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1.
Infect Drug Resist ; 14: 4783-4793, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34815676

RESUMO

Objective: This study aimed to investigate the prevalence, genetic diversity and clinical characteristics of Clostridium perfringens isolates from hospitalized clinical diarrheal patients. Methods: A prospective study was conducted on 1108 patients with diarrhea during hospitalization. Stool samples were cultured for C. perfringens, and the toxin genes were detected by PCR. The available clinical data of 112 patients were analyzed to study the clinical features of various isolates. Multi-locus sequence typing (MLST) was performed to assess phylogenetic relationship between different isolates. Results: A total of 153 (13.8%) isolates were obtained from patients' stools. C. perfringens type F (49.0%) was the major toxin type in the isolates, followed by type A (n = 59, 38.6%) and type C (n = 14, 9.2%). Patients older than 50 years and those with underlying diseases of cancer, hepatobiliary system, and ulcerative colitis (UC) were more predisposed to C. perfringens type F and type A infection than to type C. The patients infected with type C experienced more severe clinical symptoms compared to those with type A infection. There was a significant association between type FC and foodborne gastrointestinal (GI) diseases (p = 0.018), between type FP and antibiotic-associated diarrhea (AAD) (p < 0.001), and between type A and sporadic diarrhea (SD) (p < 0.001). Phylogenetic analysis indicated that type F isolates carrying a chromosomal cpe gene mainly belonged to ST77 (6/15 isolates). Type F isolates with cpe gene on a plasmid exhibited high genetic diversity. Conclusion: High prevalence and considerable genetic diversity of C. perfringens type F were found in clinical diarrheal patients. Elderly people and patients with cancer, hepatobiliary diseases or UC, or suspected of having food poisoning (FP) may be targeted for routine testing of C. perfringens toxin genes and may benefit from early detection of C. perfringens type C isolates that cause more severe clinical symptoms.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34599446

RESUMO

Air pollution is a critical risk factor for the prevalence of COVID-19. However, few studies have focused on whether air pollution affects the efficacy of the SARS-CoV-2 vaccine. To better guide the knowledge surrounding this vaccination, we conducted a cross-section study to identify the relationships between air pollutant exposure and plasma neutralizing antibody (NAb) titers of an inactivated SARS-CoV-2 vaccine (Vero cell, CoronaVac, SINOVΛC, China). We recruited 239 healthcare workers aged 21-50 years who worked at Suining Central Hospital. Of these, 207 were included in this study, depending on vaccination date. The data regarding air pollutants were collected to calculate individual daily exposure dose (DED). The geometric mean of all six pollutant DEDs was applied to estimate the combined toxic effects (DEDcomplex). Then, the participants were divided into two groups based on the mean value of DEDcomplex. The median plasma NAb titer was 12.81 AU/mL, with 85.99% vaccine efficacy in healthcare workers against SARS-CoV-2. In exposure group, observations included lower plasma NAb titers (median: 11.13 AU/mL vs. 14.56 AU/mL), more peripheral counts of white blood cells and monocytes (mean: 6.71 × 109/L vs. 6.29 × 109/L and 0.49 × 109/L vs. 0.40 × 109/L, respectively), and a higher peripheral monocyte ratio (7.38% vs. 6.50%) as compared to the reference group. In addition, elevated air pollutant DEDs were associated with decreased plasma NAb titers. To our knowledge, this study is the first to report the relationship between air pollutant exposure and plasma NAb titers of the SARS-CoV-2 vaccine. This suggests that long-term exposure to air pollutants may inhibit plasma NAb expression by inducing chronic inflammation. Therefore, to achieve early herd immunity and hopefully curb the COVID-19 epidemic, vaccinations should be administered promptly to those eligible, and environmental factors should be considered as well.

3.
Nat Commun ; 12(1): 5908, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625564

RESUMO

Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.


