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1.
Proc Natl Acad Sci U S A ; 121(25): e2316551121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38865260

RESUMO

The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here, our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhances the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a mechanism by which A20 inhibits the NLRP3 inflammasome.


Assuntos
Inflamassomos , Quinases Relacionadas a NIMA , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Ubiquitinação , Quinases Relacionadas a NIMA/metabolismo , Quinases Relacionadas a NIMA/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Inflamassomos/metabolismo , Animais , Camundongos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Humanos , Macrófagos/metabolismo , Macrófagos/imunologia , Células HEK293 , Camundongos Knockout , Ligação Proteica
2.
Nature ; 586(7830): 572-577, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32726802

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.


Assuntos
Anticorpos Antivirais/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , COVID-19 , Vacinas contra COVID-19 , Humanos , Macaca mulatta/imunologia , Macaca mulatta/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Modelos Moleculares , Domínios Proteicos , SARS-CoV-2 , Soro/imunologia , Baço/citologia , Baço/imunologia , Linfócitos T/imunologia , Vacinação
3.
J Transl Med ; 22(1): 413, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693513

RESUMO

Adoptive cell therapy has revolutionized cancer treatment, especially for hematologic malignancies. T cells are the most extensively utilized cells in adoptive cell therapy. Currently, tumor-infiltrating lymphocytes, T cell receptor-transgenic T cells and chimeric antigen receptor T cells are the three main adoptive T cell therapies. Tumor-infiltrating lymphocytes kill tumors by reinfusing enlarged lymphocytes that naturally target tumor-specific antigens into the patient. T cell receptor-transgenic T cells have the ability to specifically destroy tumor cells via the precise recognition of exogenous T cell receptors with major histocompatibility complex. Chimeric antigen receptor T cells transfer genes with specific antigen recognition structural domains and T cell activation signals into T cells, allowing T cells to attack tumors without the assistance of major histocompatibility complex. Many barriers have been demonstrated to affect the clinical efficacy of adoptive T cell therapy, such as tumor heterogeneity and antigen loss, hard trafficking and infiltration, immunosuppressive tumor microenvironment and T cell exhaustion. Several strategies to improve the efficacy of adoptive T cell therapy have been explored, including multispecific chimeric antigen receptor T cell therapy, combination with immune checkpoint blockade, targeting the immunosuppressive tumor microenvironment, etc. In this review, we will summarize the current status and clinical application, followed by major bottlenecks in adoptive T cell therapy. In addition, we will discuss the promising strategies to improve adoptive T cell therapy. Adoptive T cell therapy will result in even more incredible advancements in solid tumors if the aforementioned problems can be handled.


Assuntos
Imunoterapia Adotiva , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Animais , Microambiente Tumoral/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
4.
Cell Biol Toxicol ; 38(4): 591-609, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34170461

RESUMO

Crystalline silica (CS), an airborne particulate, is a major global occupational health hazard. While it is known as an important pathogenic factor in many severe lung diseases, the underlying mechanisms of its toxicity are still unclear. In the present study, we found that intra-tracheal instillation of CS caused rapid emergence of necrotic alveolar macrophages. Cell necrosis was a consequence of the release of cathepsin B in CS-treated macrophages, which caused dysfunction of the mitochondrial membrane. Damage to mitochondria disrupted Na+/K+ ATPase activity in macrophages, leading to intracellular sodium overload and the subsequent cell necrosis. Further studies indicate that CS-induced macrophage necrosis and the subsequent release of mitochondrial DNA could trigger the recruitment of neutrophils in the lung, which was regulated by the TLR9 signaling pathway. In conclusion, our results suggest a novel mechanism whereby CS leads to rapid macrophage necrosis through cathepsin B release, following the leakage of mitochondrial DNA as a key event in the induction of pulmonary neutrophilic inflammation. This study has important implications for the early prevention and treatment of diseases induced by CS.


