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BACKGROUND: The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents. METHODS: We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE-/- and LDLR-/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia. RESULTS: A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE-/- and LDLR-/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7-mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization. CONCLUSIONS: ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.
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Aterosclerose , Neointima , Animais , Camundongos , Proteínas ADAM/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Hiperplasia/metabolismo , Lipídeos , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Suínos , Trombospondinas/metabolismo , Vacinas de Subunidades Antigênicas/metabolismo , Proteína ADAMTS7RESUMO
PURPOSE: Metabolic syndrome (MetS) is a complex chronic disease that includes obesity and hypertension, with rising evidence demonstrating that sympathetic nervous system (SNS) activation plays a key role. Our team designed a therapeutic vaccine called ADRQß-004 targeting the α1D-adrenergic receptor (α1D-AR). This study was performed to investigate whether the ADRQß-004 vaccine improves MetS by modulating SNS activity. METHODS: C57BL/6N mice were fed a high-fat diet (HFD) and Nω-nitro-L-arginine methyl ester (L-NAME) combination diet for 18 weeks to elicit MetS. The MetS mice were subcutaneously immunized with the ADRQß-004 vaccine four times to evaluate the therapeutic efficacy in obesity and hypertension and other associated abnormalities related to MetS by conducting echocardiographic, histological, and biochemical analyses. RESULTS: The ADRQß-004 vaccine induced strong antibody production and maintained a high anti-ADR-004 antibody titer in MetS mice. The ADRQß-004 vaccine improved obesity (P < 0.001) and decreased systolic blood pressure (P < 0.001). Improvements in dysregulated glucose homeostasis and dyslipidemia resulting from the ADRQß-004 vaccine were also confirmed. Furthermore, the ADRQß-004 vaccine attenuated cardiovascular functional (P = 0.015) and structural changes (P < 0.001), decreased fat accumulation (P = 0.012) and inflammation (P = 0.050) in the epididymal white adipose tissue, and alleviated hepatic steatosis (P = 0.043) involved in MetS. Moreover, the ADRQß-004 vaccine improved systematic and visceral organs SNS activities in the MetS. CONCLUSION: This study demonstrated for the first time that the ADRQß-004 vaccine targeting α1D-AR improved obesity, hypertension, dyslipidemia, and dysglycemia, and further reduced end-organ damage, which may provide new motivation for MetS research.
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The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQß-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQß-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQß-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQß-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.
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Imunoterapia , Resistência à Insulina/imunologia , Receptores de Angiotensina/imunologia , Receptores para Leptina/imunologia , Vacinas de Partículas Semelhantes a Vírus/farmacologia , Animais , Masculino , Camundongos , Vacinas de Partículas Semelhantes a Vírus/imunologiaRESUMO
BACKGROUND: Our previous study developed ATRQß-001 vaccine, which targets peptide ATR001 from angiotensin â ¡ (Ang â ¡) receptor type 1 (AT1R). The ATRQß-001 vaccine could induce the production of anti-ATR001 monoclonal antibody (McAb-ATR) and inhibit atherosclerosis without feedback activation of the renin-angiotensin system (RAS). This study aims at investigating the underexploited mechanisms of McAb-ATR in ameliorating atherosclerosis. METHODS: AT1R-KO HEK293T cell lines were constructed to identify the specificity of McAb-ATR and key sites of ATRQß-001 vaccine. Beta-arrestin1 knock-out (Arrb1-/-) mice, Beta-arrestin2 knock-out (Arrb2-/-) mice, and low-density lipoprotein receptor knock-out (LDLr-/-) mice were used to detect potential signaling pathways affected by McAb-ATR. The role of McAb-ATR in beta-arrestin and G proteins (Gq or Gi2/i3) signal transduction events was also investigated. RESULTS: McAb-ATR could specifically bind to the Phe182-His183-Tyr184 site of AT1R second extracellular loop (ECL2). The anti-atherosclerotic effect of McAb-ATR disappeared in LDLr-/- mice transplanted with Arrb2-/- mouse bone marrow (BM) and BM-derived macrophages (BMDMs) from Arrb2-/- mice. Furthermore, McAb-ATR inhibited beta-arrestin2-dependent extracellular signal regulated kinase1/2 (ERK1/2) phosphorylation, and promoted beta-arrestin2-mediated nuclear factor kappa B p65 (NFκB p65) inactivity. Compared with conventional AT1R blockers (ARBs), McAb-ATR did not inhibit Ang â ¡-induced uncoupling of heterotrimeric G proteins (Gq or Gi2/i3) and Gq-dependent intracellular Ca2+ release, nor cause RAS feedback activation. CONCLUSIONS: Through regulating beta-arrestin2, McAb-ATR ameliorates atherosclerosis without affecting Gq or Gi2/i3 pathways. Due to high selectivity for AT1R and biased interaction with beta-arrestin2, McAb-ATR could serve as a novel strategy for treating atherosclerosis.
