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Exosomes have emerged as promising vehicles for delivering therapeutic cargoes to specific cells or tissues, owing to their superior biocompatibility, reduced immunogenicity, and enhanced targeting capabilities compared to conventional drug delivery systems. In this study, we developed a delivery platform utilizing exosomes derived from monocytes, specifically designed for targeted delivery of Bortezomib (Btz) to multiple myeloma (MM) cells. Our approach involved the genetic modification of monocytes to express antibodies targeting B cell maturation antigen (anti-BCMA), as BCMA selectively expresses on myeloma cells. This modified anti-BCMA was then efficiently incorporated into the monocyte-derived exosomes. These adapted exosomes effectively encapsulated Bortezomib, leading to enhanced drug accessibility within MM cells and sustained intracellular accumulation over an extended period. Remarkably, our results demonstrated that anti-BCMA-Exo-Btz outperformed free Btz in vitro, exhibiting a more potent myeloma-suppressive effect. In orthotopic MM xenograft models, anti-BCMA-Exo-Btz exhibited a significant anti-tumor effect compared to free Btz. Furthermore, it demonstrated remarkable specificity in targeting Bortezomib to myeloma cells in vivo. Importantly, we observed no significant histological damage in mice treated with anti-BCMA-Exo-Btz and a slight effect on PBMCs. Additionally, our study highlighted the multifunctional potential of monocyte-exosomes, which induced cell apoptosis, mediated immune responses, and enhanced the osteogenic potential of mesenchymal stromal cells. In conclusion, our study suggests that exosomes modified with targeting ligands hold therapeutic promise for delivering Bortezomib to myelomas, offering substantial potential for clinical applications.
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BACKGROUND: A comprehensive understanding of gastric signet ring cell carcinoma (SRCC) is limited. The aim of our study was to analyze metastatic patterns of gastric SRCC and evaluate impacts of gastrectomy and chemotherapy for metastatic gastric SRCC. METHODS: We obtained data of gastric cancer patients between 2010 and 2017 in the Surveillance, Epidemiology, and End Results database. Chi-square tests were used to compare data significance. Kaplan-Meier, Cox proportional hazards regression and Fine-Gray competing risk analysis were used to analyze the difference in the overall survival (OS) and cancer-specific survival (CSS). Propensity-score matching was used to adjust numerical difference. RESULTS: Among 36,459 eligible gastric cancer patients, 6264 (17.2 %) were SRCC patients. Bone metastasis was more common in SRCC patients than in non-SRCC patients. The multivariate analysis showed that chemotherapy (HR = 0.30, 95 %CI = 0.27-0.33, p < 0.01) and gastrectomy (HR = 0.51, 95 %CI = 0.45-0.59, p < 0.01) were protective prognostic factors in certain stage â £ SRCC patients. For the effect of gastrectomy, survival benefits could be found in patients with liver metastasis. The gastrectomy was not associated with improved OS in patients with lung or multiple metastases. In subgroup analysis, SRCC patients with metastasis who received gastrectomy and chemotherapy (HR = 0.17, p < 0.01; HR = 0.03, p < 0.01) had a better OS and CSS than those who had chemotherapy only (HR = 0.30, p < 0.01; HR = 0.18, p < 0.01). CONCLUSION: Our study analyzed the unique metastatic patterns of gastric SRCC and recommended chemotherapy as the first choice in metastatic SRCC. For patients with liver metastasis, gastrectomy plus chemotherapy can be considered.
