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1.
J Hypertens ; 42(4): 685-693, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38406874

RESUMO

BACKGROUND: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. METHODS: C57BL/6 mice lacking ApoE , NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal-Wallis tests were performed to determine statistical differences. RESULTS: Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3 -deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. CONCLUSION: We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.


Assuntos
Aterosclerose , MicroRNAs , Animais , Camundongos , Metaloproteinase 13 da Matriz/metabolismo , Basigina/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Células Endoteliais/metabolismo , Camundongos Endogâmicos C57BL , Matriz Extracelular/metabolismo , MicroRNAs/metabolismo , Apolipoproteínas E/genética
2.
PLoS Pathog ; 20(2): e1011989, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38315723

RESUMO

Plasmodium falciparum invasion of the red blood cell is reliant upon the essential interaction of PfRh5 with the host receptor protein basigin. Basigin exists as part of one or more multiprotein complexes, most notably through interaction with the monocarboxylate transporter MCT1. However, the potential requirement for basigin association with MCT1 and the wider role of basigin host membrane context and lateral protein associations during merozoite invasion has not been established. Using genetically manipulated in vitro derived reticulocytes, we demonstrate the ability to uncouple basigin ectodomain presentation from its transmembrane domain-mediated interactions, including with MCT1. Merozoite invasion of reticulocytes is unaffected by disruption of basigin-MCT1 interaction and by removal or replacement of the basigin transmembrane helix. Therefore, presentation of the basigin ectodomain at the red blood cell surface, independent of its native association with MCT1 or other interactions mediated by the transmembrane domain, is sufficient to facilitate merozoite invasion.


Assuntos
Plasmodium falciparum , Simportadores , Plasmodium falciparum/metabolismo , Basigina/genética , Basigina/metabolismo , Eritrócitos/metabolismo , Domínios Proteicos , Simportadores/metabolismo
3.
Cell Commun Signal ; 22(1): 129, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360687

RESUMO

BACKGROUND: Extracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-derived EVs, tissue factor (TF) and CD147 have been implicated in promoting tumor progression. In this in vitro study, we explored a novel approach to impede cancer cell migration and metastasis by simultaneously targeting these molecules on urothelial cancer-derived EVs. METHODS: Cell culture supernatants from invasive and non-invasive bladder cancer cell lines and urine samples from patients with BLCA were collected. Large, microvesicle-like EVs were isolated using sequential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and flow cytometry. The impact of urinary or cell supernatant-derived EVs on cellular phenotypes was evaluated using cell-based assays following combined treatment with a specific CD147 inhibitor alone or in combination with a tissue factor pathway inhibitor (TFPI), an endogenous anticoagulant protein that can be released by low-molecular-weight heparins. RESULTS: We observed that EVs obtained from the urine samples of patients with muscle-invasive BLCA and from the aggressive bladder cancer cell line J82 exhibited higher TF activity and CD147 expression levels than did their non-invasive counterparts. The shedding of GFP-tagged CD147 into isolated vesicles demonstrated that the vesicles originated from plasma cell membranes. EVs originating from invasive cancer cells were found to trigger migration, secretion of matrix metalloproteinases (MMPs), and invasion. The same induction of MMP activity was replicated using EVs obtained from urine samples of patients with invasive BLCA. EVs derived from cancer cell clones overexpressing TF and CD147 were produced in higher quantities and exhibited a higher invasive potential than those from control cancer cells. TFPI interfered with the effect when used in conjunction with the CD147 inhibitor, further suppressing homotypic EV-induced migration, MMP production, and invasion. CONCLUSIONS: Our findings suggest that combining a CD147 inhibitor with low molecular weight heparins to induce TFPI release may be a promising therapeutic approach for urothelial cancer management. This combination can potentially suppress the tumor-promoting actions of cancer-derived microvesicle-like EVs, including collective matrix invasion.