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Anticorpos Monoclonais/farmacologia , Aterosclerose/prevenção & controle , Receptor Tipo 1 de Angiotensina/imunologia , Receptores de LDL/metabolismo , Vacinas de Partículas Semelhantes a Vírus/farmacologia , beta-Arrestina 2/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor Tipo 1 de Angiotensina/química , Vacinas de Partículas Semelhantes a Vírus/imunologiaRESUMO
Interleukin-17A (IL-17A) produced by Th17 cells, contributes to the pathogenesis of various autoimmune diseases by stimulating the release of cytokines and chemokines and its regulation. Anti-IL-17A antibody which blocks the function of IL-17A has been proved to be an effective treatment of autoimmune disease. The aim of our study was to generate a potential humanized anti-IL-17A therapeutic monoclonal antibody (mAb) through a comprehensive panel of in vitro and in vivo biological activity studies, as well as physicochemical characterization. HZD37-5, a humanized monoclonal antibody specifically recognizing N78 loci of IL-17A, binds to human and rhesus monkeys, blocks IL-17 induced signal transduction and the release of IL-6, IL-8, CXCL-1 and G-GSF. In an in vivo efficacy mouse model, HZD37-5 significantly inhibited human IL-17A induced-keratinocyte chemoattractant (KC) secretion in a dose-dependent manner. The pharmacokinetics (PK) study result of HZD37-5 in rhesus monkeys indicated that HZD37-5 had favorable PK characteristics with limited distribution (78.0-78.8 ml/kg), slow elimination (5.00-6.45 ml/day/kg), long half-life (9.1-10.7 days) and high bioavailability (103%) following a single IV or SC dose at 1.5 mg/kg. These findings provided a comprehensive preclinical characterization of HZD37-5 and supported that it may be developed as a potential therapeutic for the treatment of autoimmune diseases, including psoriasis, psoriatic arthritis, axial spondyloarthritis, etc.
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Anticorpos Monoclonais Humanizados/farmacocinética , Doenças Autoimunes/tratamento farmacológico , Interleucina-17/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Quimiocina CXCL1/imunologia , Fatores Quimiotáticos/imunologia , Relação Dose-Resposta a Droga , Humanos , Interleucina-6/imunologia , Interleucina-8/imunologia , Queratinócitos/imunologia , Macaca mulatta , Camundongos , Coelhos , Transdução de SinaisRESUMO
PURPOSE: Our group has developed a therapeutic vaccine targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), named PCSK9Qß-003. In this study, we investigated the potential effectiveness of the PCSK9Qß-003 vaccine on atherosclerosis. METHODS: Male ApoE-/- mice were randomly assigned to three groups: a phosphate-buffered saline (PBS) group, Qß virus-like particles (VLP) group, and PCSK9Qß-003 vaccine group. Mice in the PCSK9Qß-003 group were injected with the PCSK9Qß-003 vaccine four times (100 µg/time) over a period of 18 weeks. The effects of the vaccine on atherosclerotic plaque, cholesterol transport, inflammation and apoptosis were investigated. RESULTS: The PCSK9Qß-003 vaccine obviously decreased total cholesterol and low-density lipoprotein cholesterol in ApoE-/- mice. Compared with the other groups, the PCSK9Qß-003 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. The vaccine regulated cholesterol transport in the aorta of ApoE-/- mice by up-regulating the expression level of liver X receptor α and ATP binding cassette transporter A1. Additionally, macrophage infiltration and expression of monocyte chemoattractant protein-1 and tumor necrosis factor-α were significantly decreased in the mice administered the PCSK9Qß-003 vaccine. The vaccine also markedly reduced apoptosis in the lesion area of the aorta in ApoE-/- mice. CONCLUSIONS: The results demonstrated that the PCSK9Qß-003 vaccine attenuated the progression of atherosclerosis by modulating reverse cholesterol transport and inhibiting inflammation infiltration and apoptosis, which may provide a novel therapeutic approach for atherosclerosis and greatly improve treatment compliance among patients.
