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BACKGROUND AND AIMS: Tumor microenvironment (TME) heterogeneity leads to a discrepancy in survival prognosis and clinical treatment response for patients with HCC. The clinical applications of documented molecular subtypes are constrained by several issues. APPROACH AND RESULTS: We integrated 3 single-cell data sets to describe the TME landscape and identified 6 prognosis-related cell subclusters. Unsupervised clustering of subcluster-specific markers was performed to generate transcriptomic subtypes. The predictive value of these molecular subtypes for prognosis and treatment response was explored in multiple external HCC cohorts and the Xiangya HCC cohort. TME features were estimated using single-cell immune repertoire sequencing, mass cytometry, and multiplex immunofluorescence. The prognosis-related score was constructed based on a machine-learning algorithm. Comprehensive single-cell analysis described TME heterogeneity in HCC. The 5 transcriptomic subtypes possessed different clinical prognoses, stemness characteristics, immune landscapes, and therapeutic responses. Class 1 exhibited an inflamed phenotype with better clinical outcomes, while classes 2 and 4 were characterized by a lack of T-cell infiltration. Classes 5 and 3 indicated an inhibitory tumor immune microenvironment. Analysis of multiple therapeutic cohorts suggested that classes 5 and 3 were sensitive to immune checkpoint blockade and targeted therapy, whereas classes 1 and 2 were more responsive to transcatheter arterial chemoembolization treatment. Class 4 displayed resistance to all conventional HCC therapies. Four potential therapeutic agents and 4 targets were further identified for high prognosis-related score patients with HCC. CONCLUSIONS: Our study generated a clinically valid molecular classification to guide precision medicine in patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/classificação , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Prognóstico , Transcriptoma , Masculino , Feminino , Análise de Célula Única/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-IdadeRESUMO
mRNA translation is critical for regulation of various aspects of the nervous system. Ionotropic glutamate and gamma-aminobutyric acid type A (GABAA ) receptors are fundamental synaptic ion channels that control excitatory and inhibitory synaptic transmission, respectively. However, little is known about the translation of these receptors during brain development and function. By utilizing polysome profiling, a powerful tool for investigating translational machinery and mRNA translational states, we characterized the translational patterns of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA), and GABAA receptor subunits, and compared them with total mRNA and protein levels during mouse brain development, in different brain regions, and in response to behavioral stimuli. Most of the receptor subunits exhibited developmental changes at total mRNA, translation, and protein levels, among which translation of Gria1, Gria2, Grin1, Grin2a, Gabra1, and Gabrg2 contributed greatly to their protein levels. Most of the receptor subunits also displayed differentiated levels of total mRNA, translation, and protein in the prefrontal cortex and hippocampus, among which translation of Gria1, Gria2, Gabrb2, and Gabrg2 contributed to their protein levels. Finally, we showed that acute foot shock stress had a rapid influence in both the prefrontal cortex and hippocampus, with the prefrontal cortex displaying more changes at translational and protein levels. Notably, Grin2a is translationally repressed by stress which was followed by a decrease of GluN2A protein in both brain regions. Together, this study provides a new understanding of the translational patterns of critical ionotropic synaptic receptors during brain development and behavioral stress.
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Ácido Glutâmico , Receptores de GABA , Camundongos , Animais , Ácido Glutâmico/metabolismo , Receptores de GABA/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Encéfalo/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Immunotherapy is effective only in limited patients. It is urgent to discover a novel biomarker to predict immune cells infiltration status and immunotherapy response of different cancers. CLSPN has been reported to play a pivotal role in various biological processes. However, a comprehensive analysis of CLSPN in cancers has not been conducted. METHODS: To show the whole picture of CLSPN in cancers, a pan-cancer analysis was conducted in 9125 tumor samples across 33 cancer types by integrating transcriptomic, epigenomic and pharmacogenomics data. Moreover, the role of CLSPN in cancer was validated by CCK-8, EDU, colony formation and flow cytometry in vitro and tumor cell derived xenograft model in vivo. RESULTS: CLSPN expression was generally upregulated in most cancer types and was significantly associated with prognosis in different tumor samples. Moreover, elevated CLSPN expression was closely correlated with immune cells infiltration, TMB (tumor mutational burden), MSI (microsatellite instability), MMR (mismatch repair), DNA methylation and stemness score across 33 cancer types. Enrichment analysis of functional genes revealed that CLSPN participated in the regulation of numerous signaling pathways involved in cell cycle and inflammatory response. The expression of CLSPN in LUAD patients were further analyzed at the single-cell level. Knockdown CLSPN significantly inhibited cancer cell proliferation and cell cycle related cyclin-dependent kinase (CDK) family and Cyclin family expression in LUAD (lung adenocarcinoma) both in vitro and in vivo experiments. Finally, we conducted structure-based virtual screening by modelling the structure of CHK1 kinase domain and Claspin phosphopeptide complex. The top five hit compounds were screened and validated by molecular docking and Connectivity Map (CMap) analysis. CONCLUSION: Our multi-omics analysis offers a systematic understanding of the roles of CLSPN in pan-cancer and provides a potential target for future cancer treatment.
