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Emotion regulation, essential for adaptive behavior, depends on the brain's capacity to process a range of emotions. Current research has largely focused on individual emotional circuits without fully exploring how their interaction influences physiological responses or understanding the neural mechanisms that differentiate emotional valence. Using in vivo calcium imaging, electrophysiology, and optogenetics, we examined neural circuit dynamics in the medial prefrontal cortex (mPFC), targeting two key areas: the basal lateral amygdala (BLA) and nucleus accumbens (NAc). Our results demonstrate distinct activation patterns in the mPFCâBLA and mPFCâNAc pathways in response to social stimuli, indicating a mechanism for discriminating emotions: increased mPFCâBLA activity signals anxiety, while heightened mPFCâNAc responses are linked to exploration. Additionally, chronic emotional states amplify activity in these pathways-positivity enhances mPFCâNAc, while negativity boosts mPFCâBLA. This study sheds light on the nuanced neural circuitry involved in emotion regulation, revealing the pivotal roles of mPFC projections in emotional processing. Identifying these specific circuits engaged by varied emotional states advances our understanding of emotional regulation's biological underpinnings and highlights potential targets for addressing emotional dysregulation in psychiatric conditions. Significance statement: While existing circuitry studies have underscored the significance of emotional circuits, the majority of research has concentrated on individual circuits. The assessment of whether and how the balance among multiple circuits influences overall physiological outcomes is often overlooked. This study delves into the neural underpinnings of emotion regulation, focusing on how positive and negative valences are discriminated and managed. By examining the specific pathways from the medial prefrontal cortex (mPFC) to key emotional centers-the basal lateral amygdala (BLA) for negative valence and the nucleus accumbens (NAc) for positive one-we uncovered a novel dual-balanced neural circuit mechanism that enables this essential aspect of human cognition.
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Following a stroke, the emergence of amygdala-related disorders poses a significant challenge, with severe implications for post-stroke mental health, including conditions such as anxiety and depression. These disorders not only hinder post-stroke recovery but also elevate mortality rates. Despite their profound impact, the precise origins of aberrant amygdala function after a stroke remain elusive. As a target of reduced brain pH in ischemia, acid-sensing ion channels (ASICs) have been implicated in synaptic transmission after ischemia, hinting at their potential role in reshaping neural circuits following a stroke. This study delves into the intriguing relationship between post-stroke alterations and ASICs, specifically focusing on postsynaptic ASIC1a enhancement in the amygdala following prefrontal cortex (PFC) ischemia induced by endothelin-1 (ET-1) injection. Our findings intriguingly illustrate that mPFC ischemia not only accentuates the PFC to the amygdala circuit but also implicates ASIC1a in fostering augmented synaptic plasticity after ischemia. In contrast, the absence of ASIC1a impairs the heightened induction of long-term potentiation (LTP) in the amygdala induced by ischemia. This pivotal research introduces a novel concept with the potential to inaugurate an entirely new avenue of inquiry, thereby significantly enhancing our comprehension of the intricate mechanisms underlying post-stroke neural circuit reconfiguration. Importantly, these revelations hold the promise of paving the way for groundbreaking therapeutic interventions.
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The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with a wide range of "long COVID" neurological symptoms. However, the mechanisms governing SARS-CoV-2 neurotropism and its effects on long-term behavioral changes remain poorly understood. Using a highly virulent mouse-adapted SARS-CoV-2 strain, denoted as SARS2-N501Y MA30 , we demonstrated that intranasal inoculation of SARS2-N501Y MA30 results in viral dissemination to multiple brain regions, including the amygdala and hippocampus. Behavioral assays show a significant increase in anxiety- and depression-like behaviors 14 days following viral infection. Moreover, we observed microglia activation following SARS2-N501Y MA30 infection, along with an augmentation in microglia-dependent neuronal activity in the amygdala. Pharmacological inhibition of microglial activity subsequent to viral spike inoculation mitigates microglia-dependent neuronal hyperactivity. Furthermore, transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating microglia-driven neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Overall, these data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.
