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1.
Cell ; 186(15): 3208-3226.e27, 2023 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-37379838

RESUMO

N7-methylguanosine (m7G) modification, routinely occurring at mRNA 5' cap or within tRNAs/rRNAs, also exists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved "GANGAN (N = A/C/U/G)" motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.


Assuntos
DNA Helicases , RNA Helicases , DNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/genética , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , RNA Helicases/metabolismo , Grânulos de Estresse , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação ao GTP/metabolismo , RNA Mensageiro/metabolismo , Grânulos Citoplasmáticos/metabolismo
2.
Mol Cell ; 81(5): 922-939.e9, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434505

RESUMO

R-2-hydroxyglutarate (R-2HG), a metabolite produced by mutant isocitrate dehydrogenases (IDHs), was recently reported to exhibit anti-tumor activity. However, its effect on cancer metabolism remains largely elusive. Here we show that R-2HG effectively attenuates aerobic glycolysis, a hallmark of cancer metabolism, in (R-2HG-sensitive) leukemia cells. Mechanistically, R-2HG abrogates fat-mass- and obesity-associated protein (FTO)/N6-methyladenosine (m6A)/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated post-transcriptional upregulation of phosphofructokinase platelet (PFKP) and lactate dehydrogenase B (LDHB) (two critical glycolytic genes) expression and thereby suppresses aerobic glycolysis. Knockdown of FTO, PFKP, or LDHB recapitulates R-2HG-induced glycolytic inhibition in (R-2HG-sensitive) leukemia cells, but not in normal CD34+ hematopoietic stem/progenitor cells, and inhibits leukemogenesis in vivo; conversely, their overexpression reverses R-2HG-induced effects. R-2HG also suppresses glycolysis and downregulates FTO/PFKP/LDHB expression in human primary IDH-wild-type acute myeloid leukemia (AML) cells, demonstrating the clinical relevance. Collectively, our study reveals previously unrecognized effects of R-2HG and RNA modification on aerobic glycolysis in leukemia, highlighting the therapeutic potential of targeting cancer epitranscriptomics and metabolism.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Antineoplásicos/farmacologia , Glutaratos/farmacologia , Glicólise/genética , Lactato Desidrogenases/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Fosfofrutoquinase-1 Tipo C/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/antagonistas & inibidores , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Glicólise/efeitos dos fármacos , Células HEK293 , Humanos , Células K562 , Lactato Desidrogenases/antagonistas & inibidores , Lactato Desidrogenases/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação Oxidativa/efeitos dos fármacos , Fosfofrutoquinase-1 Tipo C/antagonistas & inibidores , Fosfofrutoquinase-1 Tipo C/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
3.
PLoS Pathog ; 20(5): e1012210, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38709737

RESUMO

[This corrects the article DOI: 10.1371/journal.ppat.1008437.].

4.
J Cell Mol Med ; 28(4): e18120, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38358010

RESUMO

Our previous study confirmed that umbilical cord mesenchymal stem cells-exosomes (ucMSC-Ex) inhibit apoptosis of pancreatic acinar cells to exert protective effects. However, the relationship between apoptosis and autophagy in traumatic pancreatitis (TP) has rarely been reported. We dissected the transcriptomics after pancreatic trauma and ucMSC-Ex therapy by high-throughput sequencing. Additionally, we used rapamycin and MHY1485 to regulate mTOR. HE, inflammatory factors and pancreatic enzymatic assays were used to comprehensively determine the local versus systemic injury level, fluorescence staining and electron microscopy were used to detect the effect of autophagy, and observe the expression levels of autophagy-related markers at the gene and protein levels. High-throughput sequencing identified that autophagy played a crucial role in the pathophysiological process of TP and ucMSC-Ex therapy. The results of electron microscopy, immunofluorescence staining, polymerase chain reaction and western blot suggested that therapeutic effect of ucMSC-Ex was mediated by activation of autophagy in pancreatic acinar cells through inhibition of mTOR. ucMSC-Ex can attenuate pancreas injury by inhibiting mTOR to regulate acinar cell autophagy after TP. Future studies will build on the comprehensive sequencing of RNA carried by ucMSC-Ex to predict and verify specific non-coding RNA.


