Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 77
Filtrar
1.
PLoS Pathog ; 20(6): e1012355, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38935808

RESUMO

Stress granules (SGs), formed by untranslated messenger ribonucleoproteins (mRNPs) during cellular stress in eukaryotes, have been linked to flavivirus interference without clear understanding. This study reveals the role of Zika virus (ZIKV) NS2B as a scaffold protein mediating interaction between protein phosphatase 1α (PP1α) and eukaryotic initiation factor 2α (eIF2α). This interaction promotes eIF2α dephosphorylation by PP1α, inhibiting SG formation. The NS2B-PP1α complex exhibits remarkable stability, resisting ubiquitin-induced degradation and amplifying eIF2α dephosphorylation, thus promoting ZIKV replication. In contrast, the NS2BV35A mutant, interacting exclusively with eIF2α, fails to inhibit SG formation, resulting in reduced viral replication and diminished impact on brain organoid growth. These findings reveal PP1α's dual role in ZIKV infection, inducing interferon production as an antiviral factor and suppressing SG formation as a viral promoter. Moreover, we found that NS2B also serves as a versatile mechanism employed by flaviviruses to counter host antiviral defenses, primarily by broadly inhibiting SG formation. This research advances our comprehension of the complex interplay in flavivirus-host interactions, offering potential for innovative therapeutic strategies against flavivirus infections.


Assuntos
Fator de Iniciação 2 em Eucariotos , Proteína Fosfatase 1 , Grânulos de Estresse , Proteínas não Estruturais Virais , Replicação Viral , Infecção por Zika virus , Zika virus , Zika virus/fisiologia , Replicação Viral/fisiologia , Humanos , Infecção por Zika virus/virologia , Infecção por Zika virus/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/genética , Proteína Fosfatase 1/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Grânulos de Estresse/metabolismo , Animais
2.
J Org Chem ; 89(12): 8782-8788, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38819141

RESUMO

The total synthesis of (-)-piericone D, a potential antithrombotic dihydrochalcone featuring an [3.3.0] octane core, is reported. Salient features of our synthesis include a stereoselective ß-O-glycosylation to install the asebogenin aglycone and a late-stage global deprotection followed by simultaneous lactonization. The convergent synthesis paved the way for further structure-activity relationship (SAR) studies of (-)-piericone D.


Assuntos
Chalconas , Estereoisomerismo , Chalconas/química , Chalconas/síntese química , Estrutura Molecular , Glicosilação , Relação Estrutura-Atividade
3.
Cancer Lett ; 593: 216952, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38750719

RESUMO

Poly (ADP-ribose) polymerase-1 (PARP1) is a nuclear protein that attaches negatively charged poly (ADP-ribose) (PAR) to itself and other target proteins. While its function in DNA damage repair is well established, its role in target chromatin recognition and regulation of gene expression remains to be better understood. This study showed that PARP1 interacts with SET1/MLL complexes by binding directly to WDR5. Notably, although PARP1 does not modulate WDR5 PARylation or the global level of H3K4 methylation, it exerts locus-specific effects on WDR5 binding and H3K4 methylation. Interestingly, PARP1 and WDR5 show extensive co-localization on chromatin, with WDR5 facilitating the recognition and expression of target genes regulated by PARP1. Furthermore, we demonstrated that inhibition of the WDR5 Win site impedes the interaction between PARP1 and WDR5, thereby inhibiting PARP1 from binding to target genes. Finally, the combined inhibition of the WDR5 Win site and PARP shows a profound inhibitory effect on the proliferation of cancer cells. These findings illuminate intricate mechanisms underlying chromatin recognition, gene transcription, and tumorigenesis, shedding light on previously unrecognized roles of PARP1 and WDR5 in these processes.