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Following a stroke, the emergence of amygdala-related disorders poses a significant challenge, with severe implications for post-stroke mental health, including conditions such as anxiety and depression. These disorders not only hinder post-stroke recovery but also elevate mortality rates. Despite their profound impact, the precise origins of aberrant amygdala function after stroke remain elusive. As a target of reduced brain pH in ischemia, acid-sensing ion channels (ASICs) have been implicated in synaptic transmission after ischemia, hinting at their potential role in reshaping neural circuits following a stroke. This study delves into the intriguing relationship between post-stroke alterations and ASICs, specifically focusing on postsynaptic ASIC1a enhancement in the amygdala following prefrontal cortex (PFC) ischemia induced by endothelin-1 (ET-1) injection. Our findings intriguingly illustrate that mPFC ischemia not only accentuates the PFC to amygdala circuit but also implicates ASIC1a in fostering augmented synaptic plasticity after ischemia. In contrast, the absence of ASIC1a impairs the heightened induction of long-term potentiation (LTP) in the amygdala induced by ischemia. This pivotal research introduces a novel concept with the potential to inaugurate an entirely new avenue of inquiry, thereby significantly enhancing our comprehension of the intricate mechanisms underlying post-stroke neural circuit reconfiguration. Importantly, these revelations hold the promise of paving the way for groundbreaking therapeutic interventions.
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Neuronal activity promotes high-grade glioma progression via secreted proteins and neuron-to-glioma synapses, and glioma cells boost neuronal activity to further reinforce the malignant cycle. Whereas strong evidence supports that the activity of neuron-to-glioma synapses accelerates tumor progression, the molecular mechanisms that modulate the formation and function of neuron-to-glioma synapses remain largely unknown. Our recent findings suggest that a proton (H + ) signaling pathway actively mediates neuron-to-glioma synaptic communications by activating neuronal acid-sensing ion channel 1a (Asic1a), a predominant H + receptor in the central nervous system (CNS). Supporting this idea, our preliminary data revealed that local acid puff on neurons in high-grade glioma-bearing brain slices induces postsynaptic currents of glioma cells. Stimulating Asic1a knockout (Asic1a -/- ) neurons results in lower AMPA receptor-dependent excitatory postsynaptic currents (EPSCs) in glioma cells than stimulating wild-type (WT) neurons. Moreover, glioma-bearing Asic1a -/- mice exhibited reduced tumor size and survived longer than the glioma-bearing WT mice. Finally, pharmacologically targeting brain Asic1a inhibited high-grade glioma progression. In conclusion, our findings suggest that the neuronal H + -Asic1a axis plays a key role in regulating the neuron-glioma synapse. The outcomes of this study will greatly expand our understanding of how this deadly tumor integrates into the neuronal microenvironment.
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Background: Although Andrographis paniculata (AP) exhibits various biological functions such as anticancer, anti-inflammatory, antimalarial, antimicrobial, antioxidant, cardioprotective and immunomodulatory, its role in estrogen deficiency-related osteoporosis remains unclear. Methods: Ovariectomy (OVX)-induced estrogen deficiency-related osteoporotic mouse models and sham mouse models were established using 8-week-old female C57BL/6J mice. Micro-computed tomography (µCT) scanning was performed to assess the skeletal phenotype. The differentiation potential of bone marrow mesenchymal stem cells (BMSCs) from the OVX and sham groups was assessed by osteogenic or adipogenic induction medium in vitro. To verify the effects of AP, alizarin red S (ARS) staining, alkaline phosphatase (ALP) staining and oil red O (ORO) staining, reverse transcription assay and quantitative real-time polymerase chain reaction were applied to detect the lineage differentiation ability of BMSCs. Results: µCT scanning showed that AP treatment attenuated the osteoporotic phenotype in OVX-induced estrogen deficiency-related osteoporotic mice. The results of ARS staining, ALP staining, ORO staining and quantitative real-time polymerase chain reaction indicated that BMSCs from OVX-induced osteoporotic mice displayed a significant reduction in osteogenic differentiation and an increase in adipogenic differentiation, which could be reversed by AP treatment. Conclusions: Our findings suggested that AP regulated the differentiation potential of BMSCs and ameliorated the development of estrogen deficiency-related osteoporosis, which might be an effective therapeutic method for estrogen deficiency-related osteoporosis.
