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1.
Open Med (Wars) ; 19(1): 20240918, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38584832

RESUMO

Background: Lipid metabolism disorders lead to lipotoxicity. The hyperlipidemia-induced early stage of renal injury mainly manifests as podocyte damage. CD36 mediates fatty acid uptake and the subsequent accumulation of toxic lipid metabolites, resulting in podocyte lipotoxicity. Methods: Male Sprague-Dawley rats were divided into two groups: the normal control group and the high-fat diet group (HFD). Podocytes were cultured and treated with palmitic acid (PA) and sulfo-N-succinimidyl oleate (SSO). Protein expression was measured by immunofluorescence and western blot analysis. Boron-dipyrromethene staining and Oil Red O staining was used to analyze fatty acid accumulation. Results: Podocyte foot process (FP) effacement and marked proteinuria occurred in the HFD group. CD36 protein expression was upregulated in the HFD group and in PA-treated podocytes. PA-treated podocytes showed increased fatty acid accumulation, reactive oxygen species (ROS) production, and actin cytoskeleton rearrangement. However, pretreatment with the CD36 inhibitor SSO decreased lipid accumulation and ROS production and alleviated actin cytoskeleton rearrangement in podocytes. The antioxidant N-acetylcysteine suppressed PA-induced podocyte FP effacement and ROS generation. Conclusions: CD36 participated in fatty acid-induced FP effacement in podocytes via oxidative stress, and CD36 inhibitors may be helpful for early treatment of kidney injury.

2.
Pestic Biochem Physiol ; 200: 105831, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38582594

RESUMO

Paraquat (PQ) causes fatal poisoning that leads to systemic multiple organ fibrosis, and transforming growth factor (TGF)-ß1 plays a critical role in this process. In this study, we aimed to investigate the effects of AZ12601011 (a small molecular inhibitor of TGFßRI) on PQ-induced multiple organ fibrosis. We established a mouse model of PQ in vivo and used PQ-treated lung epithelial cell (A549) and renal tubular epithelial cells (TECs) in vitro. Haematoxylin-eosin and Masson staining revealed that AZ12601011 ameliorated pulmonary, hepatic, and renal fibrosis, consistent with the decrease in the levels of fibrotic indicators, alpha-smooth muscle actin (α-SMA) and collagen-1, in the lungs and kidneys of PQ-treated mice. In vitro data showed that AZ12601011 suppressed the induction of α-SMA and collagen-1 in PQ-treated A549 cells and TECs. In addition, AZ12601011 inhibited the release of inflammatory factors, interleukin (IL)-1ß, IL-6, and tumour necrosis factor-α. Mechanistically, TGF-ß and TGFßRI levels were significantly upregulated in the lungs and kidneys of PQ-treated mice. Cellular thermal shift assay and western blotting revealed that AZ12601011 directly bound with TGFßRI and blocked the activation of Smad3 downstream. In conclusion, our findings revealed that AZ12601011 attenuated PQ-induced multiple organ fibrosis by blocking the TGF-ß/Smad3 signalling pathway, suggesting its potential for PQ poisoning treatment.


Assuntos
Lesão Pulmonar Aguda , Paraquat , Fibrose Pulmonar , Camundongos , Animais , Paraquat/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Fator de Crescimento Transformador beta/toxicidade , Fator de Crescimento Transformador beta1/toxicidade , Fator de Crescimento Transformador beta1/metabolismo , Colágeno/toxicidade , Colágeno/metabolismo , Fatores de Crescimento Transformadores/toxicidade
3.
Biomol Biomed ; 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38581716

