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1.
Nat Immunol ; 24(1): 69-83, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36522544

RESUMO

The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.


Assuntos
Leucemia , Neoplasias , Humanos , Células-Tronco Hematopoéticas , Leucemia/genética , Fatores de Transcrição/genética , Diferenciação Celular/genética
2.
Nature ; 597(7874): 132-137, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34408321

RESUMO

Protein quality control systems are crucial for cellular function and organismal health. At present, most known protein quality control systems are multicomponent machineries that operate via ATP-regulated interactions with non-native proteins to prevent aggregation and promote folding1, and few systems that can broadly enable protein folding by a different mechanism have been identified. Moreover, proteins that contain the extensively charged poly-Asp/Glu (polyD/E) region are common in eukaryotic proteomes2, but their biochemical activities remain undefined. Here we show that DAXX, a polyD/E protein that has been implicated in diverse cellular processes3-10, possesses several protein-folding activities. DAXX prevents aggregation, solubilizes pre-existing aggregates and unfolds misfolded species of model substrates and neurodegeneration-associated proteins. Notably, DAXX effectively prevents and reverses aggregation of its in vivo-validated client proteins, the tumour suppressor p53 and its principal antagonist MDM2. DAXX can also restore native conformation and function to tumour-associated, aggregation-prone p53 mutants, reducing their oncogenic properties. These DAXX activities are ATP-independent and instead rely on the polyD/E region. Other polyD/E proteins, including ANP32A and SET, can also function as stand-alone, ATP-independent molecular chaperones, disaggregases and unfoldases. Thus, polyD/E proteins probably constitute a multifunctional protein quality control system that operates via a distinctive mechanism.


Assuntos
Proteínas Correpressoras/metabolismo , Chaperonas Moleculares/metabolismo , Dobramento de Proteína , Animais , Linhagem Celular , Células/metabolismo , Evolução Molecular , Humanos , Modelos Moleculares , Mutação , Agregados Proteicos , Agregação Patológica de Proteínas/prevenção & controle , Conformação Proteica , Domínios Proteicos , Desdobramento de Proteína , Deficiências na Proteostase/prevenção & controle , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Nature ; 592(7852): 128-132, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33536623

RESUMO

Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines1. In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum-even at steady state-reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Linfócitos/patologia , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Animais , Diferenciação Celular , Linhagem da Célula , Cromatina/genética , Modelos Animais de Doenças , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-23/imunologia , Análise de Classes Latentes , Linfócitos/classificação , Masculino , Camundongos , Psoríase/genética , RNA Citoplasmático Pequeno/genética , Reprodutibilidade dos Testes , Fatores de Tempo
4.
Small ; : e2406358, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39254280

RESUMO

4D printing (4DP) of high-performance shape memory polymers (SMPs), particularly using digital light processing (DLP), has garnered intense global attention due to its capability for rapid and high-precision fabrication of complex configurations, meeting diverse application requirements. However, the development of high-performance dynamic shape memory polymers (DSMPs) for DLP printing remains a significant challenge due to the inherent incompatibilities between the photopolymerization process and the curing/polymerization of high-strength polymers. Here, a mechanically robust DSMP compatible is developed with DLP printing, which incorporates dynamic covalent bonds of imine linking polyimide rigid segments, exhibiting remarkable mechanical performance (tensile strength ≈41.7 MPa, modulus ≈1.63 GPa) and thermal stability (Tg ∼ 113 °C, Td ∼ 208 °C). More importantly, benefiting from the solid-state plasticity conferred by dynamic covalent bonds, 4D printed structures demonstrate rapid network adaptiveness, enabling effortless realization of reconfiguration, self-healing, and recycling. Meanwhile, the extensive π-π conjugated structures bestow DSMP with an intrinsic photothermal effect, allowing controllable morphing of the 4D configuration through dual-mode triggering. This work not only greatly enriches the application scope of high-performance personalized configurations but also provides a reliable approach to addressing environmental pollution and energy crises.