Assuntos
Pneumonia , Dióxido de Silício , Catepsina B/metabolismo , DNA Mitocondrial/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Necrose/induzido quimicamente , Necrose/metabolismo , Pneumonia/induzido quimicamente , Dióxido de Silício/toxicidade
6.
Cell Commun Signal ; 17(1): 82, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345225

RESUMO

BACKGROUND: The SUMO-activating enzyme SAE1 is indispensable for protein SUMOylation. A dysregulation of SAE1 expression involves in progression of several human cancers. However, its biological roles of SAE1 in glioma are unclear by now. METHODS: The differential proteome between human glioma tissues and para-cancerous brain tissues were identified by LC-MS/MS. SAE1 expression was further assessed by immunohistochemistry. The patient overall survival versus SAE1 expression level was evaluated by Kaplan-Meier method. The glioma cell growth and migration were evaluated under SAE1 overexpression or inhibition by the CCK8, transwell assay and wound healing analysis. The SUMO1 modified target proteins were enriched from total cellular or tissue proteins by incubation with the anti-SUMO1 antibody on protein-A beads overnight, then the SUMOylated proteins were detected by Western blot. Cell apoptosis and cell cycle were analyzed by flow cytometry. The nude mouse xenograft was determined glioma growth and tumorigenicity in vivo. RESULTS: SAE1 is identified to increase in glioma tissues by a quantitative proteomic dissection, and SAE1 upregulation indicates a high level of tumor malignancy grade and a poor overall survival for glioma patients. SAE1 overexpression induces an increase of the SUMOylation and Ser473 phosphorylation of AKT, which promotes glioma cell growth in vitro and in nude mouse tumor model. On the contrary, SAE1 silence induces an obvious suppression of the SUMOylation and Ser473 phosphorylation of Akt, which inhibits glioma cell proliferation and the tumor xenograft growth through inducing cell cycle arrest at G2 phase and cell apoptosis driven by serial biochemical molecular events. CONCLUSION: SAE1 promotes glioma cancer progression via enhancing Akt SUMOylation-mediated signaling pathway, which indicates targeting SUMOylation is a promising therapeutic strategy for human glioma.


Assuntos
Neoplasias Encefálicas/patologia , Progressão da Doença , Glioma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sumoilação , Enzimas Ativadoras de Ubiquitina/metabolismo , Animais , Apoptose , Carcinogênese , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Análise de Sobrevida , Enzimas Ativadoras de Ubiquitina/deficiência , Enzimas Ativadoras de Ubiquitina/genética , Regulação para Cima
7.
J Biol Chem ; 291(16): 8591-601, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26893383

RESUMO

Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the occurrence of benign tumors in various vital organs and tissues. TSC1 and TSC2, the TSC1 and TSC2 gene products, form the TSC protein complex that senses specific cellular growth conditions to control mTORC1 signaling. TBC1D7 is the third subunit of the TSC complex, and helps to stabilize the TSC1-TSC2 complex through its direct interaction with TSC1. Homozygous inactivation of TBC1D7 causes intellectual disability and megaencephaly. Here we report the crystal structure of a TSC1-TBC1D7 complex and biochemical characterization of the TSC1-TBC1D7 interaction. TBC1D7 interacts with the C-terminal region of the predicted coiled-coil domain of TSC1. The TSC1-TBC1D7 interface is largely hydrophobic, involving the α4 helix of TBC1D7. Each TBC1D7 molecule interacts simultaneously with two parallel TSC1 helices from two TSC1 molecules, suggesting that TBC1D7 may stabilize the TSC complex by tethering the C-terminal ends of two TSC1 coiled-coils.


Assuntos
Proteínas de Transporte/química , Proteínas Supressoras de Tumor/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cristalografia por Raios X , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
8.
J Biol Chem ; 291(52): 26750-26761, 2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-27756837

RESUMO

Malignant pleural effusion (PE) and ascites, common clinical manifestations in advanced cancer patients, are associated with a poor prognosis. However, the biological characteristics of malignant PE and ascites are not clarified. Here we report that malignant PE and ascites can induce a frequent epithelial-mesenchymal transition program and endow tumor cells with stem cell properties with high efficiency, which promotes tumor growth, chemoresistance, and immune evasion. We determine that this epithelial-mesenchymal transition process is mainly dependent on VEGF, one initiator of the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway. From the clinical observation, we define a therapeutic option with VEGF antibody for malignant PE and ascites. Taken together, our findings clarify a novel biological characteristic of malignant PE and ascites in cancer progression and provide a promising and available strategy for cancer patients with recurrent/refractory malignant PE and ascites.


