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1.
Elife ; 102021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33439121

RESUMO

Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4+ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8+ T-cell primary responses remains controversial and its role in memory CD8+ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral systems. Interestingly, TSLP limited the primary CD8+ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8+ T cells generated after influenza infection. However, TSLP inhibited memory CD8+ T-cell responses to secondary viral infection with influenza or acute systemic LCMV infection. These data reveal a previously unappreciated role for TSLP on recall CD8+ T-cell responses in response to viral infection, findings with potential translational implications.

2.
Bioresour Technol ; 319: 124111, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32971335

RESUMO

Thermophilic microorganisms play vital roles in the composting process. To elucidate how raw materials affect thermophilic microbial community composition and their interactions, the succession of thermophilic bacterial and fungal communities were monitored in reed straw co-composting with four common nitrogen-rich substrates. The results of high-throughput sequencing showed that raw materials and composting process significantly changed bacterial and fungal community composition. Firmicutes and Actinobacteria drove the assembly of bacterial communities, while Ascomycetes drove the assembly of fungal communities. Network analysis indicated that during the composting process, the addition of nitrogen-rich sources abundant in easily degradable substances promoted the complexity of thermophilic microbial network. Moreover, microorganisms mainly exhibited synergistic effects, and inter-kingdom competition was more intense than intra-kingdom competition. Notably, rare species play essential roles in maintaining the network construction. Our findings provided novel insights into thermophilic microbial community assembly and their co-occurrence networks during the composting process.


Assuntos
Compostagem , Lignina , Esterco , Nitrogênio , Solo
3.
Oral Dis ; 27(2): 338-347, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32640491

RESUMO

OBJECTIVES: To investigate the effects of environmental tobacco smoke (ETS) on the inflammatory process of periodontitis by evaluating bone loss and the expression of cyclooxygenase-2 (COX-2) and Src homology phosphotyrosine phosphatase 2 (SHP-2). MATERIALS AND METHODS: Eighty 6-month-old male SD rats were randomized into four groups (10 rats/group/per time point): (a) normal group, (b) ETS group, (c) ligature-induced periodontitis group, and (d) ligature-induced periodontitis + ETS group. After treatment with ligature and/or ETS for 8 and 12 weeks, the levels of alveolar bone resorption and the expressions of COX-2 and SHP-2 in periodontal tissue were analyzed using histology and immunohistochemistry. RESULTS: The ligature-induced periodontitis group displayed increased bone resorption and elevated expression of COX-2 and SHP-2 in periodontal tissues compared to the normal and ETS groups at 8 and 12 weeks. Furthermore, bone resorption and COX-2 and SHP-2 levels in the ligature-induced periodontitis + ETS group were significantly increased compared to those in the normal and ligature-induced periodontitis groups at both 8 and 12 weeks. CONCLUSION: Environmental tobacco smoke increased alveolar bone loss in periodontitis with enhanced expression of COX-2 and SHP-2 in periodontal tissues. Further investigation is needed to explore the role of COX-2 and SHP-2 in ETS-associated periodontitis.


Assuntos
Perda do Osso Alveolar , Periodontite , Poluição por Fumaça de Tabaco , Perda do Osso Alveolar/etiologia , Animais , Ciclo-Oxigenase 2 , Masculino , Proteínas Tirosina Fosfatases , Ratos , Ratos Sprague-Dawley , Poluição por Fumaça de Tabaco/efeitos adversos
4.
Zhongguo Yi Liao Qi Xie Za Zhi ; 44(6): 476-480, 2020 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-33314852

RESUMO

Compared with conventional high energy X-ray radiotherapy, proton/carbon ion has obvious advantages because of its Bragg peak dose distribution. However, proton heavy ion facility has complex structure, high energy and various radiation types due to various nuclear reaction processes, the radiation protection safety brought by the operation of facilities has gradually attracted attention. Taking the proton/carbon ion radiotherapy facility of Shanghai Proton and Heavy Ion Center as an example, the author mainly analyzed the operation principle of proton/carbon ion treatment facility, the basis of radiation protection, analysis of key radiation source points, etc., so as to provide theoretical support and experience for radiation protection.

