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1.
ACS Chem Neurosci ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34788008

RESUMO

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in elderly individuals and characterized by impaired cognition and accumulation of ß-amyloid (Aß). Activating autophagy to clear Aß is a plausible approach for AD treatment. The levels of Aß and autophagy signaling factors in APP695/PS1-dE9 transgenic (APP/PS1) mice were detected by immuno histological analysis, real-time PCR, and the western blotting assay. The progression of AD was determined by Aß levels, activated neurons (MAP2+), and microglia (Iba-1+). The learning ability was measured using a Morris water maze. Reactive oxygen species (ROS) production, malondialdehyde (MDA) levels, and mitochondrial superoxide dismutase (SOD) activity were checked to determine oxidative stress. AD mice exhibited impaired autophagy and a decreased level of SIRT5. SIRT5 overexpression promoted autophagy, manifested by elevated Becn1 and ratio of LC3b-II/I, as well as suppressed oxidative stress. The SIRT5-ameliorated neuron damage was correlated with suppressed activation of microglia and astrocytes. Elevated SIRT5 expression decreased the inflammation in AD brains and neurons. Inhibition of autophagy abolished the protective role of SIRT5 in neurons during AD. Our findings suggested that SIRT5 overexpression could ameliorate the progression of AD both in vitro and in vivo through activating autophagy. We presented ectopic expression of SIRT5 as a promising therapeutic approach for AD.

2.
J Neuroinflammation ; 18(1): 261, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749758

RESUMO

BACKGROUND: The aim of the current study was to investigate the effect of macrophage polarization on the expression of oxytocin (OT) and the oxytocin receptor (OTR) in enteric neurons. METHODS: In this study, we used a classic colitis model and D-mannose model to observe the correlation between macrophage polarization and OT signalling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signalling system after depletion of macrophages. RESULTS: The data showed that, in vitro, following polarization of macrophages to the M1 type by LPS, the macrophage supernatant contained proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) that inhibited the expression of OT and OTR in cultured enteric neurons; following macrophage polarization to the M2 type by IL4, the macrophage supernatant contained anti-inflammatory cytokines (TGF-ß) that promoted the expression of OT and OTR in cultured enteric neurons. Furthermore, M1 macrophages decreased the expression of the OT signalling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased the expression of the OT signalling system mainly through activation of Smad2/3 and inhibition of the expression of Peg3 in cultured enteric neurons. In a colitis model, we demonstrated that macrophages were polarized to the M1 type during the inflammatory phase, with significant decreased in the expression of OT and OTR. When macrophages were polarized to the M2 type during the recovery phase, OT and OTR expression increased significantly. In addition, we found that D-mannose increased the expression of OT and OTR through polarization of macrophages to the M2 type. CONCLUSIONS: This is the first study to demonstrate that macrophage polarization differentially regulates the expression of OT and OTR in enteric neurons.

3.
JCI Insight ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34793335

RESUMO

Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells, from three left-sided and three right-sided CRC patients were profiled by scRNA-seq. Right-sided CRC harbors a significant proportion of exhausted CD8 T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of "pre-exhausted" to exhausted T cells were favorable prognostic markers. Notably, we identified a novel RBP4+ NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34770125

RESUMO

The influence of natural environmental factors and social factors on children's viral diarrhea remains inconclusive. This study aimed to evaluate the short-term effects of temperature, precipitation, air quality, and social attention on children's viral diarrhea in temperate regions of China by using the distribution lag nonlinear model (DLNM). We found that low temperature affected the increase in children's viral diarrhea infection for about 1 week, while high temperature and heavy precipitation affected the increase in children's viral diarrhea infection risk for at least 3 weeks. As the increase of the air pollution index may change the daily life of the public, the infection of children's viral diarrhea can be restrained within 10 days, but the risk of infection will increase after 2 weeks. The extreme network search may reflect the local outbreak of viral diarrhea, which will significantly improve the infection risk. The above factors can help the departments of epidemic prevention and control create early warnings of high-risk outbreaks in time and assist the public to deal with the outbreak of children's viral diarrhea.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Criança , China/epidemiologia , Diarreia/epidemiologia , Humanos , Internet , Meteorologia
6.
Environ Pollut ; 293: 118523, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34793912