Assuntos
Anticorpos/farmacologia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunidade Inata , Vírus Oncolíticos/imunologia , Animais , Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CD47 , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/imunologia , Humanos , Imunoglobulina G , Imunoterapia , Células Matadoras Naturais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Terapia Viral Oncolítica/métodos , Fagocitose , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Virol ; : JVI0096421, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34668775

RESUMO

A comprehensive analysis and characterization of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection model that mimics non-severe and severe coronavirus disease 2019 (COVID-19) in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18-hACE2 mouse model expressing human (h)ACE2 in mice, controlled by the human keratin 18 (K18) promoter, in the epithelia, including airway epithelial cells where SARS-CoV-2 infections typically start. We found that intranasal inoculation with higher viral doses (2×103 and 2×104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lung, liver, and kidney, while lower doses (2×101 and 2×102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this hACE2 mouse model, SARS-CoV-2 infection damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in post-mortem samples from COVID-19 patients. Finally, the mice that recovered from infection with a low dose of virus survived rechallenge with a high dose of virus. Compared to other existing models, the K18-hACE2 model seems to be the most sensitive COVID-19 model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human post-mortem samples from COVID-19 patients. In conclusion, the K18-hACE2 mouse model recapitulates both severe and non-severe COVID-19 in humans being dose-dependent and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19. Importance The pandemic of coronavirus disease 2019 (COVID-19) has reached nearly 240 million cases and caused nearly 5 million deaths worldwide as of October 2021, has raised an urgent need for the development of novel drugs and therapeutics to prevent the spread and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To achieve this goal, an animal model that recapitulates the features of human COVID-19 disease progress and pathogenesis is greatly needed. In this study, we have comprehensively characterized a mouse model of SARS-CoV-2 infection using K18-hACE2 transgenic mice. We infected the mice with low and high doses of SARS-CoV-2 to study the pathogenesis and survival in response to different infection patterns. Moreover, we compared the pathogenesis of the K18-hACE2 transgenic mice with that of the COVID-19 patients to show that this model could be a useful tool for the development of anti-viral drugs and therapeutics.

5.
bioRxiv ; 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34127969

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human natural defense mechanisms against SARS-CoV-2 are largely unknown. Serine proteases (SPs) including furin and TMPRSS2 cleave SARS-CoV-2 spike protein, facilitating viral entry. Here, we show that FXa, a SP for blood coagulation, is upregulated in COVID-19 patients compared to non-COVID-19 donors and exerts anti-viral activity. Mechanistically, FXa cleaves the SARS-CoV-2 spike protein, which prevents its binding to ACE2, and thus blocks viral entry. Furthermore, the variant B.1.1.7 with several mutations is dramatically resistant to the anti-viral effect of FXa compared to wild-type SARA-CoV-2 in vivo and in vitro . The anti-coagulant rivaroxaban directly inhibits FXa and facilitates viral entry, whereas the indirect inhibitor fondaparinux does not. In a lethal humanized hACE2 mouse model of SARS-CoV-2, FXa prolonged survival while combination with rivaroxaban but not fondaparinux abrogated this protection. These preclinical results identify a previously unknown SP function and associated anti-viral host defense mechanism and suggest caution in considering direct inhibitors for prevention or treatment of thrombotic complications in COVID-19 patients.

6.
Spectrochim Acta A Mol Biomol Spectrosc ; 261: 120028, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34119768

RESUMO

A novel visual nanoprobe was developed for the sequential detection of morin and zinc ion (Zn2+) based on Cl and N co-doped carbon quantum dots (ClNCQDs) via a fluorometric and colorimetric dual-readout mode. The yellow fluorescence ClNCQDs was synthesized by the one-step hydrothermal treatment of o-chlorobenzoic acid and p-phenylenediamine. The most distinctive property of the ClNCQDs is the large stokes shift (177 nm), which is significantly higher than other reported CQDs. The fluorescence of the ClNCQDs can be effectively quenched by morin based on the synergistic effect of IFE, electrostatic interaction, and dynamic quenching process, and recovered upon the addition of Zn2+ due to strong interaction between morin and Zn2+. The nanoprobe exhibited favorable selectivity and sensitivity toward morin and Zn2+ with detection limits of 0.09 µM and 0.17 µM, respectively. Simultaneously, the color of the ClNCQDs solution was changed (light-pink â†’ faint-yellow â†’ dark-yellow) along with the variation of the fluorescence signal of the ClNCQDs. This proposed nanoprobe was successfully applied for morin and Zn2+ analyses in actual samples and live cells with high accuracy. The results of this study demonstrate the great application prospects of the ClNCQDs for morin and Zn2+ detection in complex actual samples and biosystems.


