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1.
Radiographics ; 44(6): e230157, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38814798

RESUMO

High-frequency US, with a linear transducer and gray-scale, color, and spectral Doppler US techniques, is the primary imaging modality for evaluation of the penis. It can allow delineation of anatomy and assessment of dynamic blood flow; it is easily available and noninvasive or minimally invasive; it is cost effective; and it is well tolerated by patients. US assessment after pharmacologic induction of erection is an additional tool in assessing patients with suspected vasculogenic impotence, and also in selected patients with penile trauma and suspected Peyronie disease. Penile injuries, life-threatening infections, and vascular conditions such as priapism warrant rapid diagnosis to prevent long-term morbidities due to clinical misdiagnosis or delayed treatment. US can facilitate a timely diagnosis in these emergency conditions, even at the point of care such as the emergency department, which can facilitate timely treatment. In addition, color and spectral Doppler US are valuable applications in the follow-up of patients treated with endovascular revascularization procedures for vasculogenic erectile dysfunction. Image optimization and attention to meticulous techniques including Doppler US is vital to improve diagnostic accuracy. Radiologists should be familiar with the detailed US anatomy, pathophysiologic characteristics, scanning techniques, potential pitfalls, and US manifestations of a wide spectrum of vascular and nonvascular penile conditions to suggest an accurate diagnosis and direct further management. The authors review a range of common and uncommon abnormalities of the penis, highlight their key US features, discuss differential diagnosis considerations, and briefly review management. ©RSNA, 2024 Supplemental material is available for this article.


Assuntos
Doenças do Pênis , Pênis , Humanos , Masculino , Pênis/diagnóstico por imagem , Pênis/irrigação sanguínea , Doenças do Pênis/diagnóstico por imagem , Disfunção Erétil/diagnóstico por imagem , Ultrassonografia/métodos , Diagnóstico Diferencial
2.
Medicine (Baltimore) ; 102(34): e34805, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37653835

RESUMO

Coronavirus disease 2019 (COVID-19) has ravaged the world since December 2019. Up to now, it is still prevalent around the world. Vaccines are an important means to prevent the spread of COVID-19 and reduce severe disease and mortality. Currently, different types of novel coronavirus vaccines are still being developed and improved, and the relevant vaccines that have been approved for marketing have been widely vaccinated around the world. As vaccination coverage continues to grow, concerns about the efficacy and safety of vaccines after real-world use have grown. Some clinical studies have shown that vaccine effectiveness is closely related to antibody response after vaccination. Among them, the advantages of COVID-19 messenger ribonucleic acid (mRNA) vaccine, such as better adaptability to variant strains and better immune response ability, have attracted great attention. However, different populations with different genders, ages, previous COVID-19 infection history, underlying diseases and treatments will show different antibody responses after mRNA vaccination, which will affect the protection of the vaccine. Based on this, this paper reviews the reports related severe acute respiratory syndrome Coronavirus 2 mRNA vaccines, and summarizes the effectiveness of vaccines in different populations and different disease states and looked forward to the precise vaccination strategy of the vaccine in the future.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Feminino , Masculino , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle , RNA Mensageiro , Vacinas de mRNA
3.
Nat Commun ; 14(1): 6069, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770465

RESUMO

The PI3K/AKT pathway plays an essential role in tumour development. NOD-like receptors (NLRs) regulate innate immunity and are implicated in cancer, but whether they are involved in PI3K/AKT pathway regulation is poorly understood. Here, we report that NLRP6 potentiates the PI3K/AKT pathway by binding and destabilizing p85α, the regulatory subunit of PI3K. Mechanistically, NLRP6 recruits the E3 ligase RBX1 to p85α and ubiquitinates lysine 256 on p85α, which is recognized by the autophagy cargo receptor OPTN, causing selective autophagic degradation of p85α and subsequent activation of the PI3K/AKT pathway by reducing PTEN stability. We further show that loss of NLRP6 suppresses cell proliferation, colony formation, cell migration, and tumour growth in glioblastoma cells in vitro and in vivo. Disruption of the NLRP6/p85α interaction using the Pep9 peptide inhibits the PI3K/AKT pathway and generates potent antitumour effects. Collectively, our results suggest that NLRP6 promotes p85α degradation via selective autophagy to drive tumorigenesis, and the interaction between NLRP6 and p85α can be a promising therapeutic target for tumour treatment.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Carcinogênese , Autofagia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
4.
Front Immunol ; 14: 1162211, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37251408