Small particles or vesicles released by cancer cells into their surroundings have the potential to stimulate the spread and growth of cancer cells. In this study, we focused on two specific molecules presented by these cancer cell-derived vesicles that could play a role in promoting the dissemination of cancer cells: a protein related to blood clotting and a protein on the cell surface.We found that large vesicles from bladder cancer cells that have the ability to spread had higher levels of these proteins than vesicles from nonspreading cancer cells. We also found that the former could make cancer cells move about more, produce more of a substance that helps cancer cells spread, and invade other tissues.To counteract the cancer-promoting actions of these vesicles, we examined the impact of combining a naturally occurring anticlotting protein that can be released by medications derived from heparin with an inhibitor targeting the cancer cell surface protein. We found that this combination stopped the vesicles from helping cancer cells move about more, produce more of the spreading substance, and invade other tissues.This approach of simultaneously targeting the two protein molecules present on cancer cell-derived vesicles might be a new way to treat bladder cancer.


Assuntos
Basigina , Carcinoma de Células de Transição , Vesículas Extracelulares , Lipoproteínas , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Linhagem Celular Tumoral , Vesículas Extracelulares/efeitos dos fármacos , Lipoproteínas/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Basigina/antagonistas & inibidores
4.
Front Immunol ; 15: 1319939, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38318187

RESUMO

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.


Assuntos
Artrite Reumatoide , Basigina , Humanos , Artrite Reumatoide/metabolismo , Basigina/genética , Endostatinas , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz , Complexo de Endopeptidases do Proteassoma , Trombospondina 1 , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Respir Res ; 25(1): 6, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178133

RESUMO

BACKGROUND: Airway remodeling is a poorly reversible feature of asthma which lacks effective therapeutic interventions. CD147 can regulate extracellular matrix (ECM) remodeling and tissue fibrosis, and participate in the pathogenesis of asthma. In this study, the role of CD147 in airway remodeling and activation of circulating fibrocytes was investigated in asthmatic mice. METHODS: Asthmatic mouse model was established by sensitizing and challenging mice with ovalbumin (OVA), and treated with anti-CD147 or Isotype antibody. The number of eosinophils in bronchoalveolar lavage fluid (BALF) was examined by microscope, and the levels of interleukin-4 (IL-4), IL-5 and IL-13 in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The number of CD45+ and collagen I (COL-I)+ circulating fibrocytes in BALF was detected by flow cytometry. Lung tissue sections were respectively stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS) or Masson trichrome staining, or used for immunohistochemistry of CD31 and immunohistofluorescence of α-smooth muscle actin (α-SMA), CD45 and COL-I. The protein expression of α-SMA, vascular endothelial growth factor (VEGF), transforming growth factor-ß1 (TGF-ß1), Fibronectin, and COL-I was determined by western blotting. RESULTS: Anti-CD147 treatment significantly reduced the number of eosinophils and the levels of IL-4, IL-13, and IL-5 in BALF, and repressed airway inflammatory infiltration and airway wall thickening in asthmatic mice. Anti-CD147 treatment also reduced airway goblet cell metaplasia, collagen deposition, and angiogenesis in asthmatic mice, accompanied by inhibition of VEGF and α-SMA expression. The number of CD45+COL-I+ circulating fibrocytes was increased in BALF and lung tissues of OVA-induced asthmatic mice, but was decreased by anti-CD147 treatment. In addition, anti-CD147 treatment also reduced the protein expression of COL-I, fibronectin, and TGF-ß1 in lung tissues of asthmatic mice. CONCLUSION: OVA-triggered airway inflammation and airway remodeling in asthmatic mice can be repressed by anti-CD147 treatment, along with inhibiting the accumulation and activation of circulating fibrocytes.


Assuntos
Asma , Basigina , Animais , Camundongos , Remodelação das Vias Aéreas , Asma/tratamento farmacológico , Colágeno Tipo I , Fibronectinas , Interleucina-13 , Interleucina-4 , Interleucina-5 , Fator de Crescimento Transformador beta1 , Fator A de Crescimento do Endotélio Vascular
6.
Expert Opin Ther Targets ; 28(1-2): 83-95, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38235574

RESUMO

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors. METHODS: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti­tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection. RESULTS: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin. CONCLUSION: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Animais , Camundongos , Cisplatino/farmacologia , Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Apoptose , Linhagem Celular Tumoral , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Basigina/genética , Proliferação de Células
7.
Front Biosci (Landmark Ed) ; 29(1): 8, 2024 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-38287815

