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1.
Environ Pollut ; 292(Pt A): 118307, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34626713

RESUMO

Municipal sewage treatment plants (STPs) have been regarded as an important source of organic contaminants in aquatic environment. To assess the impact of STPs on occurrence and toxicity of STP-associated contaminants in receiving waterways, a novel passive sampler modified from polar organic chemical integrative sampler (m-POCIS) was deployed at the inlet and outlet of a STP and several upstream and downstream sites along a river receiving STP effluent in Guangzhou, China. Eighty-seven contaminants were analyzed in m-POCIS extracts, along with toxicity evaluation using zebrafish embryos. Polycyclic musks were the predominant contaminants in both STP and urban waterways, and antibiotics and current-use pesticides (e.g., neonicotinoids, fiproles) were also ubiquitous. The m-POCIS extracts from downstream sites caused significant deformity in embryos, yet the toxicity could not be explained by the measured contaminants, implying the presence of nontarget stressors. Sewage treatment process substantially reduced embryo deformity, chemical oxygen demand, and contamination levels of some contaminants; however, concentrations of neonicotinoids and fiproles increased after STP treatment, possibly due to the release of chemicals from perturbed sludge. Source identification showed that most of the contaminants found in urban waterways were originated from nonpoint runoff, while cosmetics factories and hospitals were likely point sources for musks and antibiotics, respectively. Although the observed embryo toxicity could not be well explained by target contaminants, the present study showed a promising future of using passive samplers to evaluate chemical occurrence and aquatic toxicity concurrently. Zebrafish embryo toxicity significantly decreased after sewage treatment, but higher toxicity was observed for downstream samples, demonstrating that urban runoff may produce detrimental effects to aquatic life, particularly in rainy season. These results highlight the relevance of monitoring nonpoint source pollution along with boosting municipal sewage treatment infrastructure.

2.
Ying Yong Sheng Tai Xue Bao ; 32(8): 2675-2684, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34664439

RESUMO

Agricultural tillage practices significantly affect the structure and function of soil micro-bial community, as well as its control over soil carbon cycling. Conservation tillage practice based on no-tillage and crop straw returning is an important measure to improve soil carbon sequestration and fertility, in which soil microorganisms play a key role. Although many previous studies focus on the structure and function of microbial communities under conservation tillage, our overall understanding of soil microbial responses at community level upon conservation tillage is still lacking, due to the complexity of the soil, environmental factors and the different selections of microbial research methods. Furthermore, previous studies paid more attention to the role of soil microorganisms as decomposers and the contribution of plant-derived carbon to the formation of soil carbon pool, but ignored the contribution of microbial-derived carbon to the formation and stability of soil carbon pool. We summarized the paradigm shift in soil organic matter formation and stability theories, reviewed the research methods of soil microbial community, focused on the effects of conservation tillage on soil microbial biomass, community diversity and composition, carbon metabolism, as well as microbial-derived carbon storage, and proposed suggestions for future study, aiming to provide support for future studies regarding microbial responses and its control over soil carbon dynamics in agroecosystem.

