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1.
Nat Immunol ; 22(6): 699-710, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34040226

RESUMO

It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.


Assuntos
Colite/imunologia , Mucosa Intestinal/imunologia , Listeriose/imunologia , Macrófagos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Proliferação de Células/genética , Colite/microbiologia , Colite/patologia , Colo/citologia , Colo/embriologia , Colo/imunologia , Colo/patologia , Citocinas/metabolismo , Toxina Diftérica/administração & dosagem , Toxina Diftérica/imunologia , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Vida Livre de Germes , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/embriologia , Mucosa Intestinal/patologia , Listeriose/microbiologia , Listeriose/patologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia
2.
Immunity ; 56(5): 1115-1131.e9, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-36917985

RESUMO

Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.


Assuntos
Estresse do Retículo Endoplasmático , Mucosa Intestinal , Células Th17 , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Diferenciação Celular , Humanos , Animais , Camundongos , Camundongos Transgênicos , Antibacterianos/farmacologia
3.
Mol Cell ; 77(1): 138-149.e5, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31735643

RESUMO

PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple metabolic pathways and contributes to tumorigenesis in a poorly understood manner. We show here that PGAM5 inhibition attenuates lipid metabolism and colorectal tumorigenesis in mice. PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. ME1 also promotes nicotinamide adenine dinucleotide phosphate (NADPH) production, lipogenesis, and colorectal cancers in which ME1 transcripts are upregulated and ME1 protein is hypophosphorylated at S336 and hyperacetylated at K337. PGAM5 and ME1 upregulation occur via direct transcriptional activation mediated by ß-catenin/TCF1. Thus, the balance between PGAM5-mediated dephosphorylation of ME1 S336 and ACAT1-mediated acetylation of K337 strongly influences NADPH generation, lipid metabolism, and the susceptibility to colorectal tumorigenesis.


Assuntos
Carcinogênese/metabolismo , Metabolismo dos Lipídeos/fisiologia , Fosforilação/fisiologia , Proteínas de Transporte Vesicular/metabolismo , Acetil-CoA C-Acetiltransferase/metabolismo , Acetilação , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADP/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Ativação Transcricional/fisiologia , Regulação para Cima/fisiologia
4.
PLoS Pathog ; 20(1): e1011983, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38271477

RESUMO

The protein basic helix-loop-helix family member e40 (BHLHE40) is a transcription factor recently emerged as a key regulator of host immunity to infections, autoimmune diseases and cancer. In this study, we investigated the role of Bhlhe40 in protective T cell responses to the intracellular bacterium Chlamydia in the female reproductive tract (FRT). Mice deficient in Bhlhe40 exhibited severe defects in their ability to control Chlamydia muridarum shedding from the FRT. The heightened bacterial burdens in Bhlhe40-/- mice correlated with a marked increase in IL-10-producing T regulatory type 1 (Tr1) cells and decreased polyfunctional CD4 T cells co-producing IFN-γ, IL-17A and GM-CSF. Genetic ablation of IL-10 or functional blockade of IL-10R increased CD4 T cell polyfunctionality and partially rescued the defects in bacterial control in Bhlhe40-/- mice. Using single-cell RNA sequencing coupled with TCR profiling, we detected a significant enrichment of stem-like T cell signatures in Bhlhe40-deficient CD4 T cells, whereas WT CD4 T cells were further down on the differentiation trajectory with distinct effector functions beyond IFN-γ production by Th1 cells. Altogether, we identified Bhlhe40 as a key molecular driver of CD4 T cell differentiation and polyfunctional responses in the FRT against Chlamydia.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linfócitos T CD4-Positivos , Infecções por Chlamydia , Chlamydia muridarum , Proteínas de Homeodomínio , Animais , Feminino , Camundongos , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Infecções por Chlamydia/imunologia , Chlamydia muridarum/fisiologia , Interleucina-10/metabolismo , Camundongos Endogâmicos C57BL , Células Th1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Homeodomínio/metabolismo
5.
Nature ; 579(7797): 152-157, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32076264

RESUMO

GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric Gs protein2, but it is unclear how GPR52 and Gs couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a Gs-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR523. A fully active state is achieved when Gs is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.


Assuntos
Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Regulação Alostérica , Sítio Alostérico , Motivos de Aminoácidos , Sequência de Aminoácidos , Apoproteínas/agonistas , Apoproteínas/química , Apoproteínas/metabolismo , Sítios de Ligação , Microscopia Crioeletrônica , Cristalografia por Raios X , Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/ultraestrutura , Humanos , Ligantes , Modelos Moleculares , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/ultraestrutura
6.
Proc Natl Acad Sci U S A ; 120(41): e2221653120, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37788309

RESUMO

Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.