RESUMO

Kidney damage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can occur even in patients with no underlying kidney disease. Signs of kidney problems can progress to a state that demands dialysis and hampering recovery. Although not without controversy, emerging evidence implicates direct infectivity of SARS-CoV-2 in the kidney. At the early stage of the pandemic, consideration was mainly on the well-recognized angiotensin-converting enzyme 2 (ACE2) receptor as being the site for viral interaction and subsequent cellular internalization. Despite the abundance of ACE2 receptors in the kidneys, researchers have expanded beyond ACE2 and identified novel viral entry pathways that could be advantageously explored as therapeutic targets. This review presents the potential involvement of toll-like receptor 4 (TLR-4), kidney injury molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1), and cluster of differentiation 147 (CD147) in SARS-CoV-2-associated renal damage. In this context, we address the unresolved issues surrounding SARS-CoV-2 renal infectivity.


Assuntos
Basigina , COVID-19 , Receptor Celular 1 do Vírus da Hepatite A , Nefropatias , Receptor 4 Toll-Like , Humanos , Enzima de Conversão de Angiotensina 2 , COVID-19/complicações , Rim/metabolismo , Mucinas , SARS-CoV-2/metabolismo
8.
Odontology ; 112(1): 148-157, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37227552

RESUMO

Extracellular matrix metalloproteinase inducer (EMMPRIN) plays critical roles in the regulation of inflammation and bone metabolism. The roles of EMMPRIN signaling in osteoclasts are worthy of deep study. The present study aimed to investigate bone resorption in periodontitis through the intervention of EMMPRIN signaling. The distribution of EMMPRIN in human periodontitis was observed. RANKL-induced osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) were treated with EMMPRIN inhibitor in vitro. Rats with ligation-induced periodontitis were treated with EMMPRIN inhibitor and harvested for microcomputed tomography scanning, histologic observation, immunohistochemistry, and double immunofluorescence analysis. Positive expressions of EMMPRIN could be found in the CD68+-infiltrating cells. Downregulated EMMPRIN restrained osteoclast differentiation of BMMs in vitro, which also inhibited MMP-9 expression (*P < 0.05). In vivo, EMMPRIN inhibitor restrained ligation-induced bone resorption by decreasing tartrate-resistant acid phosphatase-positive osteoclasts. Both EMMPRIN-positive and MMP-9-positive osteoclasts were less common in the EMMPRIN inhibitor groups than in the control groups. Intervention of EMMPRIN signaling in osteoclasts could probably provide a potential therapeutic target for attenuating ligation-induced bone resorption.


Assuntos
Reabsorção Óssea , Periodontite , Camundongos , Ratos , Humanos , Animais , Osteoclastos , Basigina/análise , Basigina/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Microtomografia por Raio-X , Reabsorção Óssea/patologia , Periodontite/patologia , Ligante RANK , Diferenciação Celular
9.
Hypertension ; 81(1): 114-125, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37955149

RESUMO

BACKGROUND: Polycystic kidney disease is the most common hereditary kidney disorder with early and frequent hypertension symptoms. The mechanisms of cyst progression in polycystic kidney disease remain incompletely understood. METHODS: Bsg (basigin) heterozygous and homozygous knockout mice were generated using cas9 system, and Bsg overexpression was achieved by adeno-associated virus serotype 9 injection. Renal morphology was investigated through histological and imaging analysis. Molecular analysis was performed through transcriptomic profiling and biochemical approaches. RESULTS: Bsg-deficient mice exhibited significantly elevated arterial blood pressure. Further investigation demonstrated that Bsg deficiency triggers spontaneous cystic formation in mouse kidneys, which shares similar cyst pathological features and common transcriptional regulatory pathways with human polycystic kidney disease. Moreover, Bsg disruption promoted polycystin-1 ubiquitination and degradation, leading to activation of polycystic kidney disease associated cAMP and AMPK signaling pathways in Bsg knockout mouse kidneys. Finally, adeno-associated virus serotype 9 mediated Bsg reexpression reversed cystic progression in Bsg knockout mice in vivo, and Bsg overexpression inhibited the expansion of Madin-Darby canine kidney cysts in vitro. CONCLUSIONS: Our findings show that Bsg deficiency leads to an early-onset spontaneous polycystic kidney phenotype, suggesting that dysregulated Bsg signaling may be a contributing factor in cystogenesis.