3.
Anesth Analg ; 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652301

RESUMO

BACKGROUND: The main symptoms of chemotherapy-induced peripheral neuropathy (CIPN) include pain and numbness. Neuronal G protein-coupled receptor kinase 2 (GRK2) plays an important role in various pain models. Cisplatin treatment can induce the activation of proinflammatory microglia in spinal cord. The purpose of this study was to investigate the role of spinal neuronal GRK2 in cisplatin-induced CIPN and in the prevention of CIPN by electroacupuncture (EA). METHODS: The pain and sensory deficit behaviors of mice were examined by von Frey test and adhesive removal test. The expression of neuronal GRK2 in the spinal cord is regulated by intraspinal injection of adeno-associated virus (AAV) containing neuron-specific promoters. The protein levels of GRK2, triggering receptor expressed on myeloid cells 2 (TREM2), and DNAX-activating protein of 12 kDa (DAP12) in spinal dorsal horn were detected by Western blot, the density of intraepidermal nerve fibers (IENFs) was detected by immunofluorescence, and microglia activation were evaluated by real-time polymerase chain reaction (PCR). RESULTS: In this study, cisplatin treatment led to the decrease of GRK2 expression in the dorsal horn of spinal cord. Overexpression of neuronal GRK2 in spinal cord by intraspinal injection of an AAV vector expressing GRK2 with human synapsin (hSyn) promotor significantly inhibited the loss of IENFs and alleviated the mechanical pain and sensory deficits induced by cisplatin. Real-time PCR analysis showed that the overexpression of neuronal GRK2 significantly inhibited the messenger RNA (mRNA) upregulation of proinflammatory cytokine interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase (iNOS), and M1 microglia marker cluster of differentiation (CD)16 induced by cisplatin. Furthermore, the TREM2 and DAP12, which has been demonstrated to play a role in microglia activation and in the development of CIPN, were also downregulated by overexpression of neuronal GRK2 in this study. Interestingly, preventive treatment with EA completely mimics the effect of overexpression of neuronal GRK2 in the spinal cord in this mouse model of cisplatin-induced CIPN. EA increased GRK2 level in spinal dorsal horn after cisplatin treatment. Intraspinal injection of AAV vector specifically downregulated neuronal GRK2, completely reversed the regulatory effect of EA on CIPN and microglia activation. All these indicated that the neuronal GRK2 mediated microglial activation contributed to the process of CIPN. CONCLUSIONS: Neuronal GRK2 in the spinal cord contributed to the preventive effect of EA on CIPN. The neuronal GRK2 may be a potential target for CIPN intervention.

4.
Nutrients ; 13(10)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34684331

RESUMO

Thyroid function has a close link with inflammation. However, it is still unknown whether the dietary inflammatory potential is associated with thyroid function. We aimed to assess the relationship among them using the data from the National Health and Nutrition Examination Survey (NHANES). This study was a cross-sectional study, where weighted multivariable linear regression, subgroup analyses, and interaction terms were employed. Thyroid function was assessed by eight indexes, including total and free T4 and T3, Tg, TgAb, TPOAb, and TSH. A total of 2346 male participants aged ≥20 years with an average age of 50.74 ± 17.68 years were enrolled. The mean DII score among participants was -0.46 ± 1.73, ranging from -4.12 to 4.41, and mean total thyroxine (T4) was 7.61 ± 1.51 µg/dL. We found a positive association between DII and total T4 (ß = 0.07; p = 0.0044). Using subgroup analysis, this association became stronger in both the iodine-deficient and obese group (iodine-deficient group: ß = 0.15, p < 0.0001; obese group: ß = 0.14, p < 0.0001). In conclusion, men adhering to a more pro-inflammatory diet appeared to have higher total T4 levels. However, these hormone variations were still within the normal clinical range and more well-designed studies are still needed to validate the causal relationship between DII and thyroid function.

5.
Thorac Cancer ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581010

RESUMO

BACKGROUND: Inflammation-nutritional markers of peripheral blood are easily assessed and can predict survival. The aim of this study was to investigate the association between inflammation-nutritional parameters and survival of anti-programmed death-1 (PD-1) therapy in non-small-cell lung cancer (NSCLC) patients. METHODS: We performed a retrospective study from March 2017 to April 2020 in advanced NSCLC patients treated with PD-1 inhibitors. Univariable and multivariable analyses were conducted to evaluate the relationship between peripheral blood parameters (absolute lymphocyte count [ALC], absolute neutrophil count [ANC], absolute monocyte count [AMC], absolute eosinocyte count [AEC], lactic dehydrogenase [LDH], plasma-albumin [ALB], neutrophil/lymphocyte ratio [NLR], and platelet/lymphocyte ratio [PLR]) measured before therapy initiation and prognosis. RESULTS: Among 184 evaluable patients, 134 (72.8%) were male and the median age was 58 years (range 33-87) with 31 (16.8%) ≥70 years. An elevated ANC (≥7500/ul), NLR (≥5), and PLR (≥200) was significantly associated with worse objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), while increased ALC (≥1000/ul) and ALB (≥3.5 g/dl) could significantly improve survival in terms of ORR, PFS, and OS. In multivariate analyses, higher AEC (≥150/ul) and AMC (≥650/ul) could significantly decrease the risk of death (hazard ratio [HR] 0.363, 95% confidence interval [CI] 0.141-0.931, p = 0.035; HR 0.370, 95% CI 0.203-0.675, p = 0.001). A higher NLR and PLR, and lower ALB were independent predictors of poor prognosis for OS (HR 1.964, 95% CI 1.027-3.755, p = 0.041; HR 4.255, 95% CI 2.364-7.658, p = 0.000; HR 1.962, 95% CI 1.213-3.174, p = 0.006, respectively). CONCLUSION: Our research illustrated that pretreatment AEC, AMC, ALB, NLR, and PLR are independent predictors for survival in advanced NSCLC patients treated with PD-1 inhibitors.