RESUMO

Carbendazim (CBZ), a broad-spectrum pesticide frequently detected in fruits and vegetables, could trigger potential toxic risks to mammals. To facilitate the assessment of health risks, this study aimed to characterize the cytochrome P450 (CYPs)-mediated metabolism profiles of CBZ by a combined experimental and computational study. Our results demonstrated that CYPs-mediated region-selective hydroxylation was a major metabolism pathway for CBZ in liver microsomes from various species including rat, mouse, minipig, dog, rabbit, guinea pig, monkey, cow and human, and the metabolite was biosynthesized and well-characterized as 6-OH-CBZ. CYP1A displayed a predominant role in the region-selective hydroxylation of CBZ that could attenuate its toxicity through converting it into a less toxic metabolite. Meanwhile, five other common pesticides including chlorpyrifos-methyl, prochloraz, chlorfenapyr, chlorpyrifos, and chlorothalonil could significantly inhibit the region-selective hydroxylation of CBZ, and consequently remarkably increased CBZ exposure in vivo. Furthermore, computational study clarified the important contribution of the key amino acid residues Ser122, and Asp313 in CYP1A1, as well as Asp320 in CYP1A2 to the hydroxylation of CBZ through hydrogen bonds. These results would provide some useful information for the metabolic profiles of CBZ by mammalian CYPs, and shed new insights into CYP1A-mediated metabolic detoxification of CBZ and its health risk assessment.

7.
Dig Dis Sci ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34751838

RESUMO

BACKGROUND: Conivaptan, a nonselective antagonist of vasopressin receptors V1a and V2, is the first drug of this class to be used for treating euvolemic and hypervolemic hyponatremia. Recently, increasing evidence supports the involvement of vasopressin in immune responses. AIMS: In this study, we investigated the effect of conivaptan on the modulation of CD4+ T cell homeostasis and the progression of experimental colitis. METHODS: The expression of the V1a receptor on CD4+ T cells was detected by immunofluorescence and western blot. The subset of isolated CD4+ T cells were examined after arginine vasopressin (AVP) incubation. CD4+ T cells were injected into DNBS-induced mice through the tail vein. The severity of colitis was evaluated according to weight, disease activity index (DAI), and morphological injury. Intracellular Ca2+ ([Ca2+]i) signaling in CD4+ T cells was measured using the Fluo-3 AM loading method. T-bet and IFN-γ mRNAs in the colon were detected by real-time polymerase chain reaction (qPCR). RESULTS: We found that CD4+ T cells expressed the V1a receptor. Activation of the V1a receptor significantly promoted the differentiation of CD4+ T cells into T helper 1 (Th1) cells. This process was blocked by conivaptan treatment. However, the activation of the V1a receptor did not evoke an increase in [Ca2+]i in CD4+ T cells. Notably, conivaptan markedly alleviated body weight loss, pathological damage, and expression of T-bet and IFN-γ in the colon of DNBS-treated mice. CONCLUSIONS: For the first time, we report that conivaptan attenuated colitis by inhibiting the differentiation of CD4+ T cells into Th1 cells. Mechanistically, the anti-inflammatory role of conivaptan is independent of [Ca2+]i.