RESUMO

The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

4.
Diab Vasc Dis Res ; 21(2): 14791641241244658, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38597578

RESUMO

BACKGROUND: The intricate interaction between oxidative stress and atherosclerotic cardiovascular disease (ASCVD) is an essential area of research because of the potential role of oxidative homeostasis in regulating ASCVD risk. This study aimed to investigate the relationship between the oxidative balance score (OBS) and the 10-years risk of ASCVD to gain insight into how oxidative balance affects cardiovascular health. METHODS: This cross-sectional study analyzed National Health and Nutrition Examination Survey (NHANES) 2011-2020 data (40-79 age group), exploring OBS's link to 10-years ASCVD risk. OBS categorized dietary and lifestyle factors. Multivariate logistic regression controlled for age, sex, race, and demographics. A restricted cubic spline examined linear relationships; robustness was ensured through subgroup analyses. RESULTS: Analysis of 4955 participants reveals a negative association between OBS and 10-years ASCVD risk. Continuous OBS adjusted OR: 0.97 (95% CI: 0.95∼0.99, p < .001). Quartile analysis shows reduced risk in Q2 0.88 (95% CI: 0.63∼1.22, p = .43), Q3 0.92 (95% CI: 0.66∼1.28, p = .614), and Q4 0.59 (95% CI: 0.42∼0.83, p = .002) compare Q1. Quartile analysis indicated decreasing risk in higher OBS quartiles. Lifestyle OBS and Dietary OBS demonstrated similar trends. Stratified analyses highlight race and hypertension as effect modifiers (p < .05). CONCLUSION: Our study suggests an association between higher OBS and a reduced 10-years ASCVD risk. However, causation should not be inferred, and in the future, more extensive clinical and fundamental research is required to delve deeper into this association.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Inquéritos Nutricionais , Estudos Transversais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Estresse Oxidativo
5.
Cancer Res ; 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38471084

RESUMO

Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastasis. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC.

6.
Huan Jing Ke Xue ; 45(2): 920-928, 2024 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-38471930

RESUMO

Coastal wetlands are important carbon sinks, and they contribute to reducing the effects of global warming. This study used the eddy covariance method to detect the CO2 flux in the restoration wetland of the Liaohe River estuary in 2021 and investigate the characteristics of ecosystem CO2 exchange and its environmental control factors. The aim was to assess the carbon source/sink capacity of salt marshes in the restored area and to provide data support and theoretical basis for evaluating the effectiveness of ecological restoration projects. The study revealed "U" curves in spring and autumn, "V" curves in summer, and horizontal lines in winter for the average daily variation curve of net ecosystem CO2 exchange (NEE) in the restored area. Its carbon sink efficiencies were -40.06, -63.62, 2.33, and 34.43 g·m-2 in the spring, summer, autumn, and winter, respectively. In the restored area, the daily cumulative variation in NEE was "V" shaped, and the monthly cumulative changes in NEE, ecosystem respiration (Reco), and gross primary productivity (GPP) were obviously different. Photosynthetically active radiation (PAR) was an important regulation factor of daytime NEE in the restored area in 2021, and they displayed a rectangular hyperbolic relationship. PAR could explain 53% of the variation in the daytime NEE. Air temperature (Ta) was the main control factor of Reco,night, and there was an exponential relationship between them. When Ta < 5.5 ℃, the temperature sensitivity of ecosystem respiration (Q10) was 2.19, and Ta could explain 42% of the variation in the Reco,night; when Ta ≥ 5.5 ℃, the Q10 was 1.81, and Ta could explain 51% of the variation in the Reco,night. Additionally, there were significant linear negative correlations between NEE and both soil water content (SWC) and vapor pressure deficit (VPD), whereas NEE was not significantly correlated with soil temperature (Ts) or relative humidity (RH). In 2021, the restored wetland in the Liaohe River estuary acted as a CO2 sink, and the total net carbon sequestration was -66.89 g·m-2. The restored salt plays a role as an important carbon sink and has long-term carbon sequestration potential.