Assuntos
Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase , Peptídeos e Proteínas de Sinalização Intracelular , Poli(ADP-Ribose) Polimerase-1 , Ligação Proteica , Humanos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Cromatina/metabolismo , Cromatina/genética , Proliferação de Células , Células HEK293 , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Histonas/metabolismo , Histonas/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
4.
Plants (Basel) ; 13(9)2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38732488

RESUMO

Dioscorea alata, commonly known as "greater yam", is a vital crop in tropical and subtropical regions of the world, yet it faces significant threats from anthracnose disease, mainly caused by Colletotrichum gloeosporioides. However, exploring disease resistance genes in this species has been challenging due to the difficulty of genetic mapping resulting from the loss of the flowering trait in many varieties. The receptor-like kinase (RLK) gene family represents essential immune receptors in plants. In this study, genomic analysis revealed 467 RLK genes in D. alata. The identified RLKs were distributed unevenly across chromosomes, likely due to tandem duplication events. However, a considerable number of ancient whole-genome or segmental duplications dating back over 100 million years contributed to the diversity of RLK genes. Phylogenetic analysis unveiled at least 356 ancient RLK lineages in the common ancestor of Dioscoreaceae, which differentially inherited and expanded to form the current RLK profiles of D. alata and its relatives. The analysis of cis-regulatory elements indicated the involvement of RLK genes in diverse stress responses. Transcriptome analysis identified RLKs that were up-regulated in response to C. gloeosporioides infection, suggesting their potential role in resisting anthracnose disease. These findings provide novel insights into the evolution of RLK genes in D. alata and their potential contribution to disease resistance.

6.
J Neurosci Res ; 102(2): e25309, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38400573

RESUMO

Synapses serve as the points of communication between neurons, consisting primarily of three components: the presynaptic membrane, synaptic cleft, and postsynaptic membrane. They transmit signals through the release and reception of neurotransmitters. Synaptic plasticity, the ability of synapses to undergo structural and functional changes, is influenced by proteins such as growth-associated proteins, synaptic vesicle proteins, postsynaptic density proteins, and neurotrophic growth factors. Furthermore, maintaining synaptic plasticity consumes more than half of the brain's energy, with a significant portion of this energy originating from ATP generated through mitochondrial energy metabolism. Consequently, the quantity, distribution, transport, and function of mitochondria impact the stability of brain energy metabolism, thereby participating in the regulation of fundamental processes in synaptic plasticity, including neuronal differentiation, neurite outgrowth, synapse formation, and neurotransmitter release. This article provides a comprehensive overview of the proteins associated with presynaptic plasticity, postsynaptic plasticity, and common factors between the two, as well as the relationship between mitochondrial energy metabolism and synaptic plasticity.


Assuntos
Sinapses , Transmissão Sináptica , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Mitocôndrias/metabolismo , Plasticidade Neuronal/fisiologia , Autofagia
7.
RNA ; 30(4): 435-447, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38296629

RESUMO

The histone lysine demethylase KDM5B is frequently up-regulated in various human cancer cells. However, its expression and functional role in human acute myeloid leukemia (AML) cells remain unclear. Here, we found that the expression level of KDM5B is high in primary human AML cells. We have demonstrated that knocking down KDM5B leads to apoptosis and impairs proliferation in primary human AML and some human AML cell lines. We further identified miR-140-3p as a downstream target gene of KDM5B. KDM5B expression was inversely correlated with the miR-140-3p level in primary human AML cells. Molecular studies showed that silencing KDM5B enhanced H3K4 trimethylation (H3K4me3) at the promoter of miR-140-3p, leading to high expression of miR-140-3p, which in turn inhibited B-cell CLL/lymphoma 2 (BCL2) expression. Finally, we demonstrate that the defective proliferation induced by KDM5B knockdown (KD) can be rescued with the miR-140-3p inhibitor or enhanced by combining KDM5B KD with a BCL2 inhibitor. Altogether, our data support the conclusion that KDM5B promotes tumorigenesis in human AML cells through the miR-140-3p/BCL2 axis. Targeting the KDM5B/miR-140-3p/BCL2 pathway may hold therapeutic promise for treating human AML.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Humanos , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Repressoras/genética
8.
Virol Sin ; 2023 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-38072230

RESUMO

Inclusion bodies (IBs) of respiratory syncytial virus (RSV) are formed by liquid-liquid phase separation (LLPS) and contain internal structures termed "IB-associated granules" (IBAGs), where anti-termination factor M2-1 and viral mRNAs are concentrated. However, the mechanism of IBAG formation and the physiological function of IBAGs are unclear. Here, we found that the internal structures of RSV IBs are actual M2-1-free viral messenger ribonucleoprotein (mRNP) condensates formed by secondary LLPS. Mechanistically, the RSV nucleoprotein (N) and M2-1 interact with and recruit PABP to IBs, promoting PABP to bind viral mRNAs transcribed in IBs by RNA-recognition motif and drive secondary phase separation. Furthermore, PABP-eIF4G1 interaction regulates viral mRNP condensate composition, thereby recruiting specific translation initiation factors (eIF4G1, eIF4E, eIF4A, eIF4B and eIF4H) into the secondary condensed phase to activate viral mRNAs for ribosomal recruitment. Our study proposes a novel LLPS-regulated translation mechanism during viral infection and a novel antiviral strategy via targeting on secondary condensed phase.