8.
Hepatol Int ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34843069

RESUMO

BACKGROUND: Mesenchymal stem cell (MSC) infusion was reported to improve liver function in patients with decompensated liver cirrhosis (DLC); however, whether the medication can improve outcome of these patients is poorly understood. METHODS: This prospective, open-labeled, randomized controlled study enrolled 219 patients with HBV-related DLC who were divided into control group (n = 111) and umbilical cord-derived MSC (UC-MSC)-treated group (n = 108), then all of them received a follow-up check from October 2010 to October 2017. The treated patients received three times of UC-MSC infusions at 4-week intervals plus conventional treatment that was only used for control group. The overall survival rate and HCC-free survival rate were calculated as primary endpoints and the liver function and adverse events associated with the medication were also evaluated. RESULTS: During the follow-up check period from 13 to 75th months, there was a significantly higher overall survival rate in the treated group than the control group, while the difference of the hepatocellular carcinoma event-free survival rate between the treated and control groups was not observed during the 75-month follow-up. UC-MSC treatment markedly improved liver function, as indicated by the levels of serum albumin, prothrombin activity, cholinesterase, and total bilirubin during 48 weeks of follow-up. No significant side effects or treatment-related complications were observed in the UC-MSC group. CONCLUSIONS: Therapy of UC-MSC is not only well tolerated, but also significantly improves long-term survival rate, as well as the liver function in patients with HBV-related DLC. UC-MSC medication, therefore, might present a novel therapeutic approach for the disease.

9.
Environ Res ; : 112147, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34606841

RESUMO

As a platform for enzyme immobilization, metal-organic frameworks (MOFs) can protect enzyme activity from the interference of external adverse environment. Although these strategies have been proven to produce good results, little consideration has been given to the functional similarity of MOFs to the encapsulated enzyme. Here, catalase (CAT) was encapsulated in Fe-BTC with peroxidase-like activity to obtain a stable composite (CAT@Fe-BTC) with synergistic catalytic activity. Depending on the superior selectivity and high catalytic activity of CAT@Fe-BTC, colorimetric sensing for the detection of hydrogen peroxide and phenol was developed. This work demonstrates that the integration of functional MOFs with natural enzyme can be well applied to the construction of efficient catalysts.

10.
Natl Sci Rev ; 8(8): nwab053, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34676098

RESUMO

Mutations and transient conformational movements of the receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting the N-terminal domain (NTD) and RBD domain of S, effective at nM concentrations. Remarkably, a combination of RBD-targeting NAbs and NTD-binding NAbs, FC05, enhanced the neutralization potency in cell-based assays and an animal model. Results of competitive surface plasmon resonance assays and cryo-electron microscopy (cryo-EM) structures of antigen-binding fragments bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in the NTD and RBD of S, when immunized in rabbits and macaques, elicited potent protective immune responses against SARS-CoV-2. More importantly, two immunizations of this combination of NTD and RBD immunogens provided complete protection in macaques against a SARS-CoV-2 challenge, without observable antibody-dependent enhancement of infection. These results provide a proof of concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD.

11.
J Am Chem Soc ; 143(44): 18652-18664, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34699720

RESUMO

The interface stability of cathode/electrolyte for Na-ion layered oxides is tightly related to the oxidized species formed during the electrochemical process. Herein, we for the first time decipher the coexistence of (O2)n- and trapped molecular O2 in the (de)sodiation process of P2-Na0.66[Li0.22Mn0.78]O2 by using advanced electron paramagnetic resonance (EPR) spectroscopy. An unstable interface of cathode/electrolyte can thus be envisaged with conventional carbonate electrolyte due to the high reactivity of the oxidized O species. We therefore introduce a highly fluorinated electrolyte to tentatively construct a stable and protective interface between P2-Na0.66[Li0.22Mn0.78]O2 and the electrolyte. As expected, an even and robust NaF-rich cathode-electrolyte interphase (CEI) film is formed in the highly fluorinated electrolyte, in sharp contrast to the nonuniform and friable organic-rich CEI formed in the conventional lowly fluorinated electrolyte. The in situ formed fluorinated CEI film can significantly mitigate the local structural degeneration of P2-Na0.66[Li0.22Mn0.78]O2 by refraining the irreversible Li/Mn dissolutions and O2 release, endowing a highly reversible oxygen redox reaction. Resultantly, P2-Na0.66[Li0.22Mn0.78]O2 in highly fluorinated electrolyte achieves a high Coulombic efficiency (CE) of >99% and an impressive cycling stability in the voltage range of 2.0-4.5 V (vs Na+/Na) under room temperature (147.6 mAh g-1, 100 cycles) and at 45 °C (142.5 mAh g-1, 100 cycles). This study highlights the profound impact of oxidized oxygen species on the interfacial stability of cathode/electrolyte and carves a new path for building stable interface and enabling highly stable oxygen redox reaction.