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Aterosclerose/prevenção & controle , Pró-Proteína Convertase 9/imunologia , Vacinas/administração & dosagem , Animais , Apolipoproteínas E/deficiência , Colesterol/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Placa Aterosclerótica/prevenção & controle , Distribuição AleatóriaRESUMO
BACKGROUND: In-stent restenosis (ISR) is the major concern of vertebral artery stenting (VAS). We aimed to investigate the feasibility and outcome of redo angioplasty for ISR of vertebral artery. METHOD: The patients were retrospectively reviewed for the significant ISR (>50%). Redo angioplasty including balloon angioplasty and stenting was performed for symptomatic ISR (>50%) or asymptomatic ISR (≥70%). The clinical follow-up was performed on the 1, 3, 6, and 12 months and then yearly in the clinic or by telephone. The angiographic follow-up was performed at 6-12 months after redo angioplasty. RESULT: A total of 72 patients had significant ISR and 48 redo angioplasty (92.3%, 48/52) were successfully achieved with 13 located in the V4 and 35 in the ostium of vertebral artery. Twenty-six lesions were implanted by the second stent and the others received balloon angioplasty. No stroke or transient ischemic attack (TIA) occurred in the perioperative time. One patient died 2 months after redo angioplasty due to nonstroke cause. Redo angioplasty nonsignificantly decreased the stroke or TIA compared with medical treatment. Sixteen patients developed the binary restenosis, which was lower in the patients receiving stent implantation than balloon angioplasty. CONCLUSION: Redo angioplasty was a feasible method for the ISR of VAS and redo stenting might be the first choice.
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Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/instrumentação , Stents , Insuficiência Vertebrobasilar/terapia , Idoso , Bases de Dados Factuais , Estudos de Viabilidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Recidiva , Retratamento , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Insuficiência Vertebrobasilar/diagnóstico por imagem , Insuficiência Vertebrobasilar/epidemiologia , Insuficiência Vertebrobasilar/fisiopatologiaRESUMO
BACKGROUND: The topographic location of acute pontine infarction is associated with clinical syndromes and prognosis. Previous studies focused on isolated pontine infarction, but the topographic location of unisolated pontine infarction has remained unclear. METHODS: This was a prospective, multicenter, longitudinal registry study. Patients with acute pontine infarction confirmed by magnetic resonance imaging (MRI) were enrolled. Based on the territory of the pontine artery, the topographic location was divided into anteromedial, anterolateral, tegmental, bilateral and unilateral multiple infarctions. RESULTS: From May 1, 2003, to Oct 31, 2017, 1003 patients were enrolled, and 330 had unisolated pontine infarction. For isolated pontine infarction, 44.9, 19.8, 16.0, 13.1 and 6.2% of patients had anteromedial, anterolateral, tegmental, bilateral and unilateral multiple pontine infarctions, respectively. For unisolated pontine infarction, 30.3, 19.7, 24.5, 15.2 and 10.3% of patients had anteromedial, anterolateral, tegmental, bilateral and unilateral multiple pontine infarctions, respectively. CONCLUSION: In this large series study, our data revealed fewer anteromedial infarctions and more tegmental and unilateral multiple infarctions in patients with unisolated pontine infarction than in patients with isolated pontine infarction.