Assuntos
Ascite/patologia , Transição Epitelial-Mesenquimal , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Derrame Pleural Maligno/patologia , Transdução de Sinais , Animais , Apoptose , Ascite/genética , Ascite/metabolismo , Western Blotting , Proliferação de Células , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/genética , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neovascularização Patológica , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Immunol ; 194(1): 429-37, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25429070

RESUMO

Hemorrhage is a common clinical manifestation in patients with cancer. Intratumor hemorrhage has been demonstrated to be a poor prognostic factor for cancer patients. In this study, we investigated the role of RBCs and hemoglobin (Hb) in the process of tumor progression and therapeutical response. RBCs and Hb potently promoted tumor cell proliferation and syngenic tumor growth. RBCs and Hb activated the reactive oxygen species-NF-κB pathway in both tumor cells and macrophages. RBCs and Hb also induced chemoresistance mediated, in part, by upregulating ABCB1 gene expression. Tumor growth induced by RBCs was accompanied by an inflammatory signature, increased tumor vasculature, and influx of M2 macrophages. In both the peritoneal cavity and tumor microenvironment, extravascular RBCs rapidly recruited monocyte-macrophages into the lesion sites. In addition, RBCs and Hb increased several nucleotide-binding oligomerization domain-like receptors' expression and induced IL-1ß release. Our results provide novel insights into the protumor function of RBCs and Hb as endogenous danger signals, which can promote tumor cell proliferation, macrophage recruitment, and polarization. Hemorrhage may represent a useful prognostic factor for cancer patients because of its role in tumor promotion and chemoresistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Eritrócitos/patologia , Hemoglobinas/farmacologia , Hemorragia/patologia , Neoplasias/patologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Proliferação de Células , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Inflamação/imunologia , Interleucina-1beta/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica , Estresse Oxidativo/efeitos dos fármacos , Paclitaxel/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição RelA/biossíntese , Fator de Transcrição RelA/metabolismo , Microambiente Tumoral/imunologia
10.
J Immunol ; 193(3): 1080-9, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24965775

RESUMO

Ammonia levels are often elevated in patients with cirrhosis or tumors. Patients with these diseases are immunocompromised. In this study, we investigated the effects of ammonia on a member of the immune cell family, the dendritic cells (DCs). Our results demonstrated that ammonia diminished cell count, phagocytosis, and lymphocyte stimulation of DCs. Ammonia also induced DC swelling, excessive reactive oxygen species production, and mitochondrial damage, which may constitute the underlying mechanism of ammonia-induced DC dysfunction. In ammonium chloride (NH4Cl)-loaded mice, DCs exhibited lowered phagocytosis and a weakened immune response to the chicken OVA vaccine. DCs from patients with cirrhosis or ammonia-treated healthy human blood both exhibited diminished phagocytosis. Moreover, tumor cell conditioned medium drove DCs into dysfunction, which could be reversed by ammonia elimination. In a murine colon carcinoma model, we found that ammonia could regulate tumor growth involving DCs and their related immune response. These findings reveal that ammonia could drive DCs into dysfunction, which contributes to the immunocompromised state of patients with cirrhosis or tumors.


Assuntos
Cloreto de Amônio/toxicidade , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Células da Medula Óssea/ultraestrutura , Contagem de Células , Linhagem Celular Tumoral , Técnicas de Cocultura , Células Dendríticas/ultraestrutura , Humanos , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Teste de Cultura Mista de Linfócitos/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/ultraestrutura , Poro de Transição de Permeabilidade Mitocondrial , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Cultura Primária de Células
11.
Breast Cancer Res Treat ; 143(3): 435-46, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24398778

