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1.
Nat Commun ; 13(1): 2674, 2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35562337

RESUMO

Emerging SARS-CoV-2 variants of concern (VOCs) harboring multiple mutations in the spike protein raise concerns on effectiveness of current vaccines that rely on the ancestral spike protein. Here, we design a quadrivalent mosaic nanoparticle vaccine displaying spike proteins from the SARS-CoV-2 prototype and 3 different VOCs. The mosaic nanoparticle elicits equivalent or superior neutralizing antibodies against variant strains in mice and non-human primates with only small reduction in neutralization titers against the ancestral strain. Notably, it provides protection against infection with prototype and B.1.351 strains in mice. These results provide a proof of principle for the development of multivalent vaccines against pandemic and potential pre-emergent SARS-CoV-2 variants.

2.
J Geriatr Cardiol ; 19(1): 61-70, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35233224

RESUMO

BACKGROUND: Growing evidence have demonstrated that thyroid hormones have been involved in the processes of cardiovascular metabolism. However, the causal relationship of thyroid function and cardiometabolic health remains partly unknown. METHODS: The Mendelian randomization (MR) was used to test genetic, potentially causal relationships between instrumental variables and cardiometabolic traits. Genetic variants of free thyroxine (FT4) and thyrotropin (TSH) levels within the reference range were used as instrumental variables. Data for genetic associations with cardiometabolic diseases were acquired from the genome-wide association studies of the FinnGen, CARDIoGRAM and CARDIoGRAMplusC4D, CHARGE, and MEGASTROKE. This study was conducted using summary statistic data from large, previously described cohorts. Association between thyroid function and essential hypertension (EHTN), secondary hypertension (SHTN), hyperlipidemia (HPL), type 2 diabetes mellitus (T2DM), ischemic heart disease (IHD), myocardial infarction (MI), heart failure (HF), pulmonary heart disease (PHD), stroke, and non-rheumatic valve disease (NRVD) were examined. RESULTS: Genetically predicted FT4 levels were associated with SHTN (odds ratio = 0.48; 95% CI = 0.04-0.82,P = 0.027), HPL (odds ratio = 0.67; 95% CI = 0.18-0.88,P = 0.023), T2DM (odds ratio = 0.80; 95% CI = 0.42-0.86,P = 0.005), IHD (odds ratio = 0.85; 95% CI = 0.49-0.98,P = 0.039), NRVD (odds ratio = 0.75; 95% CI = 0.27-0.97,P = 0.039). Additionally, genetically predicted TSH levels were associated with HF (odds ratio = 0.82; 95% CI = 0.68-0.99,P = 0.042), PHD (odds ratio = 0.75; 95% CI = 0.32-0.82,P = 0.006), stroke (odds ratio = 0.95; 95% CI = 0.81-0.97,P = 0.007). However, genetically predicted thyroid function traits were not associated with EHTN and MI. CONCLUSIONS: Our study suggests FT4 and TSH are associated with cardiometabolic diseases, underscoring the importance of the pituitary-thyroid-cardiac axis in cardiometabolic health susceptibility.

3.
Front Immunol ; 13: 823949, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35173733

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emergent coronavirus that has caused frequent zoonotic events through camel-to-human spillover. An effective camelid vaccination strategy is probably the best way to reduce human exposure risk. Here, we constructed and evaluated an inactivated rabies virus-vectored MERS-CoV vaccine in mice, camels, and alpacas. Potent antigen-specific antibody and CD8+ T-cell responses were generated in mice; moreover, the vaccination reduced viral replication and accelerated virus clearance in MERS-CoV-infected mice. Besides, protective antibody responses against both MERS-CoV and rabies virus were induced in camels and alpacas. Satisfyingly, the immune sera showed broad cross-neutralizing activity against the three main MERS-CoV clades. For further characterization of the antibody response induced in camelids, MERS-CoV-specific variable domains of heavy-chain-only antibody (VHHs) were isolated from immunized alpacas and showed potent prophylactic and therapeutic efficacies in the Ad5-hDPP4-transduced mouse model. These results highlight the inactivated rabies virus-vectored MERS-CoV vaccine as a promising camelid candidate vaccine.


