Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 251
Filtrar
1.
Cell Rep ; 37(6): 109920, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34731648

RESUMO

It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (HIF1α), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.


Assuntos
COVID-19/metabolismo , Glicólise/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pulmão/metabolismo , Organoides/metabolismo , Animais , Linhagem Celular , Chlorocebus aethiops , Células Epiteliais/metabolismo , Células HEK293 , Humanos , Células-Tronco Pluripotentes/metabolismo , SARS-CoV-2/patogenicidade , Transcriptoma/fisiologia , Células Vero
2.
Chemosphere ; : 132844, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34767854

RESUMO

2- Line ferrihydrite (Fh) is widely used as a robust amendment for rapid arsenic removal or remediation in water or soil. However, the poorly crystalline phase of Fh is unstable and leads to arsenic leaching after long-term submergence in reductive aquatic and soil environments. In this study, the synthesized As(V)-bound Fh was characterized by various spectral approaches to investigate the factors that may affect the variation in As(V)-Fh in long-term continuously submerged soil suspensions. The X-ray diffraction (XRD) results showed that hematite was the main product and that goethite was the byproduct after 360 d of incubation. Approximately 12-17% and 4-5% Fh were transformed at As/Fe mole ratios of 0.005 and 0.05, respectively. After 360 d of incubation, the hematite morphology was clearly observed by scanning electron microscopy (SEM), and the As(V)-Fh surface areas were also decreased by 17.3-27.6% and 11.9-16.6% for As/Fe mole ratios of 0.005 and 0.05, respectively. In a comparison of the two tested soils (soils sampled in Sichuan Province (SC) and Hunan Province (HN)), As(V)-Fh transformed faster in HN soil suspensions, and more hematite and goethite were formed. Furthermore, during the incubation period, As(V) was transformed to As(III), and both species were released into the suspension from the As(V)-Fh surface. It was suggested that soil pH and Fe(II) concentration were key factors controlling the As(V)-Fh transformation process, and the differences between the two soils were due to the different soil pH values and contents of available Fe. Arsenic release was mainly caused by Fh transformation and ligand competition with soil organic matter (SOM).

3.
Artigo em Inglês | MEDLINE | ID: mdl-34776378

RESUMO

T4 polynucleotide kinase phosphatase (T4 PNKP) plays a critical role in various cellular events, such as DNA damage repair, replication, and recombination. Here, we have described a novel biosensor to detect the activity of T4 PNKP based on polydopamine nanotubes (PDANTs) mediated fluorescence resonance energy transfer (FRET). A FAM-labelled (6-carboxyl-fluorescein) hairpin DNA probe with 3'-phosphoryl terminal was designed as the substrate for T4 PNKP. With the addition of PDANTs, the fluorescence of FAM-labelled hairpin DNA probe could be quenched because of the high adsorption of hairpin DNA on PDANTs. When T4 PNKP dephosphorylated the DNA probe, a double-stranded DNA (dsDNA) product was obtained by Klenow fragment polymerase (KF polymerase) on its 3'-hydroxyl terminal, which could retain most of the fluorescence due to the week adsorption of dsDNA on PDANTs. The developed method demonstrates the sensitivity for T4 PNKP assay in the range from 0.05 to 1.5 U mL-1 with the detection limit of 0.005 U mL-1, which endows the proposed strategy with high enough sensitivity for practical detection in cell lysates. With the advantages mentioned above, this novel sensitive strategy has the potential in the study of DNA damage repair mechanisms.

4.
Chem Commun (Camb) ; 57(96): 12996-12999, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34796885

RESUMO

Constructing different protein nanostructures by using identical building blocks, while realizing their structural transformation in response to external stimuli, remains a challenge. Here, we fabricated protein nanocages and nanorods by using dimeric TmFtn as a building block and reacting with Mg2+/(α, L-lysine) with polymerization degrees of 9 (PLL9) and 15 (PLL15), respectively. Notably, the reversible shape transformation of these two supramolecular protein architectures with different dimensions can be achievable in response to external stimuli.