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Infartos do Tronco Encefálico/patologia , Ponte/patologia , Adulto , Idoso , Feminino , Humanos , Infarto , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosAssuntos
Betacoronavirus , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Hospitalização/tendências , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Troponina I/sangue , Idoso , Biomarcadores/sangue , COVID-19 , Infecções por Coronavirus/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Pandemias , Pneumonia Viral/diagnóstico , Valor Preditivo dos Testes , SARS-CoV-2RESUMO
With the development of nuclear power, efficiently treating nuclear wastes generated during operation has attracted extensive attention. Hydrogels are common adsorbent materials in the treatment of wastewater due to their high swelling rate and easy post-treatment. In this work, a novel polyacrylic acid/crown-ether/graphene oxide (PAA/DB18C6/GO) hydrogel composite was synthesized by a radical cross-linking copolymerization method and characterized using various analytical tools such as SEM, FT-IR, TGA and XPS. The effects of time, pH, initial Sr2+ concentration, and temperature on Sr2+ adsorption onto the PAA/DB18C6/GO were studied. The PAA/DB18C6/GO shows a high adsorption capacity of 379.35 mg g-1 at an initial Sr2+ concentration of 772 mg L-1 due to the unique structure of dibenzo-18-crown-ether-6 and high swelling. The composite has a high selectivity for Sr2+ with a removal rate of 82.4% when concentrations of Na+ and K+ were 10 times higher than that of Sr2+. The pH and temperature have no apparent impact on adsorption performance of the PAA/DB18C6/GO under the experimental conditions. The composite shows excellent reusability with more than 92% removal rate for Sr2+ after five continuous cycles. In addition, the mechanism of Sr2+ adsorption by PAA/DB18C6/GO was analyzed by fitting the adsorption data to the theoretical models and XPS data.
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PURPOSE: Compared with monotherapy, combination therapy with multiple antihypertensive drugs has demonstrated superior efficacy in the management of hypertension. The aim of this study was to explore the efficacy of multitarget combined vaccines in achieving simultaneous antihypertensive and target organ protection effects. METHODS: Our team has developed ATRQß-001 and ADRQß-004 vaccines targeting Ang II type 1 receptor (AT1R) and α1D-adrenergic receptor (α1D-AR), respectively. In NG-nitroarginine methyl ester ( l -NAME) + abilities spontaneously hypertensive rats (SHRs) model, SHRs were simultaneously inoculated with ATRQß-001 and ADRQß-004 vaccines. Histological and biochemical analyses were performed to evaluate the antihypertensive effects and target organ protection of the ATRQß-001 and ADRQß-004 combined vaccines in comparison with those of the single vaccine. RESULTS: Both ATRQß-001 and ADRQß-004 vaccines induced robust antibody production, resulting in persistent high antibody titers in rats. Notably, the combined administration of both vaccines significantly decreased SBP in SHRs compared with treatment with a single vaccine, both before and after l -NAME administration. Furthermore, the combined vaccine regimen demonstrated superior efficacy in protecting against vascular remodeling, myocardial hypertrophy and fibrosis, and kidney injury in SHRs. Mechanistically, the combined vaccines exhibited significantly downregulated the expression of angiotensin II type 1 receptor (AT1R) and α1D-adrenergic receptor (α1D-AR). Importantly, no apparent immune-related adverse effects were observed in animals immunized with the combined vaccines. CONCLUSION: Preliminary findings from this investigation suggest that co-administration of the novel ATRQß-001 and ADRQß-004 vaccines holds potential as a groundbreaking therapeutic strategy for managing hypertension.
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Hipertensão , Receptor Tipo 1 de Angiotensina , Receptores Adrenérgicos alfa 1 , Vacinas Combinadas , Animais , Masculino , Ratos , Pressão Sanguínea , Hipertensão/terapia , NG-Nitroarginina Metil Éster , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/imunologia , Vacinas Combinadas/imunologiaRESUMO
OBJECTIVE: There is mounting evidence indicating that atherosclerosis represents a persistent inflammatory process, characterized by the presence of inflammation at various stages of the disease. Interleukin-1 (IL-1) precisely triggers inflammatory signaling pathways by binding to interleukin-1 receptor type I (IL-1R1). Inhibition of this signaling pathway contributes to the prevention of atherosclerosis and myocardial infarction. The objective of this research is to develop therapeutic vaccines targeting IL-1R1 as a preventive measure against atherosclerosis and myocardial infarction. METHODS: ILRQß-007 and ILRQß-008 vaccines were screened, prepared and then used to immunize high-fat-diet fed ApoE-/- mice and C57BL/6J mice following myocardial infarction. Progression of atherosclerosis in ApoE-/- mice was assessed primarily by oil-red staining of the entire aorta and aortic root, as well as by detecting the extent of macrophage infiltration. The post-infarction cardiac function in C57BL/6J mice were evaluated using cardiac ultrasound and histological staining. RESULTS: ILRQß-007 and ILRQß-008 vaccines stimulated animals to produce high titers of antibodies that effectively inhibited the binding of interleukin-1ß and interleukin-1α to IL-1R1. Both vaccines effectively reduced atherosclerotic plaque area, promoted plaque stabilization, decreased macrophage infiltration in plaques and influenced macrophage polarization, as well as decreasing levels of inflammatory factors in the aorta, serum, and ependymal fat in ApoE-/- mice. Furthermore, these vaccines dramatically improved cardiac function and macrophage infiltration in C57BL/6J mice following myocardial infarction. Notably, no significant immune-mediated damage was observed in immunized animals. CONCLUSION: The vaccines targeting the IL-1R1 would be a novel and promising treatment for the atherosclerosis and myocardial infarction.
