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1.
J Hepatol ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38759889

RESUMO

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme OXCT1. We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in hepatocellular carcinoma in vivo, we conducted multiplex immunohistochemistry (mIHC) experiments on human HCC specimens. To explore the role of OXCT1 in mouse hepatocellular carcinoma tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4 trimethylation (H3K4me3) level in the Arg1 promoter. In addition, Pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreasing CD8+ T-cell exhaustion and deceleration of tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in HCC patients. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping HCC progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for HCC. Here, we found that ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. And the strategic pharmacological intervention or genetic downregulation of OXCT1 in TAMs enhances the antitumor immunity and decelerated tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs is an effective approach for treating liver cancer.

2.
Int Immunopharmacol ; 134: 112258, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38744178

RESUMO

Ferroptosis, a form of regulated cell death (RCD), exhibits distinct characteristics such as iron-dependence and lipid peroxidation accumulation (ROS), setting it apart from other types of cell death like apoptosis and necrosis. Its role in cancer biology is increasingly recognized, particularly its potential interaction with tumor microenvironment (TME) and CD8 T cells in cancer immunotherapy. However, the impact of ferroptosis on TME cell infiltration remains unclear. In this study, we conducted unsupervised clustering analysis on patient data from public databases, identifying three ferroptosis patterns with distinct TME cell infiltration characteristics: immune-inflamed, immune-excluded, and immune-desert phenotypes. We developed a ferroptosis score based on differentially expressed genes (DEGs) among these patterns, which correlated with various biological features including chemotherapy-resistance and immune cells infiltration. Despite patients with high ferroptosis scores exhibiting worse prognosis, they showed increased likelihood of benefiting from immunotherapy. Our findings highlight the importance of ferroptosis-related patterns in understanding TME cell infiltration and suggest novel strategies for drug combinations and immune-related therapies.


Assuntos
Neoplasias Colorretais , Ferroptose , Microambiente Tumoral , Ferroptose/genética , Humanos , Microambiente Tumoral/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Prognóstico , Resistencia a Medicamentos Antineoplásicos/genética
3.
Nat Commun ; 15(1): 966, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38302493

RESUMO

The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.


Assuntos
Neoplasias , Ceramidase Neutra , Animais , Feminino , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Ceramidas/metabolismo , Macrófagos/metabolismo , Reprogramação Metabólica , Ceramidase Neutra/metabolismo , Microambiente Tumoral
4.
Nat Commun ; 14(1): 8154, 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38071226

RESUMO

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor de Morte Celular Programada 1/metabolismo , Exaustão das Células T , Succinatos/farmacologia , Succinatos/metabolismo , Epigênese Genética
5.
Nat Chem Biol ; 19(12): 1492-1503, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37500770

RESUMO

Enolase 1 (ENO1) is a glycolytic enzyme that plays essential roles in various pathological activities including cancer development. However, the mechanisms underlying ENO1-contributed tumorigenesis are not well explained. Here, we uncover that ENO1, as an RNA-binding protein, binds to the cytosine-uracil-guanine-rich elements of YAP1 messenger RNA to promote its translation. ENO1 and YAP1 positively regulate alternative arachidonic acid (AA) metabolism by inverse regulation of PLCB1 and HPGD (15-hydroxyprostaglandin dehydrogenase). The YAP1/PLCB1/HPGD axis-mediated activation of AA metabolism and subsequent accumulation of prostaglandin E2 (PGE2) are responsible for ENO1-mediated cancer progression, which can be retarded by aspirin. Finally, aberrant activation of ENO1/YAP1/PLCB1 and decreased HPGD expression in clinical hepatocellular carcinoma samples indicate a potential correlation between ENO1-regulated AA metabolism and cancer development. These findings underline a new function of ENO1 in regulating AA metabolism and tumorigenesis, suggesting a therapeutic potential for aspirin in patients with liver cancer with aberrant expression of ENO1 or YAP1.