Assuntos
Exossomos , Células-Tronco Mesenquimais , Pancreatite , Humanos , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Cordão Umbilical , Serina-Treonina Quinases TOR/metabolismo , Pancreatite/metabolismo , Autofagia/genética , Apoptose
5.
Plant J ; 115(1): 155-174, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37025008

RESUMO

Salicylic acid (SA) plays important roles in different aspects of plant development, including root growth, where auxin is also a major player by means of its asymmetric distribution. However, the mechanism underlying the effect of SA on the development of rice roots remains poorly understood. Here, we show that SA inhibits rice root growth by interfering with auxin transport associated with the OsPIN3t- and clathrin-mediated gene regulatory network (GRN). SA inhibits root growth as well as Brefeldin A-sensitive trafficking through a non-canonical SA signaling mechanism. Transcriptome analysis of rice seedlings treated with SA revealed that the OsPIN3t auxin transporter is at the center of a GRN involving the coat protein clathrin. The root growth and endocytic trafficking in both the pin3t and clathrin heavy chain mutants were SA insensitivity. SA inhibitory effect on the endocytosis of OsPIN3t was dependent on clathrin; however, the root growth and endocytic trafficking mediated by tyrphostin A23 (TyrA23) were independent of the pin3t mutant under SA treatment. These data reveal that SA affects rice root growth through the convergence of transcriptional and non-SA signaling mechanisms involving OsPIN3t-mediated auxin transport and clathrin-mediated trafficking as key components.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Oryza , Clatrina/metabolismo , Proteínas de Arabidopsis/metabolismo , Oryza/metabolismo , Arabidopsis/genética , Ácido Salicílico/metabolismo , Raízes de Plantas/metabolismo , Transporte Proteico , Ácidos Indolacéticos/metabolismo
6.
Br J Cancer ; 130(9): 1517-1528, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38459187

RESUMO

BACKGROUND: Circß-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown. METHODS: The qRT-PCR examination was used to detect the expression of circß-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circß-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circß-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circß-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays. RESULTS: In the present study, circß-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circß-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circß-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2. CONCLUSIONS: Our findings illustrated a novel mechanism of circß-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.


Assuntos
Proliferação de Células , Neoplasias Colorretais , Progressão da Doença , Fator de Iniciação 4A em Eucariotos , Camundongos Nus , MicroRNAs , RNA Circular , beta Catenina , MicroRNAs/genética , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , RNA Circular/genética , Animais , Camundongos , beta Catenina/metabolismo , beta Catenina/genética , Proliferação de Células/genética , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , delta Catenina , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Masculino , Feminino , Movimento Celular/genética , Camundongos Endogâmicos BALB C
7.
Biochem Biophys Res Commun ; 695: 149401, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38154264

RESUMO

Human calcium sensing receptor (CaSR) senses calcium ion concentrations in vivo and is an important class of drug targets. Mutations in the receptor can lead to disorders of calcium homeostasis, including hypercalcemia and hypocalcemia. Here, 127 CaSR-targeted nanobodies were generated from camels, and four nanobodies with inhibitory function were further identified. Among these nanobodies, NB32 can effectively inhibit the mobilization of intracellular calcium ions (Ca2+i) and suppress the G12/13 and ERK1/2 signaling pathways downstream of CaSR. Moreover, it enhanced the inhibitory effect of the calcilytics as a negative allosteric modulator (NAM). We determined the structure of complex and found NB32 bound to LB2 (Ligand-binding 2) domain of CaSR to prevent the interaction of LB2 domains of two protomers to stabilize the inactive state of CaSR.


Assuntos
Hipercalcemia , Hipocalcemia , Anticorpos de Domínio Único , Humanos , Receptores de Detecção de Cálcio/metabolismo , Cálcio/metabolismo , Hipocalcemia/genética , Hipercalcemia/genética
8.
J Viral Hepat ; 31(4): 189-196, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38235909