Assuntos
Cistos , Doenças Renais Policísticas , Animais , Cães , Humanos , Camundongos , Basigina/genética , Basigina/metabolismo , Cistos/metabolismo , Cistos/patologia , Rim/metabolismo , Camundongos Knockout , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/metabolismo
10.
BMC Cancer ; 23(1): 1214, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38066486

RESUMO

BACKGROUND: CD147, a transmembrane glycoprotein, has been implicated in various cancer-related processes but its role in breast cancer remains poorly understood. Herein, we investigated the expression of CD147 in different breast cancer cell lines and explored its functional roles, including migration, invasion, drug resistance and modulation of key proteins associated with cancer progression. METHODS: The expression of CD147 was assessed in MCF-10 A, BT549, MDA-MB-231 and MCF-7 breast cancer cell lines using qRT-PCR and Western blotting, following which lyposome transfections were performed, leading overexpression of CD147 in BT549 cells and knockdown of CD147 in MCF-7 cells. Scratch assays and Transwell invasion and were performed to evaluate the cells' migration and invasion abilities. Sensitivity to 5-FU was determined via CCK-8 assays, and the expression of Snail1, E-cadherin, Vimentin, MMP-9 and the MAPK/ERK pathway were analyzed by qRT-PCR and Western blotting. RESULTS: Compared with normal beast epithelial cells, CD147 was highly expressed in all breast cancer cell lines, with the highest overexpression observed in MCF-7 cells and the lowest overexpression observed in BT549 cells. Overexpression of CD147 in BT549 cells increased, migration, invasion, viability and resistance to 5-FU of BT549 cells, while CD147 knockdown in MCF-7 cells reduced these properties of MCF-7 cells. Furthermore, CD147 influenced the expression of Snail1, Vimentin, E-cadherin, and MMP-9, suggesting its involvement in epithelial-mesenchymal transition (EMT) regulation. The MAPK/ERK pathway was activated by CD147 in BT549 cells, as indicated by increased p-MEK/MEK ratio and p-ERK/ERK ratio. In contrast, CD147 silencing in MCF-7 cells resulted in reduced p-MEK/MEK ratio and p-ERK/ERK ratio. CONCLUSION: In summary, our findings suggest CD147 as a potential therapeutic target in breast cancer treatment, particularly in cases where drug resistance and metastasis are concerns, worthy of further explorations.


Assuntos
Basigina , Neoplasias da Mama , Sistema de Sinalização das MAP Quinases , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal/genética , Fluoruracila , Metaloproteinase 9 da Matriz/metabolismo , Células MCF-7 , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Vimentina/genética , Vimentina/metabolismo , Basigina/genética
11.
Int J Mol Sci ; 24(24)2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38139173

RESUMO

CD147/Basigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is a multifunctional molecule with various binding partners. CD147 binds to monocarboxylate transporters (MCTs) and supports their expression on plasma membranes. MTC-1 and MCT-4 export the lactic acid that is converted from pyruvate in glycolysis to maintain the intracellular pH level and a stable metabolic state. Under physiological conditions, cellular energy production is induced by mitochondrial oxidative phosphorylation. Glycolysis usually occurs under anaerobic conditions, whereas cancer cells depend on glycolysis under aerobic conditions. T cells also require glycolysis for differentiation, proliferation, and activation. Human malignant melanoma cells expressed higher levels of MCT-1 and MCT-4, co-localized with CD147 on the plasma membrane, and showed an increased glycolysis rate compared to normal human melanocytes. CD147 silencing by siRNA abrogated MCT-1 and MCT-4 membrane expression and disrupted glycolysis, inhibiting cancer cell activity. Furthermore, CD147 is involved in psoriasis. MCT-1 was absent on CD4+ T cells in CD147-deficient mice. The naïve CD4+ T cells from CD147-deficient mice exhibited a low capacity to differentiate into Th17 cells. Imiquimod-induced skin inflammation was significantly milder in the CD147-deficient mice than in the wild-type mice. Overall, CD147/Basigin is involved in the development of malignant tumors and T-cell-mediated immunological disorders via glycolysis regulation.