Assuntos
Carcinogênese , Neoplasias Hepáticas , Humanos , Ácido Araquidônico , Linhagem Celular Tumoral , Proliferação de Células , Carcinogênese/genética , Transformação Celular Neoplásica , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Neoplasias Hepáticas/genética , Aspirina/farmacologia , Proteínas de Ligação a DNA/genética , Biomarcadores Tumorais , Proteínas Supressoras de Tumor/genética
6.
World J Diabetes ; 14(6): 862-882, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37383585

RESUMO

BACKGROUND: Current approaches for the therapy of diabetic retinopathy (DR), which was one of leading causes of visual impairment, have their limitations. Animal experiments revealed that restructuring of intestinal microbiota can prevent retinopathy. AIM: To explore the relationship between intestinal microbiota and DR among patients in the southeast coast of China, and provide clues for novel ways to prevention and treatment methods of DR. METHODS: The fecal samples of non-diabetics (Group C, n = 15) and diabetics (Group DM, n = 30), including 15 samples with DR (Group DR) and 15 samples without DR (Group D), were analyzed by 16S rRNA sequencing. Intestinal microbiota compositions were compared between Group C and Group DM, Group DR and Group D, as well as patients with proliferative diabetic retinopathy (PDR) (Group PDR, n = 8) and patients without PDR (Group NPDR, n = 7). Spearman correlation analyses were performed to explore the associations between intestinal microbiota and clinical indicators. RESULTS: The alpha and beta diversity did not differ significantly between Group DR and Group D as well as Group PDR and Group NPDR. At the family level, Fusobacteriaceae, Desulfovibrionaceae and Pseudomonadaceae were significantly increased in Group DR than in Group D (P < 0.05, respectively). At the genera level, Fusobacterium, Pseudomonas, and Adlercreutzia were increased in Group DR than Group D while Senegalimassilia was decreased (P < 0.05, respectively). Pseudomonas was negatively correlated with NK cell count (r = -0.39, P = 0.03). Further, the abundance of genera Eubacterium (P < 0.01), Peptococcus, Desulfovibrio, Acetanaerobacterium and Negativibacillus (P < 0.05, respectively) were higher in Group PDR compared to Group NPDR, while Pseudomonas, Alloprevotella and Tyzzerella (P < 0.05, respectively) were lower. Acetanaerobacterium and Desulfovibrio were positively correlated with fasting insulin (r = 0.53 and 0.61, respectively, P < 0.05), when Negativibacillus was negatively correlated with B cell count (r = -0.67, P < 0.01). CONCLUSION: Our findings indicated that the alteration of gut microbiota was associated with DR and its severity among patients in the southeast coast of China, probably by multiple mechanisms such as producing short-chain fatty acids, influencing permeability of blood vessels, affecting levels of vascular cell adhesion molecule-1, hypoxia-inducible factor-1, B cell and insulin. Modulating gut microbiota composition might be a novel strategy for prevention of DR, particularly PDR in population above.

7.
Cancer Cell ; 41(6): 1118-1133.e12, 2023 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-37267951

RESUMO

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.


Assuntos
Cromatina , Metionina , Humanos , Cromatina/genética , Metionina/genética , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , DNA , Imunidade Inata , Desmetilação , Proteínas Estimuladoras de Ligação a CCAAT/genética , Ubiquitina-Proteína Ligases/genética
8.
Phys Rev Lett ; 130(19): 190201, 2023 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-37243635

RESUMO

Nonlocality arising in networks composed of several independent sources gives rise to phenomena radically different from that in standard Bell scenarios. Over the years, the phenomenon of network nonlocality in the entanglement-swapping scenario has been well investigated and demonstrated. However, it is known that violations of the so-called bilocality inequality used in previous experimental demonstrations cannot be used to certify the nonclassicality of their sources. This has put forward a stronger concept for nonlocality in networks, called full network nonlocality. Here, we experimentally observe full network nonlocal correlations in a network where the source-independence, locality, and measurement-independence loopholes are closed. This is ensured by employing two independent sources, rapid setting generation, and spacelike separations of relevant events. Our experiment violates known inequalities characterizing nonfull network nonlocal correlations by over 5 standard deviations, certifying the absence of classical sources in the realization.

9.
Phys Rev Lett ; 129(14): 140401, 2022 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-36240393

RESUMO

Quantum mechanics is commonly formulated in a complex, rather than real, Hilbert space. However, whether quantum theory really needs the participation of complex numbers has been debated ever since its birth. Recently, a Bell-like test in an entanglement-swapping scenario has been proposed to distinguish standard quantum mechanics from its real-valued analog. Previous experiments have conceptually demonstrated, yet not satisfied, the central requirement of independent state preparation and measurements and leave several loopholes. Here, we implement such a Bell-like test with two separated independent sources delivering entangled photons to three separated parties under strict locality conditions that are enforced by spacelike separation of the relevant events, rapid random setting generation, and fast measurement. With the fair-sampling assumption and closed loopholes of independent source, locality, and measurement independence simultaneously, we violate the constraints of real-valued quantum mechanics by 5.30 standard deviations. Our results disprove the real-valued quantum theory to describe nature and ensure the indispensable role of complex numbers in quantum mechanics.