12.
J Phys Chem Lett ; 12(36): 8740-8748, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34478306

RESUMO

Herein, the structure-electrochemistry relationship of O2-Li5/6(Li0.2Ni0.2Mn0.6)O2 is deliberately studied by local-structure probes including site-sensitive 7Li pj-MATPASS NMR, quantitative 6Li magic-angle spinning NMR, and electron paramagnetic resonance (EPR). The extraction and reinsertion of LiTM (Li in the transition metal layer) during the first cycle are only partially reversible, bringing about the formation of tetrahedral LiLi (Li in the Li layer) that can be reversibly (de)intercalated after the activation cycle. The high-voltage oxygen redox process is preserved beyond the first cycle, further manifesting the structural superiority of O2 stacking over O3 stacking in bolstering oxygen redox. Moreover, the (de)lithiation process is highly reversible without pronounced structural hysteresis after the rearrangement of Li and transition metal upon the activation cycle, which can explain well the variation of voltage hysteresis from the first cycle to second cycle. These insights elucidate the imperfect structural stability of O2-type Li-rich layered oxides, which could be further improved by streamlining the returning path of LiTM.

13.
Clin Infect Dis ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551104

RESUMO

BACKGROUND: We assessed the safety and immunogenicity of a recombinant adenovirus type-5 (Ad5)-vectored COVID-19 vaccine with homologous prime-boost regimens in healthy participants aged 6 years and above. METHODS: In this randomised, double-blind, placebo-controlled trial, participants received low-dose vaccine, middle-dose vaccine or placebo. Prime-booster regimens were given intramuscularly 56 days apart. ELISA antibodies to the receptor binding domain (RBD) and pseudovirus neutralising antibodies were detected. Adverse events were monitored for 28 days following each vaccination. RESULTS: A total of 430 participants were enrolled in the study, with 30 participants aged 18-55 years (MID cohort), 250 participants aged 56 years and older (OLD cohort), and 150 participants aged 6-17 years (MIN cohort). Ad5-vectored COVID-19 vaccine induced significant RBD-specific ELISA antibodies which decreased with increasing age, with geometric mean titres (GMTs) of 1037.5 in MIN cohort, 647.2 in MID cohort, and 338.0 in OLD cohort receiving 5×10 10 viral particles on day 28 following boost vaccination. Pseudovirus neutralising antibodies showed a similar pattern, with GMTs of 168.0 in MIN cohort, 76.8 in MID cohort, and 79.7 in OLD cohort. A single dose in children and adolescents induced higher antibody responses than that elicited by two doses in adults, with GMTs of 1091.6 and 96.6 in ELISA antibody and neutralising antibody, respectively. Homologous prime-boost vaccination was safety and tolerable. CONCLUSIONS: Ad5-vectored COVID-19 vaccine with a single dose was safe and induced robust immune responses in children and adolescents aged 6-17 years. A prime-boost regimen needs further exploration for Ad5-vectored COVID-19 vaccine.

14.
Chin Med J (Engl) ; 134(17): 2037-2044, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34343152

RESUMO

ABSTRACT: With the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, the importance of vaccines in epidemic prevention and public health has become even more obvious than ever. However, the emergence of multiple severe acute respiratory syndrome coronavirus 2 variants worldwide has raised concerns about the effectiveness of current COVID-19 vaccines. Here, we review the characteristics of COVID-19 vaccine candidates in five platforms and the latest clinical trial results of them. In addition, we further discuss future directions for the research and development of the next generation of COVID-19 vaccines. We also summarize the serious adverse events reported recently after the large-scale vaccination with the current COVID-19 vaccines, including the thromboembolism caused by the AstraZeneca and Johnson & Johnson vaccines.