Assuntos
Basigina , Neoplasias , Animais , Humanos , Camundongos , Basigina/genética , Basigina/metabolismo , Glicólise , RNA Interferente Pequeno/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo
12.
Exp Biol Med (Maywood) ; 248(18): 1550-1555, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37937473

RESUMO

Preeclampsia increases the risk of pregnancy-related complications, nevertheless a successful spiral vessel remodeling, and trophoblast invasion reduces disorders of pregnancy. Matrix metalloproteinase-2 (MMP-2) clears the path for trophoblast invasion, and activation of MMP-2 largely depends on extracellular matrix metalloproteinases inducer (EMMPRIN) protein. This study aimed to investigate EMMPRIN gene polymorphism and MMP-2 activity in preeclampsia patients. Archival whole blood and serum samples of 74 preeclampsia and 66 normotensive pregnant women age-matched were used in this case-control study. Genomic DNA was extracted from the whole blood samples and EMMPRIN gene amplified with specific primers following fragments sequence mutation analysis. Serum MMP-2 activity was determined using enzyme-linked immunosorbent assay (ELISA) and socio-demographic data of participants retrieved from the database. Age of preeclampsia patients (32.78 ± 6.39) years and body mass index (BMI) (33.09 ± 7.27) kg/m2 compared with the normotensive counterparts (32.33 ± 5.56) years and (32.33 ± 5.56) kg/m2,respectively, were not statistically significant (P > 0.05). Serum matrix metalloprotease-2 (MMP-2) activity was significantly reduced in preeclampsia group (16.34 ± 7.07) compared with the normotensives (25.63 ± 4.56) (P < 0.001), and rs424243T/G variant (55.6%) was overrepresented among the cases compared with the normotensives (16.7%). The single-nucleotide polymorphism T/G was found to be associated with preeclampsia (odds ratio [OR] = 7.63; 95% confidence interval [CI] = 3.95-14.75; P < 0.0001). Decreased activity of MMP-2 and rs424243T/G SNP of EMMPRIN gene was reported in preeclampsia. These preliminary data warrant a further investigation into the relationship between EMMPRIN gene polymorphism and MMP-2 activity in preeclampsia.


Assuntos
Basigina , Pré-Eclâmpsia , Adulto , Feminino , Humanos , Gravidez , Basigina/genética , Basigina/metabolismo , Estudos de Casos e Controles , Matriz Extracelular/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Polimorfismo Genético , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo
13.
Respir Res ; 24(1): 253, 2023 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-37880644

RESUMO

OBJECTIVE: CD147 is an important glycoprotein that participates in the progression of diverse cancers. This study aims to explore the specific function of CD147 in lung adenocarcinoma (LUAD) and to reveal related downstream molecular mechanisms. METHODS: Followed by silencing of CD147, the viability, migration, invasion, and apoptosis of LUAD cells were measured by CCK8, wound healing, transwell assay, and flow cytometer, respectively. The expression of CD147 and two markers of lipid metabolism (FASN and ACOX1) were detected by qRT-PCR. A xenograft tumor model was constructed to investigate the function of CD147 in vivo. Then transcriptome sequencing was performed to explore the potential mechanisms. After measuring the expression of Rap1 and p-p38 MAPK/p38 MAPK by western blot, the changes of CD147 and lipid metabolism markers (FASN, ACOX1) was detected by Immunohistochemistry. Moreover, a Rap1 activator and a Rap1 inhibitor were applied for feedback functional experiments. RESULTS: CD147 was up-regulated in LUAD cells, and its silencing inhibited cell proliferation, migration, invasion, lipid metabolism dysregulation and promoted apoptosis, while overexpression of CD147 showed the opposite results. Silencing of CD147 also inhibited the growth of tumor xenografts in mice. Transcriptome sequencing revealed 834 up-regulated differentially expressed genes (DEGs) and 602 down-regulated DEGs. After functional enrichment, the Rap1 signaling pathway was selected as a potential target, which was then verified to be blocked by CD147 silencing. In addition, the treatment of Rap1 activator weakened the inhibiting effects of si-CD147 on the proliferation, migration, invasion, and lipid metabolism in LUAD cells, while the intervention of RAP1 inhibitor showed the opposite results. CONCLUSIONS: Silencing of CD147 inhibited the proliferation, migration, invasion, lipid metabolism dysregulation and promoted apoptosis of LUAD cells through blocking the Rap1 signaling pathway.