10.
Phys Rev Lett ; 129(6): 060401, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-36018640

RESUMO

Nonlocality captures one of the counterintuitive features of nature that defies classical intuition. Recent investigations reveal that our physical world's nonlocality is at least tripartite; i.e., genuinely tripartite nonlocal correlations in nature cannot be reproduced by any causal theory involving bipartite nonclassical resources and unlimited shared randomness. Here, by allowing the fair sampling assumption and postselection, we experimentally demonstrate such genuine tripartite nonlocality in a network under strict locality constraints that are ensured by spacelike separating all relevant events and employing fast quantum random number generators and high-speed polarization measurements. In particular, for a photonic quantum triangular network we observe a locality-loophole-free violation of the Bell-type inequality by 7.57 standard deviations for a postselected tripartite Greenberger-Horne-Zeilinger state of fidelity (93.13±0.24)%, which convincingly disproves the possibility of simulating genuine tripartite nonlocality by bipartite nonlocal resources with globally shared randomness.

11.
Phys Rev Lett ; 128(25): 250401, 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35802432

RESUMO

First proposed by Mayers and Yao, self-testing provides a certification method to infer the underlying physics of quantum experiments in a black-box scenario. Numerous demonstrations have been reported to self-test various types of entangled states. However, all the multiparticle self-testing experiments reported so far suffer from both detection and locality loopholes. Here, we report the first experimental realization of multiparticle entanglement self-testing closing the locality loophole in a photonic system, and the detection loophole in a superconducting system, respectively. We certify three-party and four-party GHZ states with at least 0.84(1) and 0.86(3) fidelities in a device-independent way. These results can be viewed as a meaningful advance in multiparticle loophole-free self-testing, and also significant progress on the foundations of quantum entanglement certification.

12.
Front Oncol ; 12: 857968, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35433434

RESUMO

Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multifunctional protein that functions mainly in the nucleus and cytoplasm. However, whether SND1 regulates cellular activity through mitochondrial-related functions remains unclear. Herein, we demonstrate that SND1 is localized to mitochondria to promote phosphoglycerate mutase 5 (PGAM5)-mediated mitophagy. We find that SND1 is present in mitochondria based on mass spectrometry data and verified this phenomenon in different liver cancer cell types by performing organelle subcellular isolation. Specifically, The N-terminal amino acids 1-63 of SND1 serve as a mitochondrial targeting sequence (MTS), and the translocase of outer membrane 70 (TOM 70) promotes the import of SND1 into mitochondria. By immunoprecipitation-mass spectrometry (IP-MS), we find that SND1 interacts with PGAM5 in mitochondria and is crucial for the binding of PGAM5 to dynamin-related protein 1 (DRP1). Importantly, we demonstrate that PGAM5 and SND1-MTS are required for SND1-mediated mitophagy under FCCP and glucose deprivation treatment as well as for SND1-mediated cell proliferation and tumor growth both in vitro and in vivo. Aberrant expression of SND1 and PGAM5 predicts poor outcomes in hepatocellular carcinoma (HCC) patients. Taken together, these findings establish a previously unappreciated role of SND1 and the association of mitochondrion-localized SND1 with PGAM5 in mitophagy and tumor progression.

13.
Diabetes Metab Syndr Obes ; 15: 933-941, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370412

RESUMO

Purpose: To investigate the prevalence, clinical and metabolic characteristics of atherosclerosis (AS) in newly diagnosed patients with ketosis-prone type 2 diabetes (KPT2D) or non-ketotic type 2 diabetes (NKPT2D). Patients and Methods: About 1072 subjects with non-autoimmune new-onset diabetes were included in the cross-sectional study. Patients were classified as non-ketotic type 2 diabetes (NKPT2D, n = 662) or ketosis-prone type 2 diabetes (KPT2D, n = 410). Blood samples were collected to determine the levels of glucose, HbA1c, insulin and C-peptide. Routine liver and kidney function tests were also performed. AS was determined by vascular ultrasonography. Results: The levels of fasting blood glucose and HbA1c were significant higher in the KPT2D group when compared to the NKPT2D group (P<0.001). The levels of fasting C-peptide, 2 h C-peptide and HOMA-ß were lower in the KPT2D group than those in NKPT2D group (P<0.001). However, no significant difference was observed for HOMA-IR between the two groups. The onset age of the patients with KPT2D was significantly lower compared to NKPT2D patients (38±13 vs 49±14, P<0.001). After adjusting age of the two groups, the KPT2D patients had a higher prevalence of AS compared to the NKPT2D patients (31.4% vs 21.1%, P=0.005). In both groups, age and gender were independent risk factors for AS, whereas estimated glomerular filtration rate (eGFR) was an independent risk factor in the NKPT2D patients and 2-h postprandial plasma glucose (2h-PPG) was an independent risk factor in the KPT2D patients. Conclusion: AS was more prevalent in KPT2D patients compared to the NKPT2D cohort, which was independent of age and gender. These data suggest that KPT2D patients may have a higher risk of macrovascular complications compared to NKPT2D of the same age.