7.
World J Diabetes ; 15(2): 196-208, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38464376

RESUMO

BACKGROUND: In China, the prevalence of type 2 diabetes mellitus (T2DM) among diabetic patients is estimated to be between 90%-95%. Additionally, China is among the 22 countries burdened by a high number of tuberculosis cases, with approximately 4.5 million individuals affected by active tuberculosis. Notably, T2DM poses a significant risk factor for the development of tuberculosis, as evidenced by the increased incidence of T2DM coexisting with pulmonary tuberculosis (T2DM-PTB), which has risen from 19.3% to 24.1%. It is evident that these two diseases are intricately interconnected and mutually reinforcing in nature. AIM: To elucidate the clinical features of individuals diagnosed with both T2DM and tuberculosis (T2DM-PTB), as well as to investigate the potential risk factors associated with active tuberculosis in patients with T2DM. METHODS: T2DM-PTB patients who visited our hospital between January 2020 and January 2023 were selected as the observation group, Simple DM patients presenting to our hospital in the same period were the control group, Controls and case groups were matched 1:2 according to the principle of the same sex, age difference ( ± 3) years and disease duration difference ( ± 5) years, patients were investigated for general demographic characteristics, diabetes-related characteristics, body immune status, lifestyle and behavioral habits, univariate and multivariate analysis of the data using conditional logistic regression, calculate the odds ratio (OR) values and 95%CI of OR values. RESULTS: A total of 315 study subjects were included in this study, including 105 subjects in the observation group and 210 subjects in the control group. Comparison of the results of both anthropometric and biochemical measures showed that the constitution index, systolic blood pressure, diastolic blood pressure and lymphocyte count were significantly lower in the case group, while fasting blood glucose and high-density lipoprotein cholesterol levels were significantly higher than those in the control group. The results of univariate analysis showed that poor glucose control, hypoproteinemia, lymphopenia, TB contact history, high infection, smoking and alcohol consumption were positively associated with PTB in T2DM patients; married, history of hypertension, treatment of oral hypoglycemic drugs plus insulin, overweight, obesity and regular exercise were negatively associated with PTB in T2DM patients. Results of multivariate stepwise regression analysis found lymphopenia (OR = 17.75, 95%CI: 3.40-92.74), smoking (OR = 12.25, 95%CI: 2.53-59.37), history of TB contact (OR = 6.56, 95%CI: 1.23-35.03) and poor glycemic control (OR = 3.37, 95%CI: 1.11-10.25) was associated with an increased risk of developing PTB in patients with T2DM, While being overweight (OR = 0.23, 95%CI: 0.08-0.72) and obesity (OR = 0.11, 95%CI: 0.02-0.72) was associated with a reduced risk of developing PTB in patients with T2DM. CONCLUSION: T2DM-PTB patients are prone to worse glycemic control, higher infection frequency, and a higher proportion of people smoking, drinking alcohol, and lack of exercise. Lymphopenia, smoking, history of TB exposure, poor glycemic control were independent risk factors for T2DM-PTB, and overweight and obesity were associated with reduced risk of concurrent PTB in patients with T2DM.

9.
MycoKeys ; 103: 1-24, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38495949

RESUMO

Two new termite-pathogenic species, Ophiocordycepsglobiperitheciata and O.longistipes, are described from Yunnan Province, China. Six-locus (ITS, nrSSU, nrLSU, tef-1α, rpb1 and rpb2) phylogenetic analyses in combination with morphological observations were employed to characterize these two species. Phylogenetically, O.globiperitheciata is most closely related to Hirsutellacryptosclerotium and O.communis, whereas O.longistipes shares a sister relationship with O.fusiformis. However, O.globiperitheciata differs from H.cryptosclerotium by parasitizing Blattodea and producing clavate, unbifurcated stromata. Ophiocordycepsglobiperitheciata is distinguished from O.communis by multiple stromata, shorter asci and ascospores. Ophiocordycepslongistipes differs from O.fusiformis in producing larger stromata, perithecia, asci and ascospores, as well as smaller citriform or oval conidia. Morphological descriptions of the two new species and a dichotomous key to the 19 termite-pathogenic Ophiocordyceps species are presented.

10.
Environ Int ; 185: 108579, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38493736

RESUMO

Environmental regulations aim to reduce pollution and improve air quality and the health of residents. However, there is a lack of research focusing on the health and welfare effects of low-carbon city pilot policies. In this context, this study takes China's low-carbon city pilot policy as an entry point, focuses on the health effects of public environmental governance, and systematically investigates the effects and mechanisms of low-carbon city development on the health of middle-aged and elderly people by applying the difference-in-differences method. The study finds that low-carbon city (LCC) policy significantly improves the physical and mental health of middle-aged and elderly people, and the main transmission mechanism is the reduction in air pollution and improvement in social capital. These results hold following a series of robustness tests. Furthermore, low-carbon city construction can reduce hospitalization and outpatient costs for people over 45 years old by up to 3 % and 15.5 %, respectively. The findings of this study provide useful policy insights for ensuring sustainable improvement in environmental quality and public health.


Assuntos
Poluição do Ar , Conservação dos Recursos Naturais , Idoso , Pessoa de Meia-Idade , Humanos , Política Ambiental , China , Carbono , Cidades , Desenvolvimento Econômico
11.
Exp Gerontol ; 188: 112391, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38437929

