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1.
Mol Cell ; 81(6): 1187-1199.e5, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33581076

RESUMO

Type I interferons (IFNs) are critical cytokines in the host defense against invading pathogens. Sustained production of IFNs, however, is detrimental to the host, as it provokes autoimmune diseases. Thus, the expression of IFNs is tightly controlled. We report that the mRNA 5' cap-binding protein 4EHP plays a key role in regulating type I IFN concomitant with controlling virus replication, both in vitro and in vivo. Mechanistically, 4EHP suppresses IFN-ß production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA. miR-34a is upregulated by both RNA virus infection and IFN-ß induction, prompting a negative feedback regulatory mechanism that represses IFN-ß expression via 4EHP. These findings demonstrate the direct involvement of 4EHP in virus-induced host response, underscoring a critical translational silencing mechanism mediated by 4EHP and miR-34a to impede sustained IFN production. This study highlights an intrinsic regulatory function for miRNA and the translation machinery in maintaining host homeostasis.


Assuntos
Fator de Iniciação 4E em Eucariotos/imunologia , Imunidade Inata , MicroRNAs/imunologia , Biossíntese de Proteínas/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Animais , Fator de Iniciação 4E em Eucariotos/genética , Células HEK293 , Humanos , Interferon beta/genética , Interferon beta/imunologia , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Infecções por Vírus de RNA/genética , Vírus de RNA/genética
2.
N Engl J Med ; 388(22): 2025-2036, 2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37256974

RESUMO

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).


Assuntos
Fibrinolíticos , AVC Isquêmico , Tirofibana , Humanos , Aspirina/efeitos adversos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , AVC Isquêmico/diagnóstico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/etiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Tirofibana/efeitos adversos , Tirofibana/uso terapêutico , Resultado do Tratamento , Doenças Arteriais Cerebrais/tratamento farmacológico , Doenças Arteriais Cerebrais/etiologia
3.
Nature ; 579(7799): 368-374, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188941

RESUMO

Two-dimensional van der Waals heterostructures (vdWHs) have attracted considerable interest1-4. However, most vdWHs reported so far  are created by an arduous micromechanical exfoliation and manual restacking process5, which-although versatile for proof-of-concept demonstrations6-16 and fundamental studies17-30-is clearly not scalable for practical technologies. Here we report a general synthetic strategy for two-dimensional vdWH arrays between metallic transition-metal dichalcogenides (m-TMDs) and semiconducting TMDs (s-TMDs). By selectively patterning nucleation sites on monolayer or bilayer s-TMDs, we precisely control the nucleation and growth of diverse m-TMDs with designable periodic arrangements and tunable lateral dimensions at the predesignated spatial locations, producing a series of vdWH arrays, including VSe2/WSe2, NiTe2/WSe2, CoTe2/WSe2, NbTe2/WSe2, VS2/WSe2, VSe2/MoS2 and VSe2/WS2. Systematic scanning transmission electron microscopy studies reveal nearly ideal vdW interfaces with widely tunable moiré superlattices. With the atomically clean vdW interface, we further show that the m-TMDs function as highly reliable synthetic vdW contacts for the underlying WSe2 with excellent device performance and yield, delivering a high ON-current density of up to 900 microamperes per micrometre in bilayer WSe2 transistors. This general synthesis of diverse two-dimensional vdWH arrays provides a versatile material platform for exploring exotic physics and promises a scalable pathway to high-performance devices.