5.
Ann Rheum Dis ; 83(1): 121-132, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37666645

RESUMO

OBJECTIVES: To provide an overview and in-depth analysis of temporal trends in prevalence of musculoskeletal (MSK) disorders in women of childbearing age (WCBA) at global, regional and national levels over the last 30 years, with a special focus on their associations with age, period and birth cohort. METHODS: Estimates and 95% uncertainty intervals (UIs) for MSK disorders prevalence in WCBA were extracted from the Global Burden of Diseases, Injuries and Risk Factors Study 2019. An age-period-cohort model was adopted to estimate the overall annual percentage change of prevalence (net drift, % per year), annual percentage change of prevalence within each age group (local drift, % per year), fitted longitudinal age-specific rates adjusted for period deviations (age effects) and period/cohort relative risks (period/cohort effects) from 1990 to 2019. RESULTS: In 2019, the global number of MSK disorders prevalence in WCBA was 354.57 million (95% UI: 322.64 to 387.68). Fifty countries had at least one million prevalence, with India, China, the USA, Indonesia and Brazil being the highest accounting for 51.03% of global prevalence. From 1990 to 2019, a global net drift of MSK disorders prevalence in WCBA was -0.06% (95% CI: -0.07% to -0.05%) per year, ranging from -0.09% (95% CI: -0.10% to -0.07%) in low-middle sociodemographic index (SDI) region to 0.10% (95% CI: 0.08% to 0.12%) in high-middle SDI region, with 138 countries presenting increasing trends, 24 presenting decreasing trends and 42 presenting relatively flat trends. As reflected by local drift, higher SDI regions had more age groups showing rising prevalence whereas lower SDI regions had more declining prevalence. Globally, an increasing occurrence of MSK disorders prevalence in WCBA beyond adolescent and towards the adult stage has been prominent. Age effects illustrated similar patterns across different SDI regions, with risk increasing with age. High SDI region showed generally lower period risks over time, whereas others showed more unfavourable period risks. High, high-middle and middle SDI regions presented unfavourable prevalence deteriorations, whereas others presented favourable prevalence improvements in successively birth cohorts. CONCLUSIONS: Although a favourable overall temporal trend (net drift) of MSK disorders prevalence in WCBA was observed over the last 30 years globally, there were 138 countries showing unfavourable rising trends, coupled with deteriorations in period/cohort risks in many countries, collectively raising concerns about timely realisation of the Targets of Sustainable Development Goal. Improvements in the MSK disorders-related prevention, management and treatment programmes in WCBA could decline the relative risk for successively younger birth cohorts and for all age groups over period progressing.


Assuntos
Carga Global da Doença , Doenças Musculoesqueléticas , Adulto , Adolescente , Humanos , Feminino , Prevalência , Fatores de Risco , Estudos de Coortes , Doenças Musculoesqueléticas/epidemiologia , Saúde Global , Anos de Vida Ajustados por Qualidade de Vida , Incidência
6.
Langmuir ; 40(17): 8862-8871, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38634158

RESUMO

High-temperature-resistant and self-lubricating polymer composites with long life and high reliability are increasingly indispensable in the aerospace field. Herein, ZIF-67 grown on the MXene lamella was successfully prepared, and ZIF-67@MXene/PI composites with a regular layered structure were obtained by a hot-pressing three-dimensional network aerogel. It was revealed that incorporating ZIF-67@MXene into PI dramatically reduced the friction and abrasion with elevated temperatures. Largely, aerogel walls always paralleled the sliding direction by compressing, providing a significant antifriction effect. More notably, the presence of a vigorous tribofilm composed of a PI matrix and a diamond-type lattice MOF-modified MXene provided rolling and sliding interface friction under high temperatures, simultaneously. In addition, the uniform tribofilm with a thickness of about 200 nm can effectively avoid the direct contact of the friction pair during the sliding process. Hence, the combination of the constructed multiscale nanocomposites and nanostructured tribofilm with outstanding tribological performance endow the material potentially useful in reducing energy consumption, thus addressing the energy wastage problem caused by friction.