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Here, (-)-Tetrahydroalstonine (THA) was isolated from Alstonia scholaris and investigated for its neuroprotective effect towards oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced neuronal damage. In this study, primary cortical neurons were pre-treated with THA and then subjected to OGD/R induction. The cell viability was tested by the MTT assay, and the states of the autophagy-lysosomal pathway and Akt/mTOR pathway were monitored by Western blot analysis. The findings suggested that THA administration increased the cell viability of OGD/R-induced cortical neurons. Autophagic activity and lysosomal dysfunction were found at the early stage of OGD/R, which were significantly ameliorated by THA treatment. Meanwhile, the protective effect of THA was significantly reversed by the lysosome inhibitor. Additionally, THA significantly activated the Akt/mTOR pathway, which was suppressed after OGD/R induction. In summary, THA exhibited promising protective effects against OGD/R-induced neuronal injury by autophagy regulation through the Akt/mTOR pathway.
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Fármacos Neuroprotetores , Traumatismo por Reperfusão , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Oxigênio/metabolismo , Neurônios , Glucose/metabolismo , Traumatismo por Reperfusão/metabolismo , Fármacos Neuroprotetores/farmacologia , ApoptoseRESUMO
Ultrasound (US) has traditionally been recognised for its imaging capabilities, but its emerging role as a therapeutic modality in postoperative wound management, especially in paediatric care, has garnered significant attention. This meta-analysis aimed to evaluate the influence of US on postoperative wound healing and infection rates in paediatric patients. From an initial pool of 1236 articles, seven were deemed suitable for inclusion. Postoperative wound healing was assessed using the Redness, Edema, Ecchymosis, Discharge, and Approximation (REEDA) scale. Notably, there was a significant difference in wound healing patterns between the US-treated and control groups (I2 = 94%, standardized mean difference [SMD]: -4.60, 95% confidence intervals [CIs]: -6.32 to -2.88, p < 0.01), as illustrated in Figure 4. Additionally, a marked difference in wound infection rates was observed between the groups (I2 = 93%, SMD: -5.86, 95% CIs: -9.04 to -2.68, p < 0.01), as portrayed in Figure 5. The findings underscore the potential benefits of US in enhancing postoperative wound healing and reducing infection rates in paediatric surgical settings. However, the application of US should be judicious, considering the nuances of individual patient needs and clinical contexts.
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Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.
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Transtorno do Espectro Autista , Transtorno Autístico , Proteínas Ativadoras de GTPase/genética , Neuropeptídeos/genética , Receptores de N-Metil-D-Aspartato/genética , Proteínas rac1 de Ligação ao GTP/genética , Animais , Proteínas Ativadoras de GTPase/deficiência , Hipocampo/metabolismo , Camundongos , Camundongos Knockout , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão SinápticaRESUMO
The numbers of cases and deaths from coronavirus disease 2019 (COVID-19) are continuously increasing. Many people are concerned about the efficacy and safety of the COVID-19 vaccines. We performed a comprehensive analysis of the published trials of COVID-19 vaccines and the real-world data from the Vaccine Adverse Event Reporting System. Globally, our research found that the efficacy of all vaccines exceeded 70%, and RNA-based vaccines had the highest efficacy of 94.29%; moreover, Black or African American people, young people, and males may experience greater vaccine efficacy. The spectrum of vaccine-related adverse drug reactions (ADRs) is extremely broad, and the most frequent ADRs are pain, fatigue, and headache. Most ADRs are tolerable and are mainly grade 1 or 2 in severity. Some severe ADRs have been identified (thromboembolic events, 21-75 cases per million doses; myocarditis/pericarditis, 2-3 cases per million doses). In summary, vaccines are a powerful tool that can be used to control the COVID-19 pandemic, with high efficacy and tolerable ADRs. In addition, the spectrum of ADRs associated with the vaccines is broad, and most of the reactions appear within a week, although some may be delayed. Therefore, ADRs after vaccination need to be identified and addressed in a timely manner.