4.
Dev Biol ; 505: 1-10, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37838025

RESUMO

Flower color diversity is a key taxonomic trait in Meconopsis species, enhancing their appeal as ornamental flowers. However, knowledge of the molecular mechanisms of flower color formation in Meconopsis species is still limited. M. wilsonii subsp. australis (Australis) and M. wilsonii subsp. orientalis (Orientalis) have a developmental stage presenting red-purple flowers, while Orientalis also presents blue coloration at the full-bloom period, making them an important model for exploring the mechanism of blue flower formation in M. wilsonii. In this study, we collected petals from Australis and Orientalis at different developmental stages to compare the coloration differences between the two species and detect the molecular mechanisms of blue color in Orientalis. We identified that cyanidin was the main anthocyanin in the flowers of both species, and the blue color in Orientalis primarily arises from anthocyanins (Cyanidin-3-O-sambubioside). RNA sequencing analysis was performed to detect the gene expression in the anthocyanin biosynthesis pathway, and the results suggested that gene regulation for anthocyanin biosynthesis may not be the direct reason for blue color formation in Orientalis. In addition, the growth solid of Orientalis was rich in Fe and Mg ions, and a large amount of Fe and Mg ions accumulated in the petals of Orientalis. Combined with the gene functional enrichment results, we found that the purple and red-purple colors of these two species were presented by different glycosylation levels of cyanidin, while the violet color of Orientalis might be the results of metalloanthocyanins by Fe and Mg ions, which also relieved the toxicity caused by the high content of Fe and Mg ions in its cells. The environmental adaptation-related genes were highly expressed of in both species, such as adaptation to desiccation, water deprivation, freezing, etc. Our results revealed the coloration differences between Australis and Orientalis and described the molecular mechanisms of blue coloration in Orientalis. The data in our analysis could enrich the genetic resources for M. wilsonii for further studies.


Assuntos
Antocianinas , Papaveraceae , Antocianinas/metabolismo , Papaveraceae/metabolismo , Fenótipo , Íons/metabolismo , Flores , Pigmentação/genética , Cor , Regulação da Expressão Gênica de Plantas
5.
Nat Mater ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38777873

RESUMO

Controlling topological phases of light allows the observation of abundant topological phenomena and the development of robust photonic devices. The prospect of more sophisticated control with topological photonic devices for practical implementations requires high-level programmability. Here we demonstrate a fully programmable topological photonic chip with large-scale integration of silicon photonic nanocircuits and microresonators. Photonic artificial atoms and their interactions in our compound system can be individually addressed and controlled, allowing the arbitrary adjustment of structural parameters and geometrical configurations for the observation of dynamic topological phase transitions and diverse photonic topological insulators. Individual programming of artificial atoms on the generic chip enables the comprehensive statistical characterization of topological robustness against relatively weak disorders, and counterintuitive topological Anderson phase transitions induced by strong disorders. This generic topological photonic chip can be rapidly reprogrammed to implement multifunctionalities, providing a flexible and versatile platform for applications across fundamental science and topological technologies.

6.
J Pathol ; 262(1): 105-120, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37850574

RESUMO

HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration-resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher-grade tumors, although no significant association between HOXB13 expression and recurrence or disease-specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor-negative castration-resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non-prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration-resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Reino Unido
7.
Exp Cell Res ; 436(2): 113981, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38387697

RESUMO

Osteoarthritis (OA) is the most common type of joint disease and the leading cause of chronic disability among older adults. As an important component of the joint, synovium influences the inflammatory and degenerative process of OA. This study found that miRNA 182 (miR-182) in synovium-specific exosomes can modulate inflammation and apoptotic signaling. It also regulated different biological functions to promote the progression of OA. Experiments based on rat OA model and synovium samples from OA patients, we found that synovium-derived miR-182 regulates inflammatory response in the early stage of OA by regulating the expression level of forkhead box O-3 (FOXO3). However, the expression of miR-182 was significantly increased in synovial tissue of advanced OA, which was involved in the apoptotic signal of severe OA. These findings suggest that miR-182 may directly regulate OA progression by modulating FOXO3 production inflammation, and apoptosis.


Assuntos
Exossomos , MicroRNAs , Osteoartrite , Humanos , Ratos , Animais , Idoso , Líquido Sinovial/metabolismo , Exossomos/genética , Exossomos/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Inflamação/genética , Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Condrócitos/metabolismo
8.
Mol Cell ; 65(1): 154-167, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041912

RESUMO

Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, but almost all cancer eventually becomes castration resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feedforward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKß/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.