6.
Nat Prod Res ; : 1-6, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507519

RESUMO

Four new compounds, basjoochromene A (1), basjoochromene B (2), basjoochromene C (3) and basjoochromene D (4) were isolated from the 70% ethanol extract of the rhizomes of Musa basjoo using column chromatography techniques. Their structures were elucidated on the basis of spectroscopic data interpretation, mass spectrometric analyses.

7.
Biomed Environ Sci ; 34(8): 650-655, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34474727

RESUMO

Epstein-Barr virus (EBV) and cytomegalovirus (CMV), two of the most prevalent human herpesviruses, cause a wide spectrum of diseases and symptoms and are associated with serious health problem. In this study, we developed an internal control reference recombinase-aided amplification (ICR-RAA) assay for the rapid detection of EBV and CMV within 30 min. The assay had a sensitivity of 5 and 1 copies/test for EBV and CMV, respectively, with no cross reaction with other pathogens. In comparison with those of the commercial quantitative polymerase chain reaction (qPCR), the sensitivity of the EBV and CMV ICR-RAAs using extracted DNA was 93.33% and 84.84%, respectively; the specificity was 98.75% and 100.00%, respectively; and the Kappa values were 0.930 and 0.892 ( P < 0.05), respectively. In comparison with those of qPCR, the sensitivity of the EBV and CMV ICR-RAAs using the DNA by thermal lysis was 72.22% and 80.00%, respectively; the specificity was 100.00%; and the Kappa values were 0.764 and 0.878 ( P < 0. 05), respectively. Thus, rapid and specific detection of EBV and CMV is possible using ICR-RAA assays.


Assuntos
Citomegalovirus/genética , DNA Viral/análise , Herpesvirus Humano 4/genética , Técnicas de Amplificação de Ácido Nucleico , Recombinases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Clin Cosmet Investig Dermatol ; 14: 1215-1225, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34548802

RESUMO

Background: Questionnaires and lactic acid sting test (LAST) are two widely used methods to identify sensitive skin. However, the self-perceived sensitive skin by questionnaires was not consistent with the determination of LAST. Objective: The aim of the study was to measure the biophysical properties noninvasively of sensitive skin evaluated by questionnaire and LAST and to investigate their correlations with the scores of questionnaire and LAST. Methods: A total of 209 healthy Chinese females completed the study. Self-assessment questionnaire and LAST were both performed to identify sensitive skin. Epidermal biophysical properties, including skin hydration, transepidermal water loss (TEWL), sebum content, erythema index (EI), a* value, L* value, skin elasticity, and skin pH, were measured with noninvasive instruments. Results: The frequency of sensitive skin was 50.2% and 66.0% by questionnaire and LAST, respectively. Subjects with self-assessed sensitive skin had a slightly higher LAST positive rate. Skin hydration, sebum content, a* and EI values were significantly higher in the self-assessed sensitive skin group, while TEWL, a* and EI values increased but L* value decreased with significance in the LAST positive group. The LAST stingers among sensitive skin subjects had higher EI but not in the healthy skin subjects. In addition, questionnaire scores positively correlated with skin hydration, sebum content, a* and EI values, while a positive relationship of LAST scores with TEWL, a* and EI values was observed. The scores of questionnaire and LAST both negatively related to L* value. Conclusion: Self-assessed questionnaire is associated with sensitive skin featured by oily and red face without impaired barrier function, whereas LAST is suitable to identify fragile skin barrier and enhanced blood flow on the face. Combination of both methods to diagnose sensitive skin might be more reliable.

