increased TAPSE and PRVOFs) associated with a decrease in systolic and diastolic blood pressure, and heart rate; (5) a reduced protein expression profile of AP-1S3/ pFAK/FAK/pERK/ERK and a significant decrease in the expression levels of miRNA-145, miRNA-210, miRNA-21, and miRNA-214 along with an increase of miRNA-124 and miRNA-204. CONCLUSIONS: The siRNA AP-1-based therapy led to an improvement of pulmonary arterial and right ventricular function accompanied by a regression of perivascular and interstitial fibrosis in PA, RV and lung and a down-regulation of key inflammatory and fibrotic markers in MCT-treated hamsters.


Assuntos
MicroRNAs , Hipertensão Arterial Pulmonar , Ratos , Animais , Artéria Pulmonar/patologia , Fibronectinas , Fator de Transcrição AP-1/metabolismo , Ventrículos do Coração/patologia , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Hipertensão Arterial Pulmonar/patologia , Fibrose , MicroRNAs/metabolismo , Modelos Animais de Doenças
13.
PLoS One ; 19(2): e0296850, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38330059

RESUMO

Staphylococcus schleiferi and Staphylococcus coagulans are opportunistic pathogens of animals and humans. They were previously classified as Staphylococcus schleiferi subs. schleiferi and Staphylococcus schleiferi subs. coagulans, respectively, and recently reclassified as separate species. S. coagulans, is frequently associated with dogs, whereas S. schleiferi is more commonly isolated from humans. Coagulase activity status is a defining characteristic of the otherwise closely related species. However, the use of coagulase tests originally developed to distinguish S. aureus from non-coagulase-producing staphylococci, for this purpose is questionable and the basis for their host preference has not been elucidated. In the current study, a putative coa gene was identified and correlated with coagulase activity measured using a chromogenic assay with human and bovine prothrombin (closely related to canine prothrombin). The results of the tests performed with human prothrombin showed greater reactivity of S. coagulans isolates from humans than isolates obtained from dogs with the same substrate. Our data suggest that unlike S. coagulans isolates from humans, isolates from dogs have more coagulase activity with bovine prothrombin (similar to canine prothrombin) than human prothrombin. Differences in nuc and 16s rRNA genes suggest a divergence in S. coagulans and S. schleiferi. Phenotypic and genotypic variation based on the number of IgG binding domains, and the numbers of tandem repeats in C-terminal fibronectin binding motifs was also found in protein A, and fibronectin-binding protein B respectively. This study identified a coa gene and associated phenotypic activity that differentiates S. coagulans and S. schleiferi and identified key phylogenetic and phenotypic differences between the species.


Assuntos
Doenças do Cão , Infecções Estafilocócicas , Animais , Humanos , Cães , Bovinos , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Coagulase/genética , Coagulase/metabolismo , RNA Ribossômico 16S/genética , Fibronectinas/genética , Filogenia , Protrombina , Staphylococcus/metabolismo , Infecções Estafilocócicas/veterinária
14.
Int J Mol Sci ; 25(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38339104

RESUMO

One of the extracellular matrix proteins, tenascin-C (TN-C), is known to be upregulated in age-related inflammatory diseases such as cancer and cardiovascular diseases. Expression of this molecule is frequently detected, especially in the macrophage-rich areas of atherosclerotic lesions; however, the role of TN-C in mechanisms underlying the progression of atherosclerosis remains obscure. Previously, we found a hidden bioactive sequence termed TNIIIA2 in the TN-C molecule and reported that the exposure of this sequence would be carried out through limited digestion of TN-C by inflammatory proteases. Thus, we hypothesized that some pro-atherosclerotic phenotypes might be elicited from macrophages when they were stimulated by TNIIIA2. In this study, TNIIIA2 showed the ability to accelerate intracellular lipid accumulation in macrophages. In this experimental condition, an elevation of phagocytic activity was observed, accompanied by a decrease in the expression of transporters responsible for lipid efflux. All these observations were mediated through the induction of excessive ß1-integrin activation, which is a characteristic property of the TNIIIA2 sequence. Finally, we demonstrated that the injection of a drug that targets TNIIIA2's bioactivity could rescue mice from atherosclerotic plaque expansion. From these observations, it was shown that TN-C works as a pro-atherosclerotic molecule through an internal TNIIIA2 sequence. The possible advantages of clinical strategies targeting TNIIIA2 are also indicated.