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Vacinas contra COVID-19/efeitos adversos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Vacinação/métodos , Vacinas Sintéticas/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , População Negra , COVID-19/etnologia , COVID-19/virologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Imunogenicidade da Vacina , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , População Branca , Adulto Jovem , Vacinas de mRNARESUMO
Rac1, an important Rho GTPase that regulates the actin cytoskeleton, has long been suggested to participate in acetylcholine receptor (AChR) clustering at the postsynaptic neuromuscular junction. However, how Rac1 is regulated and how it influences AChR clusters have remained unexplored. This study shows that breaking the balance of Rac1 regulation, by either increasing or decreasing its activity, led to impaired formation and maintenance of AChR clusters. By manipulating Rac1 activity at different stages of AChR clustering in cultured myotubes, we show that Rac1 activation was required for the initial formation of AChR clusters, but its persistent activation led to AChR destabilization, and uncontrolled hyperactivation of Rac1 even caused excessive myotube fusion. Both AChR dispersal and myotube fusion induced by Rac1 were dependent on its downstream effector Pak1. Two Rac1 GAPs and six Rac1 GEFs were screened and found to be important for normal AChR clustering. This study reveals that, although general Rac1 activity remains at low levels during terminal differentiation of myotubes and AChR cluster maintenance, tightly regulated Rac1 activity controls normal AChR clustering.
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Neuropeptídeos/metabolismo , Receptores Nicotínicos/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Linhagem Celular , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Junção Neuromuscular/metabolismo , Neuropeptídeos/genética , Receptores Nicotínicos/genética , Transdução de Sinais/fisiologia , Proteínas rac1 de Ligação ao GTP/genéticaRESUMO
Ischemic stroke is one of the most lethal and highly disabling diseases that seriously affects the human health and quality of life. A therapeutic angiogenic strategy has been proposed to alleviate ischemia-induced injury by promoting angiogenesis and improving cerebrovascular function in the ischemic regions. The insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF1R) axis is crucial for cerebral angiogenesis and neurogenesis. However, effective drugs that prevent cerebral ischemic injury by inducing cerebral angiogenesis via activation of the IGF1R pathway are lacking. Here, we screened a pro-angiogenic agent ginsenoside F1 (GF1), a ginseng saponin isolated from a traditional Chinese medicine that was widely used in ischemic stroke treatment. It promoted the proliferation, mobility and tube formation of human umbilical vein endothelial cells and human brain microvascular endothelial cells, as well as pericytes recruitment to the endothelial tubes. GF1 stimulated vessel sprouting in the rat arterial ring and facilitated neovascularization in chicken embryo chorioallantoic membrane (CAM). In the in vivo experiments, GF1 rescued the axitinib-induced vascular defect in zebrafish. It also increased the microvessel density (MVD) and improved focal cerebral blood perfusion in the rat middle cerebral artery occlusion (MCAO) model. Mechanism studies revealed that GF1-induced angiogenesis depended on IGF1R activation mediated by the autocrine IGF-1 loop in endothelial cells. Based on our findings, GF1-induced activation of the IGF-1/IGF1R pathway to promote angiogenesis is an effective approach to alleviate cerebral ischemia, and GF1 is a potential agent that improves cerebrovascular function and promotes recovery from ischemic stroke.