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Aterosclerose , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Receptores Tipo I de Interleucina-1 , Animais , Aterosclerose/imunologia , Receptores Tipo I de Interleucina-1/genética , Infarto do Miocárdio/imunologia , Camundongos , Interleucina-1beta/metabolismo , Vacinas/imunologia , Masculino , Dieta Hiperlipídica , Placa Aterosclerótica/imunologia , Camundongos Knockout para ApoE , Humanos , Interleucina-1alfa/metabolismo , Interleucina-1alfa/imunologia , Macrófagos/imunologia , Camundongos Knockout , Modelos Animais de DoençasRESUMO
Vascular diseases are the leading cause of morbidity and mortality worldwide. Therefore, effective treatment strategies that can reduce the risk of vascular diseases are urgently needed. The relationship between Interleukin-11 (IL-11) and development of vascular diseases has gained increasing attention. IL-11, a target for therapeutic research, was initially thought to participate in stimulating platelet production. Additional research concluded that IL-11 is effective in treating several vascular diseases. However, the function and mechanism of IL-11 in these diseases remain unknown. This review summarizes IL-11 expression, function, and signal transduction mechanism. This study also focuses on the role of IL-11 in coronary artery disease, hypertension, pulmonary hypertension, cerebrovascular disease, aortic disease, and other vascular diseases and its potential as a therapeutic target. Consequently, this study provides new insight into the clinical diagnosis and treatment of vascular diseases.
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Aldosterone is one of the most essential hormones synthesized by the adrenal gland because it regulates water and electrolyte balance. G protein-coupled estrogen receptor (GPER) is a newly discovered aldosterone receptor, which is proposed to mediate the non-genomic pathways of aldosterone while the hormone simultaneously interacts with mineralocorticoid receptor. In contrast to its cardio-protective role in postmenopausal women via its interaction with estrogen, GPER seems to trigger vasoconstriction effects and can further induce water and sodium retention in the presence of aldosterone, indicating two entirely different binding sites and effects for estrogen and aldosterone. Accumulating evidence also points to a role of aldosterone in mediating hypertension and its risk factors via the interaction with GPER. Therefore, with this review, we aimed to summarize the research on these interactions to help (1) elucidate the role of GPER activated by aldosterone in the blood vessels, heart, and kidney; (2) compare the non-genomic actions between aldosterone and estrogen mediated by GPER; and (3) address the potential of GPER as a new promising therapeutic target for aldosterone-induced hypertension.
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Aldosterona , Hipertensão , Feminino , Humanos , Receptores de Estrogênio , Hipertensão/induzido quimicamente , Estrogênios , Receptores Acoplados a Proteínas G , Proteínas de Ligação ao GTPRESUMO
Rare earth luminescent materials demonstrate significant advantages in lighting and energy saving, and detection etc. In this paper, a series of Ca2Ga2(Ge1-xSix)O7:y%Eu2+ phosphors were synthesized by high-temperature solid-state reaction and characterized by X-ray diffraction and luminescence spectroscopy methods. The powder X-ray diffraction patterns reveal that all the phosphors are isostructural with a space group of P4¯21m. The excitation spectra of Ca2Ga2(Ge1-xSix)O7:1%Eu2+ phosphors exhibit significant overlapping of the host and the Eu2+ absorption bands, which facilitates Eu2+ absorbing the energy to increase its luminescence efficiency when excited by visible photons. The emission spectra show that the Eu2+ doped phosphors have a broad emission band with a peak centered at 510 nm arising from the 4f65d1â4f7 transition. Variable temperature fluorescence reveals that the phosphor has a strong luminescence at low temperature but has a severe thermal quenching effect when temperature rises. The optimal Ca2Ga2(Ge0.5Si0.5)O7:1.0%Eu2+ phosphor shows promise for application in the field of fingerprint identification based on the experimental results.