9.
Autism Res ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542246

RESUMO

Children and adults with autism spectrum disorder (ASD) often present with atypical gaze patterns to others' faces, a finding substantiated throughout the literature. Yet, a quantification of atypical gaze patterns to different facial regions (e.g., eyes versus mouth) in ASD remains controversial. Also few study has investigated how age and culture impacted the pattern of gaze abnormalities in ASD. This research therefore conducted a meta-analysis of eye-tracking studies to evaluate age and culture effect on atypical gaze patterns of face processing in ASD. A total of 75 articles (91 studies) and 4209 individuals (ASD: 2027; controls: 2182) across all age ranges (i.e., childhood through to adulthood) from both Eastern and Western cultures were included in this meta-analysis. Individuals with ASD yielded shorter fixation durations to the eyes than individuals without ASD. Group differences in the time spent fixating on the eyes were not modulated by age, but affected by culture. Effect size in the eastern culture was larger than that in the western culture. In contrast, group differences on time spent looking at the mouth were not significant, but changed with age and modulated by culture. Relative to the neurotypical controls, Western individuals with ASD spent more time looking at the mouth from school age, whereas Eastern individuals with ASD did not gaze longer on mouth until adulthood. These results add to the body of evidence supporting atypical gaze behaviors to eyes in ASD and provide new insights into a potential mouth compensation strategy that develops with age in ASD. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) often show atypical gaze patterns when looking at others' faces compared to neurotypical individuals. This paper examines the role of age and culture on pattern of gaze abnormalities in individuals with ASD. Results show that reduction of gaze on eyes in ASD is stable across all ages and cultures, while increase of gaze on mouth emerges as individuals with ASD get older. The findings provide a developmental insight to the gaze patterns on the autism spectrum across culture.

10.
J Neuroinflammation ; 18(1): 201, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526069

RESUMO

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. METHODS: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. RESULTS: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. CONCLUSION: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

11.
Andrologia ; : e14226, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34478154

RESUMO

The measurement of protein expression level plays a pivotal role in both biological and medical studies. Housekeeping proteins, generally encoded by housekeeping genes are used as loading control proteins to normalize protein expression. Obviously, proper reference standards are essential for adequate analysis of protein expression. However, our study showed that the widely used normalisation proteins, whose expression levels varied greatly among sperm samples, were unsuitable for data standardisation. To uncover the proteins steadily expressed in sperm, we analysed several published transcriptome data of sperm. Seven proteins whose expression levels were relatively stable (co-efficient variation values less than 0.35) were selected and further evaluated by quantitative real-time polymerase chain reaction, Western Blot (WB) and immunocytochemistry. Our results showed that among the classical housekeeping proteins, only ß-tubulin remained constant in sperm samples from 85 individuals. Compared with other classical housekeeping proteins such as glyceraldehyde 3-phosphate dehydrogenase, actin and histone H3, Cullin-1 (CUL1) and F-box only protein 7 (FBXO7) seemed to be more suitable to be used as internal controls for WB in sperm protein studies. Combined with the locations of these proteins, CUL1 and FBXO7 were suggested to be used as a housekeeping protein for total proteins.

12.
J Biol Chem ; 297(4): 101125, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34461094

RESUMO

Transient receptor potential canonical (TRPC) channels, as important membrane proteins regulating intracellular calcium (Ca2+i) signaling, are involved in a variety of physiological and pathological processes. Activation and regulation of TRPC are more dependent on membrane or intracellular signals. However, how extracellular signals regulate TRPC6 function remains to be further investigated. Here, we suggest that two distinct small molecules, M085 and GSK1702934A, directly activate TRPC6, both through a mechanism of stimulation of extracellular sites formed by the pore helix (PH) and transmembrane (TM) helix S6. In silico docking scanning of TRPC6 identified three extracellular sites that can bind small molecules, of which only mutations on residues of PH and S6 helix significantly reduced the apparent affinity of M085 and GSK1702934A and attenuated the maximal response of TRPC6 to these two chemicals by altering channel gating of TRPC6. Combing metadynamics, molecular dynamics simulations, and mutagenesis, we revealed that W679, E671, E672, and K675 in the PH and N701 and Y704 in the S6 helix constitute an orthosteric site for the recognition of these two agonists. The importance of this site was further confirmed by covalent modification of amino acid residing at the interface of the PH and S6 helix. Given that three structurally distinct agonists M085, GSK1702934A, and AM-0883, act at this site, as well as the occupancy of lipid molecules at this position found in other TRP subfamilies, it is suggested that the cavity formed by the PH and S6 has an important role in the regulation of TRP channel function by extracellular signals.