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Carcinoma de Células en Anillo de Sello , Neoplasias Hepáticas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Carcinoma de Células en Anillo de Sello/tratamiento farmacológico , Carcinoma de Células en Anillo de Sello/cirugía , Carcinoma de Células en Anillo de Sello/patología , Gastrectomía , Pronóstico , Neoplasias Hepáticas/cirugíaRESUMEN
SCOPE: Recent studies have highlighted the vital role of gut microbiota in the pathogenesis of Alzheimer's disease (AD). However, the effect of the regulation of gut microbiota by dietary components on AD remains unknown. Thus, the study explored that a high-tryptophan (Trp) diet alleviates cognitive impairment by regulating microbiota. METHODS AND RESULTS: Male APP/PS1 mice are fed 0.5% Trp diet for 4 weeks, and then cognitive function, amyloid-ß (Aß) deposition, microglial activation, proinflammatory cytokines production, and gut microbiota are detected. Moreover, the level of aryl hydrocarbon receptor (AhR) and NF-κB pathway related protein are determined. The results show that high-Trp diet significantly alleviates cognitive impairment and Aß deposits. Moreover, high-Trp diet significantly inhibits activation of microglia, decreases the level of cluster of differentiation 11b (CD11b), and restrains the activation markers of microglia, such as cyclooxygenase-2 (Cox-2), interleukin (IL)-1ß, and IL-6. Notably, high-Trp diet significantly activates AhR, inhibits the phosphorylation of p65, and improves microbiota dysbiosis. CONCLUSIONS: These findings demonstrated that high-Trp diet exerts anti-inflammatory effects via upregulating AhR and suppressing NF-κB pathway, and its mechanisms may be mediated by regulating gut microbiota, suggesting that Trp diet may be a potential strategy for AD intervention.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Microbioma Gastrointestinal , Ratones , Masculino , Animales , Triptófano/farmacología , Triptófano/metabolismo , FN-kappa B , Enfermedades Neuroinflamatorias , Receptores de Hidrocarburo de Aril , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Dieta , Ratones TransgénicosRESUMEN
Ferroptosis, a nonapoptotic form of cell death marked by iron-dependent peroxidation of phospholipids, is associated with the occurrence and progression of tumors. Erastin, a selective inhibitor of the cystine/glutamate transporter system Xc-, can induce the ferroptosis of cancer cells. Multiple myeloma (MM) has been reported to be insensitive to erastin-induced ferroptosis. However, we found the erastin sensitivity of different MM cells varied widely. Specifically, SLC7A11 abundance determined the sensitivity of MM cells to erastin-induced ferroptosis. MM cells expressing a high SLC7A11 level were more sensitive to erastin-induced ferroptosis than cells expressing a low level of SLC7A11. Moreover, the expression of SLC7A11 gradually increased with the progression of plasma cell dyscrasias. Survival analysis indicated that high levels of SLC7A11 predicted a poor prognosis for MM patients. Knocking down SLC7A11 expression significantly inhibited the proliferation of MM cells and induced ferroptotic cell death. Additionally, we revealed that the long noncoding RNA (lncRNA) SLC7A11-AS1 was a critical regulatory factor of SLC7A11 expression. SLC7A11-AS1 overexpression diminished SLC7A11 levels, leading to the ferroptosis of MM cells. In summary, our data show that heterogeneous SLC7A11 expression affects MM cell sensitivity to ferroptosis, providing a theoretical basis for improving the clinical treatment of MM.
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Ferroptosis , Mieloma Múltiple , Piperazinas , Humanos , Apoptosis/genética , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Ferroptosis/genética , Muerte Celular , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismoRESUMEN
Introduction: Recent studies have highlighted the vital role of gut microbiota in traumatic brain injury (TBI). Fecal microbiota transplantation (FMT) is an effective means of regulating the microbiota-gut-brain axis, while the beneficial effect and potential mechanisms of FMT against TBI remain unclear. Here, we elucidated the anti-neuroinflammatory effect and possible mechanism of FMT against TBI in mice via regulating the microbiota-gut-brain axis. Methods: The TBI mouse model was established by heavy object falling impact and then treated with FMT. The neurological deficits, neuropathological change, synaptic damage, microglia activation, and neuroinflammatory cytokine production were assessed, and the intestinal pathological change and gut microbiota composition were also evaluated. Moreover, the population of Treg cells in the spleen was measured. Results: Our results showed that FMT treatment significantly alleviated neurological deficits and neuropathological changes and improved synaptic damage by increasing the levels of the synaptic plasticity-related protein such as postsynaptic density protein 95 (PSD-95) and synapsin I in the TBI mice model. Moreover, FMT could inhibit the activation of microglia and reduce the production of the inflammatory cytokine TNF-α, alleviating the inflammatory response of TBI mice. Meanwhile, FMT treatment could attenuate intestinal histopathologic changes and gut microbiota dysbiosis and increase the Treg cell population in TBI mice. Conclusion: These findings elucidated that FMT treatment effectively suppressed the TBI-induced neuroinflammation via regulating the gut microbiota-gut-brain axis, and its mechanism was involved in the regulation of peripheral immune cells, which implied a novel strategy against TBI.