9.
Complement Med Res ; 30(5): 440-452, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37573779

RESUMO

OBJECTIVE: The aim of this study was to systematically evaluate the therapeutic effects of Dihuang Yinzi decoction on Alzheimer's disease (AD) and provide a medical evidence-based clinical application of traditional Chinese medicine (TCM). METHODS: A comprehensive search was conducted across multiple databases, including PubMed, Embase, Cochrane Library, China National Journals Full-text Database, VIP Database for Chinese Technical Periodicals, Wan Fang database, and SinoMed database, to collect clinical randomized controlled trials of Dihuang Yinzi decoction in the treatment of AD. Strict literature screening was performed based on predefined inclusion and exclusion criteria. The Cochrane Collaboration risk of bias assessment tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system recommendation-level method was used to assess the quality of the included studies. Review Manager 5.4 and Stata 17 software were used for data synthesis and processing, while GRADE Profiler 3.6 software was used to evaluate the quality of evidence for outcome indicators (risk ratio, standardized mean difference, and weighted mean difference). RESULTS: A total of 11 studies involving 798 patients met the inclusion criteria. Dihuang Yinzi decoction, whether used alone or in combination with conventional Western medicine, demonstrated superior efficacy compared to conventional Western medicine alone in improving the clinical effective rate, TCM syndrome score, activity of daily living score, Mini-Mental State Examination score, and Hasegawa Dementia Scale score in AD treatment. Furthermore, it exhibited a favorable safety profile. However, the GRADE evidence quality rating for the included studies was low. CONCLUSIONS: Dihuang Yinzi decoction, either used alone or in combination with conventional Western medicine, shows promising results in enhancing cognitive and memory functions as well as the self-care ability of patients with AD. However, the low GRADE evidence quality rating highlights the need for focused advancements in the planning and execution of clinical randomized controlled trials during future research attempts.ZIELZiel dieser Studie ist es, die therapeutischen Effekte von Dihuang Yinzi-Dekokt auf die Alzheimer-Krankheit systematisch zu bewerten und eine evidenzbasierte klinische Anwendung der traditionellen chinesischen Medizin (TCM) bereitzustellen.MethodenEs wurde eine umfassende Suche in mehreren Datenbanken, darunter PubMed, Embase, Cochrane Library, China National Journals Volltext-Datenbank, VIP Database for Chinese Technical Periodicals, Wan Fang Datenbank und SinoMed-Datenbank durchgeführt, um randomisierte, kontrollierte klinische Studien zu Dihuang Yinzi-Dekokt in der Behandlung der Alzheimer-Krankheit zu erfassen. Die strenge Literatursuche erfolgte auf Grundlage von vordefinierten Ein-und Ausschlusskriterien. Zur Bewertung der Qualität der eingeschlossenen Studien wurden das Risk-of-Bias-Tool von Cochrane und das GRADE (Grading of Recommendations Assessment, Development, and Evaluation)-System zur Beurteilung der Empfehlungsgrade herangezogen. Die Datensynthese und -verarbeitung erfolgten mithilfe der Review Manager 5.4- und der Stata 17-Software, während für die Bewertung der Evidenzqualität der Outcome-Indikatoren (Risikoverhältnis, standardisierte Mittelwertdifferenz und gewichtete Mittelwertdifferenz) die Software GRADE Profiler 3.6 verwendet wurde.ErgebnisseInsgesamt erfüllten 11 Studien, an denen 798 Patienten teilnahmen, die Einschlusskriterien. Dihuang Yinzi-Dekokt zeigte allein oder in Kombination mit konventioneller westlicher Medizin eine überlegene Wirksamkeit gegenüber der alleinigen Verwendung von konventioneller westlicher Medizin in Bezug auf die klinische Gesamtwirksamkeitsrate, den TCM-Syndrom-Score, den Score für die Alltagsaktivitäten, den Mini-Mental State Examination-Score und den Score der Hasegawa-Demenz-Skala in der Behandlung der Alzheimer-Krankheit. Darüber hinaus wies es ein günstiges Sicherheitsprofil auf. Die Evidenzqualität der eingeschlossenen Studien gemäß GRADE wurde jedoch als gering eingestuft.SchlussfolgerungenDihuang Yinzi-Dekokt zeigt allein oder in Kombination mit konventioneller westlicher Medizin vielversprechende Ergebnisse in Bezug auf die Verbesserung der kognitiven und Gedächtnisfunktionen sowie die Selbstversorgungsfähigkeit von Alzheimer-Patienten. Die niedrige Bewertung der Evidenzqualität gemäß GRADE unterstreicht jedoch die Notwendigkeit von zielgerichteten Weiterentwicklungen bei der Planung und Durchführung von randomisierten, kontrollierten klinischen Studien in zukünftigen Forschungsunternehmungen.