Assuntos
Calcineurina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Homeodomínio/metabolismo , Inflamação/metabolismo , MicroRNAs/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Fator de Transcrição RelA/metabolismo , Antagonistas de Androgênios/farmacologia , Animais , Antineoplásicos Hormonais/farmacologia , Calcineurina/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Genes myc , Proteínas de Homeodomínio/genética , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos Transgênicos , MicroRNAs/genética , Inibidor de NF-kappaB alfa/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Fator de Transcrição RelA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Carga Tumoral , Células Tumorais Cultivadas
9.
Proc Natl Acad Sci U S A ; 119(28): e2122534119, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867737

RESUMO

Photoinduced phase transition (PIPT) is always treated as a coherent process, but ultrafast disordering in PIPT is observed in recent experiments. Utilizing the real-time time-dependent density functional theory method, here we track the motion of individual vanadium (V) ions during PIPT in VO2 and uncover that their coherent or disordered dynamics can be manipulated by tuning the laser fluence. We find that the photoexcited holes generate a force on each V-V dimer to drive their collective coherent motion, in competing with the thermal-induced vibrations. If the laser fluence is so weak that the photoexcited hole density is too low to drive the phase transition alone, the PIPT is a disordered process due to the interference of thermal phonons. We also reveal that the photoexcited holes populated by the V-V dimerized bonding states will become saturated if the laser fluence is too strong, limiting the timescale of photoinduced phase transition.

10.
Proc Natl Acad Sci U S A ; 119(42): e2207326119, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36215478

RESUMO

Electrochemical conversion of CO2 into formate is a promising strategy for mitigating the energy and environmental crisis, but simultaneously achieving high selectivity and activity of electrocatalysts remains challenging. Here, we report low-dimensional SnO2 quantum dots chemically coupled with ultrathin Ti3C2Tx MXene nanosheets (SnO2/MXene) that boost the CO2 conversion. The coupling structure is well visualized and verified by high-resolution electron tomography together with nanoscale scanning transmission X-ray microscopy and ptychography imaging. The catalyst achieves a large partial current density of -57.8 mA cm-2 and high Faradaic efficiency of 94% for formate formation. Additionally, the SnO2/MXene cathode shows excellent Zn-CO2 battery performance, with a maximum power density of 4.28 mW cm-2, an open-circuit voltage of 0.83 V, and superior rechargeability of 60 h. In situ X-ray absorption spectroscopy analysis and first-principles calculations reveal that this remarkable performance is attributed to the unique and stable structure of the SnO2/MXene, which can significantly reduce the reaction energy of CO2 hydrogenation to formate by increasing the surface coverage of adsorbed hydrogen.

11.
Proc Natl Acad Sci U S A ; 119(32): e2204539119, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35878012

RESUMO

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-ß. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-ß production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.


Assuntos
COVID-19 , Proteínas de Transporte , Interferon Tipo I , Proteínas não Estruturais Virais , COVID-19/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , SARS-CoV-2 , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
12.
Genomics ; 116(4): 110873, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38823464

RESUMO

Goat milk exhibits a robust and distinctive "goaty" flavor. However, the underlying genetic basis of goaty flavor remains elusive and requires further elucidation at the genomic level. Through comparative genomics analysis, we identified divergent signatures of certain proteins in goat, sheep, and cow. MMUT has undergone a goat-specific mutation in the B12 binding domain. We observed the goat FASN exhibits nonsynonymous mutations in the acyltransferase domain. Structural variations in these key proteins may enhance the capacity for synthesizing goaty flavor compounds in goat. Integrated omics analysis revealed the catabolism of branched-chain amino acids contributed to the goat milk flavor. Furthermore, we uncovered a regulatory mechanism in which the transcription factor ZNF281 suppresses the expression of the ECHDC1 gene may play a pivotal role in the accumulation of flavor substances in goat milk. These findings provide insights into the genetic basis underlying the formation of goaty flavor in goat milk. STATEMENT OF SIGNIFICANCE: Branched-chain fatty acids (BCFAs) play a crucial role in generating the distinctive "goaty" flavor of goat milk. Whether there is an underlying genetic basis associated with goaty flavor is unknown. To begin deciphering mechanisms of goat milk flavor development, we collected transcriptomic data from mammary tissue of goat, sheep, cow, and buffalo at peak lactation for cross-species transcriptome analysis and downloaded nine publicly available genomes for comparative genomic analysis. Our data indicate that the catabolic pathway of branched-chain amino acids (BCAAs) is under positive selection in the goat genome, and most genes involved in this pathway exhibit significantly higher expression levels in goat mammary tissue compared to other species, which contributes to the development of flavor in goat milk. Furthermore, we have elucidated the regulatory mechanism by which the transcription factor ZNF281 suppresses ECHDC1 gene expression, thereby exerting an important influence on the accumulation of flavor compounds in goat milk. These findings provide insights into the genetic mechanisms underlying flavor formation in goat milk and suggest further research to manipulate the flavor of animal products.