5.
J Infect Chemother ; 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33358402

RESUMO

OBJECTIVES: Candida albicans and Candida auris strains are common causative species of Candidiasis. The limited number of antifungal drugs and the current situation of resistance to existing antifungals force us to search for new antifungal alternatives. METHODS: In this work, primary screening of small molecule libraries (Metabolism Compound Library and Epigenetics Compound Library) consisting of 584 compounds against Candida albicans SC5314 was performed. The dose-response assays, XTT assays, scanning electron microscopy and confocal laser scanning microscopy were used to confirm the antifungal activities of the selected compounds against Candida strains. RESULTS: Through the primary screening, we identified five compounds (U73122, disulfiram, BSK805, BIX01294, and GSKJ4) that inhibited strains growth ≥ 80% for dose-response assays. Disulfiram was identified as the most potent repositionable antifungal drug with 50% growth inhibition detected at a concentration as low as 1 mg/L. The further results showed the antifungal activity of disulfiram against biofilm formation of Candida strains with a 50% minimum inhibitory concentration ranging from 32 to 128 mg/L. Further observations by scanning electron microscopy and confocal laser scanning microscopy confirmed the destruction of biofilm architecture and the change of biofilm morphology after being exposed to disulfiram. CONCLUSION: The study indicated the potential clinical application of disulfiram as a promising antifungal drug against candidiasis.

6.
Phys Chem Chem Phys ; 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33332495

RESUMO

Promotion in power conversion efficiency is an appealing task for quantum dot-sensitized solar cells that have emerged as promising materials for the utilization of clean and sustainable energy. Doping of Mn atoms into quantum dots (QD) has been proven to be one of the effective approaches, although the origin of such a promotion remains controversial. While several procedures are involved in the power conversion process, electron injection from the QD to the semiconductor oxide substrate is focused on in this work using first-principles calculations. Based on the Marcus theory, the electron injection rates are evaluated for the quantum dot-sensitized solar cell models in which the pure and Mn-doped core-shell CdSe clusters are deposited on a semiconductor titanium dioxide substrate. Enhanced rates are obtained for the Mn-doped structure, which is in qualitative agreement with the experiments. A large number of dominant injection channels and strong QD-substrate coupling are responsible for the Mn-induced rate enhancement, which could be achieved by manipulating the band structure mapping between the QD and the semiconductor oxide. By addressing the role of an Mn dopant in the electron injection process, strategies for the promotion of electron injection rates are proposed for the design of quantum dot-sensitized solar cells.

7.
Cell Cycle ; 19(23): 3249-3259, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33164645

RESUMO

Matrine is one of the major alkaloids extracted from Sophora flavescens Ait of the traditional Chinese medicine, was the main chemical ingredient of compounds of Kushen injection. The Matrine is considered as a promising therapeutic agent for curing nonsmall cell lung cancer (NSCLC), used either alone or combined with chemotherapeutic agents. In the present study, we focused on the possible roles of Matrine exerted on the self-renewal ability of stem-like cells of the NSCLC group, as well as the cytotoxicity of chemotherapeutic agents, in vitro and in vivo. Here we reported that Matrine inhibits cancer stem-like cell (CSC) properties through upregulation of Let-7b and suppression of the Wnt pathway. Overexpression of Let-7b suppressed the ability of tumorsphere formation, decreased Wnt pathway activation through inhibiting its transcriptional activity in lung CSCs. Further studies revealed that Let-7b directly targeted CCND1 and decreased its expression, whereas Matrine increased Let-7b levels and followed by inactivation of the CCND1/Wnt signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in lung CSCs. What is more, we found that Matrine increased Let-7b level in an endoribonuclease DICER1-dependent manner. And xenografts in nude mice evidenced that Matrine increased the sensitivity of lung CSCs to 5-FU and inhibited the accumulation of CCND1 in tumor tissues induced by 5-FU. Taken together, these data illustrate the role of Let-7b in regulating lung CSCs traits and DICER1/let-7/CCND1 axis in Matrine or in combination with 5-FU intervention of lung CSCs' expansion, helping to fulfill the anti-cancer action of Matrine.