Assuntos
Doença de Alzheimer , Medicina , Humanos , Doença de Alzheimer/tratamento farmacológico , Resultado do Tratamento , Medicina Tradicional Chinesa , China
10.
Cell Insight ; 2(3): 100103, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37193093

RESUMO

Eukaryotic viruses are obligate intracellular parasites that rely on the host cell machinery to carry out their replication cycle. This complex process involves a series of steps, starting with virus entry, followed by genome replication, and ending with virion assembly and release. Negative strand RNA and some DNA viruses have evolved to alter the organization of the host cell interior to create a specialized environment for genome replication, known as IBs, which are precisely orchestrated to ensure efficient viral replication. The biogenesis of IBs requires the cooperation of both viral and host factors. These structures serve multiple functions during infection, including sequestering viral nucleic acids and proteins from innate immune responses, increasing the local concentration of viral and host factors, and spatially coordinating consecutive replication cycle steps. While ultrastructural and functional studies have improved our understanding of IBs, much remains to be learned about the precise mechanisms of IB formation and function. This review aims to summarize the current understanding of how IBs are formed, describe the morphology of these structures, and highlight the mechanism of their functions. Given that the formation of IBs involves complex interactions between the virus and the host cell, the role of both viral and cellular organelles in this process is also discussed.

11.
Invest Ophthalmol Vis Sci ; 64(5): 11, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37195657

RESUMO

Purpose: Alterations in the gut microbiota have been associated with age-related macular degeneration (AMD). However, the dysbiosis shared by different ethnicity and geographic groups, which may associate with the disease pathogenesis, remain underexplored. Here, we characterized dysbiosis of the gut microbiota in patients with AMD from Chinese and Swiss cohorts and identified cross-cohort signatures associated with AMD. Methods: Shotgun metagenomic sequencing was performed on fecal samples from 30 patients with AMD and 30 healthy subjects. Published datasets with 138 samples from Swiss patients with AMD and healthy subjects were re-analyzed. Comprehensive taxonomic profiling was conducted by matching to the RefSeq genome database, metagenome-assembled genome (MAG) database, and Gut Virome Database (GVD). Functional profiling was performed by reconstruction of the MetaCyc pathways. Results: The α-diversity of the gut microbiota was decreased in patients with AMD according to taxonomic profiles generated using MAG but not RefSeq database as reference. The Firmicutes/Bacteroidetes ratio was also decreased in patients with AMD. Among AMD-associated bacteria shared between Chinese and Swiss cohorts, Ruminococcus callidus, Lactobacillus gasseri, and Prevotellaceae (f) uSGB 2135 were enriched in patients with AMD, whereas Bacteroidaceae (f) uSGB 1825 was depleted in patients with AMD and was negatively associated with hemorrhage size. Bacteroidaceae was one of the major hosts of phages associated with AMD. Three degradation pathways were reduced in AMD. Conclusions: These results demonstrated that dysbiosis of the gut microbiota was associated with AMD. We identified cross-cohort gut microbial signatures involving bacteria, viruses, and metabolic pathways, which potentially serve as promising targets for the prevention or treatment of AMD.