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Objective: We developed and validated a clinical-radiomics nomogram to predict the prognosis of basal ganglia hemorrhage patients. Methods: Retrospective analyses were conducted in 197 patients with basal ganglia hemorrhage (training cohort: n = 136, test cohort: n = 61) who were admitted to The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital) and underwent computed tomography (CT) scan. According to different prognoses, patients with basal ganglia hemorrhage were divided into two groups. Independent clinical risk factors were derived with univariate and multivariate regression analysis. Radiomics signatures were obtained using least absolute shrinkage and selection operator. A radiomics score (Rad-score) was generated by 12 radiomics signatures of perihematomal edema (PHE) from CT images that were correlated with the prognosis of basal ganglia hemorrhage patients. A clinical-radiomics nomogram was conducted by combing the Rad-score and clinical risk factors using logistic regression analysis. The prediction performance of the nomogram was tested in the training cohort and verified in the test cohort. Results: The clinical model conducted by four clinical risk factors and 12 radiomcis features were used to establish the Rad-score. The clinical-radiomics nomogram outperformed the clinical model in the training cohort [area under the curve (AUC), 0.92 vs. 0.85] and the test cohort (AUC, 0.91 vs 0.85). The clinical-radiomics nomogram showed good calibration and clinical benefit in both the training and test cohorts. Conclusion: Radiomics features of PHE in patients with basal ganglia hemorrhage could contribute to the outcome prediction. The clinical-radiomics nomogram may help first-line clinicians to make individual clinical treatment decisions for patients with basal ganglia hemorrhage.
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Epithelial-mesenchymal transition (EMT) confers high invasive and migratory capacity to cancer cells, which limits the effectiveness of tumor therapy. Long non-coding RNAs (lncRNAs) can regulate the dynamic process of EMT at different levels through various complex regulatory networks. We aimed to comprehensively analyze and screen EMT-related lncRNAs to characterize lower-grade glioma (LGG) tumor biology and provide new ideas for current therapeutic approaches. We retrieved 1065 LGG samples from the Cancer Genome Atlas and Chinese Glioma Genome Atlas by machine learning algorithms, identified three hub lncRNAs including CRNDE, LINC00665, and NEAT1, and established an EMT-related lncRNA signature (EMTrLS). This novel signature had strong prognostic value and potential clinical significance. EMTrLS described LGG genomic alterations and clinical features including gene mutations, tumor mutational burden, World Health Organization (WHO) grade, IDH status, and 1p/19q status. Notably, stratified analysis revealed activation of malignancy-related and metabolic pathways in the EMTrLS-high cohort. Moreover, the population with increased EMTrLS scores had increased cells with immune killing function. However, this antitumor immune function may be suppressed by increased Tregs and macrophages. Meanwhile, the relatively high expression of immune checkpoints explained the immunosuppressive state of patients with high EMTrLS scores. Importantly, we validated this result by quantifying the course of antitumor immunity. In particular, EMTrLS stratification enabled assessment of the responsiveness of LGG to chemotherapeutic drug efficacy and PD1 blockade. In conclusion, our findings complement the foundation of molecular studies of LGG, provide valuable insight into our understanding of EMT-related lncRNAs, and offer new strategies for LGG therapy.