RESUMO

Spatiotemporal separation of cellular components is vital to ensure biochemical processes. Membrane-bound organelles such as mitochondria and nuclei play a major role in isolating intracellular components, while membraneless organelles (MLOs) are accumulatively uncovered via liquid-liquid phase separation (LLPS) to mediate cellular spatiotemporal organization. MLOs orchestrate various key cellular processes, including protein localization, supramolecular assembly, gene expression, and signal transduction. During viral infection, LLPS not only participates in viral replication but also contributes to host antiviral immune responses. Therefore, a more comprehensive understanding of the roles of LLPS in virus infection may open up new avenues for treating viral infectious diseases. In this review, we focus on the antiviral defense mechanisms of LLPS in innate immunity and discuss the involvement of LLPS during viral replication and immune evasion escape, as well as the strategy of targeting LLPS to treat viral infectious diseases.


Assuntos
Antivirais , Núcleo Celular , Imunidade
5.
Nat Microbiol ; 8(5): 958-972, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37081201

RESUMO

Microglia and astrocytes are subgroups of brain glia cells that support and protect neurons within the central nervous system (CNS). At early stages of viral infection in the CNS, they are predominant responding cells and lead to recruitment of peripheral immune cells for viral clearance. Inhibitor of nuclear factor κB kinase subunit epsilon (IKKi) is critical for type I interferon signalling and inflammation, which modulate heterogenic immune responses during CNS infection. Balanced autophagy is vital to maintain brain integrity, yet regulation of autophagy and immune activity within brain glia cells is poorly understood. Here we identify SHISA9 as an autophagy cargo receptor that mediates the autophagy-dependent degradation of IKKi during herpes simplex virus type 1 infection. IKKi is recognized by SHISA9 through unanchored K48-linked poly-ubiquitin chains and bridged to autophagosome membrane components GABARAPL1. Single-cell RNA sequencing analysis shows that SHISA9 has temporal characteristics while modulating both antiviral and inflammatory responses in microglia and astrocytes at different stages during viral infection. We found that Shisa9-/- mice are highly susceptible to herpes simplex virus encephalitis, have pathogenic astrocytes and display more severe neuroinflammation compared with wild-type mice. Taken together, our study unravels a critical role of selective autophagy by orchestrating immune heterogeneity of different CNS resident cells through the SHISA9-IKKi axis.


Assuntos
Doenças Neuroinflamatórias , Viroses , Animais , Camundongos , Autofagia , Encéfalo/metabolismo , Sistema Nervoso Central , Doenças Neuroinflamatórias/metabolismo , Viroses/metabolismo
6.
Signal Transduct Target Ther ; 8(1): 170, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-37100798

RESUMO

Currently, the incidence and fatality rate of SARS-CoV-2 remain continually high worldwide. COVID-19 patients infected with SARS-CoV-2 exhibited decreased type I interferon (IFN-I) signal, along with limited activation of antiviral immune responses as well as enhanced viral infectivity. Dramatic progresses have been made in revealing the multiple strategies employed by SARS-CoV-2 in impairing canonical RNA sensing pathways. However, it remains to be determined about the SARS-CoV-2 antagonism of cGAS-mediated activation of IFN responses during infection. In the current study, we figure out that SARS-CoV-2 infection leads to the accumulation of released mitochondria DNA (mtDNA), which in turn triggers cGAS to activate IFN-I signaling. As countermeasures, SARS-CoV-2 nucleocapsid (N) protein restricts the DNA recognition capacity of cGAS to impair cGAS-induced IFN-I signaling. Mechanically, N protein disrupts the assembly of cGAS with its co-factor G3BP1 by undergoing DNA-induced liquid-liquid phase separation (LLPS), subsequently impairs the double-strand DNA (dsDNA) detection ability of cGAS. Taken together, our findings unravel a novel antagonistic strategy by which SARS-CoV-2 reduces DNA-triggered IFN-I pathway through interfering with cGAS-DNA phase separation.