7.
Environ Res ; 257: 119267, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38815718

RESUMO

Natural pyrethrins are widely used in agriculture because of their good insecticidal activity. Meanwhile, natural pyrethrins play an important role in the safety evaluation of pyrethroids as precursors for structural development of pyrethroid insecticides. However, there are fewer studies evaluating the neurological safety of natural pyrethrins on non-target organisms. In this study, we used SH-SY5Y cells and zebrafish embryos to explore the neurotoxicity of natural pyrethrins. Natural pyrethrins were able to induce SH-SY5Y cells damage, as evidenced by decreased viability, cycle block, apoptosis and DNA damage. The apoptotic pathway may be related to the involvement of mitochondria and the results showed that natural pyrethrins induced a rise in Capase-3 viability, Ca2+ overload, a decrease in adenosine triphosphate (ATP) and a collapse of mitochondrial membrane potential in SH-SY5Y cells. Natural pyrethrins may mediate DNA damage in SH-SY5Y cells through oxidative stress. The results showed that natural pyrethrins induced an increase in reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and catalase (CAT) activity, and induced a decrease in glutathione peroxidase (GPx) activity in SH-SY5Y cells. In vivo, natural pyrethrins induced developmental malformations in zebrafish embryos, which were mainly characterized by pericardial edema and yolk sac edema. Meanwhile, the results showed that natural pyrethrins induced damage to the Huc-GFP axis and disturbed lipid metabolism in the head of zebrafish embryos. Further results showed elevated ROS levels and apoptosis in the head of zebrafish embryos, which corroborated with the results of the cell model. Finally, the results of mRNA expression assay of neurodevelopment-related genes indicated that natural pyrethrins exposure interfered with their expression and led to neurodevelopmental damage in zebrafish embryos. Our study may raise concerns about the neurological safety of natural pyrethrins on non-target organisms.


Assuntos
Embrião não Mamífero , Piretrinas , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Piretrinas/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Inseticidas/toxicidade , Dano ao DNA/efeitos dos fármacos , Linhagem Celular Tumoral , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos
8.
Age Ageing ; 53(9)2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39324773

RESUMO

BACKGROUND: To explore temporal trends and determine driving factors of age-related macular degeneration (AMD) burden in older adults aged 60-89 years at global, regional and national levels from 1990 to 2019. METHODS: Prevalence and years lived with disability (YLDs) were extracted. Joinpoint regression analysis was adopted to calculate average annual percentage change and to identify the year with the most significant changes. Global trends were stratified by sex, age and sociodemographic index, and regional and national trends were explored. Decomposition analysis was conducted to determine what extent the forces of population size, age structure and epidemiologic change driving alterations of AMD burden. RESULTS: Globally, prevalence rate slightly increased whereas YLDs rate decreased. The year 2005 marked a turning point where both prevalence and YLDs started to decline. Regionally, Western Sub-Saharan Africa had the highest prevalence and YLDs rates in 2019, with East Asia experiencing the most notable rise in prevalence from 1990 to 2019. Global decomposition revealed that the increased case number was primarily driven by population growth and ageing, and epidemiological change was only detected to lessen but far from offset these impacts. CONCLUSIONS: Although there was only slight increase or even decrease in prevalence and YLDs rates of AMD in older adults, the case number still nearly doubled, which may be primarily attributed to population growth and ageing, coupled with the emerging growing pattern of prevalence rate from 2015, collectively suggesting a huge challenge in control and management of AMD.


Assuntos
Saúde Global , Degeneração Macular , Humanos , Idoso , Degeneração Macular/epidemiologia , Degeneração Macular/diagnóstico , Masculino , Idoso de 80 Anos ou mais , Feminino , Prevalência , Pessoa de Meia-Idade , Saúde Global/estatística & dados numéricos , Fatores Etários , Fatores de Risco , Efeitos Psicossociais da Doença , Fatores de Tempo
9.
Biochem Genet ; 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39432129