Assuntos
Camelídeos Americanos/virologia , Camelus/virologia , Infecções por Coronavirus/veterinária , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/imunologia , Camelídeos Americanos/imunologia , Camelus/imunologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Cricetinae , Feminino , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vírus da Raiva/genética , Vírus da Raiva/imunologia , Vacinação , Vacinas Sintéticas/imunologia , Células Vero , Vacinas Virais/genética
4.
J Org Chem ; 87(5): 2730-2739, 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35133834

RESUMO

A catalyst-induced defluorinative, alkylation or metal-free hydroalkylation of gem-difluoroalkenes enabled by visible light was developed. This protocol provided a mild and practical approach to important and novel monofluoroalkenes and difluoromethylene-containing compounds with moderate to excellent yields.

5.
Genome Res ; 32(2): 228-241, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35064006

RESUMO

The pathogenesis of COVID-19 is still elusive, which impedes disease progression prediction, differential diagnosis, and targeted therapy. Plasma cell-free RNAs (cfRNAs) carry unique information from human tissue and thus could point to resourceful solutions for pathogenesis and host-pathogen interactions. Here, we performed a comparative analysis of cfRNA profiles between COVID-19 patients and healthy donors using serial plasma. Analyses of the cfRNA landscape, potential gene regulatory mechanisms, dynamic changes in tRNA pools upon infection, and microbial communities were performed. A total of 380 cfRNA molecules were up-regulated in all COVID-19 patients, of which seven could serve as potential biomarkers (AUC > 0.85) with great sensitivity and specificity. Antiviral (NFKB1A, IFITM3, and IFI27) and neutrophil activation (S100A8, CD68, and CD63)-related genes exhibited decreased expression levels during treatment in COVID-19 patients, which is in accordance with the dynamically enhanced inflammatory response in COVID-19 patients. Noncoding RNAs, including some microRNAs (let 7 family) and long noncoding RNAs (GJA9-MYCBP) targeting interleukin (IL6/IL6R), were differentially expressed between COVID-19 patients and healthy donors, which accounts for the potential core mechanism of cytokine storm syndromes; the tRNA pools change significantly between the COVID-19 and healthy group, leading to the accumulation of SARS-CoV-2 biased codons, which facilitate SARS-CoV-2 replication. Finally, several pneumonia-related microorganisms were detected in the plasma of COVID-19 patients, raising the possibility of simultaneously monitoring immune response regulation and microbial communities using cfRNA analysis. This study fills the knowledge gap in the plasma cfRNA landscape of COVID-19 patients and offers insight into the potential mechanisms of cfRNAs to explain COVID-19 pathogenesis.


Assuntos
COVID-19 , Ácidos Nucleicos Livres , RNA/sangue , COVID-19/sangue , COVID-19/genética , Ácidos Nucleicos Livres/sangue , Síndrome da Liberação de Citocina , Humanos , SARS-CoV-2
6.
J Virol ; 96(3): e0184221, 2022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-34817197

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) is a beta coronavirus that emerged in 2012, causing severe pneumonia and renal failure. MERS-CoV encodes five accessory proteins. Some of them have been shown to interfere with host antiviral immune response. However, the roles of protein 8b in innate immunity and viral virulence was rarely studied. Here, we introduced individual MERS-CoV accessory protein genes into the genome of an attenuated murine coronavirus (Mouse hepatitis virus, MHV), respectively, and found accessory protein 8b could enhance viral replication in vivo and in vitro and increase the lethality of infected mice. RNA-seq analysis revealed that protein 8b could significantly inhibit type I interferon production (IFN-I) and innate immune response in mice infected with MHV expressing protein 8b. We also found that MERS-CoV protein 8b could initiate from multiple internal methionine sites and at least three protein variants were identified. Residues 1-23 of protein 8b was demonstrated to be responsible for increased virulence in vivo. In addition, the inhibitory effect on IFN-I of protein 8b might not contribute to its virulence enhancement as aa1-23 deletion did not affect IFN-I production in vitro and in vivo. Next, we also found that protein 8b was localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, which was disrupted by C-terminal region aa 88-112 deletion. This study will provide new insight into the pathogenesis of MERS-CoV infection. IMPORTANCE Multiple coronaviruses (CoV) cause severe respiratory infections and become global public health threats such as SARS-CoV, MERS-CoV, and SARS-CoV-2. Each coronavirus contains different numbers of accessory proteins which show high variability among different CoVs. Accessory proteins are demonstrated to play essential roles in pathogenesis of CoVs. MERS-CoV contains 5 accessory proteins (protein 3, 4a, 4b, 5, 8b), and deletion of all four accessory proteins (protein 3, 4a, 4b, 5), significantly affects MERS-CoV replication and pathogenesis. However, whether ORF8b also regulates MERS-CoV infection is unknown. Here, we constructed mouse hepatitis virus (MHV) recombinant virus expressing MERS-CoV protein 8b and demonstrated protein 8b could significantly enhance the virulence of MHV, which is mediated by N-terminal domain of protein 8b. This study will shed light on the understanding of pathogenesis of MERS-CoV infection.