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Lesiones Traumáticas del Encéfalo , Eje Cerebro-Intestino , Animales , Ratones , Enfermedades Neuroinflamatorias , Trasplante de Microbiota Fecal , Lesiones Traumáticas del Encéfalo/terapia , Citocinas , Modelos Animales de EnfermedadRESUMEN
Gastrodin (Gas) has exhibited protective activity in neurological disorders. Here, we investigated the neuroprotective effect and potential mechanisms of Gas against cognitive impairment via regulating gut microbiota. APPswe/PSEN1dE9 transgenic (APP/PS1) mice were treated intragastrically with Gas for 4 weeks, and then cognitive deficits, deposits of amyloid-ß (Aß) and phosphorylation of tau were analyzed. The expression levels of insulin-like growth factor-1 (IGF-1) pathway-related proteins, such as cAMP response element-binding protein (CREB), were detected. Meanwhile, gut microbiota composition was evaluated. Our results showed that Gas treatment significantly improved cognitive deficits and Aß deposition in APP/PS1 mice. Moreover, Gas treatment increased the level of Bcl-2 and decreased level of Bax and ultimately inhibited neuronal apoptosis. Gas treatment markedly increased the expression levels of IGF-1 and CREB in APP/PS1 mice. Moreover, Gas treatment improved abnormal composition and structure of gut microbiota in APP/PS1 mice. These findings revealed that Gas actively participated in regulating the IGF-1 pathway to inhibit neuronal apoptosis via the gut-brain axis and that it can be considered a new therapeutic strategy against Alzheimer's disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Animales , Factor I del Crecimiento Similar a la Insulina , Eje Cerebro-Intestino , Ratones Transgénicos , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Disfunción Cognitiva/etiología , Modelos Animales de EnfermedadRESUMEN
Recent evidence demonstrated that functional bacteria were involved in the regulation of Parkinson's disease (PD). However, the mechanism of probiotics in improving PD was unclear. Here the antioxidant effect and the mechanism of probiotics Pediococcus pentosaceus (PP) on PD were studied by regulating the gut-brain axis. In this study, male C57BL/6J mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally to establish a PD model and were then treated with PP for 4 weeks. Subsequently, a series of neurobehavioral tests to evaluate the motor function of the mice was performed. Additionally, degeneration of dopaminergic neurons, accumulation of α-synuclein, the production of an oxidative stress response, and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related proteins were evaluated. Moreover, the gut microbial composition and the level of metabolite γ-aminobutyric acid (GABA) were assessed. The results showed that PP treatment could improve MPTP-induced motor deficits, the degeneration of dopaminergic neurons, and the accumulation of α-synuclein. Moreover, PP treatment significantly increased the levels of SOD1, Gpx1, and Nrf2, while it decreased the levels of Keap1 in the brain of MPTP-induced mice. Notably, PP treatment improved the gut microbial dysbiosis and increased the level of GABA in MPTP-induced mice. These findings indicated that PP might represent a promising candidate, due to the metabolite of GABA, that could be used for the treatment of PD.
