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1.
Cell Rep ; 37(10): 110083, 2021 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-34879274

RESUMO

Robust expansion of adoptively transferred T cells is a prerequisite for effective cancer immunotherapy, but how many genes in the genome modulate T cell expansion remains unknown. Here, we perform in vivo and in vitro CRISPR screens to systematically identify genes influencing CD8 T cell expansion. In the mouse genome, ∼2,600 and ∼1,500 genes are required for optimal CD8 T cell expansion in vivo and in vitro, respectively. In vivo-specific CD8 T cell essential genes are enriched in metabolic pathways, including mitochondrial metabolism. The strongest repressor of CD8 T cell expansion is Roquin, the ablation of which drastically boosts T cell proliferation by enhancing cell-cycle progression and upregulation of IRF4. Roquin deficiency or IRF4 overexpression potently enhances anti-tumor immunity. These data provide a functional catalog of CD8 T cell fitness genes and suggest that targeting the Roquin-IRF4 axis is an effective strategy to enhance efficacy of adoptive transfer therapy for cancer.

2.
Pharm Res ; 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893950

RESUMO

PURPOSE: The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect. METHODS: A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles (mPEG-PLG-GEM@CDDP micelles). RESULTS: Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. T1/2z of gemcitabine and cisplatin encapsulated in micelles were prolonged to 6.357 h (mPEG-PLG-GEM), 10.490 h (mPEG-PLG@CDDP), 5.463 h and 12.540 h (mPEG-PLG-GEM@CDDP) compared with GEM@CDDP solutions (T1/2z = 1.445 h and 7.740 h). The ratio of synergy between gemcitabine and cisplatin (3:1 ~ 1:1(n/n)) was guaranteed in the systemic circulation, thus improving its antitumor effect. The results of biochemical analysis showed that GEM@CDDP-Sol was more toxic to kidneys and marrow compared with mPEG-PLG-GEM@CDDP micelles. CONCLUSIONS: By prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment. Scheme. Schematic of mPEG-PLG-GEM@CDDP micelles' formation and action process.

3.
Acta Biomater ; 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34902617

RESUMO

Rational design of nanomedicine to accelerate thrombolysis and sequentially avoid thrombolysis-mediated reperfusion injury is still a challenge. Here, we develop a biomimetic nanovesicle (tPA/MNP@PM, tMP) by simple encapsulating melanin nanoparticles (MNP) and tPA with a platelet membrane vesicle (PM), which integrates the thrombus targeting property of PM, the photothermal conversion performance and free radical scavenging property of natural melanin for cascaded ischemic stroke treatment. Benefiting from natural thrombus-targeted adhesion capability of PM, nanovesicles could efficiently target thrombus site. Then near-infrared (NIR) mediated photothermal of MNP could lead to rupture of nanovesicles, thus achieving precise release of tPA in thrombus. Interestingly, local hyperthermia also increases the activity of tPA for accelerating thrombolysis. Afterwards, site specific released MNP (4.5 nm) accompanied by hemoperfusion can cross the BBB and accumulate in cerebral ischemia site, scavenging various free radicals and suppressing inflammation- and immune response-induced injury to achieve neuroprotection after thrombolysis. In addition, the biomimetic nanovesicle could block tPA-induced brain hemorrhage after stroke to improve thrombolytic therapy. The evaluation in ischemic stroke mice confirmed that the simple-prepared nanomedicine with cascaded thrombus targeting, precise thrombolysis and ischemia-reperfusion protection properties can significantly enhance the treatment effect of ischemic stroke. STATEMENT OF SIGNIFICANCE: Ischemic stroke is recognized as a leading cause of death and disability in the world. Rational design of nanomedicine to accelerate thrombolysis and sequentially avoid thrombolysis-mediated reperfusion injury is still a challenge. Herein, a biomimetic nanovesicle (tMP) was developed for sequential ischemic stroke treatment. It could overcome the drawbacks of free tPA for safe thrombolysis: i) platelet membrane biomimetic coating significantly increases thrombus targeting; ii) NIR-mediated photothermal of natural melanin precise controlled release of tPA in thrombus in situ, and local hyperthermia also increases the thrombolytic activity of tPA. Notably, released melanin nanoparticles (4.5 nm) accompanied by hemoperfusion can across BBB and avoid ischemia-reperfusion injury through free radical scavenging and inflammation/immune response suppression.