RESUMO

Aberrant fibroblast growth factor (FGF) and FGF receptor (FGFR) system have been associated with breast cancer. The objectives of our study were to investigate the effects and mechanisms of FGFR inhibition on tumor growth and metastasis on breast cancer. Our studies showed that the FGFR inhibitor PD173074 decreased the viability of several human breast cancer cells, as well as 4T1 murine mammary tumor cells. Therefore, we chose 4T1 cells to study PD173074's antitumor mechanism. Flow cytometry showed that PD173074 induced 4T1 cell apoptosis in a concentration-dependent manner. Western blot demonstrated that PD173074-induced apoptosis was correlated with the inhibition of Mcl-1 and survivin. Moreover, PD173074 also significantly increased the ratio of Bax/Bcl-2. PD173074 could also block 4T1 cell migration and invasion in vitro. In 4T1 tumor-bearing mice, PD173074 significantly inhibited tumor growth without obvious side effects. Meanwhile, PD173074 functionally reduced microvessel density and proliferation index and induced tumor apoptosis. Importantly, we found that FGFR inhibition by PD173074 reduced myeloid-derived suppressor cells (MDSCs) in the blood, spleens and tumors, accompanied by the increased infiltration of CD4(+) and CD8(+) T cells in the spleens and tumors. Furthermore, PD173074 significantly inhibited breast tumor metastasis to the lung of inoculated 4T1 breast cancer cells, which was accompanied by a reduction in MDSCs. Our findings suggested that FGFR inhibition could delay breast tumor progression, impair lung metastasis and break immunosuppression by effecting on tumor microenvironment, which may provide a promising therapeutic approach for breast cancer patient.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Pirimidinas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Neoplasias Mamárias Experimentais/genética , Camundongos , Metástase Neoplásica , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Control Release ; 369: 696-721, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38580137

RESUMO

Rare genetic diseases, often referred to as orphan diseases due to their low prevalence and limited treatment options, have long posed significant challenges to our medical system. In recent years, Messenger RNA (mRNA) therapy has emerged as a highly promising treatment approach for various diseases caused by genetic mutations. Chemically modified mRNA is introduced into cells using carriers like lipid-based nanoparticles (LNPs), producing functional proteins that compensate for genetic deficiencies. Given the advantages of precise dosing, biocompatibility, transient expression, and minimal risk of genomic integration, mRNA therapies can safely and effectively correct genetic defects in rare diseases and improve symptoms. Currently, dozens of mRNA drugs targeting rare diseases are undergoing clinical trials. This comprehensive review summarizes the progress of mRNA therapy in treating rare genetic diseases. It introduces the development, molecular design, and delivery systems of mRNA therapy, highlighting their research progress in rare genetic diseases based on protein replacement and gene editing. The review also summarizes research progress in various rare disease models and clinical trials. Additionally, it discusses the challenges and future prospects of mRNA therapy. Researchers are encouraged to join this field and collaborate to advance the clinical translation of mRNA therapy, bringing hope to patients with rare genetic diseases.


Assuntos
Terapia Genética , RNA Mensageiro , Doenças Raras , Humanos , Doenças Raras/terapia , Doenças Raras/genética , RNA Mensageiro/administração & dosagem , RNA Mensageiro/genética , Animais , Terapia Genética/métodos , Doenças Genéticas Inatas/terapia , Doenças Genéticas Inatas/genética , Nanopartículas , Edição de Genes/métodos
13.
Signal Transduct Target Ther ; 9(1): 34, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38378653

RESUMO

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases, which continuously pose one of the most serious threats to human health, attributed to factors such as the emergence of new pathogens, increasing drug resistance, changes in living environments and lifestyles, and the aging population. Despite rapid advancements in mechanistic research and drug development for these diseases, current treatments often have limited efficacy and notable side effects, necessitating the development of more effective and targeted anti-inflammatory therapies. In recent years, the rapid development of nanotechnology has provided crucial technological support for the prevention, treatment, and detection of inflammation-associated diseases. Various types of nanoparticles (NPs) play significant roles, serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability. NPs can also directly combat pathogens and inflammation. In addition, nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases. This review categorizes and characterizes different types of NPs, summarizes their applications in the prevention, treatment, and detection of infectious and inflammatory diseases. It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects. In conclusion, nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.


Assuntos
Doenças Transmissíveis , Nanopartículas , Humanos , Idoso , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/tratamento farmacológico , Portadores de Fármacos/uso terapêutico , Nanopartículas/uso terapêutico , Nanotecnologia , Inflamação/tratamento farmacológico
14.
J Clin Invest ; 134(18)2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39286971