RESUMO

Diabetic retinopathy (DR) is the most common ocular fundus disease in diabetic patients. Chronic hyperglycemia not only promotes the development of diabetes and its complications, but also aggravates the occurrence of senescence. Previous studies have shown that DR is associated with senescence, but the specific mechanism has not been fully elucidated. Here, we first detected the differentially expressed genes (DEGs) and cellular senescence level of db/db mouse retinas by bulk RNA sequencing. Then, we used single-cell sequencing (scRNA-seq) to identify the main cell types in the retina and analyzed the DEGs in each cluster. We demonstrated that p53 expression was significantly increased in retinal endothelial cell cluster of db/db mice. Inhibition of p53 can reduce the expression of SA-ß-Gal and the senescence-associated secretory phenotype (SASP) in HRMECs. Finally, we found that p53 can promote FoxO3a ubiquitination and degradation by increasing the expression of the ubiquitin-conjugating enzyme UBE2L6. Overall, our results demonstrate that p53 can accelerate the senescence process of endothelial cells and aggravate the development of DR. These data reveal new targets and insights that may be used to treat DR.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Animais , Humanos , Camundongos , Senescência Celular/genética , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Células Endoteliais/metabolismo , Retina/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinação
12.
Plant Commun ; : 100856, 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38431772

RESUMO

Actinidia arguta, the most widely distributed Actinidia species and the second cultivated species in the genus, can be distinguished from the currently cultivated Actinidia chinensis on the basis of its small and smooth fruit, rapid softening, and excellent cold tolerance. Adaptive evolution of tetraploid Actinidia species and the genetic basis of their important agronomic traits are still unclear. Here, we generated a chromosome-scale genome assembly of an autotetraploid male A. arguta accession. The genome assembly was 2.77 Gb in length with a contig N50 of 9.97 Mb and was anchored onto 116 pseudo-chromosomes. Resequencing and clustering of 101 geographically representative accessions showed that they could be divided into two geographic groups, Southern and Northern, which first diverged 12.9 million years ago. A. arguta underwent two prominent expansions and one demographic bottleneck from the mid-Pleistocene climate transition to the late Pleistocene. Population genomics studies using paleoclimate data enabled us to discern the evolution of the species' adaptation to different historical environments. Three genes (AaCEL1, AaPME1, and AaDOF1) related to flesh softening were identified by multi-omics analysis, and their ability to accelerate flesh softening was verified through transient expression assays. A set of genes that characteristically regulate sexual dimorphism located on the sex chromosome (Chr3) or autosomal chromosomes showed biased expression during stamen or carpel development. This chromosome-level assembly of the autotetraploid A. arguta genome and the genes related to important agronomic traits will facilitate future functional genomics research and improvement of A. arguta.

13.
Anal Sci ; 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38483788

RESUMO

In this paper, we optimized a method for fast and accurate determination of five impurity elements (As, Sb, Bi, Se, and Ge) in graphite samples to overcome the shortcomings of existing methods, such as complicated equipment, cumbersome process, multiple-time preparation, separate determination, and large error in results. Graphite samples were digested with HNO3-H2SO4-HClO4-HF in a high-temperature and high-pressure microwave digestion apparatus, and the elements were extracted and determined separately by AFS (atomic fluorescence spectrometry). There is no element loss during the processing and analysis of this method. The spike recoveries (As: 90.30%-102.3%, Sb: 90.73%-110.0%, Bi: 90.00%-99.67%, Se: 93.33%-110.0%, Ge: 92.26%-104.2%) and precision (RSD%; As: 1.34%-8.96%, Sb: 2.67%-7.10%, Bi: 1.83%-4.58%, Se: 0.36%-3.25%, Ge: 4.41%-8.65%) meet the requirements of the corresponding quality specifications. The method has some advantages (such as no elemental loss, fast testing, strong element targeting, and accurate results), and thus can achieve batch determination of graphite samples. The optimized method for graphite sample and final solution preparations can be used for diverse spectrometric technologies, and that for spectrometer conditions have reference value for HG-AFS instruments.

14.
Development ; 151(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38546043

RESUMO

The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.


Assuntos
Pontos de Checagem da Fase M do Ciclo Celular , Meiose , Animais , Feminino , Camundongos , Ciclossomo-Complexo Promotor de Anáfase/genética , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Oócitos/metabolismo , Ubiquitinas/metabolismo
15.
J Opt Soc Am A Opt Image Sci Vis ; 41(3): 476-488, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38437439