Assuntos
Neoplasias Colorretais , Metformina , Humanos , Proteína com Valosina/genética , Proteína com Valosina/metabolismo , Processos Neoplásicos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Ácidos Graxos/metabolismo , Metformina/farmacologia , Carnitina O-Palmitoiltransferase/metabolismo , Oxirredução
7.
Brief Bioinform ; 24(2)2023 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-36653898

RESUMO

Lysine glutarylation (Kglu) is a newly discovered post-translational modification of proteins with important roles in mitochondrial functions, oxidative damage, etc. The established biological experimental methods to identify glutarylation sites are often time-consuming and costly. Therefore, there is an urgent need to develop computational methods for efficient and accurate identification of glutarylation sites. Most of the existing computational methods only utilize handcrafted features to construct the prediction model and do not consider the positive impact of the pre-trained protein language model on the prediction performance. Based on this, we develop an ensemble deep-learning predictor Deepro-Glu that combines convolutional neural network and bidirectional long short-term memory network using the deep learning features and traditional handcrafted features to predict lysine glutaryation sites. The deep learning features are generated from the pre-trained protein language model called ProtBert, and the handcrafted features consist of sequence-based features, physicochemical property-based features and evolution information-based features. Furthermore, the attention mechanism is used to efficiently integrate the deep learning features and the handcrafted features by learning the appropriate attention weights. 10-fold cross-validation and independent tests demonstrate that Deepro-Glu achieves competitive or superior performance than the state-of-the-art methods. The source codes and data are publicly available at https://github.com/xwanggroup/Deepro-Glu.


Assuntos
Biologia Computacional , Lisina , Lisina/metabolismo , Biologia Computacional/métodos , Redes Neurais de Computação , Proteínas/metabolismo , Software
8.
PLoS Pathog ; 19(10): e1011694, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37831643

RESUMO

Alongshan virus (ALSV), a newly discovered member of unclassified Flaviviridae family, is able to infect humans. ALSV has a multi-segmented genome organization and is evolutionarily distant from canonical mono-segmented flaviviruses. The virus-encoded methyltransferase (MTase) plays an important role in viral replication. Here we show that ALSV MTase readily binds S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH) but exhibits significantly lower affinities than canonical flaviviral MTases. Structures of ALSV MTase in the free and SAM/SAH-bound forms reveal that the viral enzyme possesses a unique loop-element lining side-wall of the SAM/SAH-binding pocket. While the equivalent loop in flaviviral MTases half-covers SAM/SAH, contributing multiple hydrogen-bond interactions; the pocket-lining loop of ALSV MTase is of short-length and high-flexibility, devoid of any physical contacts with SAM/SAH. Subsequent mutagenesis data further corroborate such structural difference affecting SAM/SAH-binding. Finally, we also report the structure of ALSV MTase bound with sinefungin, an SAM-analogue MTase inhibitor. These data have delineated the basis for the low-affinity interaction between ALSV MTase and SAM/SAH and should inform on antiviral drug design.


Assuntos
Flavivirus , Metiltransferases , Humanos , Metiltransferases/genética , Flavivirus/genética , Flavivirus/metabolismo , S-Adenosilmetionina/metabolismo , Mutagênese
9.
Med Res Rev ; 44(6): 2600-2623, 2024 11.
Artigo em Inglês | MEDLINE | ID: mdl-38769656

RESUMO

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual-target drugs, especially focusing on pharmacological small-molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual-target drugs would shed light on discovering more novel candidate small-molecule drugs for the future cancer treatment.


Assuntos
Antineoplásicos , Neoplasias , Bibliotecas de Moléculas Pequenas , Humanos , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Animais , Terapia de Alvo Molecular , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos
10.
Biochem Cell Biol ; 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013204

RESUMO

Atherosclerosis (AS) is an inflammatory arterial disorder that occurs due to the deposition of the excessive lipoprotein under the artery intima, mainly including low-density lipoprotein and other apolipoprotein B-containing lipoproteins. G protein-coupled receptors (GPCRs) play a crucial role in transmitting signals in physiological and pathophysiological conditions. GPCRs recognize inflammatory mediators, thereby serving as important players during chronic inflammatory processes. It has been demonstrated that free fatty acids can function as ligands for various GPCRs, such as free fatty acid receptor (FFAR)1/GPR40, FFAR2/GPR43, FFAR3/GPR41, FFAR4/GPR120, and the lipid metabolite binding glucose-dependent insulinotropic receptor (GPR119). This review discusses GPR43 and its ligands in the pathogenesis of AS, especially focusing on its distinct role in regulating chronic vascular inflammation, inhibiting oxidative stress, ameliorating endothelial dysfunction and improving dyslipidemia. It is hoped that this review may provide guidance for further studies aimed at GPR43 as a promising target for drug development in the prevention and therapy of AS.