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Pontine infarction is the major subtype of brainstem stroke causing severe neurological deficits. The pathophysiology and treatment of pontine infarction was rarely studied. A rat model of acute pontine infarction was established via injection of endothelin-1 in the pons. Single-cell RNA sequencing was applied to detect the cellular response in pontine infarction. Based on this finding, a potential treatment for pontine infarction targeting microglia was verified. Occlusion of penetrating artery caused by endothelin-1 led to pontine infarction. Single-cell RNA sequencing revealed a subtype of activated microglia, SPP1+ microglia, which were different from M1-like or M2-like depolarization. SPP1+ microglia interacted with oligodendrocytes and contributed to the demyelination of nerve tracts. Cyclin B1 regulated the proliferation of SPP1+ microglia. Cucurbitacin E, a cyclin B1 inhibitor, reduced the proliferation of SPP1+ microglia around the injured myelin sheath and alleviated the demyelination. Moreover, cucurbitacin E treatment decreased the ischemic infarction volume and neurological deficits after pontine infarction. SPP1+ microglia contributed to axonal demyelination in the pontine infarction, and inhibition of SPP1+ microglia provided neuroprotection for pontine infarction.
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Infartos do Tronco Encefálico , Doenças Desmielinizantes , Ratos , Animais , Microglia , Ciclina B1 , Endotelina-1 , Proliferação de CélulasRESUMO
Beta-blockers are widely used in the treatment of hypertension, heart failure and ischemic heart disease. However, unstandardized medication results in diverse clinical outcomes in patients. The main causes are unattained optimal doses, insufficient follow-up and patients' poor adherence. To improve the medication inadequacy, our team developed a novel therapeutic vaccine targeting ß1-adrenergic receptor (ß1-AR). The ß1-AR vaccine named ABRQß-006 was prepared by chemical conjugation of a screened ß1-AR peptide with Qß virus like particle (VLP). The antihypertensive, anti-remodeling and cardio-protective effects of ß1-AR vaccine were evaluated in different animal models. The ABRQß-006 vaccine was immunogenic that induced high titers of antibodies against ß1-AR epitope peptide. In the NG-nitro-L-arginine methyl ester (L-NAME) + Sprague Dawley (SD) hypertension model, ABRQß-006 lowered systolic blood pressure about 10 mmHg and attenuated vascular remodeling, myocardial hypertrophy and perivascular fibrosis. In the pressure-overload transverse aortic constriction (TAC) model, ABRQß-006 significantly improved cardiac function, decreased myocardial hypertrophy, perivascular fibrosis and vascular remodeling. In the myocardial infarction (MI) model, ABRQß-006 effectively improved cardiac remodeling, reduced cardiac fibrosis and inflammatory infiltration, which was superior to metoprolol. Moreover, no significant immune-mediated damage was observed in immunized animals. The ABRQß-006 vaccine targeting ß1-AR showed the effects on hypertension and heart rate control, myocardial remodeling inhibition and cardiac function protection. These effects could be differentiated in different types of diseases with diverse pathogenesis. ABRQß-006 could be a novel and promising method for the treatment of hypertension and heart failure with different etiologies.