8.
Photobiomodul Photomed Laser Surg ; 38(11): 694-702, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33103954

RESUMO

Objective: We developed an implantable wireless blue micro light-emitting diode (micro-LED) device and evaluated the utility of continuous antimicrobial blue light (aBL) irradiation emitted from this micro-LED for root canal disinfection. Methods: An implantable wireless blue micro-LED device (peak wavelength: 410 nm, maximum power: 15 mW) was developed to be placed in the root canal. Optical transmission of the device in human dentin tissue was simulated using Monte Carlo ray-tracing method. The bactericidal effect of low-level aBL on planktonic root canal infection-related bacteria [Enterococcus faecalis, methicillin-resistant Streptococcus aureus (MRSA), and Prevotella intermedia] was evaluated by colony counting. The biocompatibility of continuous low-level aBL exposure was evaluated by infrared thermal imaging and cell viability tests. Thirty extracted intact human single-rooted teeth were prepared and the root canals were infected with E. faecalis for 14 days to form biofilm. The infected root canals were randomly divided into three groups (n = 10), and treated with normal saline (group NS), calcium hydroxide (group CH), and micro-LED device (group aBL) for 3 and 7 days. The bactericidal effect of each group was evaluated by confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Results: Monte Carlo simulation showed that blue light irradiation of the micro-LED device decreased exponentially with the light transmission distance through human dentin tissue. Planktonic E. faecalis, MRSA, and P. intermedia were significantly eliminated after irradiation with 432, 36, and 1.35 J/cm2 aBL, respectively (p < 0.05). Infrared thermal imaging and cell viability tests showed that continuous aBL exposure is biocompatible in vitro. CLSM and SEM analyses revealed that the micro-LED device had a greater antimicrobial effect than CH on E. faecalis biofilm in the root canal. Conclusions: The wireless blue micro-LED device is a promising and user-friendly approach for root canal disinfection that will facilitate infection control in the root canal using aBL.

9.
Tree Physiol ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051683

RESUMO

Robinia pseudoacacia is a legume species that is widely used in afforestation which has high N2-fixation capacity and rapid growth rate. Both nitrogen (N) supply and phenology affect plant growth, photosynthesis and leaf senescence. The aim of this study was to determine how N supply affects N2 fixation, leaf photosynthesis and senescence of R. pseudoacacia at different phenological stages. Seedlings of R. pseudoacacia were supplied with different levels of 15N-labeled NH4NO3 solution, with seedlings of Sophora japonica as reference plants to calculate the percentage of N derived from the atmospheric N2 (%Ndfa). Compared with plants supplied with a high N level, those with a low N supply had a higher %Ndfa at an early developmental stage. Nitrogen fixation compensated the effect of a low N supply on plant growth in R. pseudoacacia. A high N supply decreased biomass allocation to lateral roots and nodules, and increased the relative growth rate of plant height as well as specific leaf area. The eighth mature compound leaf of R. pseudoacacia tended to have a higher net photosynthetic rate than the fourth leaf, and the leaves still maintained a moderate photosynthetic rate in early autumn. Plants tended to allocate more biomass to leaves at an early developmental stage and to stems and roots at a later developmental stage (three months old). The N level did not affect leaf photosynthesis at different phenological stages, primarily due to 1) a high %Ndfa under low N supply at early growing stage, and a similar high %Ndfa under all N supplies at a late growing stage, and 2) the delayed greening phenotype of expanding leaves to save nutrients for mature leaves.