Assuntos
Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Vírus da Hepatite Murina/fisiologia , Domínios e Motivos de Interação entre Proteínas , Proteínas Virais Reguladoras e Acessórias/genética , Animais , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Camundongos , Mortalidade , Proteínas Virais Reguladoras e Acessórias/química , Tropismo Viral , Virulência/genética , Fatores de Virulência/genética
7.
Curr Opin Virol ; 52: 102-111, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34906757

RESUMO

Human respiratory coronaviruses (HCoVs), including the recently emerged SARS-CoV-2, the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, potentially cause severe lung infections and multiple organ damages, emphasizing the urgent need for antiviral therapeutics and vaccines against HCoVs. Small animal models, especially mice, are ideal tools for deciphering the pathogenesis of HCoV infections as well as virus-induced immune responses, which is critical for antiviral drug development and vaccine design. In this review, we focus on the antiviral innate immune response, antibody response and T cell response in HCoV infected mouse models, and discuss the potential implications for understanding the anti-HCoV immunity and fighting the COVID-19 pandemic.


Assuntos
COVID-19 , Pandemias , Animais , Humanos , Imunidade , Camundongos , SARS-CoV-2
8.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34911761

RESUMO

Arterial remodeling is an important adaptive mechanism that maintains normal fluid shear stress in a variety of physiologic and pathologic conditions. Inward remodeling, a process that leads to reduction in arterial diameter, plays a critical role in progression of such common diseases as hypertension and atherosclerosis. Yet, despite its pathogenic importance, molecular mechanisms controlling inward remodeling remain undefined. Mitogen-activated protein kinases (MAPKs) perform a number of functions ranging from control of proliferation to migration and cell-fate transitions. While the MAPK ERK1/2 signaling pathway has been extensively examined in the endothelium, less is known about the role of the MEKK3/ERK5 pathway in vascular remodeling. To better define the role played by this signaling cascade, we studied the effect of endothelial-specific deletion of its key upstream MAP3K, MEKK3, in adult mice. The gene's deletion resulted in a gradual inward remodeling of both pulmonary and systematic arteries, leading to spontaneous hypertension in both vascular circuits and accelerated progression of atherosclerosis in hyperlipidemic mice. Molecular analysis revealed activation of TGFß-signaling both in vitro and in vivo. Endothelial-specific TGFßR1 knockout prevented inward arterial remodeling in MEKK3 endothelial knockout mice. These data point to the unexpected participation of endothelial MEKK3 in regulation of TGFßR1-Smad2/3 signaling and inward arterial remodeling in artery diseases.


Assuntos
Hipertensão Pulmonar/patologia , MAP Quinase Quinase Quinase 1/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Remodelação Vascular/fisiologia , Animais , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Membro Posterior/irrigação sanguínea , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão Pulmonar/metabolismo , Isquemia , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 3/genética , Camundongos , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Moduladores Seletivos de Receptor Estrogênico/toxicidade , Transdução de Sinais , Tamoxifeno/toxicidade , Fator de Crescimento Transformador beta/genética
9.
Foods ; 10(10)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34681393

RESUMO

The market size of varied carbonated teas and bottled ready-to-drink tea products in Taiwan has surpassed that of traditional Taiwan tea with hot infusion. The consumption behavior of Taiwanese consumers for new and varied types of cold infusion tea products has also differed from that of traditional hot infusion ones. More kinds of Taiwan tea with different fermentation levels are gradually being used as raw materials for various cold infusion tea products. Therefore, to study consumers' responses towards cold-brewed tea has become more important for the market of tea in Taiwan. This study recruited Taiwanese consumers to taste seven Taiwanese specialty tea infusions with various degrees of fermentation, and their opinions were gathered by questionnaires composed of check-all-that-apply (CATA), and temporal check-all-that-apply (TCATA) questions and hedonic scales. We found that both CATA and TCATA data agreed that the sensory features of unfermented and lightly semi-fermented tea infusions could be plainly distinguished from the ones of heavily semi-fermented and fully fermented teas based on correspondence analyses. Through CATA and TCATA, the sensory characteristics of the cold-brewed tea of various fermentation degrees could be clearly identified. The first-hand information of cold tea beverages analyzed through this study could be useful for the development of the market in Taiwan. The proper level of bitterness, astringency, fresh tea leaf flavor, and late sweetness were the essential qualities of cold infusions brewed from lightly fermented teas, which could be the best raw materials for production of cold tea beverages to satisfy as many consumers as possible.