Assuntos
Aterosclerose , Células Espumosas , Placa Aterosclerótica , Animais , Camundongos , Proteínas da Matriz Extracelular , Fibronectinas/metabolismo , Células Espumosas/metabolismo , Lipídeos , Peptídeos/química , Tenascina/metabolismo
15.
J Biomed Mater Res B Appl Biomater ; 112(2): e35390, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38356151

RESUMO

Silane chemistry has emerged as a powerful tool for surface modification, offering a versatile means to enhance the properties of various substrates, such as dental implant abutment materials. In this study, we investigated the stability of the 3-aminopropyldiisopropylethoxysilane (APDS) layer on yttria-partially stabilized zirconia (Y-TZP) surfaces after mechanical, acid, and thermal treatment in order to simulate fluctuations within the oral cavity. To accomplish that, the viability of human gingival fibroblasts on APDS-modified surfaces after applied treatment strategies was assessed by live/dead staining. Moreover, the hydrolysis stability and enzymatic degradation resistance of crosslinked fibronectin to the APDS layer was examined by immunostaining and western blot. The results revealed that the applied modifications were not affected by the different treatment conditions and could withstand the fluctuations in the oral cavity. Furthermore, crosslinked fibronectin on silanized Y-TZP was stable against hydrolysis over 21 days and enzymatic degradation. We thus can conclude that the proposed functionalization method has high potential to tolerate harmful effects within the oral cavity and remains unchanged on the surface.


Assuntos
Fibronectinas , Zircônio , Humanos , Microscopia Eletrônica de Varredura , Teste de Materiais , Propriedades de Superfície , Zircônio/química , Ítrio/química , Materiais Dentários
16.
PLoS One ; 19(2): e0297550, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38359069

RESUMO

BACKGROUND: Delayed diagnosis and inadequate treatment of infectious and inflammatory diseases, such as Brucella, lead to high rates of mortality and morbidity. The aim of our study was to investigate the association between serum levels of apelin, presepsin, and irisin with inflammation, laboratory parameters, and blood culture in patients with brucella. PATIENTS AND METHODS: This prospective case-control study involves 30 patients with brucellosis and 30 healthy, matched control subjects. Thirty patients who were diagnosed with brucellosis were aged ≥ 18 years. Blood samples were taken from the patients on the first day they were diagnosed with brucellosis. The values of irisin, presepsin, and apelin were studied. In addition, blood samples were also taken from 30 healthy individuals for the control group. Irisin, presepsin, and apelin values that were measured in the patients on the first day were compared with those values measured in the control group. RESULTS: The sex and age statuses of the subjects are matched among the groups. The levels of irisin were significantly higher in patients with brucellosis compared to the control group (p<0.045). There was no significant difference between the two groups in terms of apelin and presepsin levels (p values 0.087 and 0.162, respectively). There was a positive correlation between irisin levels and elevated ALT levels, as well as positive blood cultures. CONCLUSIONS: It appears that the measurement of irisin levels may be beneficial in patients with brucellosis. Irisin can be used as a diagnostic marker for brucella infection and may greatly clinicians to predict the severity disease and treatment response.


Assuntos
Brucella , Brucelose , Humanos , Apelina , Estudos de Casos e Controles , Fibronectinas , Brucelose/diagnóstico , Biomarcadores , Fragmentos de Peptídeos , Receptores de Lipopolissacarídeos
17.
Biophys Chem ; 307: 107193, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38320409

RESUMO

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a moonlighting enzyme. Apart from its primary role in the glycolytic pathway, in many bacterial species it is found in the extracellular milieu and also on the bacterial surface. Positioning on the bacterial surface allows the GAPDH molecule to interact with many host molecules such as plasminogen, fibrinogen, fibronectin, laminin and mucin etc. This facilitates the bacterial colonization of the host. Helicobacter pylori is a major human pathogen that causes a number of gastrointestinal infections and is the main cause of gastric cancer. The binding analysis of H. pylori GAPDH (HpGAPDH) with host molecules has not been carried out. Hence, we studied the interaction of HpGAPDH with holo-transferrin, lactoferrin, haemoglobin, fibrinogen, fibronectin, catalase, plasminogen and mucin using biolayer interferometry. Highest and lowest binding affinity was observed with lactoferrin (4.83 ± 0.70 × 10-9 M) and holo-transferrin (4.27 ± 2.39 × 10-5 M). Previous studies established GAPDH as a heme chaperone involved in intracellular heme trafficking and delivery to downstream target proteins. Therefore, to get insights into heme binding, the interaction between HpGAPDH and hemin was analyzed. Hemin binds to HpGAPDH with an affinity of 2.10 µM while the hemin bound HpGAPDH does not exhibit activity. This suggests that hemin most likely binds at the active site of HpGAPDH, prohibiting substrate binding. Blind docking of hemin with HpGAPDH also supports positioning of hemin at the active site. Metal ions were found to inhibit the activity of HpGAPDH, suggesting that it also possibly occupies the substrate binding site. Furthermore, with metal-bound HpGAPDH, hemin binding was not observed, suggesting metal ions act as an inhibitor of hemin binding. Since GAPDH has been identified as a heme chaperone, it will be interesting to analyse the biological consequences of inhibition of heme binding to GAPDH by metal ions.