Assuntos
Microbioma Gastrointestinal , Degeneração Macular , Humanos , Metagenoma , Microbioma Gastrointestinal/genética , Disbiose/microbiologia , Bactérias/genética , Bactérias/metabolismo , Bacteroidetes , Degeneração Macular/genética
12.
Bio Protoc ; 13(10): e4681, 2023 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-37251098

RESUMO

Fast and accurate detection of pathogenic bacterial infection in patients with severe pneumonia is significant to its treatment. The traditional culture method currently used by most medical institutions relies on a time-consuming culture process (over two days) that is unable to meet clinical needs. Rapid, accurate, and convenient species-specific bacterial detector (SSBD) has been developed to provide timely information on pathogenic bacteria. The SSBD was designed based on the fact that Cas12a indiscriminately cleaves any DNA following the binding of the crRNA-Cas12a complex to the target DNA molecule. SSBD involves two processes, starting with PCR of the target DNA using primers specific for the pathogen, followed by detection of the existence of pathogen target DNA in the PCR product using the corresponding crRNA and Cas12a protein. Compared to the culture test, the SSBD can obtain accurate pathogenic information in only a few hours, dramatically shortening the detection time and allowing more patients to benefit from timely clinical treatment.

13.
Zhongguo Zhong Yao Za Zhi ; 48(6): 1673-1681, 2023 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-37005855

RESUMO

This study employed bibliometrics tools to review the studies of traditional Chinese medicine(TCM) treatment of Alzheimer's disease(AD) in recent ten years, aiming to explore the research status, hotspots, and future trends in this field at home and abroad. The relevant literature published from January 1, 2012 to August 15, 2022 was retrieved from Web of Science and CNKI. CiteSpace 6.1R2 and VOSviewer 1.6.15 were used for the visual analysis of authors, countries, institutions, keywords, journals, etc. A total of 2 254 Chinese articles and 545 English articles were included. The annual number of articles published showed a rising trend with fluctuations. The country with the largest number of relevant articles published and the largest centrality was China. SUN Guo-jie and WANG Qi were the authors publishing the most Chinese articles and English articles, respectively. Hubei University of Chinese Medicine and Beijing University of Chinese Medicine published the most articles in Chinese and English, respectively. Journal of Ethnopharmacology and Neuroscience Letters published the articles with the highest cited frequency and the highest centrality. According to the keywords, the research on TCM treatment of AD mainly focused on the mechanism of action and treatment methods. Metabolomics, intestinal flora, oxidative stress, tau hyperphosphorylation, ß-amyloid(Aß), inflammatory cytokines, and autophagy were the focuses of the research on mechanism of action. Acupuncture, clinical effect, kidney deficiency and phlegm stasis, and dredging governor vessel to revitalize mind were the hotspots of clinical research. This research field is still in the stage of exploration and development. Exchanges and cooperation among institutions should be encouraged to carry out more high-quality basic research on TCM treatment of AD, obtain high-level evidence, and clarify the pathogenesis and prescription mechanism.


Assuntos
Terapia por Acupuntura , Doença de Alzheimer , Medicina , Humanos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Medicina Tradicional Chinesa
14.
Cell Rep ; 42(4): 112286, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-36952345

RESUMO

ER-phagy is a form of autophagy that is mediated by ER-phagy receptors and selectively degrades endoplasmic reticulum (ER). Coronaviruses have been shown to use the ER as a membrane source to establish their double-membrane vesicles (DMVs). However, whether viruses modulate ER-phagy to drive viral DMV formation and its underlying molecular mechanisms remains largely unknown. Here, we demonstrate that coronavirus subverts ER-phagy by hijacking the ER-phagy receptors FAM134B and ATL3 into p62 condensates, resulting in increased viral replication. Mechanistically, we show that viral protein ORF8 binds to and undergoes condensation with p62. FAM134B and ATL3 interact with homodimer of ORF8 and are aggregated into ORF8/p62 liquid droplets, leading to ER-phagy inhibition. ORF8/p62 condensates disrupt ER-phagy to facilitate viral DMV formation and activate ER stress. Together, our data highlight how coronavirus modulates ER-phagy to drive viral replication by hijacking ER-phagy receptors.