RESUMO

Hepatocellular carcinoma (HCC) is one common malignant tumour with a high immunosuppressive tumour microenvironment and poor outcomes. This study investigated the influence of hsa_circ_0010882 on M1/M2 macrophage polarization in the progression of HCC. A total of 125 paired tissue specimens from HCC patients who underwent hepatectomy were collected. M1 and M2 phenotypes macrophages were induced using THP-1. After co-cultured with macrophages and transfected HCC cells, the viability, migration and invasion of HCC cells were detected by cellular experiments. Bioinformatic databases and dual-luciferase reporter assays were used to predict and validate the interaction between circ_0010882 and miR-382. Expression of circ_0010882 was increased in HCC tissues and associated with shorter overall survival outcomes. The mRNA expression of M2 macrophage markers Arg-1, CD163 and CD206 were elevated in HCC tissues. Interfering with circ_0010882 increased M1-type macrophage markers (TNF-α and iNOS) while decreasing M2-type macrophage markers (Arg-1 and CD206). Silencing of circ_0010882 strengthened the capacity of M1 macrophages to suppress HCC cell viability, migration capacities and invasion potential while reducing the ability of M2 macrophages to promote above cellular abilities. MiR-382 was a direct target miRNA of circ_0010882. The circ_0010882 expression was increased in HCC tissues and associated with poor prognosis of HCC patients. Silencing of circ_0010882 inhibits macrophage M2 polarization in HCC progression by regulating miR-382 expression. Circ_0010882 may serve as a biomarker to provide novel strategies for the treatment of HCC and patient rehabilitation, thereby improving the prognosis of patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Macrófagos/metabolismo , Macrófagos/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular , Proliferação de Células/genética , Linhagem Celular Tumoral , Microambiente Tumoral
9.
Plant Physiol ; 192(1): 666-679, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-36881883

RESUMO

The active structural change of actin cytoskeleton is a general host response upon pathogen attack. This study characterized the function of the cotton (Gossypium hirsutum) actin-binding protein VILLIN2 (GhVLN2) in host defense against the soilborne fungus Verticillium dahliae. Biochemical analysis demonstrated that GhVLN2 possessed actin-binding, -bundling, and -severing activities. A low concentration of GhVLN2 could shift its activity from actin bundling to actin severing in the presence of Ca2+. Knockdown of GhVLN2 expression by virus-induced gene silencing reduced the extent of actin filament bundling and interfered with the growth of cotton plants, resulting in the formation of twisted organs and brittle stems with a decreased cellulose content of the cell wall. Upon V. dahliae infection, the expression of GhVLN2 was downregulated in root cells, and silencing of GhVLN2 enhanced the disease tolerance of cotton plants. The actin bundles were less abundant in root cells of GhVLN2-silenced plants than in control plants. However, upon infection by V. dahliae, the number of actin filaments and bundles in the cells of GhVLN2-silenced plants was raised to a comparable level as those in control plants, with the dynamic remodeling of the actin cytoskeleton appearing several hours in advance. GhVLN2-silenced plants exhibited a higher incidence of actin filament cleavage in the presence of Ca2+, suggesting that pathogen-responsive downregulation of GhVLN2 could activate its actin-severing activity. These data indicate that the regulated expression and functional shift of GhVLN2 contribute to modulating the dynamic remodeling of the actin cytoskeleton in host immune responses against V. dahliae.


Assuntos
Ascomicetos , Verticillium , Gossypium/metabolismo , Resistência à Doença/genética , Actinas/metabolismo , Cálcio/metabolismo , Verticillium/fisiologia , Ascomicetos/metabolismo , Citoesqueleto de Actina/metabolismo , Doenças das Plantas/microbiologia , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo
10.
Plant Cell Environ ; 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39262203

RESUMO

Stomata are channels through which plants exchange H2O and CO2 with the external environment. The regulation of stomatal movement has significant impacts on plant growth, development and stress adaptation. Here, we present a maize R2R3 -MYB transcription factor, ZmMYB56, which regulates high CO2-induced stomatal closure in maize seedlings. ZmMYB56 is highly expressed in stomatal guard cells and is negatively regulated by CO2 and HCO3 -. Loss of ZmMYB56 function leads to insensitivity to high CO2. As a transcription factor, ZmMYB56 binds to a cis-acting element in the ZmHLT1 promoter and regulates its expression. ZmHLT1 plays a key role in CO2- induced maize stomatal movement, and its absence causes a severe weakening of maize's response to ambient CO2. ZmHLT1 expression is negatively regulated by bicarbonate, which does not occur in Zmmyb56 mutants, highlighting the significance of this regulatory relationship in plant responses to CO2 and HCO3 -. Taken together, these results show that ZmMYB56-regulated ZmHLT1 expression is important for high CO2-induced stomatal closure in maize. Our findings provide insight into genetic pathways that could be manipulated to improve maize growth and stress tolerance, especially under increasing atmospheric CO2 concentrations.