10.
J Reprod Immunol ; 142: 103208, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33002799

RESUMO

Immune checkpoint molecules may play a crucial role in safeguarding pregnancy by regulating immune responses at the maternal-fetal interface. In this study, we aim to investigate the expression of PD-1, GITR, HLA-G, and CTLA-4 on T cell subsets in peripheral blood (PB), retroplacental blood (RPB), and cord blood (CB) in normal pregnancy (NP), preeclampsia (PE) and gestational diabetes mellitus (GDM). PB, RPB, and CB were collected immediately after delivery, and the expression of PD-1, GITR, HLA-G, and CTLA-4 on T cell subsets were measured by flow cytometric analysis. The proportions of Tregs in PB, RPB, and CB from NP were significantly higher than those of PE and GDM (P < 0.01, respectively). PD-1+ and GITR+ T cell subsets (CD3+, CD4+, and CD8+ T cells, and Tregs) in PB, as well as PD-1+ T cell subsets in RPB from NP, were significantly higher than those of PE and GDM (P < 0.01, respectively). In NP, PE, and GDM, the proportion of PD-1+ Tregs was significantly decreased in CB as compared to those of PB and RPB (P < 0.05, respectively) and the proportion of GITR+ Tregs was significantly higher in PB as compared to those of CB and RPB (P < 0.01, respectively). The proportion of HLA-G+ Tregs in PB was significantly lower than those of CB and RPB (P < 0.01, respectively). In conclusion, decreased PD-1+ and GITR+ T cell subsets and decreased proportion of Tregs in PB and RPB may play a role in chronic inflammatory immune activation of effector T cells in PE and GDM.

11.
EMBO J ; 39(20): e105938, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32914439

RESUMO

COVID-19, caused by SARS-CoV-2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral life cycle. Here, we solved the crystal structures of the N- and C-terminal domains (N-NTD and N-CTD) of SARS-CoV-2 N protein, at 1.8 and 1.5 Å resolution, respectively. Both structures show conserved features from other CoV N proteins. The binding sites targeted by small molecules against HCoV-OC43 and MERS-CoV, which inhibit viral infection by blocking the RNA-binding activity or normal oligomerization of N protein, are relatively conserved in our structure, indicating N protein is a promising drug target. In addition, certain areas of N-NTD and N-CTD display distinct charge distribution patterns in SARS-CoV-2, which may alter the RNA-binding modes. The specific antigenic characteristics are critical for developing specific immune-based rapid diagnostic tests. Our structural information can aid in the discovery and development of antiviral inhibitors against SARS-CoV-2 in the future.


Assuntos
Antivirais/farmacologia , Betacoronavirus/química , Desenho de Fármacos , Proteínas do Nucleocapsídeo/química , Betacoronavirus/efeitos dos fármacos , Cristalografia por Raios X , Sistemas de Liberação de Medicamentos , Humanos , Modelos Moleculares , Proteínas do Nucleocapsídeo/efeitos dos fármacos , Fosfoproteínas , Conformação Proteica , Domínios Proteicos , Proteínas Recombinantes/química
12.
ISA Trans ; 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32829888

RESUMO

Choke finger system represents a vital piece of component within a wind tunnel system. Real time grasping the dynamic characteristics of the choke finger system accurately plays an important role in improving the controller design of a wind tunnel system. This research focuses on recursive identifying the choke finger system of the wind tunnel in China Aerodynamics Research and Development Center. According to the analysis results of experiment data, the choke finger system is expressed by a block-oriented model. Based on the model structure, a recursive algorithm is proposed to on-line estimate the unknown model parameters. The algorithm is modified according to the convergence analysis, which enlarges the convergence domain. Applying the proposed algorithm to the wind tunnel test, reasonable parameter estimates and accurate system output estimates are obtained from identification results.