4.
New Phytol ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724229

RESUMO

FLOWERING LOCUS M (FLM) is a well-known MADS-box transcription factor that is required for preventing early flowering under low temperatures in Arabidopsis thaliana. Alternative splicing of FLM is involved in the regulation of temperature-responsive flowering. However, how the basic transcript level of FLM is regulated is largely unknown. Here, we conducted forward genetic screening and identified a previously uncharacterized flowering repressor gene, UBA2c. Genetic analyses indicated that UBA2c represses flowering at least by promoting FLM transcription. We further demonstrated that UBA2c directly binds to FLM chromatin and facilitates FLM transcription by inhibiting histone H3K27 trimethylation, a histone marker related to transcriptional repression. UBA2c encodes a protein containing two putative RNA recognition motifs (RRMs) and one prion-like domain (PrLD). We found that UBA2c forms speckles in the nucleus and that both the RRMs and PrLD are required not only for forming the nuclear speckles but also for the biological function of UBA2c. These results identify a previously unknown flowering repressor and provide insights into the regulation of flowering time.

5.
iScience ; 24(10): 103101, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34622156

RESUMO

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that would permanently damage the affected joints. Unfortunately, a large proportion of RA patients fail to respond adequately to current treatments. Here, repurposing hemin and its ultra-long-acting formulation were explored for the effective treatment of RA in animal models. We provided evidence that hemin prevented the onset and ameliorated the clinical course of RA. Notably, hemin treatment rescued the dysregulated gene expression in animal models of RA, resulting in attenuation of Th1/Th17 cell-mediated responses and proinflammatory cytokines. Moreover, we further formulated hemin into the in-situ forming implant, and a single injection of the ultra-long-acting hemin exerted potent disease-modifying effects for at least six weeks with a remarkable dose reduction. Taken together, given the potent anti-inflammatory and immunosuppressive effects, the once-monthly hemin injection holds promise for rapid clinical translation, and represents a potential strategy to treat RA and possibly other autoimmune diseases.

6.
J Cell Physiol ; 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34698390

RESUMO

Alcohol metabolism causes hepatocytes to release damage-associated molecular patterns (DAMPs). This includes mitochondrial DNA (mtDNA), which is generated and released from damaged hepatocytes and contributes to liver injury by producing proinflammatory cytokines. STING is a pattern recognition receptor of DAMPs known to control the induction of innate immunity in various pathological processes. However, the expression profile and functions of STING in the Gao binge ethanol model remain poorly understood. We demonstrated that STING is upregulated in the Gao binge ethanol model. STING functions as an mtDNA sensor in the Kupffer cells of the liver and induces STING-signaling pathway-dependent inflammation and further aggravates hepatocyte apoptosis in the Gao binge ethanol model. This study provides novel insights into predicting disease progression and developing targeted therapies for alcoholic liver injury.

7.
Mol Ther Nucleic Acids ; 26: 269-279, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34513309

RESUMO

Cisplatin-based chemotherapy remains the standard care for non-small cell lung cancer (NSCLC) patients. Relapse after chemotherapy-induced dormancy affects the overall survival of patients. The evolution of cancer cells under chemotherapy stress is regulated by transcription factors (TFs) with binding sites initially buried deep within inaccessible chromatin. The transcription machinery and dynamic epigenetic alterations during the process of dormancy-reactivation of lung cancer cells after chemotherapy need to be investigated. Here, we investigated the chromatin accessibility of lung cancer cells after cisplatin treatment, using an assay for transposase-accessible chromatin sequencing (ATAC-seq). We observed that global chromatin accessibility was extensively improved. Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRRUST) v.2 was used to elucidate TF-target interaction during the process of dormancy and reactivation. Enhancer regions and motifs specific to key TFs including JUN, MYC, SMAD3, E2F1, SP1, CTCF, SMAD4, STAT3, NFKB1, and KLF4 were enriched in differential loci ATAC-seq peaks of dormant and reactivated cancer cells induced by chemotherapy. The findings suggest that these key TFs regulated gene expressions during the process of dormancy and reactivation of cancer cells through altering promoter accessibility of target genes. Our study helps advance understanding of how cancer cells adapt to the stress induced by chemotherapy through TF binding motif accessibility.