RESUMO

Color constancy is a basic step for achieving stable color perception in both biological visual systems and the image signal processing (ISP) pipeline of cameras. So far, there have been numerous computational models of color constancy that focus on scenes under normal light conditions but are less concerned with nighttime scenes. Compared with daytime scenes, nighttime scenes usually suffer from relatively higher-level noise and insufficient lighting, which usually degrade the performance of color constancy methods designed for scenes under normal light. In addition, there is a lack of nighttime color constancy datasets, limiting the development of relevant methods. In this paper, based on the gray-pixel-based color constancy methods, we propose a robust gray pixel (RGP) detection method by carefully designing the computation of illuminant-invariant measures (IIMs) from a given color-biased nighttime image. In addition, to evaluate the proposed method, a new dataset that contains 513 nighttime images and corresponding ground-truth illuminants was collected. We believe this dataset is a useful supplement to the field of color constancy. Finally, experimental results show that the proposed method achieves superior performance to statistics-based methods. In addition, the proposed method was also compared with recent deep-learning methods for nighttime color constancy, and the results show the method's advantages in cross-validation among different datasets.

16.
Opt Lett ; 49(5): 1229-1232, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38426980

RESUMO

High-dimensional quantum systems expand quantum channel capacity and information storage space. By implementing high-dimensional quantum logic gates, the speed of quantum computing can be practically enhanced. We propose a deterministic 4 × 4-dimensional controlled-not (CNOT) gate for a hybrid system without ancillary qudits required, where the spatial and polarization states of a single photon serve as a control qudit of four dimensions, whereas two electron-spin states in nitrogen-vacancy (NV) centers act as a four-dimensional target qudit. As the control qudits are easily operated employing simple optical elements and the target qudits are available for storage, the CNOT gate works in a deterministic way, and it can be flexibly extended to n × n-dimensional (n > 4) quantum gates for other hybrid systems or different photonic degrees of freedoms. The efficiency and fidelity of the CNOT gate are analyzed aligning with current technological capabilities, finding that they have satisfactory performances.

17.
J Virol ; 98(3): e0198223, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38411106

RESUMO

Continuously emerging highly pathogenic coronaviruses remain a major threat to human and animal health. Porcine deltacoronavirus (PDCoV) is a newly emerging enterotropic swine coronavirus that causes large-scale outbreaks of severe diarrhea disease in piglets. Unlike other porcine coronaviruses, PDCoV has a wide range of species tissue tropism, including primary human cells, which poses a significant risk of cross-species transmission. Nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) has a key role in linking host innate immunity to microbes and the regulation of inflammatory pathways. We now report a role for NLRP1 in the control of PDCoV infection. Overexpression of NLRP1 remarkably suppressed PDCoV infection, whereas knockout of NLRP1 led to a significant increase in PDCoV replication. A mechanistic study revealed that NLRP1 suppressed PDCoV replication in cells by upregulating IL-11 expression, which in turn inhibited the phosphorylation of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor U0126 effectively hindered PDCoV replication in pigs. Together, our results demonstrated that NLRP1 exerted an anti-PDCoV effect by IL-11-mediated inhibition of the phosphorylation of the ERK signaling pathway, providing a novel antiviral signal axis of NLRP1-IL-11-ERK. This study expands our understanding of the regulatory network of NLRP1 in the host defense against virus infection and provides a new insight into the treatment of coronaviruses and the development of corresponding drugs.IMPORTANCECoronavirus, which mainly infects gastrointestinal and respiratory epithelial cells in vivo, poses a huge threat to both humans and animals. Although porcine deltacoronavirus (PDCoV) is known to primarily cause fatal diarrhea in piglets, reports detected in plasma samples from Haitian children emphasize the potential risk of animal-to-human spillover. Finding effective therapeutics against coronaviruses is crucial for controlling viral infection. Nucleotide-binding oligomerization-like receptor (NLR) family pyrin domain-containing 1 (NLRP1), a key regulatory factor in the innate immune system, is highly expressed in epithelial cells and associated with the pathogenesis of viruses. We demonstrate here that NLRP1 inhibits the infection of the intestinal coronavirus PDCoV through IL-11-mediated phosphorylation inhibition of the ERK signaling pathway. Furthermore, the ERK phosphorylation inhibitor can control the infection of PDCoV in pigs. Our study emphasizes the importance of NLRP1 as an immune regulatory factor and may open up new avenues for the treatment of coronavirus infection.