Assuntos
Pontos Quânticos , Carbono , Colorimetria , Flavonoides , Limite de Detecção , Zinco
7.
bioRxiv ; 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34127971

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer patients are usually immunocompromised and thus are particularly susceptible to SARS-CoV-2 infection resulting in COVID-19. Although many vaccines against COVID-19 are being preclinically or clinically tested or approved, none have yet been specifically developed for cancer patients or reported as having potential dual functions to prevent COVID-19 and treat cancer. Here, we confirmed that COVID-19 patients with cancer have low levels of antibodies against the spike (S) protein, a viral surface protein mediating the entry of SARS-CoV-2 into host cells, compared with COVID-19 patients without cancer. We developed an oncolytic herpes simplex virus-1 vector-based vaccine named oncolytic virus (OV)-spike. OV-spike induced abundant anti-S protein neutralization antibodies in both tumor-free and tumor-bearing mice, which inhibit infection of VSV-SARS-CoV-2 and wild-type (WT) live SARS-CoV-2 as well as the B.1.1.7 variant in vitro. In the tumor-bearing mice, OV-spike also inhibited tumor growth, leading to better survival in multiple preclinical tumor models than the untreated control. Furthermore, OV-spike induced anti-tumor immune response and SARS-CoV-2-specific T cell response without causing serious adverse events. Thus, OV-spike is a promising vaccine candidate for both preventing COVID-19 and enhancing the anti-tumor response. One Sentence Summary: A herpes oncolytic viral vector-based vaccine is a promising vaccine with dual roles in preventing COVID-19 and treating tumor progression.

8.
Mikrochim Acta ; 188(6): 183, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33970343

RESUMO

Carbon dots (CDs) are a rising star in the field of cellular imaging, especially cytoplasmic imaging, attributing to the super-stable optical performance and ultra-low biological toxicity. Nucleolus can accurately reflect the expression state of a cell and is strongly linked to the occurrence and development of many diseases, so exploring bran-new CDs for nucleolus-orientation imaging with no-wash technology has important theoretical value and practical significance. Herein, nitrogen-doped carbon dots (N-CDs) with green fluorescence (the relative fluorescence quantum yield of 24.4%) was fabricated by the hydrothermal treatment of m-phenylenediamine and p-aminobenzoic acid. The N-CDs possess small size, bright green fluorescence, abundant surface functional groups, excellent fluorescence stability and good biocompatibility, facilitating that the N-CDs are an excellent imaging reagent for cellular imaging. N-CDs can particularly bind to RNA in nucleoli to enhance their fluorescence, which ensures that the N-CDs can be used in nucleolus-orientation imaging with high specificity and wash-free technique. This study demonstrates that the N-CDs have a significant feasibility to be used for nucleolus-orientation imaging in biomedical analysis and clinical diagnostic applications.

9.
Pathogens ; 10(2)2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33668502

RESUMO

Neither inactivated nor attenuated vaccines can effectively prevent and control the infection and spread of porcine reproductive and respiratory syndrome virus (PRRSV). Therefore, it is necessary to broaden new horizons and to conceive effective preventive strategies. The main components of Tea polyphenol (TPP) are catechins and their derivatives. TPP has many physiological activities and has certain antiviral and antifungal effects. However, whether TPP shows anti-PRRSV activity remains unclear. We found that TPP effectively inhibited PRRSV infection in Marc-145 cells by suppressing the stages of viral attachment, internalization, replication, and release. TPP exhibited a potent anti-PRRSV effect regardless of pre-treatment or post-treatment. In addition, we demonstrated that TPP restrained PRRSV-induced p65 entry into the nucleus to suppress the activation of the NF-κB signaling pathway, which ultimately leads to the inhibition of the expression of inflammatory cytokines. Furthermore, TPP limited the synthesis of viral non-structural protein 2 (nsp2), the core component of viral replication transcription complexes, which may contribute to the inhibition of viral RNA replication. TPP has the potential to develop into an effective antiviral agent for PRRSV prevention and control in the future.