8.
Thorac Cancer ; 12(19): 2601-2610, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34520129

RESUMO

BACKGROUND: Cisplatin-based chemotherapy is a therapeutic strategy against non-small cell lung cancer (NSCLC). However, cancers relapse after chemotherapy due to a dormant state of residual cancer cells. Extracellular vesicles and particles (EVPs) are active carriers of proteins and nucleic acid. Here, we aimed to study the molecular alterations and proteomic characteristics of EPV in dormant and reactivated cancer cells induced by cisplatin. METHODS: We used a short-term single dose of cisplatin to induce the dormant and reactivated cell status. We examined the gene expressional profiling and proteomic profiling of EVPs from dormant and reactivated cancer cells by RNA-sequencing and LC-MS/MS. RESULTS: We found substantial changes in gene expression and protein level in EVP. The genes with higher expression in dormant cancer cells were lipid transporter- and lipid metabolic-related genes. A total of 111 EVP proteins were upregulated in dormant cancer cells compared to those in control cells. Fifty differential expressed proteins (DEPs) were identified in EVPs from reactivated cancer cells compared to those in dormant cancer cells. Among the DEPs, we found that apolipoproteins such as APOA1 and APOE were significantly increased in dormant cancer cell-derived EVPs. Integration of EVP proteomes with transcriptional profiles of cancer cells revealed that the proteomic profiling of EVP derived from cancer cells can reflect the cellular status of cancer cells, which showed an activated lipid metabolism in dormant state. CONCLUSION: Lipoproteins enriched in EVPs reflect the activated lipid metabolism in dormant cancer cells and may provide potential biomarkers or therapeutic targets for cisplatin-based therapy.

9.
Front Physiol ; 12: 714104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34393830

RESUMO

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus play an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

10.
Sci China Life Sci ; 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34406569

RESUMO

Spinal cord injury (SCI) often results in an inhibitory environment at the injury site. In our previous studies, transplantation of a scaffold combined with stem cells was proven to induce neural regeneration in animal models of complete SCI. Based on these preclinical studies, collagen scaffolds loaded with the patients' own bone marrow mononuclear cells or human umbilical cord mesenchymal stem cells were transplanted into SCI patients. Fifteen patients with acute complete SCI and 51 patients with chronic complete SCI were enrolled and followed up for 2 to 5 years. No serious adverse events related to functional scaffold transplantation were observed. Among the patients with acute SCI, five patients achieved expansion of their sensory positions and six patients recovered sensation in the bowel or bladder. Additionally, four patients regained voluntary walking ability accompanied by reconnection of neural signal transduction. Among patients with chronic SCI, 16 patients achieved expansion of their sensation level and 30 patients experienced enhanced reflexive defecation sensation or increased skin sweating below the injury site. Nearly half of the patients with chronic cervical SCI developed enhanced finger activity. These long-term follow-up results suggest that functional scaffold transplantation may represent a feasible treatment for patients with complete SCI.