11.
Anal Chem ; 96(42): 16793-16801, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39391952

RESUMO

Nanolabels can enhance the detection performance of electrochemical biosensing methods, yet their practical application is hindered by complex preparation, batch-to-batch variability, and poor long-term storage stability. Herein, we present a novel electrochemical method for miRNA detection based on the just-in-time generation of zeolitic imidazolate framework-8 (ZIF-8) nanolabels initiated by nucleic acids. In this design, the target miRNA-21 is captured with magnetic beads and polyadenylated by Escherichia coli Poly(A) polymerase (EPP), producing miRNA-21 molecules with poly(A) tails (miR-21-poly(A)). These molecules are then adsorbed onto a bare gold electrode (AuE) surface via adenine-gold affinity interactions, serving as nucleation sites for the rapid in situ formation of ZIF-8 nanoparticles. The ZIF-8 nanoparticles function as signal labels, impeding electron transfer at the electrode interfaces and thereby generating a notable electrochemical signal. The developed method demonstrated exceptional sensitivity, with a detection limit (LOD) as low as 2.3 aM and a linear detection range from 10 aM to 1000 fM. The practical application of the developed method was validated by using it to evaluate miRNA-21 expression levels in various biological samples, including cell lines, tumor tissues, and clinical blood samples from non-small cell lung cancer (NSCLC) patients. This approach simplifies the detection process by eliminating the need for presynthesized nanomaterials and premodified electrodes. Its simplicity and high sensitivity make this method a promising tool for point-of-care testing and a wide range of biomedical research applications.


Assuntos
Técnicas Eletroquímicas , Eletrodos , MicroRNAs , MicroRNAs/análise , MicroRNAs/sangue , Humanos , Limite de Detecção , Técnicas Biossensoriais , Ouro/química , Estruturas Metalorgânicas/química , Biomineralização , Zeolitas/química , Imidazóis
12.
J Transl Med ; 22(1): 6, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167440

RESUMO

BACKGROUND: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. METHODS: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. CONCLUSIONS: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.


Assuntos
Neoplasias da Mama , Animais , Camundongos , Humanos , Feminino , Neoplasias da Mama/patologia , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Ácidos Graxos , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , PTEN Fosfo-Hidrolase/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica
13.
J Transl Med ; 22(1): 326, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566102

RESUMO

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Microbioma Gastrointestinal , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia , Receptores ErbB/genética , Antibacterianos/uso terapêutico
14.
Hepatology ; 77(5): 1499-1511, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35398929

RESUMO

BACKGROUND AND AIMS: Cholesterol ester (CE) biosynthesis and homeostasis play critical roles in many cancers, including HCC, but their exact mechanistic contributions to HCC disease development require further study. APPROACH AND RESULTS: Here, we report on a proposed role of tumor suppressor P53 in its repressing ubiquitin-specific peptidase 19 (USP19) and sterol O-acyltransferase (SOAT) 1, which maintains CE homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis (HCG) by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and HCG in P53-deficient mice fed with either a normal chow diet or a high-cholesterol, high-fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD-maintained P53-deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in the mouse model, the P53-USP19-SOAT1 signaling axis is also dysregulated in human HCCs. CONCLUSIONS: Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Esterificação , Carcinoma Hepatocelular/genética , Proteína Supressora de Tumor p53/genética , Neoplasias Hepáticas/genética , Colesterol , Endopeptidases
15.
Phys Rev Lett ; 132(7): 076501, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38427873

RESUMO

Transport measurement, which applies an electric field and studies the migration of charged particles, i.e., the current, is the most widely used technique in condensed matter studies. It is generally assumed that the quantum phase remains unchanged when it hosts a sufficiently small probing current, which is, surprisingly, rarely examined experimentally. In this Letter, we study the ultra-high-mobility two-dimensional electron system using a propagating surface acoustic wave, whose traveling speed is affected by the electrons' compressibility. The acoustic power used in our Letter is several orders of magnitude lower than previous reports, and its induced perturbation to the system is smaller than the transport current. Therefore we are able to observe the quantum phases become more incompressible when hosting a perturbative current.

16.
Circ Res ; 130(10): 1550-1564, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35430873

RESUMO

BACKGROUND: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. METHODS: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8+ T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. RESULTS: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. CONCLUSIONS: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.