10.
Spectrochim Acta A Mol Biomol Spectrosc ; 252: 119506, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33561684

RESUMO

Azithromycin (AZM)1 is one of the most widely used antibiotics. AZM abuse is easy to cause great harm to human body, so developing a rapid and sensitive method to detect AZM is of great importance. Herein, 3-aminothiophenol as only reaction precursor, nitrogen and sulfur co-doped carbon quantum dots (N,S-CQDs)2 were fabricated by one-step hydrothermal carbonization method. All characteristics demonstrate that N,S-CQDs possess good water solubility, high fluorescence stability and low cytotoxicity. Without being disturbed by amino acids and drugs, the most interesting finding is that AZM can efficiently quench the fluorescence of N,S-CQDs by a synergistic effect of electrostatic interaction and static quenching. A fluorescent probe for the detection of AZM was constructed with high selectivity and good sensitivity, achieving two linear ranges of 2.5-32.3 µM and 37.2-110 µM and a limit of detection of 0.76 µM. The proposed fluorescent method was used for the detection of AZM in cells with fulfilling results. More importantly, the fluorescent probe was successfully used to the detection of AZM in tablets and human urine with recovery rate and relative standard deviations of 98.2-104.8% and 0.04-3.46%, respectively, which was confirmed by the standard method of HPLC-UV. This finding illustrates the usefulness and feasibility of N,S-CQDs as an effective fluorescent probe for the detection of AZM in tablets and human urine, which is helpful for supervising and guiding pharmacy.


Assuntos
Pontos Quânticos , Azitromicina , Carbono , Humanos , Nitrogênio , Comprimidos
11.
Mikrochim Acta ; 188(1): 16, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33399925

RESUMO

Nitrogen, sulfur, phosphorus, and chlorine co-doped carbon nanodots (NSPCl-CNDs) were fabricated by acid-base neutralization and exothermic carbonization of glucose. The obtained NSPCl-CNDs possess excellent fluorescence properties and good biocompatibility. Curcumin (Cur) can dramatically quench the fluorescence of NSPCl-CNDs based on a synergistic effect of electrostatic interaction, inner filter effect, and static quenching, so a "turn-off" fluorescent probe for Cur detection was constructed with linear ranges of 0.24-13.16 µM and 13.62-57.79 µM. The LOD and LOQ of this fluorescent probe for Cur are 8.71 nM and 29.03 nM, respectively. More importantly, the fluorescence of the NSPCl-CNDs-Cur system can be recovered by europium ion (Eu3+), so a "turn-on" fluorescent probe for Eu3+ determination was established. The linear range, LOD, and LOQ for the detection of Eu3+ were 2.36-32.91 µΜ, 73.29 nM, and 244.30 nM, respectively. The proposed fluorescence methods were successfully utilized for Cur and Eu3+ determination in real samples with recoveries in the range 95.64-104.13% and 97.06-98.70%, respectively. Furthermore, the qualitative analysis of Cur can be realized by reagent strips with satisfying results. Finally, the as-constructed "off-on" fluorescent probe was successfully used to sequentially analyze Cur and Eu3+ at the cellular level. This method is simple and easy to implement, manifesting that NSPCl-CNDs have potential application value in fluorescent probing, food and drug testing, environmental monitoring, and cellular labeling. Graphical abstract.