11.
Microb Pathog ; 193: 106768, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38960217

RESUMO

Fowl cholera is an infectious disease that affects both poultry and wild birds, characterized by hemorrhagic and septicemic symptoms, caused by Pasteurella multocida (P. multocida), and leading to substantial economic losses in the poultry sector. The development of genetic engineering vaccines against avian P. multocida encountered early-stage challenges due to the limited availability of effective gene editing tools. Presently, NgAgoDM-enhanced homologous recombination stands as a potent technique for achieving efficient gene knockout in avian P. multocida. Hence, this study employed NgAgoDM-enhanced homologous recombination to target and knockout hyaE (239-359aa), hyaD, hexABC, and hexD, denoted as ΔhyaE (239-359aa), ΔhyaD, ΔhexABC, and ΔhexD, respectively. Additionally, we generated a hyaD recovery strain with two point mutations, designated as mhyaD. Thus, this study systematically examined the impact of capsular synthetic gene clusters on the pathogenicity of P. multocida. Moreover, the study demonstrated the critical role of hyaD activity in the virulence of avian P. multocida. This study offers novel insights for enhancing attenuated vaccines further.


Assuntos
Infecções por Pasteurella , Pasteurella multocida , Doenças das Aves Domésticas , Pasteurella multocida/genética , Pasteurella multocida/patogenicidade , Animais , Infecções por Pasteurella/veterinária , Infecções por Pasteurella/microbiologia , Virulência/genética , Doenças das Aves Domésticas/microbiologia , Vacinas Bacterianas/imunologia , Vacinas Bacterianas/genética , Recombinação Homóloga , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/genética , Técnicas de Inativação de Genes , Galinhas/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Aves/microbiologia , Família Multigênica , Fatores de Virulência/genética , Aves Domésticas/microbiologia
12.
BMC Cancer ; 24(1): 1323, 2024 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-39468461

RESUMO

OBJECTIVE: To compare the diagnostic performance of pancreatic lesions using percutaneous ultrasound (US)-guided core needle biopsy (CNB) with and without contrast-enhanced ultrasound (CEUS). METHOD: The patients were divided into two groups, US and CEUS group, based on whether CEUS was performed prior to biopsy. Before and after propensity score matching (PSM), the CNB-relevant characteristics of the two groups, including the first puncture success rate, the number of sampling, complication rate, type of complications, and degree of abdominal pain, were compared. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of percutaneous US-guided CNB were compared between the groups. RESULTS: This study included 277 patients (173 men and 104 women) with pancreatic lesions who underwent percutaneous CNB before PSM; 190 patients in the CEUS group, and 87 in the US group prior to CNB. After controlling for potential biases using PSM, no significant differences were observed in the complication rate, type of complications, or degree of abdominal pain between the CEUS and US groups (P > 0.05). However, significant differences were observed in the first puncture success rate and the number of sampling (P < 0.05). Importantly, before and after PSM, the CEUS group achieved a higher first-puncture success rate while obtaining a lower number of sampling (P < 0.05). Compared to the US group, the CEUS group demonstrated improved accuracy, sensitivity, specificity, PPV, and NPV of 13.1%, 14.9%, 13.4%, 2.5%, and 38.7%, respectively. Furthermore, the significant difference was observed in the AUC for diagnostic performance between the two groups when compared using DeLong's test (P = 0.043). CONCLUSIONS: Performing CEUS before percutaneous CNB for pancreatic lesions can help achieve better biopsy results, reduce the number of punctures samples, increase the success rate of biopsies, and avoid the need for repeat biopsies.