Assuntos
Adenocarcinoma de Pulmão , Basigina , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/patologia , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos/genética , Neoplasias Pulmonares/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Inativação Gênica , Basigina/genética
14.
J Pharm Biomed Anal ; 236: 115729, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-37778199

RESUMO

Studies reveal that alterations in membrane protein (MP) patterns are associated with underlying drug resistance to chemotherapy. Therefore, the tryptic-digested MPs from the bladder cancer cell line were subjected to global proteomics using LC-MS/MS to identify the highly expressed potential MPs in bladder cancer cells. Our findings revealed the identification of MP biomarkers, CD147, and caveolin-1. Immunocytochemistry analysis confirmed the presence of CD147 on the cell membrane, while caveolin-1 showed positive signals without apparent staining on the membrane, suggesting its existence in multiple locations. Western blot analysis confirmed the higher expression of CD147 in non-invasive (RT 112) and metastatic (UM-UC-13) bladder cancer cells compared to invasive bladder cancer cells (5637 and J82), suggesting its potential as an MP biomarker for both of the former subtypes. The identified MPs could be used as drug therapy targets aimed at improving drug sensitivity and enhancing treatment outcomes in bladder cancer patients. SIGNIFICANCE: Identification of the membrane proteins associated with bladder cancer recurrence is crucial to understanding the mechanisms underlying the drug resistance to chemotherapy.


Assuntos
Proteínas de Membrana , Neoplasias da Bexiga Urinária , Humanos , Proteínas de Membrana/metabolismo , Caveolina 1/metabolismo , Cromatografia Líquida , Basigina/metabolismo , Espectrometria de Massas em Tandem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Biomarcadores , Linhagem Celular Tumoral
15.
Elife ; 122023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37796723

RESUMO

Basigin is an essential host receptor for invasion of Plasmodium falciparum into human erythrocytes, interacting with parasite surface protein PfRH5. PfRH5 is a leading blood-stage malaria vaccine candidate and a target of growth-inhibitory antibodies. Here, we show that erythrocyte basigin is exclusively found in one of two macromolecular complexes, bound either to plasma membrane Ca2+-ATPase 1/4 (PMCA1/4) or to monocarboxylate transporter 1 (MCT1). PfRH5 binds to each of these complexes with a higher affinity than to isolated basigin ectodomain, making it likely that these are the physiological targets of PfRH5. PMCA-mediated Ca2+ export is not affected by PfRH5, making it unlikely that this is the mechanism underlying changes in calcium flux at the interface between an erythrocyte and the invading parasite. However, our studies rationalise the function of the most effective growth-inhibitory antibodies targeting PfRH5. While these antibodies do not reduce the binding of PfRH5 to monomeric basigin, they do reduce its binding to basigin-PMCA and basigin-MCT complexes. This indicates that the most effective PfRH5-targeting antibodies inhibit growth by sterically blocking the essential interaction of PfRH5 with basigin in its physiological context.


Assuntos
Malária Falciparum , Plasmodium falciparum , Humanos , Plasmodium falciparum/fisiologia , Basigina , Eritrócitos/parasitologia , Anticorpos Neutralizantes , Malária Falciparum/parasitologia , Proteínas de Protozoários/metabolismo , Ligação Proteica , Antígenos de Protozoários
16.
Fish Shellfish Immunol ; 142: 109123, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37813154