Assuntos
Cabras , Leite , Animais , Cabras/genética , Cabras/metabolismo , Leite/metabolismo , Leite/química , Paladar , Genômica , Transcriptoma , Feminino , Ovinos/genética , Ovinos/metabolismo , Bovinos/genética , Bovinos/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo
13.
Mol Cancer ; 23(1): 82, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664722

RESUMO

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-ß1, the principal form of exosomal TGF-ß1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-ß signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-ß1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-ß1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-ß1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.


Assuntos
Exossomos , Neoplasias Pulmonares , Fator de Crescimento Transformador beta1 , Neoplasias de Mama Triplo Negativas , Exossomos/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/genética , Fator de Crescimento Transformador beta1/metabolismo , Acetilação , Animais , Feminino , Camundongos , Linhagem Celular Tumoral , Microambiente Tumoral
14.
Nat Prod Rep ; 41(1): 25-58, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-37791885

RESUMO

Covering: 1925 to July 2023Among the sesquiterpenoids with rich structural diversity and potential bioactivities, lindenane sesquiterpenoids (LSs) possess a characteristic cis, trans-3,5,6-carbocyclic skeleton and mainly exist as monomers and diverse oligomers in plants from the Lindera genus and Chloranthaceae family. Since the first identification of lindeneol from Lindera strychnifolia in 1925, 354 natural LSs and their oligomers with anti-inflammatory, antitumor, and anti-infective activities have been discovered. Structurally, two-thirds of LSs exist as oligomers with interesting skeletons through diverse polymeric patterns, especially Diels-Alder [4 + 2] cycloaddition. Fascinated by their diverse bioactivities and intriguing polycyclic architectures, synthetic chemists have engaged in the total synthesis of natural LSs in recent decades. In this review, the research achievements related to LSs from 1925 to July of 2023 are systematically and comprehensively summarized, focusing on the classification of their structures, chemical synthesis, and bioactivities, which will be helpful for further research on LSs and their oligomers.


Assuntos
Anti-Infecciosos , Sesquiterpenos , Sesquiterpenos/química , Anti-Infecciosos/química , Reação de Cicloadição , Anti-Inflamatórios
15.
Prostate ; 84(10): 954-958, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38641986

RESUMO

BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors are approved for the treatment of some men with advanced prostate cancer. Rare but serious side effects include myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The impact of PARP inhibitors on clonal hematopoiesis (CH), a potential precursor lesion associated with MDS and AML, is incompletely understood in prostate cancer. We hypothesized that PARP inhibitors would increase CH prevalence and abundance. METHODS: We prospectively enrolled participants with advanced prostate cancer treated with PARP inhibitors. The presence of CH was assessed from leukocytes using an ultra-deep error-corrected dual unique molecular identifiers sequencing method targeting 49 genes most commonly mutated in CH and myeloid malignancies. Variant allele frequencies (VAF) of ≥0.5% were considered clinically significant. Blood samples were collected before and after PARP inhibitor treatment. RESULTS: Ten men were enrolled; mean age of 67 years. Six patients had Gleason 7 disease, and four had Gleason ≥8 disease at diagnosis. Nine had localized disease at diagnosis, and eight had prior treatment with radiation. The mean time between pre- and post-treatment blood samples was 11 months (range 2.6-31 months). Six patients (60%) had CH identified prior to PARP inhibitor treatment, three with multiple clones. Of 11 CH clones identified in follow-up, 5 (45%) appeared or increased after treatment. DNMT3A, TET2, and PPM1D were the most common CH alterations observed. The largest post-treatment increase involved the PPM1D gene. CONCLUSION: CH alterations are frequently found after treatment with PARP inhibitors in patients with prostate cancer and this may be one mechanism by which PARP inhibitors lead to increased risk of MDS/AML.