RESUMO

Proliferative diabetic retinopathy (PDR), the most common type of diabetic retinopathy, is a main cause of visual and impairment blindness. Abnormal neovascularization, endothelial dysfunction, and vascular inflammation are important mechanisms for the development of PDR. Ets2 regulates angiogenesis-related genes and inflammation, however, the effect of Ets2 in PDR procession has not been clarified. Thus, this study is performed to investigate whether Ets2 exerts key functions in PDR. In this study, 10-week-old mice were used for establishing STZ-induced diabetic mice, and Ets2 expression was analyzed in retina tissues. Besides, newborn mice were applied to construct oxygen-induced retinopathy (OIR) models. The Ets2 expression, oxidative stress, and inflammation were detected in retina tissues. We found that Ets2 was highly expressed in retina tissues both in diabetic mice and OIR mice. Oxidative stress and inflammatory processes are two factors contributing to the pathogenesis of PDR. In retinal tissues of OIR mice, Ets2 knockdown inhibited expression of inflammatory mediators VEGFA, IL-6, and IL-8, and biomarkers of oxidative stress MCP-1, VCAM-1, and iNOS. ROS production was also inhibited by silencing Ets2. Ets2 deficiency inhibited endothelial cell proliferation in the retina. Furthermore, Ets2 knockdown contributed to suppressing the expression of angiogenesis-related genes VEGFA, JUNB, MMP-9, Tie2, Ang-2, and EphB4. Our study highlights that Ets2 accelerates PDR procession by promoting the proliferation of endothelial cells, oxidative stress, and inflammation, which provides a novel target against PDR.

10.
Environ Toxicol ; 39(1): 97-105, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37665110

RESUMO

Emamectin benzoate (EMB) is an insecticide for the control of agricultural lepidoptera pests, and also an anti-parasiticide for the control of exoparasites in aquaculture industry. Increased studies suggest that EMB could cause toxicity to non-targeted organisms, but its immunotoxicity to human remains unclear. In this study, zebrafish were used to investigate the immunotoxic effects induced by environmentally relevant doses of EMB. We observed that EMB exposure led to embryo mortality and delayed hatching, as well as increased malformations. Meanwhile, zebrafish exposed to EMB exhibited a significant decrease in the number of neutrophils and macrophages. In addition, untargeted metabolomics approach was developed to elucidate the mechanism of EMB-induced immunotoxicity. We found that a total of 10 shared biomarkers were identified in response to EMB exposure. Furthermore, pathway analysis identified glycerophospholipid metabolism was the most relevant pathway. Within this pathway, it was observed abnormal increases in glycerol 3-phosphate content, which could be attributed to the increased expression of GK5 and decreased expression of GPAT3. Our study provided novel and robust perspectives, which showed that EMB exposure to zebrafish embryos could cause metabolic disturbances that adversely affected development and immune system.


Assuntos
Inseticidas , Peixe-Zebra , Animais , Humanos , Ivermectina/toxicidade , Inseticidas/toxicidade , Macrófagos
11.
Chem Res Toxicol ; 36(7): 1151-1161, 2023 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-37385980

RESUMO

The health risks associated with glyphosate (GLY) have recently received increasing attention. However, its potential vascular toxic effects in occupationally exposed populations remain unclear. This study assessed the effects of GLY on human aortic vascular smooth muscle cells (HAVSMCs) and the relationship between GLY and atherosclerosis. The results demonstrate that GLY induces a relatively larger and more flattened cell morphology, which is typical of cellular senescence and promotes senescence-associated ß-galactosidase activity, as well as the expression of p53, p21, and p16 proteins in HAVSMCs. Regarding toxic effects, GLY induces the accumulation of reactive oxygen species, DNA damage, and mitochondrial damage in HAVSMCs. Mechanistically, the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 pathway is activated in response to oxidative stress produced by GLY. In an in vivo model, GLY led to dyslipidemia and macrophage recruitment in zebrafish vasculature. In conclusion, our results demonstrate that GLY induces vascular toxicity and may be a potential risk for atherosclerosis. These findings highlight the need for concern about cardiovascular risk in occupational populations chronically exposed to GLY.


Assuntos
Aterosclerose , Músculo Liso Vascular , Animais , Humanos , Músculo Liso Vascular/metabolismo , Peixe-Zebra , Senescência Celular , Aterosclerose/metabolismo , Lipídeos , Glifosato
12.
Environ Res ; 231(Pt 1): 116116, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37182831