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BACKGROUND: photodynamics therapy (PDT) induces tumor cell death through oxidative stress and is closely associated with the expression of hypoxia inducible factor-1a (HIF1a), which activates multiple downstream survival signaling pathways. Therefore, the purpose of this study was to investigate the expression levels of HIF1a proteins in PDT-treated GBM cells and to determine whether inhibition of HIF1a reduces survival signals to enhance the efficacy of PDT. RESULTS: PDT combined with Acriflavine (ACF, PA) decreased the expression of HIF1a and regulated the downstream expression of GLUT-1, GLUT-3, HK2 and other gluconeogenic pathway proteins. PA group significantly suppressed tumor growth to improve the efficacy of PDT. METHODS: We first performed the correlation of HIF1a, GLUT-1, GLUT-3, and HK2, and quantified the expression of HIF1a on tumor grades and IDH mutation classification by TCGA and CGGA databases. Then, we used immunohistochemistry method to detect four gene expression levels in human GBM tissues. Besides, we examined the effects of different treatments on the proliferation, migration and invasion ability of GBM cell lines by CCK8, wound healing and transwell assays. ACF, a HIF1a/HIF1ß dimerization inhibitor, was used to evaluate its adjuvant effect on the efficacy of PDT. CONCLUSION: HIF1a is activated in GBM cell lines and contributes to the survival of tumor cells after PDT in vitro and in vivo. PA group inhibited HIF1a expression and improved PDT efficacy in the treatment of recalcitrant GBM.
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Glioblastoma , Fotoquimioterapia , Acriflavina/farmacologia , Acriflavina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Glioblastoma/tratamento farmacológico , Humanos , Fator 1 Induzível por Hipóxia/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Transdução de SinaisRESUMO
The epithelial-mesenchymal transition (EMT) is an important process that drives progression, metastasis, and oncology treatment resistance in cancers. Also, the adjacent non-tumor tissue may affect the biological properties of cancers and have potential prognostic implications. Our study aimed to identify EMT-related genes in LGG samples, explore their impact on the biological properties of lower grade gliomas (LGG) through the multi-omics analysis, and reveal the potential mechanism by which adjacent non-tumor tissue participated in the malignant progression of LGG. Based on the 121 differentially expressed EMT-related genes between normal samples from the GTEx database and LGG samples in the TCGA cohort, we identified two subtypes and constructed EMTsig. Because of the genetic, epigenetic, and transcriptomic heterogeneity, malignant features including clinical traits, molecular traits, metabolism, anti-tumor immunity, and stemness features were different between samples with C1 and C2. In addition, EMTsig could also quantify the EMT levels, variation in prognosis, and oncology treatment sensitivity of LGG patients. Therefore, EMTsig could assist us in developing objective diagnostic tools and in optimizing therapeutic strategies for LGG patients. Notably, with the GSVA, we found that adjacent non-tumor tissue might participate in the progression, metastasis, and formation of the tumor microenvironment in LGG. Therefore, the potential prognostic implications of adjacent non-tumor tissue should be considered when performing clinical interventions for LGG patients. Overall, our study investigated and validated the effects of EMT-related genes on the biological properties from multiple perspectives, and provided new insights into the function of adjacent non-tumor tissue in the malignant progression of LGG.
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Background: In recent years, glioblastoma multiforme (GBM) has been a concern of many researchers, as it is one of the main drivers of cancer-related deaths worldwide. GBM in general usually does not responding well to immunotherapy due to its unique microenvironment. Methods: To uncover any further informative immune-related prognostic signatures, we explored the immune-related distinction in the genetic or epigenetic features of the three types (expression profile, somatic mutation, and DNA methylation). Twenty eight immune-related hub genes were identified by Weighted Gene Co-Expression Network Analysis (WGCNA). The findings showed that three genes (IL1R1, TNFSF12, and VDR) were identified to construct an immune-related prognostic model (IRPM) by lasso regression. Then, we used three hub genes to construct an IRPM for GBM and clarify the immunity, mutation, and methylation characteristics. Results: Survival analysis of patients undergoing anti-program cell death protein 1 (anti-PD-1) therapy showed that overall survival was superior in the low-risk group than in the high-risk group. The high-risk group had an association with epithelial-mesenchymal transition (EMT), high immune cell infiltration, immune activation, a low mutation number, and high methylation, while the low-risk group was adverse status. Conclusions: In conclusion, IRPM is a promising tool to distinguish the prognosis of patients and molecular and immune characteristics in GBM, and the IRPM risk score can be used to predict patient sensitivity to checkpoint inhibitor blockade therapy. Thus, three immune-related signatures will guide us in improving treatment strategies and developing objective diagnostic tools.