Assuntos
Meios de Contraste , Biópsia Guiada por Imagem , Neoplasias Pancreáticas , Pontuação de Propensão , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico , Idoso , Biópsia com Agulha de Grande Calibre/métodos , Biópsia Guiada por Imagem/métodos , Biópsia Guiada por Imagem/efeitos adversos , Adulto , Pâncreas/patologia , Pâncreas/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia de Intervenção/métodos , Sensibilidade e Especificidade , Ultrassonografia/métodos , Idoso de 80 Anos ou mais
13.
Anticancer Drugs ; 35(3): 271-276, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37948349

RESUMO

Lung cancer is one of the most common malignant tumors with the highest incidence. Gene mutations are rare in small-cell lung carcinoma (SCLC), resulting in targeted therapy being only a third-line recommendation. Surufatinib (Sulanda) is an oral angio-immune kinase inhibitor used to treat solid tumors. We report a case of SCLC treated with surufatinib combined with camrelizumab, with good therapeutic results in our department. The patient experienced over 18 months of progression-free survival and over 28 months of overall survival. This suggests that surufatinib combined with camrelizumab is an effective third-line treatment for SCLC patients. However, the response rate to surufatinib treatment in all patients with SCLC remains unknown and needs to be determined in a large population.


Assuntos
Indóis , Neoplasias Pulmonares , Pirimidinas , Carcinoma de Pequenas Células do Pulmão , Sulfonamidas , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Anticorpos Monoclonais Humanizados/uso terapêutico
14.
J Org Chem ; 89(4): 2090-2103, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38271667

RESUMO

Triphenylphosphine oxide is a well-known industrial waste byproduct, and thousands of tons of it are generated every year. Due to its chemical stability and limited applications, settlement of this waste issue has drawn extensive attention from chemists. The reduction of triphenylphosphine oxide to triphenylphosphine is heretofore the most employed solution, and is well reviewed. In view of our recent studies on the selective and efficient conversion of Ph3P(O) to other valuable organophosphorus chemicals by using sodium, the present perspective mainly highlights the advances on the utilization of Ph3P(O) to prepare a diverse range of functional organophosphorus compounds, except Ph3P, via selective P-C, C-H, and P-O bond cleavages.

15.
J Org Chem ; 89(7): 5109-5117, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38483841

RESUMO

A novel strategy for the selective construction of a C(sp3)-P(III) or -P(V) bond from >P(O)-H compounds and aldehydes is disclosed. By using the H3PO3/I2 system, various secondary phosphine oxides could react with both aromatic and aliphatic aldehydes to afford valuable phosphines (isolated as sulfides) and phosphine oxides in good yields. This method features a wide substrate scope and simple reaction conditions and avoids the use of toxic halides and metals.

16.
J Org Chem ; 89(10): 7047-7057, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38669210

RESUMO

An efficient method for the construction of C-P(V) and C-P(III) bonds via the iron-catalyzed phosphorylation of alcohols under ligand-free conditions is disclosed. This strategy represents a straightforward process to prepare a series of phosphine oxides and phosphine compounds in good to excellent yields from the readily available alcohols and P-H compounds. A plausible mechanism is also proposed. We anticipate that this mode of transforming simple alcohols would apply in chemical synthesis widely.

17.
Biomarkers ; : 1-35, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39484861

RESUMO

The age-induced disruption of gut flora, termed gut dysbiosis, is intimately tied to compromised immune function, augmented oxidative stress, and a spectrum of age-linked disorders. This review examines the fundamental mechanisms employed by probiotic strains to modulate gut microbiota composition and metabolic profiles, mitigate cognitive decline via the gut-brain axis, modulate gene transcription, and alleviate inflammatory responses and oxidative stress. We elucidate the capacity of probiotics as a precision intervention to restore gut microbiome homeostasis and alleviate age-related conditions, thereby offering a theoretical framework for probiotics to decelerate aging, manage age-related diseases, and elevate quality of life.