RESUMO

The NF-κB pathway plays an important role in immune regulation. Basigin, an immunoglobulin superfamily membrane protein, is involved in the activation of NF-κB. However, its role in NF-κB signaling in response to pathogen infection remains unclear. In this study, we identified the Basigin gene from Pacific white shrimp, Penaeus vannamei, a representative species for studying the innate immune system of invertebrates. Basigin promoted the degradation of the IκB homolog Cactus, facilitated the nuclear translocation of the NF-κB family member Dorsal, and positively regulated the expression of Dorsal pathway downstream antimicrobial peptide genes. Interestingly, recombinant Basigin protein could bind a variety of Gram-positive and Gram-negative bacteria. Silencing of Basigin inhibited the Dorsal signaling activated by V. parahaemolyticus infection and significantly decreased the survival rate of V. parahaemolyticus-infected shrimp. The expression levels of the antimicrobial peptides ALF1 and ALF2 were downregulated, and the phagocytosis of hemocytes was attenuated in Basigin-silenced shrimp. Similar results were observed in shrimp treated with a recombinant extracellular region of the Basigin protein that was able to compete with endogenous Basigin. Therefore, to the best of our knowledge, this study is the first to demonstrate the function of Basigin as a pathogen recognition receptor that activates NF-κB signaling for antibacterial immunity in shrimp.


Assuntos
Penaeidae , Vibrio parahaemolyticus , Vírus da Síndrome da Mancha Branca 1 , Animais , NF-kappa B/metabolismo , Basigina , Antibacterianos , Proteínas de Artrópodes , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Imunidade Inata/genética , Vibrio parahaemolyticus/fisiologia , Vírus da Síndrome da Mancha Branca 1/fisiologia
17.
Acta Biochim Biophys Sin (Shanghai) ; 55(10): 1640-1649, 2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37700592

RESUMO

The mechanism of extracellular matrix metalloproteinase inducer (EMMPRIN) in the regulation of liver fibrosis has not been clarified. This study aims to investigate the role of EMMPRIN S-nitrosylation (SNO) in the regulation of hepatic stellate cell (HSC) migration and matrix metalloproteinase (MMP) activities in liver fibrosis. The results from the tissue microarrays and rat/mouse liver tissues suggest that EMMPRIN mRNA and protein levels in the fibrotic livers are lower than those in the corresponding normal control livers, but higher SNO level of EMMPRIN in fibrotic liver area was shown by immunohistochemistry, immunofluorescence staining, and biotin-switch assay conversely in vivo. Primary EMMPRIN comes from hepatocytes and liver sinus epithelial cells (LSECs) rather than quiescent HSCs. To mimic the uptake of extrinsic EMMPRIN, supernatants from mouse primary hepatocytes/293 cells transfected with EMMPRIN wild-type plasmids (WT) and EMMPRIN SNO site (cysteine 87) mutation plasmids (MUT) were collected and added to JS-1/LX2 cell medium. The MUT EMMPRIN diminishes SNO successfully, enhances the activities of MMP2 and MMP9, and subsequently increases HSC migration. In conclusion, SNO of EMMPRIN influences HSC migration and MMP activities in liver fibrosis. This finding may shed light on the possible regulatory mechanism of MMPs in ECM accumulation in liver fibrosis.


Assuntos
Basigina , Cirrose Hepática , Animais , Camundongos , Ratos , Basigina/genética , Basigina/metabolismo , Células Epiteliais/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , Células Estreladas do Fígado/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo
18.
PLoS Pathog ; 19(9): e1011182, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37713419

RESUMO

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is the current leading blood-stage malaria vaccine candidate. PfRH5 functions as part of the pentameric PCRCR complex containing PTRAMP, CSS, PfCyRPA and PfRIPR, all of which are essential for infection of human red blood cells (RBCs). To trigger RBC invasion, PfRH5 engages with RBC protein basigin in a step termed the RH5-basigin binding stage. Although we know increasingly more about how antibodies specific for PfRH5 can block invasion, much less is known about how antibodies recognizing other members of the PCRCR complex can inhibit invasion. To address this, we performed live cell imaging using monoclonal antibodies (mAbs) which bind PfRH5 and PfCyRPA. We measured the degree and timing of the invasion inhibition, the stage at which it occurred, as well as subsequent events. We show that parasite invasion is blocked by individual mAbs, and the degree of inhibition is enhanced when combining a mAb specific for PfRH5 with one binding PfCyRPA. In addition to directly establishing the invasion-blocking capacity of the mAbs, we identified a secondary action of certain mAbs on extracellular parasites that had not yet invaded where the mAbs appeared to inactivate the parasites by triggering a developmental pathway normally only seen after successful invasion. These findings suggest that epitopes within the PfCyRPA-PfRH5 sub-complex that elicit these dual responses may be more effective immunogens than neighboring epitopes by both blocking parasites from invading and rapidly inactivating extracellular parasites. These two protective mechanisms, prevention of invasion and inactivation of uninvaded parasites, resulting from antibody to a single epitope indicate a possible route to the development of more effective vaccines.