11.
Plant Cell ; 33(10): 3250-3271, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34270751

RESUMO

In the INO80 chromatin remodeling complex, all of the accessory subunits are assembled on the following three domains of INO80: N-terminal domain (NTD), HSA domain, and ATPase domain. Although the ATPase and HSA domains and their interacting accessory subunits are known to be responsible for chromatin remodeling, it is largely unknown how the accessory subunits that interact with the INO80 NTD regulate chromatin status. Here, we identify both conserved and nonconserved accessory subunits that interact with the three domains in the INO80 complex in Arabidopsis thaliana. While the accessory subunits that interact with all the three INO80 domains can mediate transcriptional repression, the INO80 NTD and the accessory subunits interact with it can contribute to transcriptional activation even when the ATPase domain is absent, suggesting that INO80 has an ATPase-independent role. A subclass of the COMPASS histone H3K4 methyltransferase complexes interact with the INO80 NTD in the INO80 complex and function together with the other accessory subunits that interact with the INO80 NTD, thereby facilitating H3K4 trimethylation and transcriptional activation. This study suggests that the opposite effects of the INO80 complex on transcription are required for the balance between vegetative growth and flowering under diverse environmental conditions.

12.
J Genet Genomics ; 48(5): 369-383, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34144927

RESUMO

The Arabidopsis thaliana RPD3-type histone deacetylases have been known to form conserved SIN3-type histone deacetylase complexes, but whether they form other types of complexes is unknown. Here, we perform affinity purification followed by mass spectrometry and demonstrate that the Arabidopsis RPD3-type histone deacetylases HDA6 and HDA19 interact with several previously uncharacterized proteins, thereby forming three types of plant-specific histone deacetylase complexes, which we named SANT, ESANT, and ARID. RNA-seq indicates that the newly identified components function together with HDA6 and HDA19 and coregulate the expression of a number of genes. HDA6 and HDA19 were previously thought to repress gene transcription by histone deacetylation. We find that the histone deacetylase complexes can repress gene expression via both histone deacetylation-dependent and -independent mechanisms. In the mutants of histone deacetylase complexes, the expression of a number of stress-induced genes is up-regulated, and several mutants of the histone deacetylase complexes show severe retardation in growth. Considering that growth retardation is thought to be a trade-off for an increase in stress tolerance, we infer that the histone deacetylase complexes identified in this study prevent overexpression of stress-induced genes and thereby ensure normal growth of plants under nonstress conditions.

13.
J Neurosci ; 41(26): 5734-5746, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34031163

RESUMO

Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel ß-arrestin/ß2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT2CR desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization.SIGNIFICANCE STATEMENT By demonstrating that the combination of barbadin (Bar) with a G-protein-coupled receptor (GPCR) agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate Bar as a safe and effective medicine or to use Bar as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of serotonin 2C receptor (5-HT2CR) desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin (Lor) or other 5-HT2CR agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines.


Assuntos
Benzazepinas/farmacologia , Neurônios/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Perda de Peso/efeitos dos fármacos , Animais , Apetite/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/metabolismo , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Tempo
14.
Immunity ; 54(5): 976-987.e7, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33979589

RESUMO

Aerobic glycolysis-the Warburg effect-converts glucose to lactate via the enzyme lactate dehydrogenase A (LDHA) and is a metabolic feature of effector T cells. Cells generate ATP through various mechanisms and Warburg metabolism is comparatively an energy-inefficient glucose catabolism pathway. Here, we examined the effect of ATP generated via aerobic glycolysis in antigen-driven T cell responses. Cd4CreLdhafl/fl mice were resistant to Th17-cell-mediated experimental autoimmune encephalomyelitis and exhibited defective T cell activation, migration, proliferation, and differentiation. LDHA deficiency crippled cellular redox balance and inhibited ATP production, diminishing PI3K-dependent activation of Akt kinase and thereby phosphorylation-mediated inhibition of Foxo1, a transcriptional repressor of T cell activation programs. Th17-cell-specific expression of an Akt-insensitive Foxo1 recapitulated the defects seen in Cd4CreLdhafl/fl mice. Induction of LDHA required PI3K signaling and LDHA deficiency impaired PI3K-catalyzed PIP3 generation. Thus, Warburg metabolism augments glycolytic ATP production, fueling a PI3K-centered positive feedback regulatory circuit that drives effector T cell responses.