RESUMO

Autoimmune eye diseases (AEDs), a collection of autoimmune inflammatory ocular conditions resulting from the dysregulation of immune system at the ocular level, can target both intraocular and periorbital structures leading to severe visual deficit and blindness globally. The roles of air pollution and meteorological factors in the initiation and progression of AEDs have been increasingly attractive, among which the systemic and local mechanisms are both involved in. Exposure to excessive air pollution and extreme meteorological conditions including PM2.5/PM0.1, environmental tobacco smoke, insufficient sunshine, and high temperature, etc., can disturb Th17/Treg balance, regulate macrophage polarization, activate neutrophils, induce systemic inflammation and oxidative stress, decrease retinal blood flow, promote tissue fibrosis, activate sympathetic nervous system, adversely affect nutrients synthetization, as well as induce heat stress, therefore may together deteriorate AEDs. The crosstalk among inflammation, oxidative stress and dysregulated immune system appeared to be prominent. In the present review, we will concern and summarize the potential mechanisms underlying linkages of air pollution and meteorological factors to ocular autoimmune and inflammatory responses. Moreover, we concentrate on the specific roles of air pollutants and meteorological factors in several major AEDs including uveitis, Graves' ophthalmopathy (GO), ocular allergic disease (OAD), glaucoma, diabetic retinopathy (DR), etc.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Doenças Autoimunes , Oftalmopatias , Humanos , Poluição do Ar/efeitos adversos , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Conceitos Meteorológicos , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/epidemiologia , Inflamação/induzido quimicamente , Inflamação/epidemiologia , Material Particulado/toxicidade , China
13.
Ecotoxicol Environ Saf ; 261: 115112, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37290295

RESUMO

Glyphosate (GLY), the preeminent herbicide utilized globally, is known to be exposed to the environment and population on a chronic basis. Exposure to GLY and the consequent health risks are alarming public health problems that are attracting international attention. However, the cardiotoxicity of GLY has been a matter of dispute and uncertainty. Here, AC16 cardiomyocytes and zebrafish were exposed to GLY. This study found that low concentrations of GLY lead to morphological enlargement of AC16 human cardiomyocytes, indicating a senescent state. The increased expression of P16, P21, and P53 following exposure to GLY demonstrated that GLY causes senescence in AC16. Moreover, it was mechanistically confirmed that GLY-induced senescence in AC16 cardiomyocytes was produced by ROS-mediated DNA damage. In terms of in vivo cardiotoxicity, GLY decreased the proliferative capacity of cardiomyocytes in zebrafish through the notch signaling pathway, resulting in a reduction of cardiomyocytes. It was also found that GLY caused zebrafish cardiotoxicity associated with DNA damage and mitochondrial damage. KEGG analysis after RNA-seq shows a significant enrichment of protein processing pathways in the endoplasmic reticulum (ER) after GLY exposure. Importantly, GLY induced ER stress in AC16 cells and zebrafish by activating PERK-eIF2α-ATF4 pathway. Our study has thus provided the first novel insights into the mechanism underlying GLY-induced cardiotoxicity. Furthermore, our findings emphasize the need for increased attention to the potential cardiotoxic effects of GLY.


Assuntos
Cardiotoxicidade , Peixe-Zebra , Animais , Humanos , Cardiotoxicidade/metabolismo , Estresse do Retículo Endoplasmático , Senescência Celular , Proliferação de Células , Apoptose , Glifosato
14.
Environ Toxicol ; 38(5): 1053-1062, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36896474

RESUMO

Emamectin benzoate (EMB) is an insecticide extensively used in agricultural area. Assessing the toxic effects of EMB in mammals or humans and its endogenous metabolites alteration are the appropriate means of evaluating its risks to human health. In the study, THP-1 macrophage, a human immune model, was applied to investigate the immunotoxicity of EMB. A global metabolomics approach was developed to analyze metabolic perturbation on macrophages and discover the potential biomarkers of EMB-induced immunotoxicity. The results indicated that EMB could inhibit immune functions of macrophages. Based on metabolomics analysis, our results illustrated that EMB caused significant alterations in metabolic profiles on macrophages. 22 biomarkers associated with immune response were screened by pattern recognition and multivariate statistical analysis. Furthermore, pathway analysis identified purine metabolism was the most relevant pathway in the metabolic process and the abnormal conversion of AMP to xanthosine regulated by NT5E might be a potential mechanism of immunotoxicity induced by EMB. Our study provides important insights for understanding and underlying mechanism of immunotoxicity exposed to EMB.