12.
Anal Chim Acta ; 1144: 1-13, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33453785

RESUMO

The fluorescent sensor, especially ratiometric fluorescent sensor, is one of the most important applications for CQDs, which is becoming a research hotspot. Herein, carbon quantum dots co-doped with nitrogen, phosphorus and chlorine (NPCl-CQDs) were synthesized by acid-base neutralization reaction exothermic carbonization method. The as-fabricated NPCl-CQDs could emit blue fluorescence and possess excellent fluorescence properties. Based on the FRET, multifunctional and ratiometric fluorescent sensors for "on-off-on" sequential determination of riboflavin, Ag+, and Cys with good selectivity and high sensitivity were established. The linear range of riboflavin, Ag+, and Cys are 0.50-10.18 µM and 15.89-27.76 µM, 0.66-1.46 mM and 1.50-4.20 mM, and 0.01-0.15 µM and 0.15-0.36 µM with the limit of detection of 3.50 nM, 26.38 µM, and 0.96 nM, respectively. Furthermore, the sensors were successfully used to determine riboflavin, Ag+, and Cys in tablets, river water, and human urine with the recoveries of 95.2-104.0%, 95.6-102.0%, and 94.8-106.4%, respectively. More importantly, the as-constructed "on-off-on" NPCl-CQDs-based ratiometric fluorescent sensors were applied for detecting riboflavin, Ag+, and Cys in HeLa cells with satisfying results. The finding of this study shows the feasibility and effectiveness of the NPCl-CQDs as the available ratiometric fluorescent sensors for the determination of riboflavin, Ag+, and Cys in real samples and living cells.


Assuntos
Pontos Quânticos , Carbono , Cisteína , Células HeLa , Humanos , Riboflavina , Prata
13.
Cell Rep Med ; 2(1): 100189, 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33495758

RESUMO

The SARS-CoV-2 proteome shares regions of conservation with endemic human coronaviruses (CoVs), but it remains unknown to what extent these may be cross-recognized by the antibody response. Here, we study cross-reactivity using a highly multiplexed peptide assay (PepSeq) to generate an epitope-resolved view of IgG reactivity across all human CoVs in both COVID-19 convalescent and negative donors. PepSeq resolves epitopes across the SARS-CoV-2 Spike and Nucleocapsid proteins that are commonly targeted in convalescent donors, including several sites also recognized in some uninfected controls. By comparing patterns of homologous reactivity between CoVs and using targeted antibody-depletion experiments, we demonstrate that SARS-CoV-2 elicits antibodies that cross-recognize pandemic and endemic CoV antigens at two Spike S2 subunit epitopes. We further show that these cross-reactive antibodies preferentially bind endemic homologs. Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous CoV exposures and which have the potential to raise broadly neutralizing responses.

14.
Spectrochim Acta A Mol Biomol Spectrosc ; 247: 119085, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33161261

RESUMO

Many reports have suggested that near-infrared (NIR) fluorescent probes are one of the most promising molecules for improving the sensitivity of fluorescence sensing and imaging. Herein, gold nanoclusters with excellent near-infrared photoluminescence (PL) were synthesized by a simply hydrothermal treatment of hydrogen tetrachloroaurate(III) trihydrate and glutathione (GSH). The NIR PL of GSH-capped gold nanoclusters (GSH-AuNCs) can be significantly quenched by Fe3+, which follows a dynamic quenching mechanism. However, the NIR PL of the GSH-AuNCs/Fe3+ system can be recovered after the addition of ascorbic acid (AA). The decrease and increase of NIR PL intensities of GSH-AuNCs were linearly correlated with the concentration of Fe3+ and AA, respectively. Therefore, a turn-off-on NIR PL sensing strategy can be constructed for sequential detection of Fe3+ and AA with the linear range of 0.7-180 µM and 0.5-120 µM, respectively. The proposed NIR PL sensor exhibits excellent sensing performance and has been applied to the determination of Fe3+ and AA in real samples with satisfactory results.