11.
Proc Natl Acad Sci U S A ; 118(37)2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34504019

RESUMO

Endothelial cell (EC) sensing of wall fluid shear stress (FSS) from blood flow governs vessel remodeling to maintain FSS at a specific magnitude or set point in healthy vessels. Low FSS triggers inward remodeling to restore normal FSS but the regulatory mechanisms are unknown. In this paper, we describe the signaling network that governs inward artery remodeling. FSS induces Smad2/3 phosphorylation through the type I transforming growth factor (TGF)-ß family receptor Alk5 and the transmembrane protein Neuropilin-1, which together increase sensitivity to circulating bone morphogenetic protein (BMP)-9. Smad2/3 nuclear translocation and target gene expression but not phosphorylation are maximal at low FSS and suppressed at physiological high shear. Reducing flow by carotid ligation in rodents increases Smad2/3 nuclear localization, while the resultant inward remodeling is blocked by the EC-specific deletion of Alk5. The flow-activated MEKK3/Klf2 pathway mediates the suppression of Smad2/3 nuclear translocation at high FSS, mainly through the cyclin-dependent kinase (CDK)-2-dependent phosphosphorylation of the Smad linker region. Thus, low FSS activates Smad2/3, while higher FSS blocks nuclear translocation to induce inward artery remodeling, specifically at low FSS. These results are likely relevant to inward remodeling in atherosclerotic vessels, in which Smad2/3 is activated through TGF-ß signaling.


Assuntos
Artérias Carótidas/fisiologia , Doenças das Artérias Carótidas/prevenção & controle , Células Endoteliais/fisiologia , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Estresse Mecânico , Remodelação Vascular , Animais , Artérias Carótidas/citologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Células Endoteliais/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de Sinais , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
12.
Cell Discov ; 7(1): 65, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385423

RESUMO

The current COVID-19 pandemic, caused by SARS-CoV-2, poses a serious public health threat. Effective therapeutic and prophylactic treatments are urgently needed. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, which binds to the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Here, we developed recombinant human ACE2-Fc fusion protein (hACE2-Fc) and a hACE2-Fc mutant with reduced catalytic activity. hACE2-Fc and the hACE2-Fc mutant both efficiently blocked entry of SARS-CoV-2, SARS-CoV, and HCoV-NL63 into hACE2-expressing cells and inhibited SARS-CoV-2 S protein-mediated cell-cell fusion. hACE2-Fc also neutralized various SARS-CoV-2 strains with enhanced infectivity including D614G and V367F mutations, as well as the emerging SARS-CoV-2 variants, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.1 (Kappa), and B.1.617.2 (Delta), demonstrating its potent and broad-spectrum antiviral effects. In addition, hACE2-Fc proteins protected HBE from SARS-CoV-2 infection. Unlike RBD-targeting neutralizing antibodies, hACE2-Fc treatment did not induce the development of escape mutants. Furthermore, both prophylactic and therapeutic hACE2-Fc treatments effectively protected mice from SARS-CoV-2 infection, as determined by reduced viral replication, weight loss, histological changes, and inflammation in the lungs. The protection provided by hACE2 showed obvious dose-dependent efficacy in vivo. Pharmacokinetic data indicated that hACE2-Fc has a relative long half-life in vivo compared to soluble ACE2, which makes it an excellent candidate for prophylaxis and therapy for COVID-19 as well as for SARS-CoV and HCoV-NL63 infections.

13.
Chin Med J (Engl) ; 134(9): 1064-1069, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33942801

RESUMO

BACKGROUND: Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS: The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS: The results demonstrated that increased TSH levels were significantly associated with higher TC (ß = 0.052, P = 0.002) and LDL (ß = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (ß = 0.240, P = 0.033) and LDL (ß = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION: Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility.