5.
Front Neurosci ; 15: 724391, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34690672

RESUMO

Preterm is a worldwide problem that affects infants' lives significantly. Moreover, the early impairment is more than limited to isolated brain regions but also to global and profound negative outcomes later, such as cognitive disorder. Therefore, seeking the differences of brain connectome between preterm and term infant brains is a vital step for understanding the developmental impairment caused by preterm. Existing studies revealed that studying the relationship between brain function and structure, and further investigating their differentiable connectomes between preterm and term infant brains is a way to comprehend and unveil the differences that occur in the preterm infant brains. Therefore, in this article, we proposed a novel canonical correlation analysis (CCA) with locality preserving projection (LPP) approach to investigate the relationship between brain functional and structural connectomes and how such a relationship differs between preterm and term infant brains. CCA is proposed to study the relationship between functional and structural connections, while LPP is adopted to identify the distinguishing features from the connections which can differentiate the preterm and term brains. After investigating the whole brain connections on a fine-scale connectome approach, we successfully identified 89 functional and 97 structural connections, which mostly contributed to differentiate preterm and term infant brains from the functional MRI (fMRI) and diffusion MRI (dMRI) of the public developing Human Connectome Project (dHCP) dataset. By further exploring those identified connections, the results innovatively revealed that the identified functional connections are short-range and within the functional network. On the contrary, the identified structural connections are usually remote connections across different functional networks. In addition, these connectome-level results show the new insights that longitudinal functional changes could deviate from longitudinal structural changes in the preterm infant brains, which help us better understand the brain-behavior changes in preterm infant brains.

7.
J Biol Chem ; 297(6): 101331, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34688661

RESUMO

Nonalcohol-associated fatty liver disease (NAFLD) is characterized by excessive hepatic accumulation of fat that can progress to steatohepatitis, and currently, therapeutic options are limited. Using a high-fat diet (HFD) mouse model of NAFLD, we determined the effects of the synthetic retinoid, AC261066, a selective retinoic acid receptor ß2 (RARß2) agonist, on the global liver transcriptomes and metabolomes of mice with dietary-induced obesity (DIO) using genome-wide RNA-seq and untargeted metabolomics. We found that AC261066 limits mRNA increases in several presumptive NAFLD driver genes, including Pklr, Fasn, Thrsp, and Chchd6. Importantly, AC261066 limits the increases in the transcript and protein levels of KHK, a key enzyme for fructose metabolism, and causes multiple changes in liver metabolites involved in fructose metabolism. In addition, in cultured murine hepatocytes, where exposure to fructose and palmitate results in a profound increase in lipid accumulation, AC261066 limits this lipid accumulation. Importantly, we demonstrate that in a human hepatocyte cell line, RARß is required for the inhibitory effects of AC261066 on palmitate-induced lipid accumulation. Finally, our data indicate that AC261066 inhibits molecular events underpinning fibrosis and exhibits anti-inflammatory effects. In conclusion, changes in the transcriptome and metabolome indicate that AC261066 affects molecular changes underlying multiple aspects of NAFLD, including steatosis and fibrosis. Therefore, we suggest that AC261066 may have potential as an effective therapy for NAFLD.

8.
ACS Appl Mater Interfaces ; 13(39): 46391-46405, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34570465

RESUMO

Proteins are like miracle machines, playing important roles in living organisms. They perform vital biofunctions by further combining together and/or with other biomacromolecules to form assemblies or condensates such as membraneless organelles. Therefore, studying the self-assembly of biomacromolecules is of fundamental importance. In addition to their biological activities, protein assemblies also exhibit extra properties that enable them to achieve applications beyond their original functions. Herein, this study showed that in the presence of monosaccharides, ethylene glycols, and amino acids, ß-lactoglobulin (ß-LG) can form assemblies with specific structures, which were highly reproducible. The mechanism of the assembly process was studied through multi-scale observations and theoretical analysis, and it was found that the assembling all started from the formation of solute-rich liquid droplets via liquid-liquid phase separation (LLPS). These droplets then combined together to form condensates with elaborate structures, and the condensates finally evolved to form assemblies with various morphologies. Such a mechanism of the assembly is valuable for studying the assembly processes that frequently occur in living organisms. Detailed studies concerning the properties and applications of the obtained ß-LG assemblies showed that the assemblies exhibited significantly better performances than the protein itself in terms of autofluorescence, antioxidant activity, and metal ion absorption, which indicates broad applications of these assemblies in bioimaging, biodetection, biodiagnosis, health maintenance, and pollution treatment. This study revealed that biomacromolecules, especially proteins, can be assembled via LLPS, and some unexpected application potentials could be found beyond their original biological functions.