13.
J Neuropathol Exp Neurol ; 80(9): 844-855, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34343334

RESUMO

Gastrointestinal dysfunction is the main nonmotor characteristic of Parkinson disease (PD), manipulation of gastrointestinal function by altering gut-brain axis is a potentially novel entry point for the treatment of PD. Acupuncture has been reported to confer beneficial effects in the gastrointestinal diseases. Therefore, this study aimed to explore the effects and mechanism of acupuncture on the pathophysiology and gastrointestinal function of PD. A PD mouse model was established by rotenone, and electroacupuncture was used to regulate the gastrointestinal function. Rotenone was found to induce the types of brain pathologies and gastrointestinal dysfunction that are similar to those observed with PD. Electroacupuncture significantly increased the spontaneous activity of mice with PD and increased the expression of tyrosine hydroxylase, while reducing the expression of Iba-1 in substantia nigra (SN), suggesting that motor dysfunction and neurological damage was alleviated. In addition, electroacupuncture significantly reduced the deposition of α-synuclein in both colon and SN, reduced intestinal inflammation, and exerted protective effects on enteric nervous system and intestinal barrier. In conclusion, electroacupuncture confers beneficial effects on the gastrointestinal system of mice with PD and can alleviate neuroinflammation and neuropathic injury by inhibiting intestinal inflammation, promoting intestinal barrier repair and reducing α-synuclein deposition in the colon.

14.
ACS Appl Mater Interfaces ; 13(33): 40070-40078, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34387999

RESUMO

Aminothiols are closely related to chronic kidney disease, but little is known regarding levels of related aminothiols in the urine of immunoglobulin A vasculitis with nephritis (IgAVN) patients. Herein, a well-defined core-shell Zr-based metal-organic framework (Zr-MOF) composite SiO2@50Benz-Cys was constructed as a mercury ion affinity material via a solvent-assisted ligand exchange strategy for the selective extraction and enrichment of low-concentration aminothiols in IgAVN patient urine. SiO2@50Benz-Cys was competent to enrich the total glutathione (GSH) and total homocysteine (Hcy) in virtue of the excellent affinity after chelation with mercury ions. The extraction efficiencies were closely related to the pH, dithiothreitol amount, and the dose of functional Zr-MOF. Coupled with HPLC-MS/MS in optimized conditions, GSH and Hcy were determined with low detection limits of 0.5 and 1 nmol L-1, respectively. The recoveries of GSH and Hcy for the urine sample at three spiked levels were in the range of 85.3-105% and 79.5-103%, which showed good precision and accuracy. Benefiting from the matrix interference elimination in the process of extraction, the simultaneous detection of aminothiols in the urine of the healthy group and immunoglobulin A vasculitis (IgAV) and IgAVN patients was successfully carried out, suggesting that the Zr-MOF and the robust method together provided a potential application in the analysis of urinary biomolecules. The analysis of variance (ANOVA) showed that the levels of GSH and Hcy had significant differences between the patients and the control. This work is very valuable as it provides a better understanding of concentration alterations of GSH and Hcy in urine involved with IgAVN for clinical research.


Assuntos
Glutationa/urina , Homocisteína/urina , Estruturas Metalorgânicas/química , Nefrite/diagnóstico , Zircônio/química , Técnicas Biossensoriais , Cromatografia Líquida de Alta Pressão , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Dióxido de Silício , Coloração e Rotulagem/métodos , Compostos de Sulfidrila/química , Espectrometria de Massas em Tandem
15.
Signal Transduct Target Ther ; 6(1): 317, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446699