RESUMO

Soluble host factors in the upper respiratory tract can serve as the first line of defense against SARS-CoV-2 infection. In this study, we described the identification and function of a human airway trypsin-like protease (HAT), capable of reducing the infectivity of ancestral SARS-CoV-2. Further, in mouse models, HAT analogue expression was upregulated by SARS-CoV-2 infection. The antiviral activity of HAT functioned through the cleavage of the SARS-CoV-2 spike glycoprotein at R682. This cleavage resulted in inhibition of the attachment of ancestral spike proteins to host cells, which inhibited the cell-cell membrane fusion process. Importantly, exogenous addition of HAT notably reduced the infectivity of ancestral SARS-CoV-2 in vivo. However, HAT was ineffective against the Delta variant and most circulating Omicron variants, including the BQ.1.1 and XBB.1.5 subvariants. We demonstrate that the P681R mutation in Delta and P681H mutation in the Omicron variants, adjacent to the R682 cleavage site, contributed to HAT resistance. Our study reports what we believe to be a novel soluble defense factor against SARS-CoV-2 and resistance of its actions in the Delta and Omicron variants.


Assuntos
COVID-19 , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , COVID-19/virologia , COVID-19/metabolismo , COVID-19/genética , Animais , Camundongos , Serina Endopeptidases/metabolismo , Serina Endopeptidases/genética , Células HEK293 , Mutação , Mutação de Sentido Incorreto , Chlorocebus aethiops
15.
MedComm (2020) ; 5(5): e539, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38680520

RESUMO

Urgent research into innovative severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccines that may successfully prevent various emerging emerged variants, particularly the Omicron variant and its subvariants, is necessary. Here, we designed a chimeric adenovirus-vectored vaccine named Ad5-Beta/Delta. This vaccine was created by incorporating the receptor-binding domain from the Delta variant, which has the L452R and T478K mutations, into the complete spike protein of the Beta variant. Both intramuscular (IM) and intranasal (IN) vaccination with Ad5-Beta/Deta vaccine induced robust broad-spectrum neutralization against Omicron BA.5-included variants. IN immunization with Ad5-Beta/Delta vaccine exhibited superior mucosal immunity, manifested by higher secretory IgA antibodies and more tissue-resident memory T cells (TRM) in respiratory tract. The combination of IM and IN delivery of the Ad5-Beta/Delta vaccine was capable of synergically eliciting stronger systemic and mucosal immune responses. Furthermore, the Ad5-Beta/Delta vaccination demonstrated more effective boosting implications after two dosages of mRNA or subunit recombinant protein vaccine, indicating its capacity for utilization as a booster shot in the heterologous vaccination. These outcomes quantified Ad5-Beta/Delta vaccine as a favorable vaccine can provide protective immunity versus SARS-CoV-2 pre-Omicron variants of concern and BA.5-included Omicron subvariants.

16.
Mol Cancer ; 12(1): 125, 2013 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-24139065

RESUMO

BACKGROUND: The lung squamous cell carcinoma survival rate is very poor despite multimodal treatment. It is urgent to discover novel candidate biomarkers for prognostic assessment and therapeutic targets to lung squamous cell carcinoma (SCC). RESULTS: Herein a two-dimensional gel electrophoresis and ESI-Q-TOF MS/MS-based proteomic approach was used to identify differentially expressed proteins between lung SCC and adjacent normal tissues. 31 proteins with significant alteration were identified. These proteins were mainly involved in metabolism, calcium ion binding, signal transduction and so on. Cathepsin B (CTSB) was one of the most significantly altered proteins and was confirmed by western blotting. Immunohistochemistry showed the correlation between higher CTSB expression and lower survival rate. No statistically significant difference between CTSB-shRNA treated group and the controls was observed in tumor volume, tumor weight, proliferation and apoptosis. However, the CTSB-shRNA significantly inhibited tumor metastases and prolonged survival in LL/2 metastatic model. Moreover, CTSB, Shh and Ptch were up-regulated in patients with metastatic lung SCC, suggesting that hedgehog signaling might be activated in metastatic lung SCC which could affect the expression of CTSB that influence the invasive activity of lung SCC. CONCLUSIONS: These data suggested that CTSB might serve as a prognostic and therapeutic marker for lung SCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/enzimologia , Catepsina B/metabolismo , Neoplasias Pulmonares/enzimologia , Idoso , Sequência de Aminoácidos , Animais , Biomarcadores Tumorais/química , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Catepsina B/química , Catepsina B/genética , Linhagem Celular Tumoral , Eletroforese em Gel Bidimensional , Feminino , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Dados de Sequência Molecular , Transplante de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Proteoma/metabolismo , Estudos Retrospectivos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Carga Tumoral
17.
Oncol Res ; 20(10): 473-82, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24308158