Assuntos
Infecções por Coronavirus , Deltacoronavirus , Doenças dos Suínos , Animais , Criança , Humanos , Diarreia , Haiti , Interleucina-11/metabolismo , Proteínas NLR/metabolismo , Nucleotídeos/metabolismo , Fosforilação , Transdução de Sinais , Suínos , Zoonoses/metabolismo
18.
Biomater Sci ; 12(7): 1871-1882, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38411574

RESUMO

Chemodynamic therapy (CDT) is a promising cancer treatment strategy. However, mild acidic pH, insufficient H2O2 content, and overexpressed glutathione (GSH) in the tumor microenvironment (TME) severely impair CDT efficiency. In this study, a novel therapeutic nanosystem (Cu/ZIF-8/Vc-Ca/HA) was constructed for H2O2 self-supply and GSH depletion co-enhanced CDT. Typically, calcium ascorbate (Vc-Ca) loaded on the surface of Cu2+-doped ZIF-8 (Cu/ZIF-8) was designed as an original source for H2O2 generation, and a hyaluronic acid (HA) shell was subsequently coated to act as a tumor-targeted "guide" and protective layer. Along with the HA shell disintegrated in the TME, exposed Cu/ZIF-8/Vc-Ca dissociated in the tumor acidic microenvironment, thus triggering the release of Vc-Ca and Cu2+. Vc-Ca selectively produced H2O2 in tumor cells, which provided abundant H2O2 for boosting Fenton-like reactions. Meanwhile, the released Cu2+ could get converted into Cu+ by consuming excess intracellular GSH, which could reduce the tumor antioxidant capability of the nanosystem. Moreover, byproduct Cu+ reacted with abundant H2O2 by a highly efficient Fenton-like reaction to generate toxic ˙OH. Biological assays indicated that the Cu/ZIF-8/HA@Vc-Ca nanosystem showed significant anticancer activity by enhancing the CDT process. This study may provide a new strategy for improving the effectiveness of CDT.


Assuntos
Ácido Ascórbico , Estruturas Metalorgânicas , Neoplasias , Humanos , Cobre , Peróxido de Hidrogênio , Glutationa , Ácido Hialurônico , Microambiente Tumoral , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico
19.
Plant Physiol ; 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38412470

RESUMO

Poplar (Populus) is a well-established model system for tree genomics and molecular breeding, and hybrid poplar is widely used in forest plantations. However, distinguishing its diploid homologous chromosomes is difficult, complicating advanced functional studies on specific alleles. In this study, we applied a trio-binning design and PacBio High-Fidelity long-read sequencing to obtain haplotype-phased telomere-to-telomere genome assemblies for the two parents of the well-studied F1 hybrid "84K" (Populus alba × P. tremula var. glandulosa). Almost all chromosomes, including the telomeres and centromeres, were completely assembled for each haplotype subgenome apart from two small gaps on one chromosome. By incorporating information from these haplotype assemblies and extensive RNA-seq data, we analyzed gene expression patterns between the two subgenomes and alleles. Transcription bias at the subgenome level was not uncovered, but extensive expression differences were detected between alleles. We developed machine-learning (ML) models to predict allele-specific expression (ASE) with high accuracy and identified underlying genome features most highly influencing ASE. One of our models with 15 predictor variables achieved 77% accuracy on the training set and 74% accuracy on the testing set. ML models identified gene body CHG methylation, sequence divergence, and transposon occupancy both upstream and downstream of alleles as important factors for ASE. Our haplotype-phased genome assemblies and ML strategy highlight an avenue for functional studies in Populus and provide additional tools for studying ASE and heterosis in hybrids.

20.
Pathogens ; 13(2)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38392912

RESUMO

Swine enteric coronaviruses (SECoVs), including porcine deltacoronavirus (PDCoV), transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and swine acute diarrhea syndrome coronavirus (SADS-CoV), have caused high mortality in piglets and, therefore, pose serious threats to the pork industry. Coronaviruses exhibit a trend of interspecies transmission, and understanding the host range of SECoVs is crucial for improving our ability to predict and control future epidemics. Here, the replication of PDCoV, TGEV, and PEDV in cells from different host species was compared by measuring viral genomic RNA transcription and protein synthesis. We demonstrated that PDCoV had a higher efficiency in infecting human lung adenocarcinoma cells (A549), Madin-Darby bovine kidney cells (MDBK), Madin-Darby canine kidney cells (MDCK), and chicken embryonic fibroblast cells (DF-1) than PEDV and TGEV. Moreover, trypsin can enhance the infectivity of PDCoV to MDCK cells that are nonsusceptible to TGEV. Additionally, structural analyses of the receptor ectodomain indicate that PDCoV S1 engages Aminopeptidase N (APN) via domain II, which is highly conserved among animal species of different vertebrates. Our findings provide a basis for understanding the interspecies transmission potential of these three porcine coronaviruses.

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