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Indutores da Angiogênese/farmacologia , Ginsenosídeos/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Ratos Sprague-Dawley , Ratos Wistar , Peixe-ZebraRESUMO
Two pairs of new diarylheptanoid-monoterpene adduct enantiomers, (±)-alpininoids A and B [(±)-1 and (±)-2], as well as three pairs of new diarylheptanoid-sesquiterpene adduct enantiomers, (±)-alpininoids C-E [(±)-3-(±)-5], together with four known diarylheptanoids (6-9) were isolated from the rhizomes of Alpinia officinarum. Their structures with absolute configurations were elucidated on the basis of comprehensive spectroscopic analyses and computational calculation methods. The skeletons of these cyclohexene-containing hybrid natural products were hypothesized to be generated via a crucial Diels-Alder cycloaddition between the diarylheptanoids (7 and 8) and terpenes, of which 1 represents a new carbon skeleton. All isolated compounds were evaluated for their neuroprotective effects against MPP+ (1-methyl-4-phenylpyridinium)-induced cortical neuron injury. At a concentration of 16 µM, (+)-1 significantly increased cell viability when compared with MPP+ treatment alone.
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Alpinia/química , Diarileptanoides/química , Diarileptanoides/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Terpenos/química , Terpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Espectroscopia de Ressonância Magnética/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Rizoma/química , Sesquiterpenos/química , Sesquiterpenos/farmacologia , EstereoisomerismoRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Increasing evidence has shown that ß-amyloid protein (Aß) production is the key pathological cause of AD. 7-(4-Hydroxy-3-methoxyphenyl)-1-phenyl-4E-hepten-3-one (AO-2), a natural diarylheptanoid, is previously found to have activities in neuronal differentiation and neurite outgrowth, and its analogue shows protective effects against Aß. In this study, we further investigated the function of AO-2 toward Aß-induced injuries in PC12 cells and hippocampal neurons. Pretreatment of PC12 cells with AO-2 restored cell viability in a concentration-dependent manner against Aß-induced neurotoxicity. Moreover, the Aß stimulated apoptosis and caspase-3 activation were markedly inhibited by AO-2. We found that AO-2 prevented the downregulation of PI3K-Akt-mTOR signaling after Aß damage, and blockade of either PI3K or mTOR activity led to the failure of AO-2 on caspase-3 inhibition. We further showed that AO-2 was protective against two devastating effects of Aß, increased reactive oxygen species (ROS) production and dendrite injury, and this protection was also dependent on PI3K and mTOR activities. Taken together, this study showed that AO-2 acts against Aß-induced damages in PC12 cells and hippocampal neurons through PI3K-mTOR pathways, thus providing a new neuroprotective compound which may shed light on drug development of AD.
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Peptídeos beta-Amiloides/fisiologia , Diarileptanoides/farmacologia , Fragmentos de Peptídeos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Epithelial-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis; thus, developing EMT inhibitors may be a feasible treatment for metastatic PCa. Here, we discovered that arenobufagin and four other bufadienolides suppressed PC3 cell EMT. These compounds modulated EMT marker expression with elevating E-cadherin and reducing ZEB1, vimentin and slug expression, and attenuated the migration and invasion of PC3 cells. Among these five compounds, arenobufagin exhibited the most potent activity. We found that the mRNA and protein expression of ß-catenin and ß-catenin/TCF4 target genes, which are related to tumor invasion and metastasis, were down-regulated after arenobufagin treatment. Overexpression of ß-catenin in PC3 cells antagonized the EMT inhibition effect of arenobufagin, while silencing ß-catenin with siRNA enhanced the inhibitory effect of arenobufagin on EMT. In addition, arenobufagin restrained xenograft tumor EMT, as demonstrated by decreased mesenchymal marker expression and increased epithelial marker expression, and reduced the tumor metastatic foci in lung. This study demonstrates a novel anticancer activity of arenobufagin, which inhibits PC3 cell EMT by down-regulating ß-catenin, thereby reducing PCa metastasis. In addition, it also provides new evidence for the development of arenobufagin as a treatment for metastatic prostate cancer.