9.
Int J Biol Macromol ; 191: 152-160, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34547309

RESUMO

The favorable physicochemical properties are essential for the application of protein-based nanovehicles in the field of biomaterials. Herein, we found that the thermal stability of Marsupenaeus japonicus ferritin (MjFer) (Tm = 109.1 ± 0.4 °C) is markedly higher than human H-chain ferritin (HuHF) (Tm = 87.7 ± 0.3 °C), although they share a high structural similarity. Multiple results indicated that the promoted thermal stability of MjFer is mainly derived from the salt bridges located at the C3 interface. Consequently, MjFer exhibits strong protective effects on encapsulated curcumin upon exposure at high temperatures. In contrast, most of the curcumin loaded HuHF composites precipitated rapidly under the same conditions. These findings elucidated the molecular mechanism of the hyperthermostability of MjFer and illustrated that MjFer could act as a robust insulation nanocarrier for bioactive compounds against various thermal treatments.

10.
Nat Commun ; 12(1): 4849, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381032

RESUMO

Although various artificial protein nanoarchitectures have been constructed, controlling the transformation between different protein assemblies has largely been unexplored. Here, we describe an approach to realize the self-assembly transformation of dimeric building blocks by adjusting their geometric arrangement. Thermotoga maritima ferritin (TmFtn) naturally occurs as a dimer; twelve of these dimers interact with each other in a head-to-side manner to generate 24-meric hollow protein nanocage in the presence of Ca2+ or PEG. By tuning two contiguous dimeric proteins to interact in a fully or partially side-by-side fashion through protein interface redesign, we can render the self-assembly transformation of such dimeric building blocks from the protein nanocage to filament, nanorod and nanoribbon in response to multiple external stimuli. We show similar dimeric protein building blocks can generate three kinds of protein materials in a manner that highly resembles natural pentamer building blocks from viral capsids that form different protein assemblies.


Assuntos
Nanoestruturas/química , Proteínas/química , Cálcio/química , Ferritinas/química , Nanoestruturas/ultraestrutura , Nanotecnologia , Polietilenoglicóis/química , Multimerização Proteica , Thermotoga maritima
11.
Crit Rev Food Sci Nutr ; : 1-16, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382897

RESUMO

As the second most abundant trace element in the human body, zinc nutrition is constantly a hot topic. More than one-third population is suffering zinc deficiency, which results in various types of diseases or nutritional deficiencies. Traditional ways of zinc supplementation seem with low absorption rates and significant side effects. Zinc supplements with dietary components are easily accessible and improve zinc utilization rate significantly. Also, mechanisms of maintaining zinc homeostasis are of broad interest. The present review focuses on zinc nutrition in human health in inductive methods. Mainly elaborate on different diseases relating to zinc disorder, highlighting the impact on the immune system and the recent COVID-19. Then raise food-derived zinc-binding compounds, including protein, peptide, polysaccharide, and polyphenol, and also analyze their possibilities to serve as zinc complementary. Finally, illustrate the way to maintain zinc homeostasis and the corresponding mechanisms. The review provides data information for maintaining zinc homeostasis with the food-derived matrix.

12.
Stem Cell Reports ; 16(9): 2274-2288, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34403650

RESUMO

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. Here, using an established in vivo hamster model, we demonstrate that SARS-CoV-2 can be detected in cardiomyocytes of infected animals. Furthermore, we found damaged cardiomyocytes in hamsters and COVID-19 autopsy samples. To explore the mechanism, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be productively infected by SARS-CoV-2, leading to secretion of the monocyte chemoattractant cytokine CCL2 and subsequent monocyte recruitment. Increased CCL2 expression and monocyte infiltration was also observed in the hearts of infected hamsters. Although infected CMs suffer damage, we find that the presence of macrophages significantly reduces SARS-CoV-2-infected CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and suggests a mechanism of immune cell infiltration and histopathology in heart tissues of COVID-19 patients.


Assuntos
COVID-19/patologia , Quimiocina CCL2/metabolismo , Traumatismos Cardíacos/virologia , Monócitos/imunologia , Miócitos Cardíacos/metabolismo , Animais , Comunicação Celular/fisiologia , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Modelos Animais de Doenças , Humanos , Macrófagos/imunologia , Masculino , Miócitos Cardíacos/virologia , Células-Tronco Pluripotentes/citologia , Células Vero
13.
EBioMedicine ; 69: 103457, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34224975

RESUMO

BACKGROUND: Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification. METHODS: We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays. FINDINGS: We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts. INTERPRETATION: Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC. FUNDING: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun).