Assuntos
Helicobacter pylori , Hemina , Humanos , Hemina/metabolismo , Helicobacter pylori/metabolismo , Fibronectinas/metabolismo , Lactoferrina/metabolismo , Ligação Proteica , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Heme/metabolismo , Fibrinogênio , Plasminogênio/metabolismo , Íons/metabolismo , Mucinas/metabolismo
18.
Life Sci ; 341: 122503, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38354974

RESUMO

AIMS: To explore cardiac structural and functional parameters and myocardial sensitivity to ischemia in a rat model of chronic arthritis, pristane-induced arthritis (PIA), and to investigate the effects of a running exercise protocol on cardiac disorders related to rheumatoid arthritis (RA). MAIN METHODS: 3 groups of male Dark Agouti rats were formed: Controls, PIA and PIA-Exercise. The PIA-Exercise group was subjected to an individualized treadmill running protocol during the remission phase. At acute and chronic phases of PIA, cardiac structure was analyzed by histology. Cardiac function was explored in isolated hearts to measure left ventricular developed pressure (LVDP), cardiac compliance and infarct size before and after ischemia/reperfusion. Cardiac inflammation was evaluated through VCAM-1 mRNA expression by RT-qPCR. Plasma irisin levels were measured by ELISA. KEY FINDINGS: PIA rats exhibited myocardial hypertrophy fibrosis and inflammation at the 2 inflammatory phases of the model. At chronic phase only, LVDP and cardiac compliance were lower in PIA compared to controls. As compared to sedentary PIA, exercise did not change cardiac function but reduced fibrosis, inflammation, infarct size, and arthritis severity and increased irisin levels. Cardiac inflammation positively correlated with fibrosis, while irisin levels negatively correlated with cardiac inflammation and fibrosis. SIGNIFICANCE: In the PIA model that recapitulated most cardiac disorders of RA, a daily program of treadmill running alleviated cardiac fibrosis and inflammation and improved resistance to ischemia. These data provide arguments to promote the practice of exercise in RA patients for cardiac diseases prevention.


Assuntos
Artrite Experimental , Artrite Reumatoide , Cardiopatias , Terpenos , Humanos , Ratos , Masculino , Animais , Artrite Experimental/metabolismo , Fibronectinas/efeitos adversos , Inflamação , Artrite Reumatoide/metabolismo , Isquemia , Infarto , Fibrose
19.
Cells ; 13(3)2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38334669

RESUMO

Disorders of cardiomyocyte metabolism play a crucial role in many cardiovascular diseases, such as myocardial infarction, heart failure and ischemia-reperfusion injury. In myocardial infarction, cardiomyocyte metabolism is regulated by mitochondrial changes and biogenesis, which allows energy homeostasis. There are many proteins in cells that regulate and control metabolic processes. One of them is irisin (Ir), which is released from the transmembrane protein FNDC5. Initial studies indicated that Ir is a myokine secreted mainly by skeletal muscles. Further studies showed that Ir was also present in various tissues. However, its highest levels were observed in cardiomyocytes. Ir is responsible for many processes, including the conversion of white adipose tissue (WAT) to brown adipose tissue (BAT) by increasing the expression of thermogenin (UCP1). In addition, Ir affects mitochondrial biogenesis. Therefore, the levels of FNDC5/Ir in the blood and myocardium may be important in cardiovascular disease. This review discusses the current knowledge about the role of FNDC5/Ir in cardiovascular disease.


Assuntos
Doenças Cardiovasculares , Infarto do Miocárdio , Humanos , Fibronectinas/metabolismo , Doenças Cardiovasculares/metabolismo , Tecido Adiposo Branco/metabolismo , Músculo Esquelético/metabolismo , Fatores de Transcrição/metabolismo , Infarto do Miocárdio/metabolismo
20.
Int J Mol Sci ; 25(3)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38339161

RESUMO

Physical exercise (EX) is well established for its positive impact on brain health. However, conventional EX may not be feasible for certain individuals. In this regard, this study explores electromyostimulation (EMS) as a potential alternative for enhancing cognitive function. Conducted on both human participants and rats, the study involved two sessions of EMS applied to the quadriceps with a duration of 30 min at one-week intervals. The human subjects experienced assessments of cognition and mood, while the rats underwent histological and biochemical analyses on the prefrontal cortex, hippocampus, and quadriceps. Our findings indicated that EMS enhanced executive functions and reduced anxiety in humans. In parallel, our results from the animal studies revealed an elevation in brain-derived neurotrophic factor (BDNF), specifically in the hippocampus. Intriguingly, this increase was not associated with heightened neuronal activity or cerebral hemodynamics; instead, our data point towards a humoral interaction from muscle to brain. While no evidence of increased muscle and circulating BDNF or FNDC5/irisin pathways could be found, our data highlight lactate as a bridging signaling molecule of the muscle-brain crosstalk following EMS. In conclusion, our results suggest that EMS could be an effective alternative to conventional EX for enhancing both brain health and cognitive function.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Condicionamento Físico Animal , Humanos , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transdução de Sinais/fisiologia , Músculos/metabolismo , Condicionamento Físico Animal/fisiologia , Encéfalo/metabolismo , Fibronectinas/metabolismo
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