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Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Próstata/metabolismo , beta Catenina/metabolismo , Animais , Antineoplásicos/uso terapêutico , Bufanolídeos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , beta Catenina/genéticaAssuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , Humanos , Retina/patologia , Retina/virologia , SARS-CoV-2RESUMO
Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (Dock4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including autism and schizophrenia. Nonetheless, the neuronal function of Dock4 is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies that Dock4 is critical for neurite differentiation and extension. This regulation is through activation of Rac1 and modulation of the dynamics of actin-enriched protrusions on the neurites. In cultured hippocampal neurons, Dock4 regulates the establishment of the axon-dendrite polarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletion Dock4 mutant linked to autism and dyslexia that lacks the GEF domain leads to defective neurite outgrowth and neuronal polarization. Further analysis reveals that the SH3 domain-mediated interaction of Dock4 is required for its activity toward neurite differentiation, whereas its proline-rich C terminus is not essential for this regulation. Together, our findings reveal an important role of Dock4 for neurite differentiation during early neuronal development.
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Actinas/metabolismo , Diferenciação Celular , Proteínas Ativadoras de GTPase/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuritos/metabolismo , Neuropeptídeos/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Actinas/genética , Animais , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Linhagem Celular Tumoral , Dislexia/genética , Dislexia/metabolismo , Ativação Enzimática , Proteínas Ativadoras de GTPase/genética , Hipocampo/citologia , Humanos , Camundongos , Mutação , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Ratos , Ratos Sprague-Dawley , Proteínas rac de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/genética , Domínios de Homologia de srcRESUMO
Human adenovirus (HAdV) type 40 in species F (HAdV-F40) and HAdV-F41 represent the third most prevalent causative agents of non-bacterial acute gastroenteritis in infants and young children, following norovirus and rotavirus. Despite their significant contribution to global child morbidity, vaccines to preemptively combat these viruses remain elusive. In this study, we investigate the potential for cross-neutralization between HAdV-F40 and HAdV-F41 using immune sera with the short fiber knob (SFK). We implemented a series of assays to evaluate the responses, including enzyme-linked immunosorbent, micro-neutralization, immunofluorescence, and quantitative polymerase chain reaction. Our results demonstrate that immune sera with HAdV-F40 SFK or HAdV-F41 SFK could effectively neutralize both HAdV-F40 and HAdV-F41, indicating a mutual cross-neutralizing effect. Notably, the immune sera with HAdV-F40 SFK demonstrated a stronger neutralization effect, suggesting the potential to develop a subunit vaccine that can simultaneously counteract both viruses. These findings underscore the potential of SFK immunization in evoking a cross-neutralizing antibody response between HAdV-F40 and HAdV-F41. This suggests a promising avenue for developing subunit vaccines against HAdV-F40 and HAdV-F41 and provides a novel perspective on the potential of neutralizing antibodies to protect against these two types of HAdV.
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Colorectal cancer (CRC) exhibits significant heterogeneity, impacting immunotherapy efficacy, particularly in immune desert subtypes. Neuromedin U receptor 1 (NMUR1) has been reported to perform a vital function in immunity and inflammation. Through comprehensive multi-omics analyses, we have systematically characterized NMUR1 across various tumors, assessing expression patterns, genetic alterations, prognostic significance, immune infiltration, and pathway associations at both the bulk sequencing and single-cell scales. Our findings demonstrate a positive correlation between NMUR1 and CD8+ T cell infiltration, with elevated NMUR1 levels in CD8+ T cells linked to improved immunotherapy outcomes in patients with CRC. Further, we have validated the NMUR1 expression signature in CRC cell lines and patient-derived tissues, revealing its interaction with key immune checkpoints, including lymphocyte activation gene 3 and cytotoxic T-lymphocyte-associated protein 4. Additionally, NMUR1 suppression enhances CRC cell proliferation and invasiveness. Our integrated analyses and experiments open new avenues for personalized immunotherapy strategies in CRC treatment.