13.
Nucleic Acids Res ; 48(17): 9571-9588, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32813023

RESUMO

Iron is essential for all bacteria. In most bacteria, intracellular iron homeostasis is tightly regulated by the ferric uptake regulator Fur. However, how Fur activates the iron-uptake system during iron deficiency is not fully elucidated. In this study, we found that YdiV, the flagella gene inhibitor, is involved in iron homeostasis in Escherichia coli. Iron deficiency triggers overexpression of YdiV. High levels of YdiV then transforms Fur into a novel form which does not bind DNA in a peptidyl-prolyl cis-trans isomerase SlyD dependent manner. Thus, the cooperation of YdiV, SlyD and Fur activates the gene expression of iron-uptake systems under conditions of iron deficiency. Bacterial invasion assays also demonstrated that both ydiV and slyD are necessary for the survival and growth of uropathogenic E. coli in bladder epithelial cells. This reveals a mechanism where YdiV not only represses flagella expression to make E. coli invisible to the host immune system, but it also promotes iron acquisition to help E. coli overcome host nutritional immunity.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Escherichia coli/metabolismo , Ferro/metabolismo , Peptidilprolil Isomerase/metabolismo , Proteínas Repressoras/metabolismo , Escherichia coli Uropatogênica/patogenicidade , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Linhagem Celular , DNA Bacteriano/metabolismo , Células Epiteliais/microbiologia , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Homeostase , Humanos , Peptidilprolil Isomerase/genética , Conformação Proteica , Proteínas Repressoras/química , Proteínas Repressoras/genética , Bexiga Urinária/microbiologia , Escherichia coli Uropatogênica/genética , Escherichia coli Uropatogênica/crescimento & desenvolvimento , Escherichia coli Uropatogênica/metabolismo
14.
Waste Manag Res ; : 734242X20939619, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32662340

RESUMO

The poorly controlled discharge of coffee husks in Ethiopia causes severe environmental pollution and is a waste of resources. The volatile solid and carbon content in coffee husks waste indicates that it is rich in organic matter and has huge potential to produce biogas. This study investigated the feasibility of coffee husks to produce biomass through anaerobic digestion, based on temperature, initial pH, inoculum/substrate (I/S) ratio and carbon/nitrogen (C/N) ratio. The study demonstrated that the maximum production of biogas and methane reached 3359.6 ml and 2127.30 ml, respectively, under the conditions of mesophilic temperature (35±1°C), an initial pH of 7, an I/S ratio of 0.75 and a C/N ratio of 30. Based on this result, the effects of trace elements (Fe2+, Ni2+, Co2+) on biogas production and methane content were also explored. Compared with the group with no addition of trace elements, the experiment adding trace elements had significant enhancement effects on the production of biogas and methane, in which Fe2+ played a leading role (p<0.05). Fe2+ promoted the hydrolysis and acidification of coffee husks, resulting in the production of a series of intermediates such as volatile fatty acids and the other kinds of dissolved organic matter. Furthermore, the cooperation of Ni2+, Co2+ and Fe2+ enhanced the activity of the enzyme system in methanogens, promoting methane production. The results in this paper show that coffee husks have clear biogas potential through anaerobic digestion, and its effective utilization could fulfill the dual purpose of solid waste reclamation and local environmental protection in Ethiopia.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32485615

RESUMO

COMBINING HYDRAULIC: and carbon-related measurements can help elucidate drought-induced plant mortality. To study drought mortality mechanisms, seedlings of two woody species, including the anisohydric Robinia pseudoacacia and isohydric Quercus acutissima, were cultivated in a greenhouse and subjected to intense drought by withholding water and mild drought by adding half of the amount of daily water lost. Patterns of leaf and root gas exchange, leaf surface areas, growth, leaf and stem hydraulics, and carbohydrate dynamics were determined in drought-stressed and control seedlings. We detected a complete loss of hydraulic conductivity and partial depletion of total nonstructural carbohydrates contents (TNC) in the dead seedlings. We also found that intense drought triggered a more rapid decrease in plant water potential and a faster drop in net photosynthesis below zero, and a greater TNC loss in dead seedlings than mild drought. Additionally, anisohydric R. pseudoacacia suffered a rapider death than the isohydric Q. acutissima. Based on these findings, we propose that hydraulic conductivity loss and carbon limitation jointly contributed to drought-induced death, while the relative contributions could be altered by drought intensity. We thus believe that it is important to illustrate the mechanistic relationships between stress intensity and carbon-hydraulics coupling in the context of isohydric vs. anisohydric hydraulic strategies.