Assuntos
COVID-19 , Interferon Tipo I , Humanos , COVID-19/genética , DNA , DNA Helicases/genética , Interferon Tipo I/genética , Proteínas do Nucleocapsídeo/genética , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , SARS-CoV-2/genética
7.
Nat Commun ; 13(1): 5204, 2022 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-36057605

RESUMO

In addition to investigating the virology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), discovering the host-virus dependencies are essential to identify and design effective antiviral therapy strategy. Here, we report that the SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) and provide evidence indicating that prevention of ACE2 SUMOylation can block SARS-CoV-2 infection. E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. TOLLIP deficiency results in the stabilization of ACE2 and elevated SARS-CoV-2 infection. In conclusion, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination as a potential way to combat SARS-CoV-2 infection.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Autofagia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismo , Sumoilação , Ubiquitina-Proteína Ligases/metabolismo
8.
Autophagy ; 18(10): 2288-2302, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35100065

RESUMO

Deubiquitination plays an important role in the regulation of the crosstalk between macroautophagy/autophagy and innate immune signaling, yet its regulatory mechanisms are not fully understood. Here we identify the deubiquitinase OTUD7B as a negative regulator of antiviral immunity by targeting IRF3 (interferon regulatory factor 3) for selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3, and activates IRF3-associated cargo receptor SQSTM1/p62 (sequestosome 1) by removing its K63-linked poly-ubiquitin chains at lysine 7 (K7) to enhance SQSTM1 oligomerization. Moreover, viral infection increased the expression of OTUD7B, which forms a negative feedback loop by promoting IRF3 degradation to balance type I interferon (IFN) signaling. Taken together, our study reveals a specific role of OTUD7B in mediating the activation of cargo receptors in a substrate-dependent manner, which could be a potential target against excessive immune responses.Abbreviations: Baf A1: bafilomycin A1; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; DSS: dextran sodium sulfate; DUBs: deubiquitinating enzymes; GFP: green fluorescent protein; IFN: interferon; IKKi: IKBKB/IkappaB kinase inhibitor; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMPs: pathogen-associated molecular patterns; SeV: Sendai virus; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; Ub: ubiquitin; WT: wild-type; VSV: vesicular stomatitis virus.


Assuntos
Fator Regulador 3 de Interferon , Interferon Tipo I , Antivirais , Autofagia , Enzimas Desubiquitinantes/metabolismo , Dextranos/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Quinase I-kappa B , Imunidade Inata/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Lisina , Nucleotidiltransferases/metabolismo , Moléculas com Motivos Associados a Patógenos , RNA Interferente Pequeno , Proteína Sequestossoma-1/metabolismo , Ubiquitinas/metabolismo
9.
Protein Cell ; 13(1): 47-64, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34676498

RESUMO

As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.


Assuntos
Senescência Celular , Cromossomos Humanos/metabolismo , Instabilidade Genômica , Mitose , Nucleotidiltransferases/metabolismo , Telômero/metabolismo , Cromossomos Humanos/genética , Células HeLa , Humanos , Nucleotidiltransferases/genética , Telômero/genética
10.
World J Radiol ; 13(5): 102-121, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34141091

RESUMO

In coronavirus disease 2019 (COVID-19), medical imaging plays an essential role in the diagnosis, management and disease progression surveillance. Chest radiography and computed tomography are commonly used imaging techniques globally during this pandemic. As the pandemic continues to unfold, many healthcare systems worldwide struggle to balance the heavy strain due to overwhelming demand for healthcare resources. Changes are required across the entire healthcare system and medical imaging departments are no exception. The COVID-19 pandemic had a devastating impact on medical imaging practices. It is now time to pay further attention to the profound challenges of COVID-19 on medical imaging services and develop effective strategies to get ahead of the crisis. Additionally, preparation for operations and survival in the post-pandemic future are necessary considerations. This review aims to comprehensively examine the challenges and optimization of delivering medical imaging services in relation to the current COVID-19 global pandemic, including the role of medical imaging during these challenging times and potential future directions post-COVID-19.

11.
Signal Transduct Target Ther ; 6(1): 167, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895773

RESUMO

The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid-liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.


Assuntos
COVID-19/metabolismo , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , NF-kappa B/metabolismo , RNA Viral/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais , Células A549 , Acrilatos/farmacologia , Animais , COVID-19/patologia , Chlorocebus aethiops , Células HEK293 , Células HeLa , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fosfoproteínas/metabolismo , Células Vero , Tratamento Farmacológico da COVID-19
13.
Signal Transduct Target Ther ; 5(1): 221, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024073
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