Assuntos
Ivermectina , Metabolômica , Animais , Humanos , Ivermectina/toxicidade , Macrófagos , Biomarcadores , Mamíferos
15.
Environ Toxicol ; 38(3): 500-510, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36269090

RESUMO

Emamectin benzoate (EMB) as one of the typical biological pesticides has a wide range of applications in agriculture. However, the immune toxic effects of EMB in human received limited attention. In our study, THP-1 macrophage as an in vitro model was used to evaluate immune functions exposed to EMB. We observed that EMB inhibited phagocytic activity and respiratory burst capacity of macrophages without inducing cellular toxicity, implying the potential immunosuppression. Besides, EMB disturbed the cytokines balance embodied in the increase of TNF-α, IL-1ß, IL-6, CCL27, CXCL8 mRNA expression and the decrease of IL-4, IL-13, IL-10 mRNA expression. EMB could exhibit pro-inflammatory responses in macrophages and promote the conversion of macrophages to M1 phenotype. Moreover, NF-κB pathway involved in regulating immune function from KEGG pathway analysis. EMB exposure could activate the NF-κB pathway in THP-1 macrophages by exploring the critical proteins. This research provided insights on immunotoxicity evaluation and clarified EMB-induced immunotoxicity was related to NF-κB pathway activation.


Assuntos
Macrófagos , NF-kappa B , Humanos , NF-kappa B/metabolismo , Ivermectina/toxicidade , Citocinas/metabolismo , RNA Mensageiro/metabolismo
16.
Molecules ; 28(5)2023 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-36903447

RESUMO

The widespread and excessive use of ivermectin (IVM) will not only cause serious environmental pollution, but will also affect metabolism of humans and other mammals that are exposed. IVM has the characteristics of being widely distributed and slowly metabolized, which will cause potential toxicity to the body. We focused on the metabolic pathway and mechanism of toxicity of IVM on RAW264.7 cells. Colony formation and LDH detection assay showed that IVM significantly inhibited the proliferation of and induced cytotoxicity in RAW264.7 cells. Intracellular biochemical analysis using Western blotting assay showed that LC3-B and Beclin-1 were upregulated and p62 was down-regulated. The combination of confocal fluorescence, calcein-AM/CoCl2, and fluorescence probe results showed that IVM could induce the opening of the mitochondrial membrane permeability transition pore, reduce mitochondrial content, and increase lysosome content. In addition, we focused on induction of IVM in the autophagy signal pathway. The Western blotting results showed that IVM increased expression of p-AMPK and decreased p-mTOR and p-S6K expression in protein levels, indicating that IVM activated the AMPK/mTOR signaling pathway. Therefore, IVM may inhibit cell proliferation by inducing cell cycle arrest and autophagy.


Assuntos
Proteínas Quinases Ativadas por AMP , Ivermectina , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Ivermectina/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Camundongos , Células RAW 264.7
17.
Environ Toxicol ; 37(3): 650-659, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34877763

RESUMO

Difenoconazole (DFC) is a typical triazole fungicide. Because of its effective bactericidal activity, it has been widely used in agricultural products such as fruits and vegetables. This study revealed the cytotoxic effect of fungicide DFC on mouse monocyte macrophage RAW264.7. The results showed that the IC50 value of DFC on RAW264.7 cells was 37.08 µM (24 h). DFC can significantly inhibit the viability of RAW264.7 cells, induce DNA damage and enhance apoptosis. The established cytotoxicity test showed that DFC-induced DNA double strand breaks in RAW264.7 cells. DFC-treated cells showed typical morphological changes of apoptosis, including chromatin condensation and nuclear lysis. In addition, DFC can induce the release of Cyt c, promote the collapse of mitochondrial membrane potential and increase the Bax/Bcl-2 ratio in RAW264.7 cells. Through this research, people further understand the toxicity of DFC and provide a more scientific basis for its safety application and risk management.