Assuntos
Hematopoiese Clonal , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata , Humanos , Masculino , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Idoso , Pessoa de Meia-Idade , Hematopoiese Clonal/genética , Estudos Prospectivos , Progressão da Doença , Prevalência , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA , Dioxigenases
16.
Prostate ; 84(10): 909-921, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38619005

RESUMO

INTRODUCTION: Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes. METHODS: Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On-target effects were assessed in relevant prostate cancer cell models by measuring proliferation and H3K4 methylation using western blot analysis. In vivo, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bomedemstat are also described. RESULTS: Structural, biochemical, and PK/PD properties of bomedemstat, an irreversible, orally-bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has >2500-fold greater specificity for LSD1 over monoamine oxidase (MAO)-A and -B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient-derived xenografts. Significant intra-tumoral accumulation of orally-administered bomedemstat is measured with micromolar levels achieved in vivo (1.2 ± 0.45 µM at the 7.5 mg/kg dose and 3.76 ± 0.43 µM at the 15 mg/kg dose). Daily oral dosing of bomedemstat at 40 mg/kg/day is well-tolerated, with on-target thrombocytopenia observed that is rapidly reversible following treatment cessation. CONCLUSIONS: Bomedemstat provides enhanced specificity against LSD1, as revealed by structural and biochemical data. PK/PD data display an overall safety profile with manageable side effects resulting from LSD1 inhibition using bomedemstat in preclinical models. Altogether, our results support clinical testing of bomedemstat in the setting of mCRPC.


Assuntos
Histona Desmetilases , Neoplasias de Próstata Resistentes à Castração , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Masculino , Humanos , Animais , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Camundongos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Benzamidas , Piperazinas , Triazóis
17.
Antimicrob Agents Chemother ; : e0044824, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38742904

RESUMO

Phage-antibiotic combination treatment is a novel noteworthy drug delivery method in anti-infection. In the current study, we have isolated a new phage, pB23, against carbapenem-resistant Acinetobacter baumannii 2023. Synergistic antibacterial effect between phage pB23 and meropenem combination could be more stable, using moderate doses of phage (multiplicity of infection ranging from 0.1 to 1,000) based on results of in vitro antibacterial activity. Phage pB23 and meropenem combination could effectively clear mature biofilms and prevent biofilm formation of carbapenem-resistant Acinetobacter baumannii in vitro. Phage pB23 and meropenem combination also has good synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii in different growth phases under static culture conditions. The pig skin explant model shows that phage pB23 and meropenem combination has a synergistic effect to remove bacteria from wounds ex vivo. Phage pB23 and meropenem combination also exhibited a synergistic antibacterial effect in vivo using a zebrafish infection mode. The potential promotion of phage proliferation by meropenem and the sensitivity recovery of phage-resistant bacteria to meropenem might elucidate the mechanism of the synergistic antimicrobial activity. In summary, our study illustrates that phage pB23 and meropenem combination could produce synergistic antibacterial effects against carbapenem-resistant Acinetobacter baumannii under static growth conditions. This study also demonstrates that phage-antibiotic combination will become an effective strategy to enhance antibacterial activity of individual drug and provide a new idea of the drug development for the treatment of infections due to carbapenem-resistant Acinetobacter baumannii and other multidrug-resistant bacteria.

18.
Anal Chem ; 96(24): 10074-10083, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38848224

RESUMO

Numerous high-performance nanotechnologies have been developed, but their practical applications are largely restricted by the nanomaterials' low stabilities and high operation complexity in aqueous substrates. Herein, we develop a simple and high-reliability hydrogel-based nanotechnology based on the in situ formation of Au nanoparticles in molybdenum disulfide (MoS2)-doped agarose (MoS2/AG) hydrogels for electrophoresis-integrated microplate protein recognition. After the incubation of MoS2/AG hydrogels in HAuCl4 solutions, MoS2 nanosheets spontaneously reduce Au ions, and the hydrogels are remarkably stained with the color of as-synthetic plasmonic Au hybrid nanomaterials (Au staining). Proteins can precisely mediate the morphologies and optical properties of Au/MoS2 heterostructures in the hydrogels. Consequently, Au staining-based protein recognition is exhibited, and hydrogels ensure the comparable stabilities and sensitivities of protein analysis. In comparison to the fluorescence imaging and dye staining, enhanced sensitivity and recognition performances of proteins are implemented by Au staining. In Au staining, exfoliated MoS2 semiconductors directly guide the oriented growth of plasmonic Au nanostructures in the presence of formaldehyde, showing environment-friendly features. The Au-stained hydrogels merge the synthesis and recognition applications of plasmonic Au nanomaterials. Significantly, the one-step incubation of the electrophoretic hydrogels leads to high simplicity of operation, largely challenging those multiple-step Ag staining routes which were performed with high complexity and formaldehyde toxicity. Due to its toxic-free, simple, and sensitive merits, the Au staining integrated with electrophoresis-based separation and microplate-based high-throughput measurements exhibits highly promising and improved practicality of those developing nanotechnologies and largely facilitates in-depth understanding of biological information.