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Multidrug resistance (MDR) is a major obstacle to successful chemotherapy for cancer; thus, novel MDR reversers are urgently needed. In the present study, we assessed whether two synthetic derivatives of 23-hydroxybetulinic acid, 3,23-O-diacetyl-17-1,4'-bipiperidinyl betulinic amide (DABB) and 3,23-O-dihydroxy-17-1,4'-bipiperidinyl betulinic amide (DHBB), could reverse MDR induced by ATP-binding cassette (ABC) transporters. Using the MTT assay, we found that DABB and DHBB could enhance the cytotoxicities of ABCB1 substrates doxorubicin, vincristine, and paclitaxel in ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells, whereas that of a non-ABCB1 substrate cisplatin was unaffected. The ABCB1 substrate accumulation and efflux assay showed that DABB and DHBB not only enhanced the retention of doxorubicin and rhodamine123 but also inhibited the efflux of rhodamine123. Further mechanistic studies by reverse transcription PCR, western blot, and ABCB1 ATPase activity assay indicated that DABB and DHBB suppressed ABCB1 ATPase activity, but did not alter mRNA or protein expression of ABCB1. ABCB1 siRNA pretreatment attenuated the reversal effect of DABB and DHBB, indicating that their reversal effects were partially dependent on ABCB1. Docking analysis also implied that DABB and DHBB bind directly to ABCB1 at a site partly overlapped with that of verapamil. Taken together, our findings suggest that two bipiperidinyl derivatives of 23-hydroxybetulinic acid reverse ABCB1-mediated MDR through modulation of ABCB1 ATPase activity, thereby inhibiting its efflux function in both HepG2/ADM and MCF-7/ADR cells. These findings may contribute toward the development of novel MDR reversers using DABB and DHBB as adjuvant anticancer chemotherapy.
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Antineoplásicos/química , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piperidinas/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células Hep G2/efeitos dos fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Piperidinas/química , Rodamina 123/farmacocinética , Verapamil/metabolismo , Verapamil/farmacologia , Vincristina/farmacologiaRESUMO
Patients with gastric precancerous lesions (GPL) have a higher risk of gastric cancer (GC). However, the transformation of GPL into GC is an ongoing process that takes several years. At present, several factors including H.Pylori (Hp), flora imbalance, inflammatory factors, genetic variations, Claudin-4, gastric stem cells, solute carrier family member 26 (SLC26A9), bile reflux, exosomes, and miR-30a plays a considerable role in the transformation of GPL into GC. Moreover, timely intervention in the event of GPL can reduce the risk of GC. In clinical practice, GPL is mainly treated with endoscopy, acid suppression therapy, Hp eradication, a cyclooxygenase-2 inhibitor, aspirin, and diet. Currently, the use of traditional Chinese medicine (TCM) or combination with western medication to remove Hp and the use of TCM to treat GPL are common in Asia, particularly China, and have also demonstrated excellent clinical efficacy. This review thoroughly discussed the combining of TCM and Western therapy for the treatment of precancerous lesions as conditions allow. Consequently, this review also focuses on the causes of the development and progression of GPL, as well as its current treatment. This may help us understand GPL and related treatment.
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Bronchiolitis obliterans (BO) is a chronic airway disease that was often indicated by the pathological presentation of narrowed and irreversible airways. However, the molecular mechanisms of BO pathogenesis remain unknown. Although neutrophil extracellular traps (NETs) can contribute to inflammatory disorders, their involvement in BO is unclear. This study aims to identify potential signaling pathways in BO by exploring the correlations between NETs and BO. GSE52761 and GSE137169 datasets were downloaded from gene expression omnibus (GEO) database. A series of bioinformatics analyses such as differential expression analysis, gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were performed on GSE52761 and GSE137169 datasets to identify BO potential signaling pathways. Two different types of BO mouse models were constructed to verify NETs involvements in BO. Additional experiments and bioinformatics analysis using human small airway epithelial cells (SAECs) were also performed to further elucidate differential genes enrichment with their respective signaling pathways in BO. Our study identified 115 differentially expressed genes (DEGs) that were found up-regulated in BO. Pathway enrichment analysis revealed that these genes were primarily involved in inflammatory signaling processes. Besides, we found that neutrophil extracellular traps (NETs) were formed and activated during BO. Our western blot analysis on lung tissue from BO mice further confirmed NETs activation in BO, where neutrophil elastase (NE) and myeloperoxidase (MPO) expression were found significantly elevated. Transcriptomic and bioinformatics analysis of NETs treated-SAECs also revealed that NETs-DEGs were primarily associated through inflammatory and epithelial-to-mesenchymal transition (EMT) -related pathways. Our study provides novel clues towards the understanding of BO pathogenesis, in which NETs contribute to BO pathogenesis through the activation of inflammatory and EMT associated pathways. The completion of our study will provide the basis for potential novel therapeutic targets in BO treatment.