Assuntos
COVID-19 , Vacinas , Vacinas contra COVID-19 , Humanos , SARS-CoV-2
15.
J Clin Pharm Ther ; 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34363237

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Pregnant women are increasingly being exposed to metformin for conditions including gestational diabetes mellitus and type 2 diabetes mellitus. Metformin has been found to exhibit maternal to foetal transfer, and the long-term influence is uncertain. We conducted a meta-analysis to compare the efficacy and safety of metformin alone or as add-on therapy to insulin and insulin in pregnancy with gestational diabetes mellitus or type 2 diabetes mellitus. METHODS: We performed a comprehensive literature search of PubMed, Embase, Cochrane Library and ClinicalTrials.gov for randomized controlled trials (RCTs) that compared metformin to insulin in pregnancy. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to synthesize the results. Two authors independently extracted the data, evaluated study quality and calculated pooled estimates. RESULTS: Twenty-one studies involving 4,545 patients were included in this meta-analysis. Compared with insulin, metformin significantly reduced the risks of maternal weight gain [MD -1.51 kg, 95%CI (-1.90 kg, -1.12 kg), P < 0.00001], gestational age at birth [MD -0.12 week, 95%CI (-0.21 week, -0.02 week), P = 0.02], gestational hypertension [RR 0.63, 95%CI (0.48, 0.82), P = 0.0006], maternal hypoglycaemia [RR 0.33, 95%CI (0.15, 0.73), P = 0.006], birthweight [MD -0.13 kg, 95%CI (-0.20 kg, -0.07 kg), P < 0.0001], neonatal hypoglycaemia [RR 0.56, 95%CI (0.49, 0.64), P < 0.00001], neonatal intensive care unit admission [RR 0.73, 95%CI (0.64, 0.83), P < 0.00001], birthweight ≥4000 g [RR 0.70, 95%CI (0.59, 0.83), P < 0.0001], and large for gestational age [RR 0.83, 95%CI (0.72, 0.97), P = 0.02] and significantly increased the risk of small for gestational age [RR 1.43, 95%CI (1.08, 1.89), P = 0.01] in pregnancy. WHAT IS NEW AND CONCLUSION: Metformin may have potential benefits for pregnant women and newborns in terms of maternal and foetal outcomes. More studies with long-term follow-up of offspring exposed to metformin in utero are needed to provide evidence for the future use of metformin in pregnancy.

16.
Proc Natl Acad Sci U S A ; 118(33)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34385309

RESUMO

Circular RNAs (circRNAs) have emerged as key regulators of human cancers, yet their modes of action in gastric cancer (GC) remain largely unknown. Here, we identified circURI1 back-spliced from exons 3 and 4 of unconventional prefoldin RPB5 interactor 1 (URI1) from circRNA profiling of five-paired human gastric and the corresponding nontumor adjacent specimens (paraGC). CircURI1 exhibits the significantly higher expression in GC compared with paraGC and inhibitory effects on cell migration and invasion in vitro and GC metastasis in vivo. Mechanistically, circURI1 directly interacts with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to modulate alternative splicing of genes, involved in the process of cell migration, thus suppressing GC metastasis. Collectively, our study expands the current knowledge regarding the molecular mechanism of circRNA-mediated cancer metastasis via modulating alternative splicing.