18.
J Immunol ; 208(2): 501-513, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34911774

RESUMO

Protein arginine methyltransferase 5 (PRMT5) participates in the symmetric dimethylation of arginine residues of proteins and contributes to a wide range of biological processes. However, how PRMT5 affects the transcriptional and epigenetic programs involved in the establishment and maintenance of T cell subset differentiation and roles in antitumor immunity is still incompletely understood. In this study, using single-cell RNA and chromatin immunoprecipitation sequencing, we found that mouse T cell-specific deletion of PRMT5 had greater effects on CD8+ than CD4+ T cell development, enforcing CD8+ T cell differentiation into Klrg1+ terminal effector cells. Mechanistically, T cell deficiency of PRMT5 activated Prdm1 by decreasing H4R3me2s and H3R8me2s deposition on its loci, which promoted the differentiation of Klrg1+CD8+ T cells. Furthermore, effector CD8+ T cells that transited to memory precursor cells were decreased in PRMT5-deficient T cells, thus causing dramatic CD8+ T cell death. In addition, in a mouse lung cancer cell line-transplanted tumor mouse model, the percentage of CD8+ T cells from T cell-specific deletion of PRMT5 mice was dramatically lost, but CD8+Foxp3+ and CD8+PDL1+ regulatory T cells were increased compared with the control group, thus accelerating tumor progression. We further verified these results in a mouse colon cancer cell line-transplanted tumor mouse model. Our study validated the importance of targeting PRMT5 in tumor treatment, because PRMT5 deficiency enforced Klrg1+ terminal CD8+ T cell development and eliminated antitumor activity.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/genética , Lectinas Tipo C/metabolismo , Proteína-Arginina N-Metiltransferases/deficiência , Receptores Imunológicos/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Hematopoese/fisiologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Ativação Linfocitária/imunologia , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteína-Arginina N-Metiltransferases/genética , RNA-Seq , Transdução de Sinais/genética , Análise de Célula Única
19.
J Nat Prod ; 87(10): 2441-2449, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39413018

RESUMO

Penicamins A-L (1-12), 12 highly oxygenated novel diterpenes, were obtained from the fungus Penicillium camemberti JSB-7212. Compounds 1-12 share the same 7/6/5 tricyclic skeleton as valparane-type diterpenes but differ in the absolute configurations at C-7, C-11, and C-14, as well as in the oxidation levels at C-6 and C-8, which were determined through extensive spectroscopic data interpretation. Stereochemical assignments of compounds 1, 2, and 4-12 were established by single-crystal X-ray diffraction, and the absolute configuration of 3 was determined by analysis of the NOESY data and biogenetic consideration. Compounds 2 and 3 were immunosuppressive against lipopolysaccharide (LPS)-induced B cells, with IC50 values of 3.0 and 7.9 µM, respectively. They also moderately suppressed concanavalin A (ConA)-induced T cell proliferation, with IC50 values of 19 and 20 µM, respectively.


Assuntos
Diterpenos , Penicillium , Penicillium/química , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Estrutura Molecular , Animais , Camundongos , Linfócitos T/efeitos dos fármacos , Imunossupressores/farmacologia , Imunossupressores/química , Imunossupressores/isolamento & purificação , Linfócitos B/efeitos dos fármacos , Cristalografia por Raios X
20.
J Nat Prod ; 87(4): 966-975, 2024 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-38441877

RESUMO

Ten new (1-10) and nine known (11-19) austocystins, along with four known anthraquinones (20-23), were isolated from the culture of Aspergillus ustus NRRL 5856 by bioactivity-guided fractionation. The structures of the new compounds were elucidated by spectroscopic data analysis, X-ray crystallographic study, the modified Mosher's method, [Rh2(OCOCF3)4]-induced ECD spectral analysis, and comparison of the experimental ECD spectra with those of the similar analogues. Compounds 1-8 represent the first examples of austocystins with a C-4' oxygenated substitution. The absolute configuration of 1″-hydroxy austocystin D (11) was determined by single-crystal X-ray diffraction and consideration of its biosynthetic origin. Compounds 5, 9, and 11 exhibited significant inhibitory effects against the proliferation of ConA-induced T cells with IC50 values of 1.1, 1.0, and 0.93 µM, respectively. Furthermore, these compounds suppressed the expression of IL-6 in a dose-dependent manner. Compounds 10-12 and 14 showed pronounced cytotoxicities against MCF-7 with IC50 values of 3.9, 1.3, 0.46, and 2.3 µM, respectively.


Assuntos
Aspergillus , Imunossupressores , Aspergillus/química , Humanos , Imunossupressores/farmacologia , Imunossupressores/química , Imunossupressores/isolamento & purificação , Estrutura Molecular , Cristalografia por Raios X , Interleucina-6/metabolismo , Antraquinonas/farmacologia , Antraquinonas/química , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Linfócitos T/efeitos dos fármacos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos
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