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Dasatinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias Pulmonares/genética , Transcriptoma , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Dasatinibe/administração & dosagem , Sinergismo Farmacológico , Humanos , Isocitrato Desidrogenase/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Variantes Farmacogenômicos , Fatores de Transcrição/genética , Vorinostat/administração & dosagem , Vorinostat/uso terapêutico
14.
Cell Rep ; 36(4): 109421, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34320342

RESUMO

Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.

15.
Environ Res ; 200: 111416, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34090892

RESUMO

It is generally accepted that the sand mining industry causes severe destruction in river basin environments. In this study, six sediment cores were collected, and sequential extraction was applied in conjunction with the diffusive gradients in the thin films (DGT) technique to explore the effect of sand mining on the remobilization of Cu and Zn in the sediments. The results showed that Cu and Zn were mainly bound in the residual fraction in the sediments. CDGT-Cu/Zn in the sediments presented obvious increasing trends at the bottom (-9 to -12 cm) at the four sites that experienced sand mining and a decreasing trend at the sites with no sand mining disturbance. Cu and Zn also tended to be transported from the sediments to the overlying water at the four sand mining sites. A correlation analysis found that F1 and F3 correlated well with CDGT-Cu/Zn, indicating that the water/exchangeable fraction and oxidized fraction were the main fractions that led to increases in DGT-labile Cu and Zn in the sediments. Further analysis found that the introduction of oxygen (O2) was the main reason for the simultaneous release of sulfur (S), Cu and Zn in the sediments, as indicated by the "dark area" of AgI gel appearing at the same position as the "hot spot area" of Chelex gel. Two main sand mining effects on the release of Cu and Zn were hypothesized: (1) intense sand disturbance leads to the transfer of the water/exchangeable fraction (F1) to the DGT-labile fraction and (2) O2 introduction promotes the reaction of stable sulfide (F3), thus transferring it to the DGT-labile fraction. The above results indicated that the sand mining industry should be paid much attention in the Jialing River, as it can obviously cause labile Cu and Zn release into the water.


Assuntos
Metais Pesados , Poluentes Químicos da Água , Cobre/análise , Monitoramento Ambiental , Sedimentos Geológicos , Metais Pesados/análise , Mineração , Rios , Areia , Poluentes Químicos da Água/análise , Zinco/análise
16.
bioRxiv ; 2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34100019

RESUMO

SARS-CoV-2 infection during pregnancy leads to an increased risk of adverse pregnancy outcomes. Although the placenta itself can be a target of virus infection, most neonates are virus free and are born healthy or recover quickly. Here, we investigated the impact of SARS-CoV-2 infection on the placenta from a cohort of women who were infected late during pregnancy and had tested nasal swab positive for SARS-CoV-2 by qRT-PCR at delivery. SARS-CoV-2 genomic and subgenomic RNA was detected in 23 out of 54 placentas. Two placentas with high virus content were obtained from mothers who presented with severe COVID-19 and whose pregnancies resulted in adverse outcomes for the fetuses, including intrauterine fetal demise and a preterm delivered baby still in newborn intensive care. Examination of the placental samples with high virus content showed efficient SARS-CoV-2 infection, using RNA in situ hybridization to detect genomic and replicating viral RNA, and immunohistochemistry to detect SARS-CoV-2 nucleocapsid protein. Infection was restricted to syncytiotrophoblast cells that envelope the fetal chorionic villi and are in direct contact with maternal blood. The infected placentas displayed massive infiltration of maternal immune cells including macrophages into intervillous spaces, potentially contributing to inflammation of the tissue. Ex vivo infection of placental cultures with SARS-CoV-2 or with SARS-CoV-2 spike (S) protein pseudotyped lentivirus targeted mostly syncytiotrophoblast and in rare events endothelial cells. Infection was reduced by using blocking antibodies against ACE2 and against Neuropilin 1, suggesting that SARS-CoV-2 may utilize alternative receptors for entry into placental cells.