Assuntos
Coronavirus , Proteínas de Membrana , Proteínas de Membrana/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Autofagia/fisiologia , Replicação Viral
15.
J Invertebr Pathol ; 197: 107900, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36806462

RESUMO

Enterocytozoon hepatopenaei (EHP), an obligate intracellular parasite classified as microsporidia, is an emerging pathogen with a significant impact on the global shrimp aquaculture industry. The understanding of how microsporidia germinate has been a key factor in exploring its infection process. However, the germination process of EHP was rarely reported. To gain insight into the germination process, we conducted a high-throughput sequencing analysis of purified EHP spores that had undergone in vitro germination treatment. This analysis revealed 137 differentially expressed genes, with 84 up-regulated and 53 down-regulated genes. While the functions of some of the genes remain unknown, this study provides important data on the transcriptomic changes before and after EHP germination, which can aid in further studies on the EHP infection mechanism.


Assuntos
Enterocytozoon , Penaeidae , Animais , Transcriptoma , Penaeidae/parasitologia , Perfilação da Expressão Gênica , Enterocytozoon/genética , Esporos
16.
Eur J Cell Biol ; 102(2): 151295, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36758343

RESUMO

Histone H3 lysine 4 (H3K4) methylation is generally recognized as a prominent marker of gene activation. While Set1/Mll complexes are major methyltransferases that are responsible for H3K4 methylation, the mechanism of how these complexes are recruited into the target gene promotor is still unclear. Here, starting with an affinity purification-mass spectrometry approach, we have found that Isl1, a highly tissue-specific expressed LIM/homeodomain transcription factor, is physically associated with Set1/Mll complexes. We then show that Wdr5 directly binds to Isl1. And this binding is likely mediated by the homeodomain of Isl1. Functionally, using mouse ß-cell and human neuroblastoma tumor cell lines, we show that both Wdr5 binding and H3K4 methylation level at promoters of some Isl1 target genes are significantly reduced upon depletion of Isl1, suggesting Isl1 is required for efficient locus-specific H3K4 methylation. Taken together, our results establish a critical role of Set1/Mll complexes in regulating the target gene expression of Isl1.


Assuntos
Histonas , Proteínas Nucleares , Animais , Humanos , Camundongos , Proteínas de Ligação a DNA/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica
17.
Front Nutr ; 9: 1064764, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36505249

RESUMO

The increasing burden and health risks of antimicrobial resistance (AMR) pose a great threat to society overall. Lipopeptides exhibit great potential as novel and safe alternatives to traditional antibiotics. In this study, the strain YA215, which was isolated from the mangrove area in Beibu Gulf, Guangxi, China, was identified as Bacillus velezensis. Then, YA215 lipopeptide extracts (YA215LE) from B. velezensis was found to exhibit a wide spectrum of antibacterial and antifungal activities. Additionally, YA215LE was identified and found to contain three groups of lipopeptides (surfactin, iturin, and fengycin). Furthermore, one separation fraction (BVYA1) with significant antibacterial activity was obtained. Additionally, liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis of BVYA1 showed three molecular ion peaks ([M + H]+: m/z 980.62; 994.66; 1008.66) corresponding to conventional surfactin homologs. By MS/MS analysis, BVYA1 was identified as sufactin with the precise amino acid sequence Glu-Leu/Ile-Leu-Val-Asp-Leu-Leu/Ile and hydroxyl fatty acids with 11-13 carbons. [M + H]+ at m/z 980.62 was detected for the first time in B. velezensis, which demonstrates that the strain corresponds to a new surfactin variant. In particular, BVYA1 showed antibacterial activity with the minimum inhibitory concentration (MIC) values of 7.5-15 µg/ml. Finally, the preliminary mechanism of inhibiting E. coli treated with BVYA1 showed that BVYA1 effectively permeabilized the cytoplasmic membrane and disrupted the morphology of targeted bacterial cells. In conclusion, this study suggests that the YA215LE from B. velezensis YA215 might be a potential candidate for a bactericide.