14.
Cell Rep ; 38(13): 110560, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35354041

RESUMO

It is not clear how the complex interactions between diet and intestinal immune cells protect the gut from infection. Neutral ceramidase (NcDase) plays a critical role in digesting dietary sphingolipids. We find that NcDase is an essential factor that controls intestinal immune cell dynamics. Mice lacking NcDase have reduced cluster of differentiation (CD) 8αß+ T cells and interferon (IFN)-γ+ T cells and increased macrophages in the intestine and fail to clear bacteria after Citrobacter rodentium infection. Mechanistically, cellular NcDase or extracellular vesicle (EV)-related NcDase generates sphingosine, which promotes macrophage-driven Th1 immunity. Loss of NcDase influences sphingosine-controlled glycolytic metabolism in macrophages, which regulates the bactericidal activity of macrophages. Importantly, administration of dietary sphingomyelin and genetic deletion or pharmacological inhibition of SphK1 can protect against C. rodentium infection. Our findings demonstrate that sphingosine profoundly alters macrophage glycolytic metabolism, leading to intestinal macrophage activation and T cell polarization, which prevent pathogen colonization of the gut.


Assuntos
Ceramidase Neutra , Esfingosina , Animais , Homeostase , Intestino Delgado/metabolismo , Macrófagos/metabolismo , Camundongos , Ceramidase Neutra/genética , Ceramidase Neutra/metabolismo , Esfingosina/metabolismo
15.
Nat Cancer ; 3(1): 75-89, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35121990

RESUMO

α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.


Assuntos
Carcinoma Hepatocelular , Ferroptose , Proteína 1 Reguladora do Ferro/metabolismo , Neoplasias Hepáticas , Biomarcadores Tumorais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Ferroptose/genética , Humanos , Ferro/metabolismo , Proteína 1 Reguladora do Ferro/genética , Neoplasias Hepáticas/genética , Fosfopiruvato Hidratase/genética , RNA Mensageiro/genética , Proteínas Supressoras de Tumor/metabolismo
16.
Phys Rev Lett ; 127(23): 230503, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34936806

RESUMO

Quantum self-testing is a device-independent way to certify quantum states and measurements using only the input-output statistics, with minimal assumptions about the quantum devices. Because of the high demand on tolerable noise, however, experimental self-testing was limited to two-photon systems. Here, we demonstrate the first robust self-testing for multiphoton genuinely entangled quantum states. We prepare two examples of four-photon graph states, the Greenberger-Horne-Zeilinger states with a fidelity of 0.957(2) and the linear cluster states with a fidelity of 0.945(2). Based on the observed input-output statistics, we certify the genuine four-photon entanglement and further estimate their qualities with respect to realistic noise in a device-independent manner.

17.
Cytogenet Genome Res ; 161(8-9): 449-462, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34657040

RESUMO

PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) can inhibit tumor growth by inhibiting telomerase activity. However, only few studies investigated the expression and function of PinX1 in nonalcoholic fatty liver disease (NAFLD). Thus, here we aimed to explore the roles of PinX1 in high-fat diet (HFD)-induced NAFLD in mice and in isolated hepatocytes. The mRNA expression of PinX1 and mTERT as well as telomere length were analyzed by RT-PCR. Pathological changes were detected by HE staining and oil red O staining. Triglyceride, cholesterol, alanine aminotransferase, aspartic aminotransferase, and telomerase activity were detected by ELISA. Hepatocyte apoptosis was determined by TUNEL and flow cytometry, and protein expression was analyzed by western blotting. We found that the expression of PinX1 was upregulated in the HFD group compared with the WT group. PinX1 knockout improved HFD-induced liver injury in mice and exhibited less lipid accumulation in hepatocytes. Moreover, telomere length, telomerase activity, and mTERT expression were significantly reduced in liver tissues of HFD-induced mice and palmitic acid-induced hepatocytes, while PinX1 knockout attenuated the effect. Furthermore, HFD-induced PinX1-/- mice exhibited less hepatocyte apoptosis than HFD-induced WT mice. Besides, PinX1 knockout inhibited the increase of cleaved caspase-3 and cleaved PARP expression in vivo and in vitro. Moreover, inhibition of mTERT reversed the effect of PinX1 knockout in hepatocytes. Taken together, our findings indicate that PinX1 promotes hepatocyte apoptosis and lipid accumulation by decreasing telomere length and telomerase activity in the development of NAFLD. PinX1 might be a target for the treatment of NAFLD.