RESUMO

Heme oxygenase-1 [HO-1, also called heat shot protein 32 (HSP32)] can specifically metabolize heme to carbon monoxide, biliverdin, and ferrous iron and plays an important role in the processes of anti-inflammation, tissue protection, and antioxidative stress reaction. It has been reported that HO-1 can promote tumorigenesis and metastasis of many tumors. However, the detailed mechanisms of how HO-1 affects tumor progress are not clear. Here, we used ZnPPIX (a specific inhibitor of HO-1) to evaluate its potential effects on mouse breast cancer and tumor-associated macrophages (TAMs). We found out that mouse 4T1 breast cancer growth can be effectively suppressed through inhibition of HO-1 in vitro and in vivo. Moreover, in the 4T1 mouse model, when HO-1 was suppressed in TAMs, alternatively activated macrophages (M2 type) switched to classically activated macrophages (M1 type). In conclusion, 4T1 breast cancer growth was modulated by HO-1 expression. Furthermore, inhibition of HO-1 may induce tumor-associated immune response by activating TAMs' alternative proliferation. These data suggest that HO-1 may be an important target of breast cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Protoporfirinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Heme Oxigenase-1/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Macrófagos/patologia , Neoplasias Mamárias Experimentais/enzimologia , Neoplasias Mamárias Experimentais/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Necrose , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos
18.
Signal Transduct Target Ther ; 8(1): 9, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36604431

RESUMO

Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.


Assuntos
Vacinas Anticâncer , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Antígenos de Neoplasias/genética , Imunoterapia
19.
Front Immunol ; 14: 1291836, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38106416

RESUMO

Recent progressions in immunotherapy have transformed cancer treatment, providing a promising strategy that activates the immune system of the patient to find and eliminate cancerous cells. Bispecific antibodies, which engage two separate antigens or one antigen with two distinct epitopes, are of tremendous concern in immunotherapy. The bi-targeting idea enabled by bispecific antibodies (BsAbs) is especially attractive from a medical standpoint since most diseases are complex, involving several receptors, ligands, and signaling pathways. Several research look into the processes in which BsAbs identify different cancer targets such angiogenesis, reproduction, metastasis, and immune regulation. By rerouting cells or altering other pathways, the bispecific proteins perform effector activities in addition to those of natural antibodies. This opens up a wide range of clinical applications and helps patients with resistant tumors respond better to medication. Yet, further study is necessary to identify the best conditions where to use these medications for treating tumor, their appropriate combination partners, and methods to reduce toxicity. In this review, we provide insights into the BsAb format classification based on their composition and symmetry, as well as the delivery mode, focus on the action mechanism of the molecule, and discuss the challenges and future perspectives in BsAb development.


Assuntos
Anticorpos Biespecíficos , Neoplasias , Humanos , Anticorpos Biespecíficos/uso terapêutico , Imunoterapia/métodos , Transdução de Sinais
20.
MedComm (2020) ; 4(3): e263, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37125241

RESUMO

The XBB.1.5 subvariant has drawn great attention owing to its exceptionality in immune evasion and transmissibility. Therefore, it is essential to develop a universally protective coronavirus disease 2019 vaccine against various strains of Omicron, especially XBB.1.5. In this study, we evaluated and compared the immune responses induced by six different spike protein vaccines targeting the ancestral or various Omicron strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in mice. We found that spike-wild-type immunization induced high titers of neutralizing antibodies (NAbs) against ancestral SARS-CoV-2. However, its activity in neutralizing Omicron subvariants decreased sharply as the number of mutations in receptor-binding domain (RBD) of these viruses increased. Spike-BA.5, spike-BF.7, and spike-BQ.1.1 vaccines induced strong NAbs against BA.5, BF.7, BQ.1, and BQ.1.1 viruses but were poor in protecting against XBB and XBB.1.5, which have more RBD mutations. In sharp contrast, spike-XBB.1.5 vaccination can activate strong and broadly protective immune responses against XBB.1.5 and other common subvariants of Omicron. By performing correlation analysis, we found that the NAbs titers were negatively correlated with the number of RBD mutations in the Omicron subvariants. Vaccines with more RBD mutations can effectively overcome the immune resistance caused by the accumulation of RBD mutations, making spike-XBB.1.5 the most promising vaccine candidate against universal Omicron variants.

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