Assuntos
Acetato de Desoxicorticosterona , Hipertensão , Animais , Linfócitos T CD8-Positivos/metabolismo , Acetato de Desoxicorticosterona/metabolismo , Acetato de Desoxicorticosterona/farmacologia , Modelos Animais de Doenças , Hipertensão/metabolismo , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/patologia , Camundongos , Sódio/metabolismo , Simportadores de Cloreto de Sódio/metabolismo , Cloreto de Sódio na Dieta
17.
Br J Clin Pharmacol ; 90(9): 2188-2199, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38845212

RESUMO

AIMS: Although there are various model-based approaches to individualized vancomycin (VCM) administration, few have been reported for adult patients with periprosthetic joint infection (PJI). This work attempted to develop a machine learning (ML)-based model for predicting VCM trough concentration in adult PJI patients. METHODS: The dataset of 287 VCM trough concentrations from 130 adult PJI patients was split into a training set (229) and a testing set (58) at a ratio of 8:2, and an independent external 32 concentrations were collected as a validation set. A total of 13 covariates and the target variable (VCM trough concentration) were included in the dataset. A covariate model was respectively constructed by support vector regression, random forest regression and gradient boosted regression trees and interpreted by SHapley Additive exPlanation (SHAP). RESULTS: The SHAP plots visualized the weight of the covariates in the models, with estimated glomerular filtration rate and VCM daily dose as the 2 most important factors, which were adopted for the model construction. Random forest regression was the optimal ML algorithm with a relative accuracy of 82.8% and absolute accuracy of 67.2% (R2 =.61, mean absolute error = 2.4, mean square error = 10.1), and its prediction performance was verified in the validation set. CONCLUSION: The proposed ML-based model can satisfactorily predict the VCM trough concentration in adult PJI patients. Its construction can be facilitated with only 2 clinical parameters (estimated glomerular filtration rate and VCM daily dose), and prediction accuracy can be rationalized by SHAP values, which highlights a profound practical value for clinical dosing guidance and timely treatment.


Assuntos
Antibacterianos , Aprendizado de Máquina , Infecções Relacionadas à Prótese , Vancomicina , Humanos , Feminino , Masculino , Vancomicina/farmacocinética , Vancomicina/administração & dosagem , Vancomicina/sangue , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Pessoa de Meia-Idade , Idoso , Infecções Relacionadas à Prótese/tratamento farmacológico , Adulto , Taxa de Filtração Glomerular , Estudos Retrospectivos , Modelos Biológicos , Idoso de 80 Anos ou mais
18.
J Org Chem ; 89(19): 14447-14453, 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39319749

RESUMO

A copper-catalyzed oxidative annulation of sydnones with perfluorocarboxylic anhydride for the synthesis of 3-aryl-5-fluoroalkyl-1,3,4-oxadiazol-2(3H)-ones is developed. A diverse array of 3-aryl-5-fluoroalkyl-1,3,4-oxadiazol-2(3H)-ones are prepared with good yields (>73 examples, yields up to 95%). The synthetic utility of the developed protocol was demonstrated by gram-scale synthesis, and the synthetic transformation to 1,2,4-triazol-3-one products. A mechanistic study suggests that the reaction proceeds via the extrusion of carbon dioxide to generate the hydrazide intermediate, which then undergoes intramolecular cyclization and oxidation.

19.
Inorg Chem ; 63(37): 17157-17165, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39236295

RESUMO

Conventional fluorescent materials frequently exhibit narrow-band emissions with a small full width at half-maximum (fwhm) due to localized-state characteristics, but electroluminescence is less efficient owing to the utilization of only singlet excitons. In this work, taking advantage of naphthalimide (NAI)-acetylide derivatives with a rigid planar structure and localized transition characteristics, we elaborately designed two mononuclear Pt(II) complexes with weak double emissions of fluorescence and phosphorescence. Taking them as synthetic precursors, we prepared three PtAu2 heteronuclear clusters and successfully attained highly efficient narrow-band red phosphorescence with the fwhm below 30 nm. Both theoretical and experimental results suggest that the phosphorescence of PtAu2 clusters mainly originates from the naphthalimide-localized 3IL (intraligand) triplet state. Solution-processed organic light-emitting diodes (OLEDs) achieved highly efficient narrow-band red electroluminescence with an external quantum efficiency (EQE) of 16.7%. The CIE coordinates of the electroluminescence (0.69, 0.31) closely match the standard red emission for ultrahigh-definition display.

20.
J Nat Prod ; 87(5): 1479-1486, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38728656

RESUMO

Bioinspired skeleton transformation of a tricyclic lathyrane-type Euphorbia diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic Euphorbia diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.


Assuntos
Diterpenos , Euphorbia , Diterpenos/química , Diterpenos/isolamento & purificação , Euphorbia/química , Estrutura Molecular , Biomimética , Produtos Biológicos/química
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