RESUMO

Owing to the limitations of the present efforts on drug discovery against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the lack of the understanding of the biological regulation mechanisms underlying COVID-19, alternative or novel therapeutic targets for COVID-19 treatment are still urgently required. SARS-CoV-2 infection and immunity dysfunction are the two main courses driving the pathogenesis of COVID-19. Both the virus and host factors are potential targets for antiviral therapy. Hence, in this study, the current therapeutic strategies of COVID-19 have been classified into "target virus" and "target host" categories. Repurposing drugs, emerging approaches, and promising potential targets are the implementations of the above two strategies. First, a comprehensive review of the highly acclaimed old drugs was performed according to evidence-based medicine to provide recommendations for clinicians. Additionally, their unavailability in the fight against COVID-19 was analyzed. Next, a profound analysis of the emerging approaches was conducted, particularly all licensed vaccines and monoclonal antibodies (mAbs) enrolled in clinical trials against primary SARS-CoV-2 and mutant strains. Furthermore, the pros and cons of the present licensed vaccines were compared from different perspectives. Finally, the most promising potential targets were reviewed, and the update of the progress of treatments has been summarized based on these reviews.


Assuntos
COVID-19/imunologia , COVID-19/terapia , Interações Hospedeiro-Patógeno/imunologia , SARS-CoV-2/fisiologia , COVID-19/epidemiologia , Ensaios Clínicos como Assunto , Humanos
16.
J Am Chem Soc ; 143(34): 13731-13737, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34410122

RESUMO

The controlling synthesis of novel nanoclusters of noble metals (Au, Ag) and the determination of their atomically precise structures provide opportunities for investigating their specific properties and applications. Here we report a novel silver nanocluster [Ag307Cl62(SPhtBu)110] (Ag307) whose structure is determined by X-ray single crystal diffraction. The structure analysis shows that nanocluster Ag307 contains a Ag167 core, a surface shell of [Ag140Cl2S110], and a Cl60 intermediate layer located between Ag167 and [Ag140Cl2S110]. It is a first example that such many chlorides are intercalated into a Ag nanocluster. Chlorides are released in situ from solvent CHCl3. Nanocluster Ag307 exhibits superstability. Differential pulse voltammetry experiment reveals that Ag307 has continuous charging/discharging behavior with a capacitance value of 1.39 aF, while the Ag307 has a surface plasmonic feature. These characteristics show that Ag307 is of metallic behavior. However, its electron paramagnetic resonance (EPR) spectra display a spin magnetic behavior which could be originated from the unpassivated dangling bonds of surface atoms. The direct capture of EPR signals can be attributed to the Cl- intercalating layer which partly suppresses the electronic interactions between core and surface atoms, resulting in the relatively independent electronic states for core and surface atoms.

17.
Toxicol Appl Pharmacol ; 426: 115640, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34242566

RESUMO

Benzo[a]pyrene (BaP) is a strong carcinogen for lung cancer, and forkhead-box A1 (FOXA1) plays an oncogenic role in BaP-transformed cell THBEc1. To explore the remodeling of metabolic pattern caused by BaP-induced transformation and the possible role FOXA1 might play in it, we compared metabolic patterns between THBEc1 cells and control using untargeted metabolomics and lipidomics analysis, and determined the effects of FOXA1 knockout on the metabolic pattern of THBEc1 cells. Metabolomics and lipidomics identified a total of 15 and 46 differential metabolites and lipids between THBEc1 and 16HBE cells, respectively, and a total of 4 and 1 differential metabolites and lipids between FOXA1 knockout cell THBEc1-ΔFOXA1-c34 and control cell THBEc1-ctrl, respectively. Analysis results of metabolites and metabolic pathways indicated the metabolic pattern remodeling may be related to the alteration in glucose metabolism during BaP-induced transformation. Western blotting revealed the up-regulation of enolase-2 (ENO2), pyruvate carboxylase (PCB), aconitase-2 (ACO2) and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) (Thr202/Tyr204), the down-regulation of succinate dehydrogenase complex subunit A (SDHA) and phosphoenolpyruvate carboxykinase 2 (PCK2) in THBEc1 cells. The detection results of metabolites related to glucose metabolism demonstrated the decreasing of lactic acid content in cells, lactic acid production in culture medium and citric acid content in mitochondria, and the increasing of ATP production of THBEc1 cells. FOXA1 knockout partially reversed the changes of ENO2, SDHA, PCK2 and p-ERK1/2 (Thr202/Tyr204) levels, lactic acid release, citric acid content in mitochondria of THBEc1 cells. In conclusion, FOXA1 knockout partially reversed the remodeling of glucose metabolism caused by BaP-induced malignant transformation. Our findings provide a clue for the possible role of FOXA1 in glucose metabolism regulation.