Assuntos
Fungicidas Industriais , Animais , Apoptose , Dano ao DNA , Dioxolanos , Fungicidas Industriais/toxicidade , Macrófagos , Camundongos , Triazóis/toxicidade
18.
Int J Mol Sci ; 23(11)2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35682839

RESUMO

Whole-genome amplification is a crucial first step in nearly all single-cell genomic analyses, with the following steps focused on its products. Bias and variance caused by the whole-genome amplification process add numerous challenges to the world of single-cell genomics. Short tandem repeats are sensitive genomic markers used widely in population genetics, forensics, and retrospective lineage tracing. A previous evaluation of common whole-genome amplification targeting ~1000 non-autosomal short tandem repeat loci is extended here to ~12,000 loci across the entire genome via duplex molecular inversion probes. Other than its improved scale and reduced noise, this system detects an abundance of heterogeneous short tandem repeat loci, allowing the allelic balance to be reported. We show here that while the best overall yield is obtained using RepliG-SC, the maximum uniformity between alleles and reproducibility across cells are maximized by Ampli1, rendering it the best candidate for the comparative heterozygous analysis of single-cell genomes.


Assuntos
Genética Populacional , Repetições de Microssatélites , Alelos , Repetições de Microssatélites/genética , Reprodutibilidade dos Testes , Estudos Retrospectivos
19.
Molecules ; 27(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35956994

RESUMO

Actinomycetes play a vital role as one of the most important natural resources for both pharmaceutical and agricultural applications. The actinomycete strain SPRI-371, isolated from soil collected in Jiangsu province, China, was classified as Streptomyces aureus based on its morphological, physiological, biochemical and molecular biological characteristics. Its bacterial activity metabolites were identified as aureonuclemycin (ANM), belonging to adenosine derivatives with the molecular formula C16H19N5O9 for ANM A and C10H13N5O3 for ANM B. Simultaneously, the industrial fermentation process of a mutated S. aureus strain SPRI-371 was optimized in a 20 m3 fermentation tank, featuring a rotation speed of 170 rpm, a pressure of 0.05 MPa, an inoculum age of 36−40 h and a dissolved oxygen level maintained at 1−30% within 40−80 h and at >60% in the later period, resulting in an ANM yield of >3700 mg/L. In the industrial separation of fermentation broth, the sulfuric acid solution was selected to adjust pH and 4# resin was used for adsorption. Then, it was resolved with 20% ethanol solution and concentrated in a vacuum (60−65 °C), with excellent results. Antibacterial experiments showed that ANM was less active or inactive against Xanthomonas oryzae pv. oryzae, Xanthomonas citri subsp. citri and Xanthomonas oryzae pv. oryzicola and most bacteria, yeast and fungi in vitro. However, in vivo experiments showed that ANM exhibited extremely significant protective and therapeutic activity against diseases caused by X. oryzae pv. oryzae and X. oryzae pv. oryzicola in rice and X. citri in oranges and lemons. In field trials, ANM A 150 gai/ha + ANM B 75 gai/ha exhibited excellent therapeutic activity against rice bacterial leaf blight, citrus canker and rice bacterial leaf streak. Furthermore, as the dosage and production cost of ANM are lower than those of commercial drugs, it has good application prospects.


Assuntos
Oryza , Xanthomonas , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Oryza/microbiologia , Doenças das Plantas/microbiologia , Staphylococcus aureus , Streptomyces , Virulência
20.
Korean J Parasitol ; 60(6): 419-421, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36588419

RESUMO

To improve our understanding of the migration of sparganum in humans, we report a case of ocular sparganosis having the migratory episode from the muscle cone to the subconjunctiva. A 34-year-old woman was admitted to the Hospital of Anhui Medical University (Hefei, China), in December 2019. She presented with conjunctival hemorrhage and recurrent pain in the left eye. A foreign body was found in the muscle cone of the eye. Two months later, a ribbon-like white material was found under the conjunctiva on slit-lamp examination. A long and slender, actively moving parasite was extracted by surgery. The extracted worm was approximately 8 cm long and 2 mm wide. The worm was whitish, wrinkled, ribbon shaped, and had a slightly enlarged scolex. The worm sample was morphologically identified as a plerocercoid larva (sparganum) of the Spirometra tapeworm. Her conjunctival blood suffusion and eye pain ceased within 1 week after operation. She has been in good health without any symptoms during the 2-year follow-up. A case of ocular sparganosis, in which larval worm migrated from the muscle cone to the subconjunctiva is reported from China.


Assuntos
Cestoides , Oftalmopatias , Esparganose , Spirometra , Humanos , Animais , Feminino , Adulto , Esparganose/diagnóstico , Esparganose/cirurgia , Esparganose/parasitologia , Plerocercoide , Músculos , China , Larva
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