Assuntos
Trifosfato de Adenosina/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/fisiologia , Células Th17/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem Celular , Proliferação de Células/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Glucose/metabolismo , Doença de Depósito de Glicogênio/metabolismo , Glicólise/fisiologia , L-Lactato Desidrogenase/deficiência , L-Lactato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
15.
Poult Sci ; 100(6): 101115, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33975040

RESUMO

This experiment examined the separate and combined effects of daidzein (Da) and Chinese herbs (CH) on laying performance and egg quality of post-peak laying hens. Additionally, we explored potential mechanisms of action for these 2 additives by examining plasma hormone levels. After 4 wk of acclimation to caging, 60-week-old Hyline Brown hens (360) were selected and randomly divided into 4 groups with 6 replicates and 15 chickens per replicate. The following 4 dietary groups were utilized: 1) control group (basal diet); 2) Da group (basal diet + 0.03 kg/t DA); 3) CH group (basal diet +0.6 kg/t CH); 4) Da + CH group (basal diet + 0.03 kg/t Da + 0.6 kg/t CH). Data were analyzed in a completely randomized design with a 2×2 factorial arrangement of treatments. Egg production and FCR treatment averages were analyzed in the following 3 phases: wk 1-4, 5-8, and 1-8 of treatment administration. Results revealed that Da increased egg production but decreased FCR (P < 0.05) for wk 1-8 and especially during wk 5-8 (P < 0.05). CH decreased FCR in wk 1-4 and 5-8 (P < 0.05), but increased egg production only during wk 5-8 (P < 0.05). Da increased Haugh units (P < 0.05) on wk 4 and 8; CH increased Haugh units (P < 0.05) but decreased yolk ratio (P < 0.05) on wk 4 and 8. Da increased the plasma levels of T3, PROG, FSH, LH and E2 (P < 0.05); CH increased the plasma level of T3 (P < 0.05). Additionally, Da x CH interactions existed for albumen height, Haugh units, albumen ratio and the level of T3 on wk 8 (P < 0.05), indicating that the combination of Da and CH was more effective than administration of either of these dietary components independently. In conclusion, Da and CH, both independently and in combination, increase laying performance, egg quality and plasma hormones levels in post-peak laying hens. Therefore, these treatments may be able to provide prolonged economic benefits to aged laying hens.


Assuntos
Ração Animal , Galinhas , Ração Animal/análise , Animais , China , Dieta/veterinária , Suplementos Nutricionais , Feminino , Hormônios , Isoflavonas
16.
Clin Sci (Lond) ; 135(10): 1213-1232, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33871024

RESUMO

BACKGROUND AND AIMS: Alcoholic fatty liver (AFL) is an early form of alcoholic liver disease (ALD) that usually manifests as lipid synthesis abnormalities in hepatocytes. ß-arrestin2 (Arrb2) is involved in multiple biological processes. The present study aimed to explore the role of Arrb2 in the regulation of lipid metabolism in AFL and the underlying mechanism and identify potential targets for the treatment of AFL. METHODS: The expression of Arrb2 was detected in liver tissues obtained from AFL patients and Gao-binge AFL model mice. In addition, we specifically knocked down Arrb2 in AFL mouse liver in vivo and used Arrb2-siRNA or pEX3-Arrb2 to silence or overexpress Arrb2 in AML-12 cells in vitro to explore the functional role and underlying regulatory mechanism of Arrb2 in AFL. Finally, we investigated whether Arrb2 could cause changes in hepatic lipid metabolites, thereby leading to dysregulation of lipid metabolism based on liquid chromatography-mass spectrometry (LC-MS) analysis. RESULTS: Arrb2 was up-regulated in the livers of AFL patients and AFL mice. The in vivo and in vitro results confirmed that Arrb2 could induce lipid accumulation and metabolism disorders. Mechanistically, Arrb2 induced hepatic metabolism disorder via AMP-activated protein kinase (AMPK) pathway. The results of LC-MS analysis revealed that hepatic lipid metabolites with the most significant differences were primary bile acids. CONCLUSIONS: Arrb2 induces hepatic lipid metabolism disorders via AMPK pathway in AFL. On one hand, Arrb2 increases fatty acid synthesis. On the other hand, Arrb2 could increase the cholesterol synthesis, thereby leading to the up-regulation of primary bile acid levels.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Hepatopatias Alcoólicas/etiologia , beta-Arrestina 2/metabolismo , Adolescente , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Fígado/metabolismo , Hepatopatias Alcoólicas/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade
17.
Mol Plant ; 14(7): 1071-1087, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33737195