Assuntos
Dissulfetos , Ouro , Hidrogéis , Molibdênio , Molibdênio/química , Dissulfetos/química , Ouro/química , Hidrogéis/química , Nanopartículas Metálicas/química , Eletroforese , Proteínas/análise , Proteínas/química
19.
BMC Plant Biol ; 24(1): 18, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166751

RESUMO

Camellia reticulata Lindl., also known as Yunnan Camellia, is an important ornamental plant in China, especially for its large and stunning flowers. A comprehensive understanding of their coloration mechanisms can aid breeders in developing new cultivars and improving their ornamental value; however, it is still unclear in Yunnan Camellia, especially in mixed-color flowers. In this study, we conducted metabolic and transcriptomic comparison analyses to investigate the coloration differences in three Yunnan Camellia cultivars: C. reticulata 'Shizitou' (SZT), C. reticulata 'Damanao' (MN), and C. reticulata 'Tongzimian' (TZM). Our results revealed that the initial flowering stage may play a critical role in the color change of MN. Metabolome analysis demonstrated that cyanidin was the primary anthocyanin in SZT and MN's red region, while its content was low in TZM and MN's white region. According to the transcriptome analysis, the anthocyanins biosynthesis pathway was reconstructed in Yunnan Camellia, and the low expression of CHS was detected in TZM and MN's white region, while ANR maintained a high expression level, which may lead to the low content of cyanidin in them. Transcription factors MYBs, bHLH, and bZIP may play a key role in regulating anthocyanin-structural genes. The co-expression analysis showed that the meristem tissue may play a crucial role in the formation of the mixed white-red color in MN. Our study enriched the genetic basis of flower coloration differences in Yunnan Camellia which will be a valuable genomic resource to understanding the biology of coloration formation and for breeding the Camellia cultivars.


Assuntos
Camellia , Camellia/genética , Camellia/metabolismo , Antocianinas/metabolismo , China , Melhoramento Vegetal , Perfilação da Expressão Gênica , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Transcriptoma , Pigmentação/genética
20.
BMC Plant Biol ; 24(1): 543, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38872082

RESUMO

BACKGROUND: Bracts are important for ornamental plants, and their developmental regulation process is complex; however, relatively little research has been conducted on bracts. In this study, physiological, biochemical and morphological changes in Bougainvillea glabra leaves, leaf buds and bracts during seven developmental periods were systematically investigated. Moreover, transcriptomic data of B. glabra bracts were obtained using PacBio and Illumina sequencing technologies, and key genes regulating their development were screened. RESULTS: Scanning electron microscopy revealed that the bracts develop via a process involving regression of hairs and a color change from green to white. Transcriptome sequencing revealed 79,130,973 bp of transcript sequences and 45,788 transcripts. Differential gene expression analysis revealed 50 expression patterns across seven developmental periods, with significant variability in transcription factors such as BgAP1, BgFULL, BgCMB1, BgSPL16, BgSPL8, BgDEFA, BgEIL1, and BgBH305. KEGG and GO analyses of growth and development showed the involvement of chlorophyll metabolism and hormone-related metabolic pathways. The chlorophyll metabolism genes included BgPORA, BgSGR, BgPPH, BgPAO and BgRCCR. The growth hormone and abscisic acid signaling pathways involved 44 and 23 homologous genes, and coexpression network analyses revealed that the screened genes BgAPRR5 and BgEXLA1 are involved in the regulation of bract development. CONCLUSIONS: These findings improve the understanding of the molecular mechanism of plant bract development and provide important guidance for the molecular regulation and genetic improvement of the growth and development of ornamental plants, mainly ornamental bracts.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Nyctaginaceae , Nyctaginaceae/genética , Nyctaginaceae/metabolismo , Transcriptoma , Folhas de Planta/genética , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Genes de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Flores/genética , Flores/crescimento & desenvolvimento
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