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Microbioma Gastrointestinal , Enfermedad de Parkinson , Probióticos , Ratones , Masculino , Animales , alfa-Sinucleína/metabolismo , alfa-Sinucleína/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Pediococcus pentosaceus/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Microbioma Gastrointestinal/fisiología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones Endogámicos C57BL , Eje Cerebro-Intestino , Estrés Oxidativo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Background: Most previous studies have focused on the intrinsic carcinogenic pathways of tumors; however, little is known about the potential role of N6-methyladenosine (m6A) methylation in the tumor immune microenvironment (TIME). To better diagnose and treat acute myeloid leukemia (AML), we sought to examine the correlation between m6A regulatory factors and immune infiltration in cases of AML. At the same time, a prognostic model was constructed to predict the survival of AML. Methods: We extracted data from The Cancer Genome Atlas (TCGA) database, including ribonucleic acid sequencing (RNA-seq) transcriptome data and data on the corresponding clinical characteristics of AML patients. We identified two m6A modification patterns with distinct clinical outcomes and found a significant relationship between them. Simultaneous discovery of distinct m6A clusters associated with the tumor immune microenvironment [immune cell types and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm] are closely related. Next, we implemented Lasso (Least Absolute Shrinkage and Selection Operator) Cox regression to build a predictive model in the 2-m6A regulator TCGA dataset to further explore m6A prognostic features in AML, and perform correlation validation. Results: We identified 2 molecular subtypes (Clusters 1 and 2) by the consistent clustering of significant m6A regulators in AML. Cluster 2 was associated with a higher immune score and obvious immune cell infiltration, and thus patients in Cluster 2 had a poorer prognosis than those in Cluster 1 (P<0.05). Additionally, the 2 m6A-related signatures representing the independent prognostic factors in AML were screened to construct a prognostic risk-score model. We found that patients with low-risk scores had higher immune scores than those with high-risk scores (P<0.05). Conclusions: Our research confirmed that m6A methylation plays an important role in AML. Further provide new directions for the prognosis and treatment of AML.
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The fungal microbiota may be involved in the regulation of cognition and behavior, while the role of probiotic fungi against cognitive impairment is unclear. Here, we explored the idea that probiotic Saccharomyces boulardii could participate in the regulation of microglia-induced neuroinflammation in Alzheimer's disease (AD) model mice. Cognitive deficits, deposits of amyloid-ß (Aß) and phosphorylation of tau, synaptic plasticity, microglia activation, and neuroinflammatory reactions were observed. The expression levels of Toll-like receptors (TLRs) pathway-related proteins were detected. Meanwhile, intestinal barrier integrity and fungal microbiota composition were evaluated. Our results showed fungal microbiota dysbiosis in APP/PS1 mice, which might result in the neuroinflammation of AD. The increased levels of interleukin (IL)-6, IL-1ß, and cluster of differentiation 11b (CD11b) were observed in APP/PS1 mice, which were associated with activation of microglia, indicative of a broader recognition of neuroinflammation mediated by fungal microbiota compared to hitherto appreciated. Probiotic S. boulardii treatment improved dysbiosis, alleviated the neuroinflammation as well as synaptic injury, and ultimately improved cognitive impairment. Moreover, S. boulardii therapy could inhibit microglia activation and the TLRs pathway, which were reversed by antifungal treatment. These findings revealed that S. boulardii actively participated in regulating the TLRs pathway to inhibit the neuroinflammation via the gut-brain axis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Micobioma , Probióticos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Eje Cerebro-Intestino , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Disbiosis/metabolismo , Hongos/metabolismo , Ratones , Ratones Transgénicos , MicroglíaRESUMEN
BACKGROUND: Recent retrospective studies have reported that breast-conserving therapy (BCT) led to improved overall survival (OS) than mastectomy in some populations. We aimed to compare the efficacy of BCT and mastectomy using the SEER database. MATERIALS AND METHODS: Between 2010 and 2015, 99,790 eligible patients were identified. We included early-stage breast cancer patients with 5cm or smaller tumors and three or fewer positive lymph nodes in our study. We compared the OS and breast cancer-specific survival (BCSS) results among patients with BCT and those with mastectomy. Kaplan-Meier plots, Cox proportional hazard regressions, competing risk analysis, and multivariate regressions were used to evaluate the outcomes. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. RESULTS: In our study, 77,452 (77.6%) patients underwent BCT and 22,338 (22.4%) underwent mastectomy. The 5-year OS rate was 94.7% in the BCT group and 87.6% in the mastectomy group, and the 5-year BCSS was 97.2% in the BCT and 94.3% in the mastectomy group. Multivariate analysis in the matched cohort showed that women underwent mastectomy was associated with worse OS (Hazard ratio (HR) = 1.79; 95% confidence intervals (CIs) = 1.59-2.02, p < 0.001) and BCSS (HR = 1.88; 95% CIs = 1.61-2.18, p < 0.001) results compared with those underwent BCT. Patients with different subtypes and age group (>50 years old; ≤50 years old) received BCT showed significantly better OS and BCSS results than those received mastectomy. The effect of surgery choice on survival yielded similar results either for all patients or matched cohorts. CONCLUSIONS: Our study showed that BCT was associated with improved survival compared with mastectomy in early-stage breast cancer patients. It seems advisable to encourage patients to receive BCT rather than mastectomy in early-stage patients when feasible and appropriate.