Assuntos
Basigina , Merozoítos , Humanos , Animais , Plasmodium falciparum , Anticorpos Monoclonais , Epitopos
19.
Nephrology (Carlton) ; 28(11): 629-638, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37562415

RESUMO

AIM: Irrespective of the cause, albumin/proteinuria induces tubulointerstitial damage and accelerates the progression of kidney diseases. Our series of studies demonstrated that proteinuria, an independent prognostic factor for chronic kidney disease (CKD), is correlated with urinary basigin/CD147 (Bsg) levels. We examined the morphology and origin of Bsg in the tubular lumen through the effects of filtered glucose and protein solutes on the tubules. METHODS: Diabetic kidney disease (DKD) patients (N = 50) were treated with spironolactone 25 mg for 4 weeks or by conservative treatment. The associations between urinary Bsg values and clinical indicators were examined. Primary-cultured proximal tubular epithelial cells (PTECs) from human adult kidneys were exposed to high glucose or bovine serum albumin (BSA). RESULTS: In patients with early phase DKD, urinary Bsg levels were closely correlated with proteinuria but not HbA1c. Full-length Bsg on extracellular vesicles (EVs) was investigated primarily in urine collected from DKD patients. EVs obtained from the urine of DKD patients included Bsg and SGLT2 proteins. Notably, spironolactone treatment concomitantly suppressed the release of Bsg-bearing EVs in correlation with decreased albuminuria. Exposure of PTECs to BSA (but not high glucose) enhanced the storage of supernatant Bsg in EVs despite the absence of exposure-specific changes in Bsg transcription. CONCLUSION: Proteinuria induces the release of Bsg-bearing EVs derived from PTECs into the tubular lumen.


Assuntos
Vesículas Extracelulares , Insuficiência Renal Crônica , Adulto , Humanos , Albuminúria/tratamento farmacológico , Albuminúria/metabolismo , Basigina/metabolismo , Espironolactona/metabolismo , Epitélio/metabolismo , Proteinúria , Insuficiência Renal Crônica/metabolismo
20.
Clin Chim Acta ; 548: 117510, 2023 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-37562522

RESUMO

BACKGROUND: The mortality rate of colorectal cancer (CRC) can be decreased with effective screening and early diagnosis. Exosomes are released from cancer cells into the bloodstream, and circulating exosomes may serve as novel biomarkers. This study aimed to identify a sensitive and rapid method of exosome collection and measurement using specific antibodies. METHODS: ExoCounter, a high-sensitive exosome-counting system, allows the identification of exosomes without enrichment or purification, based on the identification of the transmembrane protein-CD147-on serum exosomes that are associated with CRC. RESULTS: Receiver operating characteristic curves between healthy donors and CRC patients were described and assessed by CD147-specific exosomes (exo-CD147), CEA, and CA19-9. And area under curves for exo-CD147, CEA, and CA19-9 were 0.827 (95%CI: 0.764-0.891), 0.630 (95%CI: 0.536-0.724), and 0.659 (95%CI: 0.559-0.759), respectively. Drawing a clinical decision curve of exo-CD147 for the diagnosis of CRC metastases showed that when the threshold probability of exo-CD147 was between 20% and 92%, the net clinical utilization rate was higher than for all patients with or without metastases. A nomogram was constructed using multivariate COX regression analysis to select significant variables such as the high CD147 group (>34 × 105 particles). Calibration curves for 1-, 3-, and 5-year survival rates of CRC patients showed that the actual 1-, 3-, and 5-year survival rates were in excellent agreement with the survival rates predicted by the nomogram. CONCLUSIONS: The increased CD147 expression in exosomes could serve as a diagnostic and prognostic biomarker for CRC.


Assuntos
Basigina , Neoplasias Colorretais , Exossomos , Humanos , Biomarcadores Tumorais , Antígeno CA-19-9 , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Exossomos/metabolismo , Prognóstico , Basigina/análise
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