Assuntos
Carboidratos/análise , Secas , Quercus/fisiologia , Plântula/fisiologia , Água/fisiologia , Folhas de Planta
16.
Materials (Basel) ; 13(10)2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32443707

RESUMO

Influences and mechanisms of chemically synthesized nano-C-S-H gel addition on fresh properties of the cement-based materials with sucrose as a retarder were investigated in this study. The results showed that the flow value of the fresh cement paste was gradually but slightly reduced with increasing nano-C-S-H gel addition due to its fibrous but well-dispersed characteristic in both water and cement paste. The semi-adiabatic calorimetry testing results verified that incorporation of nano-C-S-H gel could greatly mitigate the retarding effect of sucrose on cement hydration. The total organic carbon (TOC) indicated that the addition of the nano-C-S-H gel helps to reduce adsorption of the sucrose molecules into the protective layer, thus the semi-permeability of the protective layer was less reduced and that is why the addition of the nano-C-S-H gel can mitigate the retardation caused by the sucrose. Through XRD analysis, it was found that the CH crystals are more prone to grow along the (0001) plane with larger size in the paste with nano-C-S-H addition before the induction period starts, because the C-S-H nanoparticles can form 3D network to slow down the diffusion rate of the released ions and eliminate the convection in the paste, thus suppress the 3D nucleation and growth of the CH crystals. The XRD analysis also indicated a refinement of the ettringite crystals in the paste with sucrose addition, but introduction of nano-C-S-H gel did not show further refinement, which was also verified by the SEM observation.

18.
Sci Rep ; 10(1): 5826, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242029

RESUMO

Research in recent decades has confirmed that biodiversity influences ecosystem productivity; however, the potential mechanisms regulating this process remain subject to controversy, due to variation across ecosystems. Here, the effects of biodiversity on ecosystem productivity were evaluated using three variables of biodiversity (taxonomic diversity, functional identity, and functional diversity) and surrounding environmental conditions in a coastal saline meadow located on the south coast of Laizhou Bay, China. At this site, the shrub and field layers were primarily dominated by Tamarix chinensis and natural mesic grasses, respectively. Our results showed that functional identity, which is quantified as the community weighted mean of trait values, had greater explanatory ability than taxonomic and functional diversity. Thus, ecosystem productivity was determined disproportionately by the specific traits of dominant species. T. chinensis coverage was a biotic environmental factor that indirectly affected ecosystem productivity by increasing the community weighted mean of plant maximum height, which simultaneously declined with species richness. The present study advances our understanding of the mechanisms driving variation in the productivity of temperate coastal saline meadows, providing evidence supporting the "mass ratio" hypothesis.

19.
Proc Natl Acad Sci U S A ; 117(11): 6047-6055, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123114

RESUMO

Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1 While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Inibidores Enzimáticos/farmacologia , Interleucinas/metabolismo , L-Lactato Desidrogenase/antagonistas & inibidores , Melanoma Experimental/terapia , Células-Tronco/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral/transplante , Humanos , Memória Imunológica , Imunoterapia Adotiva/métodos , Interleucina-2/imunologia , Interleucina-2/metabolismo , Interleucinas/imunologia , L-Lactato Desidrogenase/metabolismo , Melanoma Experimental/imunologia , Camundongos , Cultura Primária de Células , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
20.
J Cell Biochem ; 121(3): 2139-2149, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31595560

RESUMO

Matrine, a natural product extracted from the root of Sophora flavescens Ait, was the main chemical ingredient of compounds of Kushen injection, which has been widely used for its remarkable anticancer effects for years. The underlying mechanisms for Matrine regulations of human breast cancer stem cells (BrCSCs) are barely known. LIN28, a well-characterized suppressor of Let-7 microRNA biogenesis, playing vital roles in regulations of stem cells' renewal and tumorigenesis. Here we show that the compounds of Kushen injection derived Matrine could suppress the BrCSCs differentiation and self-renewal through downregulating the expression of Lin28A, resulting in the inactivation of Wnt pathway through a Let-7b-dependent way. In opposite to Matrine, Cisplatin treatment increases the ability of tumorsphere formation and the expression of BrCSCs markers, which was partially blocked by either Let-7b overexpression or CCND1 inhibition. Furthermore, Matrine sensitized BrCSCs to cisplatin's suppression of cancer expansion in vitro and in vivo. Our study uncovers the role of the LIN28A/Let-7 in BrCSCs renewal, and more importantly, elucidated a novel mechanism by which Matrine induces breast cancer involution.

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