RESUMO

The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex is an evolutionarily conserved histone acetyltransferase complex that has a critical role in histone acetylation, gene expression, and various developmental processes in eukaryotes. However, little is known about the composition and function of the SAGA complex in plants. In this study, we found that the SAGA complex in Arabidopsis thaliana contains not only conserved subunits but also four plant-specific subunits: three functionally redundant paralogs, SCS1, SCS2A, and SCS2B (SCS1/2A/2B), and a TAF-like subunit, TAFL. Mutations in SCS1/2A/2B lead to defective phenotypes similar to those caused by mutations in the genes encoding conserved SAGA subunits HAG1 and ADA2B, including delayed juvenile-to-adult phase transition, late flowering, and increased trichome density. Furthermore, we demonstrated that SCS1/2A/2B are required for the function of the SAGA complex in histone acetylation, thereby promoting the transcription of development-related genes. These results together suggest that SCS1/2A/2B are core subunits of the SAGA complex in Arabidopsis. Compared with SAGA complexes in other eukaryotes, the SAGA complexes in plants have evolved unique features that are necessary for normal growth and development.

18.
J Phys Chem Lett ; 12(7): 1793-1802, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33577324

RESUMO

In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC50 of 1.81 ± 0.04 µM and inhibit SARS-CoV-2 viral infection in cells with an EC50 of 71.6 µM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/tratamento farmacológico , Desenho de Fármacos , Receptores de Coronavírus/metabolismo , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Estilbenos/farmacologia , Animais , Chlorocebus aethiops , Simulação por Computador , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Ligação Proteica , SARS-CoV-2/metabolismo , Células Vero
19.
J Integr Plant Biol ; 63(4): 787-802, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33433058

RESUMO

Trimethylated histone H3 lysine 27 (H3K27me3) is a repressive histone marker that regulates a variety of developmental processes, including those that determine flowering time. However, relatively little is known about the mechanism of how H3K27me3 is recognized to regulate transcription. Here, we identified BAH domain-containing transcriptional regulator 1 (BDT1) as an H3K27me3 reader. BDT1 is responsible for preventing flowering by suppressing the expression of flowering genes. Mutation of the H3K27me3 recognition sites in the BAH domain disrupted the binding of BDT1 to H3K27me3, leading to de-repression of H3K27me3-enriched flowering genes and an early-flowering phenotype. We also found that BDT1 interacts with a family of PHD finger-containing proteins, which we named PHD1-6, and with CPL2, a Pol II carboxyl terminal domain (CTD) phosphatase responsible for transcriptional repression. Pull-down assays showed that the PHD finger-containing proteins can enhance the binding of BDT1 to the H3K27me3 peptide. Mutations in all of the PHD genes caused increased expression of flowering genes and an early-flowering phenotype. This study suggests that the binding of BDT1 to the H3K27me3 peptide, which is enhanced by PHD proteins, is critical for preventing early flowering.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Flores/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Flores/genética , Regulação da Expressão Gênica de Plantas/genética , Regulação da Expressão Gênica de Plantas/fisiologia , Mutação/genética
20.
Science ; 371(6527): 405-410, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479154

RESUMO

Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Glicólise , Lactato Desidrogenase 5/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Linfócitos T CD8-Positivos/enzimologia , Proteína Forkhead Box O1/metabolismo , Humanos , Lactato Desidrogenase 5/genética , Listeria monocytogenes , Listeriose/enzimologia , Listeriose/imunologia , Camundongos , Camundongos Mutantes , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Efeito Warburg em Oncologia
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