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Neoplasias de la Mama , Mastectomía , Mama/patología , Neoplasias de la Mama/patología , Femenino , Humanos , Mastectomía/métodos , Mastectomía Segmentaria , Persona de Mediana Edad , Puntaje de PropensiónRESUMEN
The mechanisms of coffee against Parkinson disease (PD) remained incompletely elucidated. Numerous studies suggested that gut microbiota played a crucial role in the pathogenesis of PD. Here, we explored the further mechanisms of coffee against PD via regulating gut microbiota. C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a PD mouse model, then treated with coffee for 4 consecutive weeks. Behavioral tests consisting of the pole test and beam-walking test were conducted to evaluate the motor function of mice. The levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) were assessed for dopaminergic neuronal loss. The levels of occludin, glial fibrillary acidic protein (GFAP), Bcl-2, Bax, cleaved caspase-3, and cytochrome c (Cyt c) were detected. Moreover, microbial components were measured by 16s rRNA sequencing. Our results showed that coffee significantly improved the motor deficits and TH neuron loss, and reduced the level of α-syn in the MPTP-induced mice. Moreover, coffee increased the level of BBB tight junction protein occludin and reduced the level of astrocyte activation marker GFAP in the MPTP-induced mice. Furthermore, coffee significantly decreased the levels of proapoptotic proteins, including Bax, cleaved caspase-3, and cytochrome c, while it increased the level of antiapoptotic protein Bcl-2, consequently preventing MPTP-induced apoptotic cascade. Moreover, coffee improved MPTP-induced gut microbiota dysbiosis. These findings suggested that the neuroprotective effects of coffee on PD were involved in the regulation of gut microbiota, which might provide a novel option to elucidate the effects of coffee on PD.
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Microbioma Gastrointestinal , Fármacos Neuroprotectores , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Café , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16SRESUMEN
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy diagnosed in children and is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. C-C chemokine receptor type 5 (CCR5) is a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. A highly potent competitive antagonist of CCR5, maraviroc, recently has been identified with suppression of cancer cells aggressive in a variety of cancers. However, the effects of maraviroc on ALL cells have not yet been defined. Here we report that CCR5 selective inhibitor significantly inhibited ALL cells SUP-B15 growth and induced SUP-B15 cells to undergo cell apoptosis. This cell apoptosis was associated with increased levels of cleavage of caspase-3 and caspase-9, and Poly (ADP-ribose) polymerase (PARP). Moreover, we demonstrated that maraviroc strongly inhibited SUP-B15 cells migration to C-X-C motif chemokine ligand 12 (CXCL12) and CXCL13, and adhesion to fibronectin and vascular cell adhesion molecule 1 (VCAM-1) in vitro. Importantly, CCR5-activated signaling proteins Janus Kinase 1 (JAK1), JAK2 and signal transducer and activator of transcription (STAT3) were inhibited by maraviroc. Finally, maraviroc suppressed the growth of SUP-B15 xenograft tumors in athymic mice. Collectively, this study demonstrated that CCR5 inhibition by maraviroc has the potential for the treatment of human ALL.