15.
Cell Signal ; 78: 109848, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33246003

RESUMO

We have recently reported that capping protein regulator and myosin 1 linker 3 (CARMIL3), first identified as an oncofetal-like gene, is required for metastasis of breast and prostate cancer cells via regulating the actin cytoskeletal dynamics near the plasma membrane. Here, we demonstrate a novel function of CARMIL3 as an essential regulator of the transcription of several key proinflammatory cytokines in macrophages engulfing apoptotic cells and/or exposed to lipopolysaccharides (LPS). CARMIL3-deficient macrophages expressed strongly abrogated levels of interleukin (IL)-6, TNF-α, IL-1ß and IL-23 in response to LPS, whereas IL-10 expression was enhanced. An RNA-seq analysis of CARMIL3-deficient and wild-type (WT) RAW264.7 cells stimulated with LPS revealed many differentially expressed genes, impacting several important inflammatory pathways. At the molecular level, CARMIL3 deficiency caused a strong impairment in LPS-activated nuclear factor-κB (NF-κB) signaling with decreased IKKα/ß and IκBα phosphorylation and severely reduced p65 protein levels. This study uncovers a crucial role of CARMIL3 in impacting the balance between inflammation and tissue homeostasis via regulating major cytokines production in phagocytic cells.

16.
Food Chem Toxicol ; 146: 111848, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33166671

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP), which is widely used as an industrial plasticizer, may cause liver damage. Concomitantly, bad dietary habits can exacerbate the liver burden. In this study, high-fat diet (HFD)-fed rats were treated with DEHP (10, 100, or 300 mg/kg bw) for 5 weeks, and a biochemical method was adopted to detect serum lipid contents. Key metabolic genes and pathological changes were assessed by different methods (RT-PCR, Western Bloting, ELISA and HE staining). The rats which were exposed to DEHP at a dose of 10 mg/kg bw exhibited dyslipidemia and increased transcription of SREBP-1 and its target FAS, thereby prompting de novo lipogenesis, but they did not become obese. Instead, DEHP at a dose of 300 mg/kg bw elevated the levels of AMPK phosphorylation and the mRNA levels of PPAR-α, PGC-1α, CPT-1 and lipin-1 in the liver, which led to fatty acid oxidation. Additionally, DEHP at the highest dose increased the TNF-α mRNA expression in the liver. Based on these findings, we conclude that excess fatty acid oxidation might increase the inflammatory response. No toxic effects on hepatic function were observed. These findings suggest that different doses of DEHP have the potential to disturb hepatic metabolic imbalance in HFD-fed rats.


Assuntos
Dietilexilftalato/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Proliferação de Células , Dieta Hiperlipídica , Ácidos Graxos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inflamação/induzido quimicamente , Masculino , Ratos , Ratos Wistar
17.
Analyst ; 145(21): 7018-7024, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-32870184

RESUMO

We presented a novel red-emission fluorescent probe (MSO) for selectively monitoring lysosomal pH fluctuation in living cells. The probe was designed by employing rhodamine B as the off-on pH sensitive moiety owing to the unique spirocycle group and morpholine as the lysosome targetable unit. Based on the H+-induced spirocyclic ring opening process, MSO displayed significant pH sensing properties around 590 nm, with a pKa value of 5.42 and a good linear pH response ranging from 5.00 to 6.00. Besides, the probe possessed other prominent photophysical properties such as good selectivity and excellent photostability as well as low cytotoxicity, together making the red-emission probe more favorable for long-time and real-time imaging in live cells. Furthermore, MSO selectively accumulated into lysosomes and successfully visualized the mitophagy, cell apoptosis and heat shock processes by monitoring the rise of lysosomal pH.


Assuntos
Corantes Fluorescentes , Mitofagia , Apoptose , Corantes Fluorescentes/toxicidade , Humanos , Concentração de Íons de Hidrogênio , Lisossomos
18.
bioRxiv ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32743570

RESUMO

A high-resolution understanding of the antibody response to SARS-CoV-2 is important for the design of effective diagnostics, vaccines and therapeutics. However, SARS-CoV-2 antibody epitopes remain largely uncharacterized, and it is unknown whether and how the response may cross-react with related viruses. Here, we use a multiplexed peptide assay ('PepSeq') to generate an epitope-resolved view of reactivity across all human coronaviruses. PepSeq accurately detects SARS-CoV-2 exposure and resolves epitopes across the Spike and Nucleocapsid proteins. Two of these represent recurrent reactivities to conserved, functionally-important sites in the Spike S2 subunit, regions that we show are also targeted for the endemic coronaviruses in pre-pandemic controls. At one of these sites, we demonstrate that the SARS-CoV-2 response strongly and recurrently cross-reacts with the endemic virus hCoV-OC43. Our analyses reveal new diagnostic and therapeutic targets, including a site at which SARS-CoV-2 may recruit common pre-existing antibodies and with the potential for broadly-neutralizing responses.