18.
Theranostics ; 12(17): 7267-7288, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36438489

RESUMO

Rationale: N6-methyladenosine (m6A) is involved in critical cancerous processes. Pseudogenes play various roles in carcinogenesis and progression. However, the functional roles of m6A-associated pseudogenes in head and neck squamous cell carcinoma (HNSCC) are largely unknown. Methods: We systematically analyzed the mRNA profile of 24 m6A regulators and 13931 pseudogenes from The Cancer Genome Atlas HNSCC dataset and ultimately identified 10 m6A-associated prognostic pseudogenes, which were validated in the Gene Expression Omnibus and our hospital datasets. Based on the risk score of m6A-associated pseudogenes, comprehensive analytical frameworks and experimental validation were implemented among pseudogene-defined low-/high-risk subtypes. Results: Here, we found expression pattern of m6A-associated pseudogenes was significantly associated with infiltrating immune cell compositions, and the expression of antitumor immune response markers, including T cell exhaustion, antigen presentation, interferon, and kinase genes. The m6A-associated pseudogenes, which had dramatic m6A peaks and higher m6A levels, could regulate the expression of targeted immune-involved genes through miRNAs. We experimentally validate the oncogene PDIA3P1, and tumor-suppressor RRN3P3, which promote the RNA and protein expression of their targeted immune-involved genes AKT1 and EZH2 via miR-34a-5p and miR-26b-5p, respectively. Moreover, HNSCC patients in the high-risk subtype could benefit more from immune checkpoint inhibitors therapy. Furthermore, doxorubicin and topotecan were considered to hold the most promising therapeutic potential robustly in silico evidence and in vitro experiments for HNSCC patients in the high-risk subtype. Conclusions: Our discovery revealed that the 10 m6A-associated prognostic pseudogenes significantly contribute to predicting immunotherapy benefits and therapeutic agents, which might bring some potential implications for both immunotherapy and chemotherapy in HNSCC.


Assuntos
Adenosina , Neoplasias de Cabeça e Pescoço , Pseudogenes , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/imunologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Fatores Imunológicos , Imunoterapia , MicroRNAs/genética , Prognóstico , Pseudogenes/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
19.
Opt Express ; 30(16): 28840-28852, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-36299072

RESUMO

We survey the propagation properties of the out-of-phase (OOP) dipole solitons and the single-charged vortex (SCV) soliton in a periodic photonic moiré lattice with θ=arctan⁡(3/4) under self-focusing nonlinearity media. Since the rotation angle, periodic photonic moiré lattices have peculiar energy band structures, with highly flat bands and the bandgaps being much more extensive, which is very favorable for the realization and stability of the solitons. When exciting a single point on-site with the OOP dipole beam, its evolution shows a periodic rollover around the lattice axis. Whereas, when exciting a single point on-site with the SCV beam, it transmits counterclockwise rotating periodically. Both the OOP dipole solitons and the SVC soliton maintain the local state, but their phase exhibits different variations. The phase of the OOP dipole solitons is flipped, while that of the SCV is rotated counterclockwise. Our work further complements the exploration of solitons in photonic moiré lattice with nonlinearity.

20.
PLoS Pathog ; 18(9): e1010856, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36108090

RESUMO

We previously found that, among human parainfluenza virus type 3 (HPIV3) proteins, the interaction of nucleoprotein (N) and phosphoprotein (P) provides the minimal requirement for the formation of cytoplasmic inclusion bodies (IBs), which are sites of RNA synthesis, and that acetylated α-tubulin enhances IB fusion and viral replication. In this study, using immunoprecipitation and mass spectrometry assays, we determined that vimentin (VIM) specifically interacted with the N-P complex of HPIV3, and that the head domain of VIM was responsible for this interaction, contributing to the inhibition of IB fusion and viral replication. Furthermore, we found that VIM promoted the degradation of α-tubulin acetyltransferase 1 (α-TAT1), through its head region, thereby inhibiting the acetylation of α-tubulin, IB fusion, and viral replication. In addition, we identified a 20-amino-acid peptide derived from the head region of VIM that participated in the interaction with the N-P complex and inhibited viral replication. Our findings suggest that VIM inhibits the formation of HPIV3 IBs by downregulating α-tubulin acetylation via enhancing the degradation of α-TAT1. Our work sheds light on a new mechanism by which VIM suppresses HPIV3 replication.


Assuntos
Corpos de Inclusão Viral , Vírus da Parainfluenza 3 Humana , Humanos , Acetilação , Nucleoproteínas/metabolismo , Vírus da Parainfluenza 3 Humana/metabolismo , Fosfoproteínas/metabolismo , RNA/metabolismo , Tubulina (Proteína)/metabolismo , Vimentina/metabolismo , Replicação Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...