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Insuficiência Cardíaca , Hipertensão , Vacinas , Animais , Anti-Hipertensivos/uso terapêutico , Remodelação Vascular , Insuficiência Cardíaca/tratamento farmacológico , Cardiomegalia/tratamento farmacológico , Vacinas/uso terapêutico , Fibrose , Receptores Adrenérgicos/uso terapêutico , Remodelação VentricularRESUMO
The heterogeneity in therapeutic antibodies arising from buried unpaired cysteines has not been well studied. This paper describes the characterization of two unpaired cysteines in a recombinant humanized IgG1 monoclonal antibody (referred to as mAb A). The reversed-phase high-performance liquid chromatography (RP-HPLC) analysis of mAb A samples showed three distinct peaks, indicating the presence of three species. The heterogeneities observed in the RP-HPLC have been determined to arise from unpaired cysteines (Cys-22 and Cys-96) that are buried in the V(H) domain. The Fab containing free thiols (referred to as "free-thiol Fab") and the Fab containing the disulfide (referred to as "intact Fab") of mAb A were generated through limited Lys-C digestion and purified with an ion exchange chromatography method. The binding of free-thiol Fab and intact Fab to its antigen was measured in a cell-based binding assay and an enzyme linked immunosorbent assay. The unpaired cysteines in the Fab of mAb A were found to have no significant impact on the binding to its target. Consistent with these Fab binding data, the enriched intact mAb A containing free thiols was determined to be fully active in a potency assay. The data reported here demonstrate that the redox status of cysteines is potentially a major source of heterogeneity for an antibody.
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Anticorpos Monoclonais/química , Cisteína , Imunoglobulina G/química , Proteínas Recombinantes/química , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/toxicidade , Antígenos CD20/imunologia , Células CHO , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Cromatografia de Fase Reversa , Cricetinae , Cricetulus , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/toxicidade , Espectrometria de Massas , Desnaturação Proteica , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/toxicidade , Compostos de Sulfidrila/químicaRESUMO
PURPOSE: To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a monoclonal antibody directed against the B-cell activating factor (BAFF) receptor 3 (BR3), following intravenous (IV) and subcutaneous (SC) administration in mice. METHODS: Single IV doses of 0.2, 2.0 and 20 mg/kg and a single SC injection of 20 mg/kg of anti-BR3 antibody was administered to mice. Serum drug and BAFF concentrations and splenic B-cell concentrations were measured at various time points. Pooled PK profiles were described by a two-compartmental model with time-dependent nonlinear elimination, and BAFF profiles were defined by an indirect response model. Fractional receptor occupancy served as the driving function for a competitive reversible antagonism model to characterize B-cell dynamics. RESULTS: Noncompartmental analysis revealed a decrease in drug clearance (31.3 to 7.93 mL/day/kg) with increasing IV doses. The SC dose exhibited slow absorption (T(max) = 2 days) and complete bioavailability. All doses resulted in a dose-dependent increase in BAFF concentrations and decrease in B-cell counts. The proposed model reasonably captured complex PK/PD profiles of anti-BR3 antibody after IV and SC administration. CONCLUSIONS: A mechanistic model was developed that describes the reversible competition between anti-BR3 antibody and BAFF for BR3 receptors and its influence on B-cell pharmacodynamics.
Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Receptor do Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/metabolismo , Administração Intravenosa/métodos , Animais , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Fator Ativador de Células B/sangue , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Disponibilidade Biológica , Injeções Subcutâneas/métodos , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Modelos BiológicosRESUMO
Background: Epilepsy is one of the leading neurological diseases. Our study is aimed to determine whether there is a focal region of high epilepsy prevalence in China. Methods: All studies published between 1981 and 2020 investigating the prevalence of epilepsy in China were systematically reviewed. The geographical location, sample size, number of cases, urbanization rate, gross domestic product (GDP) per capita, percentage of <15 years old, and medical insurance per capita were derived and analyzed. Criteria for a provincial region of high prevalence was defined as with higher epilepsy prevalence than the average prevalence of epilepsy in China. Results: A total of 60 studies provided data on the prevalence of epilepsy in 29 of 33 provincial regions of China. The average prevalence in China was 1.68 per 1,000, and 12 provincial regions met our criteria for a region of high epilepsy prevalence and constitute an epilepsy belt ranging along the division between the second step and the third step of China. The prevalence in the epilepsy belt was 331.9 per 100,000 population compared with 125.3 per 100,000 in regions outside the belt (P < 0.05). Surprisingly, there was no significant difference in sample size, number of cases, urbanization rate, GDP per capita, percentage of <15 years old, or medical insurance per capita between the regions in and outside the epilepsy belt. Conclusions: An epilepsy belt of high prevalence exists in 12 provincial regions locating along the division between the second step and the third step of China.