19.
Food Front ; 1(1): 70-82, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32368735

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a low survival rate (9%). Epidemiologic studies show that healthy dietary patterns enriched of fruits and vegetables lower the risk of PDAC. We previously showed that supplementing black raspberries (BRBs) to patients with colorectal cancer increased tumor-infiltrating NK cells and their cytotoxicity. We aimed to determine whether BRBs combat PDAC by modulating cancer immunity. NOD.SCID mice lacking T and B cells were injected with human Panc-1-Luc cells orthotopically, and immunocompetent Kras LSL.G12D/+ -Trp53 LSL.R172H/+ -Pdx-1-Cre mice were fed BRBs. Peripheral blood mononuclear cells (PBMCs) from PDAC patients were treated with butyrate, a microbial metabolite of BRBs. The absence of T and B cells did not dampen BRBs' anti-tumor effects in the NOD.SCID mice. In the Kras LSL.G12D/+ -Trp53 LSL.R172H/+ -Pdx-1-Cre mice, BRBs significantly prolonged survival (189 days versus 154 days). In both models, BRBs decreased tumor-infiltrating CD11b+ cells and the expression of IL-1ß, sEH, and Ki67. BRBs also increased tumor-infiltrating NKp46+ cells and the expression of CD107a, a functional marker of cytolytic NK and CD8+ T cells. In Kras LSL.G12D/+ -Trp53 LSL.R172H/+ -Pdx-1-Cre mice, tumor infiltration of CD8+ T cells was increased by BRBs. Further using the PBMCs from PDAC patients, we show that butyrate decreased the population of myeloid-derived suppressor cells (MDSCs). Butyrate also reversed CD11b+ cell-mediated suppression on CD8+ T cells. Interestingly, there is a negative association between MDSC changes and patients' survival, suggesting that the more decrease in MDSC population induced by butyrate treatment, the longer the patient had survived. Our study suggests the immune-modulating potentials of BRBs in PDAC.

20.
PLoS Pathog ; 16(5): e1008543, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32401783

RESUMO

Triggering receptor expressed on myeloid cells 2 (TREM2) serves as an anti-inflammatory receptor, negatively regulating the innate immune response. TREM2 is mainly expressed on dendritic cells and macrophages, the target cells of porcine reproductive and respiratory syndrome virus (PRRSV). Thus, we investigated the potential role of TREM2 in PRRSV infection in porcine alveolar macrophages (PAMs). We found that there was an increased expression of TREM2 upon PRRSV infection in vitro. TREM2 silencing restrained the replication of PRRSV, whereas TREM2 overexpression facilitated viral replication. The cytoplasmic tail domain of TREM2 interacted with PRRSV Nsp2 to promote infection. TREM2 downregulation led to early activation of PI3K/NF-κB signaling, thus reinforcing the expression of proinflammatory cytokines and type I interferons. Due to the enhanced cytokine expression, a disintegrin and metalloproteinase 17 was activated to promote the cleavage of membrane CD163, which resulted in suppression of infection. Furthermore, exogenous soluble TREM2 (sTREM2)-mediated inhibition of PRRSV attachment might be attributed to its competitive binding to viral envelope proteins. In pigs, following PRRSV challenge in vivo, the expression of TREM2 in lungs and lymph nodes as well as the production of sTREM2 were significantly increased. These novel findings indicate that TREM2 plays a role in regulating PRRSV replication via the inflammatory response. Therefore, our work describes a novel antiviral mechanism against PRRSV infection and suggests that targeting TREM2 could be a new approach in the control of the PRRSV infection.


Assuntos
Glicoproteínas de Membrana/imunologia , NF-kappa B/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Transdução de Sinais/imunologia , Animais , Inflamação/imunologia , Inflamação/patologia , Inflamação/virologia , Síndrome Respiratória e Reprodutiva Suína/patologia , Suínos
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