Assuntos
Apoptose , Proteínas de Ciclo Celular/deficiência , Fígado , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/patologia , Telomerase/metabolismo , Proteínas Supressoras de Tumor/deficiência , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Hepatócitos/citologia , Hepatócitos/enzimologia , Hepatócitos/patologia , Fígado/citologia , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
18.
Asia Pac J Clin Nutr ; 30(3): 497-503, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34587709

RESUMO

BACKGROUND AND OBJECTIVES: Carotid intima-media thickness (IMT) is a risk predictor for myocardial infarction and stroke. Patients with type 2 diabetes mellitus are at higher risk for such conditions. The association of alcohol consumption with IMT is still controversial. METHODS AND STUDY DESIGN: We undertook a cross-sectional study of patients hospitalized in the Department of Endocrinology at Zhoushan Hospital from January 1st, 2013 to December 31st, 2015. Patients with a past medical history of cerebrovascular events, acute myocardial ischemia or unable to provide a detailed alcohol consumption history were excluded. Carotid IMT, together with blood biochemical examinations were collected. Data were analyzed using least significant difference t test, Tamhane's T2 test, Levene test, χ2-test and binary logistic regression model. RESULTS: 281 patients were enrolled in the study. The number of patients with elevated carotid IMT in moderate alcohol consumers was apparently less than alcohol non/heavy-consumers. In addition, the number of participants with elevated carotid IMT in liqueur consumers was higher than alcohol non-consumers and rice wine/beer consumers. Systolic blood pressure, C-reactive protein, glycosylated hemoglobin, low density lipoprotein cholesterol, triglyceride, gamma glutamyl transpeptidase, uric acid, cholesterol and creatinine levels were higher in elevated IMT patients, while high density lipoprotein cholesterol level was levels were significantly lower (p value<0.05). CONCLUSIONS: Moderate alcohol consumption has a protective effect on atherosclerosis in patients with type 2 diabetes mellitus, requiring consideration to dietary intake and physical activity, among other influences. Inflammation theory and lipid metabolism could be involved in such prophylaxis effects.


Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Consumo de Bebidas Alcoólicas , Espessura Intima-Media Carotídea , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Humanos
19.
Transl Oncol ; 14(8): 101129, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34051623

RESUMO

'Don't eat me' signal of CD47 is activated via its interaction with SIRPα protein on myeloid cells, especially phagocytic cells, and prevents malignant cells from anti-tumor immunity in which pyroglutamate modification of CD47 by glutaminyl-peptide cyclotransferase-like protein (isoQC) takes an important part evidenced by our previous report that isoQC is an essential regulator for CD47-SIRPα axis with a strong inhibition on macrophage-mediated phagoctyosis. Therefore, we screened for potential isoQC inhibitors by fluorescence-activated cell sorting assay and identified luteolin as a potent compound that blocked the pyroglutamation of CD47 by isoQC. We further demonstrated that luteolin directly bound to isoQC using pull-down assay and isothermal calorimetric (ITC) assay. In consistency, we showed that luteolin markedly abrogated the cell-surface interaction between CD47 and SIRPα in multiple myeloma H929 cells and consequently promoted the macrophage-mediated phagocytosis. Collectively, our study discovered a promising lead compound targeting isoQC, luteolin, which functions distinctly from current CD47 antibody-based drugs and therefore may potentially overcome the clinical side effects associated with CD47 antibody treatment-induced anemia.

20.
Phys Rev Lett ; 126(14): 140501, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33891463

RESUMO

Heralded entangling quantum gates are an essential element for the implementation of large-scale optical quantum computation. Yet, the experimental demonstration of genuine heralded entangling gates with free-flying output photons in linear optical system, was hindered by the intrinsically probabilistic source and double-pair emission in parametric down-conversion. Here, by using an on-demand single-photon source based on a semiconductor quantum dot embedded in a micropillar cavity, we demonstrate a heralded controlled-NOT (CNOT) operation between two single photons for the first time. To characterize the performance of the CNOT gate, we estimate its average quantum gate fidelity of (87.8±1.2)%. As an application, we generated event-ready Bell states with a fidelity of (83.4±2.4)%. Our results are an important step towards the development of photon-photon quantum logic gates.

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