Assuntos
Benzo(a)pireno/toxicidade , Carcinógenos/toxicidade , Transformação Celular Neoplásica/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Metaboloma/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Linhagem Celular , Ácido Cítrico/metabolismo , Glucose/metabolismo , Humanos , Ácido Láctico/metabolismo , Metabolômica
18.
Front Pharmacol ; 12: 670081, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305590

RESUMO

Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME-N-terminal fragment cleavage and pyroptosis were reduced by caspase-3-specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.

19.
Front Neurol ; 12: 670784, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290662

RESUMO

Objectives: The present study aimed to compare the clinicopathological features of patients with seronegative immune-mediated necrotizing myopathy (IMNM) and those positive for anti-signal recognition particle (SRP) or anti-3-hydroxy-3-methylglutarylcoenzyme-a reductase (HMGCR) antibodies. Methods: We retrospectively analyzed the data of patients with IMNM treated in the Neurology Department of Tongji Hospital from January 1, 2013, to December 31, 2019. Results: Among the 117 patients with IMNM, 30.8% (36/117) were positive for anti-SRP antibodies, 6.0% (7/117) were positive for anti-HMGCR antibodies, and 13.7% (16/117) were seronegative. Myalgia at presentation (62.5 vs. 23.3%, p = 0.0114) was more commonly observed in patients with seronegative IMNM than in those with seropositive IMNM. Subclinical cardiac involvement was more frequently detected in seronegative IMNM than in seropositive IMNM (6/13 vs. 5/33, p = 0.0509, echocardiogram; 7/7 vs. 12/24, p = 0.0261, cardiac MRI). Deposition of membrane attack complex (MAC) on the sarcolemma of myofibers in biopsied muscle was less commonly observed in patients with seronegative IMNM than in patients with seropositive IMNM (16.7 vs. 68.2%, p = 0.0104). The rate of marked improvement following immunotherapy tended to be higher in patients with seronegative IMNM than in those with seropositive IMNM (87.5 vs. 61%, p = 0.0641). Conclusions: Patients with seronegative IMNM more frequently present with myalgia at onset, exhibit more subclinical cardiac involvement and uncommon MAC deposition on myofibers, and experience better outcomes than those with seropositive IMNM.

20.
Acta Neurol Scand ; 144(5): 535-545, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34131900

RESUMO

OBJECTIVE: To estimate the direct economic burden of tuberculous meningitis (TBM) in China for the first time. METHODS: Patients who were first diagnosed with TBM from December 2015 to December 2018 in Western China Hospital were enrolled. We retrospectively collected data on demographic and clinical features, resource utilization, costs, and long-term outcomes. The patients were followed up for 15-53 months. We performed a cost-of-illness study and analyzed the cost contributors with a generalized linear model. RESULTS: In total, the cases of 154 TBM patients (95 males, 59 females, aged 14-82 years) were reviewed. The average total direct cost per person was USD (United States dollars) 9,484 (range 1,822-67,285), with a mean direct medical cost of USD 8,901 (range 1,189-67,049). The average inpatient cost and drug cost after discharge were USD 6,837 (range 845-52,921) and USD 1,967 (range 0-60,423), respectively. The mean direct nonmedical cost was USD 583 (range 33-3,817), which accounted for 6.2% of the total direct cost. The average length of stay (LOS) in hospital was 25.0 days (range 6-152). A total of 117 of the patients (76.0%) had good outcomes (mRS = 0-2). There was no significant difference in the costs, LOS, or outcomes between rural and urban patients. Contributors to total direct cost were definite TBM, fever, coma, seizures, multidrug resistance, hydrocephalus, and poor long-term outcome. CONCLUSIONS: Although the accessibility of medical resources in remote and rural regions has significantly improved in China, the cost of TBM imposes a catastrophic burden on patients.

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