17.
Oncogene ; 40(40): 5913-5924, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34363020

RESUMO

N6-methyladenosine (m6A) is the most prevalent RNA epigenetic regulator in cancer. However, the understanding of m6A modification on lipid metabolism regulation in colorectal cancer (CRC) is very limited. Here, we observed that human CRCs exhibited increased m6A mRNA methylation mediated by dysregulation of m6A erasers and readers. By performing methylated RNA-immunoprecipitation sequencing (MeRIP-seq) and transcriptomic sequencing (RNA-seq), we identified DEGS2 as a downstream target of m6A dysregulation. Overexpression or knockdown of DEGS2 confirmed the role of DEGS2 in proliferation, invasion and metastasis of CRC both in vitro and in vivo. Mechanistic studies identified the specific m6A modification site within DEGS2 mRNA, and mutation of this target site was found to drastically enhance the proliferative and invasive ability of CRC cells in vitro and promote tumorigenicity in vivo. Lipidome analysis showed that lipid metabolism was dysregulated in CRC. Moreover, ceramide synthesis was suppressed due to DEGS2 upregulation mediated by m6A modification in CRC tissues. Our findings highlight that the function of DEGS2 m6A methylation in CRC and extend the understanding of the importance of RNA epigenetics in cancer biology.

18.
Anal Chem ; 93(30): 10477-10486, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34292723

RESUMO

Timely and effective diagnosis is of great significance for improving the survival rate of lung cancer patients. Although histopathology is the main diagnostic tool among the existing methods for lung cancer diagnosis, it is not suitable for high-risk groups, early lung cancer patients, patients with advanced-stage disease, and other situations wherein tumor tissues cannot be obtained. In view of this, we proposed an innovative lung cancer diagnosis method employing for the first time a microfluidic technology for high-efficiency isolation and high-throughput single-cell analysis of exfoliated tumor cells (ETCs) in sputum. This method fully combines the advantages of traditional sputum cytology and microfluidic technology and realizes the diagnosis of lung cancer by using a small amount of repeatable ETCs instead of the tumor tissue. This method is expected to provide a practical strategy for the non-invasive detection of lung cancer patients and lung cancer screening for high-risk groups.


Assuntos
Neoplasias Pulmonares , Escarro , Biópsia , Detecção Precoce de Câncer , Humanos , Neoplasias Pulmonares/diagnóstico , Análise de Célula Única
19.
Signal Transduct Target Ther ; 6(1): 271, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267185

RESUMO

COVID-19 vaccines from multiple manufacturers are needed to cope with the problem of insufficient supply. We did two single-center, randomised, double-blind, placebo-controlled phase 1 and phase 2 trials to assess the safety, tolerability and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older in China. Eligible participants were enrolled, the ratio of candidate vaccine and placebo within each dose group was 3:1 (phase 1) or 5:1 (phase 2). From August 28, 2020, 168 participants were sequentially enrolled and randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 28 days or 0, 14, 28 days in phase 1 trial. From November 18, 2020, 960 participants were randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 21 days or 0, 14, 28 days in phase 2 trial. The most common solicited injection site adverse reaction within 7 days in both trials was pain. The most common solicited systematic adverse reactions within 7 days were fatigue, cough, sore throat, fever and headache. ELISA antibodies and neutralising antibodies increased at 14 days, and peaked at 28 days (phase 1) or 30 days (phase 2) after the last dose vaccination. The GMTs of neutralising antibody against live SARS-CoV-2 at 28 days or 30 days after the last dose vaccination were highest in the adult high dose group (0, 14, 28 days), with 102.9 (95% CI 61.9-171.2) and 102.6 (95% CI 75.2-140.1) in phase 1 and phase 2 trials, respectively. Specific T-cell response peaked at 14 days after the last dose vaccination in phase 1 trial. This vaccine is safe, and induced significant immune responses after three doses of vaccination.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunogenicidade da Vacina , SARS-CoV-2/imunologia , Adolescente , Adulto , COVID-19/sangue , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Adv Sci (Weinh) ; 8(13): 2100209, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34258163

RESUMO

Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Here, it is observed that insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2)-deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. However, the IGF2BP2-/- macrophages are refractory to interleukin-4 (IL-4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6-methyladenosine (m6A)-dependent manner. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)-high mobility group AT-hook 2-IGF2BP2-peroxisome proliferator activated receptor-γ axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.

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