17.
J Environ Manage ; 295: 113097, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34186318

RESUMO

Fertilizers are important for agricultural production because they can effectively promote crop productivity. However, long-term fertilization can cause heavy metal accumulation in soils and crops. This study utilized sequential extraction, the diffusive gradient in the thin films (DGT) technique and risk assessment models to estimate the effects of the longest long-term fertilization (38 years) in China on cadmium (Cd) and arsenic (As) accumulation in soils. The treatments included no fertilization (CK); inorganic nitrogen, phosphorus, and potassium fertilization (NPK); manure fertilization (M); and NPK plus M cofertilization (NPKM). The results indicated that the soils treated with NPKM, M and NPK had significantly increased total and available concentrations of Cd and As after 38 years of long-term fertilization. Cd mainly originates from cattle manure, while As originates from phosphate fertilizer. Sequential extraction results indicated that the application of manure increased the acid/exchangeable fraction (F1) and organic matter-bound fraction (F3) of Cd and As. The risk assessment results showed that the environmental risks of both Cd and As increased during long-term fertilization, and Cd contamination in the soil was at a moderate-high level, while As remained at a relatively low level. According to the calculations of the maximum numbers of years of soil productivity and rice production, Cd was labile and accumulated in the soils, and As was more labile than Cd in terms of accumulating in rice, indicating that the true risk from As in rice is higher than that from Cd. Controlling the heavy metals in fertilizers, mitigating effective amendments, and identifying plant types that accumulate low amounts of contaminants may be good choices for cleaner crop production.


Assuntos
Arsênio , Solo , Animais , Cádmio/análise , Bovinos , China , Fertilização , Fertilizantes/análise , Esterco/análise
18.
Cell Metab ; 33(8): 1577-1591.e7, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081913

RESUMO

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.


Assuntos
COVID-19/virologia , Transdiferenciação Celular , Células Secretoras de Insulina/virologia , SARS-CoV-2/patogenicidade , Acetamidas/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , COVID-19/mortalidade , Transdiferenciação Celular/efeitos dos fármacos , Chlorocebus aethiops , Cicloexilaminas/farmacologia , Citocinas/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Glucagon , Interações Hospedeiro-Patógeno , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais , Técnicas de Cultura de Tecidos , Tripsina/metabolismo , Células Vero , Adulto Jovem
19.
Cell Death Dis ; 12(6): 559, 2021 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-34052832

RESUMO

Primordial follicle pool established perinatally is a non-renewable resource which determines the female fecundity in mammals. While the majority of primordial follicles in the primordial follicle pool maintain dormant state, only a few of them are activated into growing follicles in adults in each cycle. Excessive activation of the primordial follicles accelerates follicle pool consumption and leads to premature ovarian failure. Although previous studies including ours have emphasized the importance of keeping the balance between primordial follicle activation and dormancy via molecules within the primordial follicles, such as TGF-ß, E-Cadherin, mTOR, and AKT through different mechanisms, the homeostasis regulatory mechanisms of primordial follicle activation remain unclear. Here, we reported that HDAC6 acts as a key negative regulator of mTOR in dormant primordial follicles. In the cytoplasm of both oocytes and granulosa cells of primordial follicles, HDAC6 expressed strong, however in those activated primordial follicles, its expression level is relatively weaker. Inhibition or knockdown of HDAC6 significantly promoted the activation of limited primordial follicles while the size of follicle pool was not affected profoundly in vitro. Importantly, the expression level of mTOR in the follicle and the activity of PI3K in the oocyte of the follicle were simultaneously up-regulated after inhibiting of HDAC6. The up-regulated mTOR leads to not only the growth and differentiation of primordial follicles granulosa cells (pfGCs) into granulosa cells (GCs), but the increased secretion of KITL in these somatic cells. As a result, inhibition of HDAC6 awaked the dormant primordial follicles of mice in vitro. In conclusion, HDAC6 may play an indispensable role in balancing the maintenance and activation of primordial follicles through mTOR signaling in mice. These findings shed new lights on uncovering the epigenetic factors involved physiology of sustaining female reproduction.


Assuntos
Desacetilase 6 de Histona/metabolismo , Folículo Ovariano/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Proliferação de Células/fisiologia , Feminino , Camundongos , Oócitos/citologia , Oócitos/metabolismo , Folículo Ovariano/citologia , Transdução de Sinais
20.
Transl Lung Cancer Res ; 10(4): 1857-1872, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34012798

RESUMO

Background: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown. Methods: The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment. Results: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation. Conclusions: Ferroptosis-inducing therapy shows promise in EGFR-activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi) Vorinostat can further promote ferroptosis by inhibiting xCT expression.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...