Assuntos
Análise da Randomização Mendeliana , Glândula Tireoide , Metabolismo dos Lipídeos/genética , Testes de Função Tireóidea , Tireotropina , Tiroxina , Tri-Iodotironina
14.
Signal Transduct Target Ther ; 6(1): 155, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859163

RESUMO

Disease progression prediction and therapeutic drug target discovery for Coronavirus disease 2019 (COVID-19) are particularly important, as there is still no effective strategy for severe COVID-19 patient treatment. Herein, we performed multi-platform omics analysis of serial plasma and urine samples collected from patients during the course of COVID-19. Integrative analyses of these omics data revealed several potential therapeutic targets, such as ANXA1 and CLEC3B. Molecular changes in plasma indicated dysregulation of macrophage and suppression of T cell functions in severe patients compared to those in non-severe patients. Further, we chose 25 important molecular signatures as potential biomarkers for the prediction of disease severity. The prediction power was validated using corresponding urine samples and plasma samples from new COVID-19 patient cohort, with AUC reached to 0.904 and 0.988, respectively. In conclusion, our omics data proposed not only potential therapeutic targets, but also biomarkers for understanding the pathogenesis of severe COVID-19.


Assuntos
COVID-19/sangue , COVID-19/tratamento farmacológico , Descoberta de Drogas , Lipidômica , Proteômica , SARS-CoV-2/metabolismo , Biomarcadores/sangue , Feminino , Humanos , Masculino
15.
Signal Transduct Target Ther ; 6(1): 167, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895773

RESUMO

The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid-liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.


Assuntos
COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , NF-kappa B/metabolismo , RNA Viral/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais , Células A549 , Acrilatos/farmacologia , Animais , COVID-19/tratamento farmacológico , COVID-19/patologia , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fosfoproteínas/metabolismo , Células Vero
16.
Mol Psychiatry ; 26(10): 6074-6082, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33828237

RESUMO

Amyloid-ß (Aß) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the Aß produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aß clearance remain largely unknown. The kidney is thought to be responsible for Aß clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aß in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on Aß clearance via the kidney were assessed. We detected Aß in the kidneys and urine of both humans and animals and found that the Aß level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aß deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain Aß levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aß from the blood, suggesting that facilitation of Aß clearance via the kidney represents a novel potential therapeutic approach for AD.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Rim/metabolismo , Camundongos , Camundongos Transgênicos , Presenilina-1/metabolismo
17.
Mitochondrial DNA B Resour ; 6(3): 868-869, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33796661

RESUMO

The complete chloroplast genome of Quercus virginiana was sequenced with Illumina HiSeq 2000 platform. It was a typical quadruple structure as other plants of Quercus with 161,221 bp in length, including a large single-copy (LSC: 90,553 bp) region and a small single-copy (SSC: 19,016 bp) which were separated by a pair of inverted repeats (IRa, b: 25,826 bp) region. The overall GC content is 36.9%. A total of 131 genes was annotated which contained 86 protein-coding genes including the Trans splicing gene of rps12, 37 tRNA genes, and 8 rRNA genes. ML phylogenetic analysis compared with 17 expressed chloroplast genomes revealed that Q. virginiana was a sister to other species of Quercus, which were grouped together with five species of Section Quercus and another 12 species of Quercus were divided into another group.

18.
Acta Pharm Sin B ; 11(9): 2850-2858, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33723501

RESUMO

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

20.
ACS Nano ; 15(2): 2738-2752, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33464829

RESUMO

The coronavirus disease pandemic of 2019 (COVID-19) caused by the novel SARS-CoV-2 coronavirus resulted in economic losses and threatened human health worldwide. The pandemic highlights an urgent need for a stable, easily produced, and effective vaccine. SARS-CoV-2 uses the spike protein receptor-binding domain (RBD) to bind its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and initiate membrane fusion. Thus, the RBD is an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticle vaccine candidates, namely, RBD-Ferritin (24-mer), RBD-mi3 (60-mer), and RBD-I53-50 (120-mer), via covalent conjugation using the SpyTag-SpyCatcher system. When mice were immunized with the RBD-conjugated nanoparticles (NPs) in conjunction with the AddaVax or Sigma Adjuvant System, the resulting antisera exhibited 8- to 120-fold greater neutralizing activity against both a pseudovirus and the authentic virus than those of mice immunized with monomeric RBD. Most importantly, sera from mice immunized with RBD-conjugated NPs more efficiently blocked the binding of RBD to ACE2 in vitro, further corroborating the promising immunization effect. Additionally, the vaccine has distinct advantages in terms of a relatively simple scale-up and flexible assembly. These results illustrate that the SARS-CoV-2 RBD-conjugated nanoparticles developed in this study are a competitive vaccine candidate and that the carrier nanoparticles could be adopted as a universal platform for a future vaccine development.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Nanopartículas/uso terapêutico , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Animais , COVID-19/metabolismo , Vacinas contra COVID-19/farmacologia , Chlorocebus aethiops , Feminino , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Glicoproteína da Espícula de Coronavírus/química , Células Vero
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