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Angiogenesis is a complex process in the immunosuppressed low-grade gliomas (LGG) microenvironment and is regulated by multiple factors. N6-methyladenosine (m6A), modified by the m6A modification regulators ("writers" "readers" and "erasers"), can drive LGG formation. In the hypoxic environment of intracranial tumor immune microenvironment (TIME), m6A modifications in glioma stem cells are predominantly distributed around neovascularization and synergize with complex perivascular pathological ecology to mediate the immunosuppressive phenotype of TIME. The exact mechanism of this phenomenon remains unknown. Herein, we elucidated the relevance of the angiogenesis-related genes (ARGs) and m6A regulators (MAGs) and their influencing mechanism from a macro perspective. Based on the expression pattern of MAGs, we divided patients with LGG into two robust categories via consensus clustering, and further annotated the malignant related mechanisms and corresponding targeted agents. The two subgroups (CL1, CL2) demonstrated a significant correlation with prognosis and clinical-pathology features. Moreover, WGCNA has also uncovered the hub genes and related mechanisms of MAGs affecting clinical characters. Clustering analysis revealed a synergistic promoting effect of M6A and angiogenesis on immunosuppression. Based on the expression patterns of MAGs, we established a high-performance gene-signature (MASig). MASig revealed somatic mutational mechanisms by which MAGs affect the sensitivity to treatment in LGG patients. In conclusion, the MAGs were critical participants in the malignant process of LGG, with a vital potential in the prognosis stratification, prediction of outcome, and therapeutic sensitivity of LGG. Findings based on these strategies may facilitate the development of objective diagnosis and treatment systems to quantify patient survival and other outcomes, and in some cases, to identify potential unexplored targeted therapies.
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Regulação Neoplásica da Expressão Gênica , Glioma , Biomarcadores Tumorais/genética , Glioma/tratamento farmacológico , Glioma/genética , Glioma/patologia , Humanos , Terapia de Imunossupressão , Prognóstico , Microambiente Tumoral/genéticaRESUMO
Glioma is one of the most human malignant diseases and the leading cause of cancer-related deaths worldwide. Nevertheless, the present stratification systems do not accurately predict the prognosis and treatment benefit of glioma patients. Currently, no comprehensive analyses of multi-omics data have been performed to better understand the complex link between pyroptosis and immune. In this study, we constructed four pyroptosis immune subgroups by pyroptosis regulators and obtained nine pyroptosis immune signatures by analyzing the differentially expressed genes between the four pyroptosis immune subgroups. Nine novel pyroptosis immune signatures were provided for assessing the complex heterogeneity of glioma by the analyses of multi-omics data. The pyroptosis immune prognostic model (PIPM) was constructed by pyroptosis immune signatures, and the PIPM risk score was established for glioma cohorts with a total of 1716 samples. Then, analyses of the tumor microenvironment revealed an unanticipated correlation of the PIPM risk score with stemness, immune checkpoint expression, infiltrating the immune system, and therapy response in glioma. The low PIPM risk score patients had a better response to immunotherapy and showed sensitivity to radio-chemotherapy. The results of the pan-cancer analyses revealed the significant correlation between the PIPM risk score and clinical outcome, immune infiltration, and stemness. Taken together, we conclude that pyroptosis immune signatures may be a helpful tool for overall survival prediction and treatment guidance for glioma and other tumors patients.
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Background: Although ferroptosis has been validated to play a crucial role in some types of tumors, the influence of ferroptosis-related genes (FRGs) on the immune microenvironment in low-grade glioma (LGG) remains unclear. In this research, we screen the FRGs to assess the prognosis value and immune microenvironment in LGG, to provide reliable diagnosis and treatment evidence for the clinic. Methods: A total of 1,239 patients of LGG samples were selected for subsequent analyses from The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and the Repository of Molecular Brain Neoplasia Data datasets. Univariate Cox regression analysis was used to screen for prognostic FRGs. Consensus clustering was utilized to determine ferroptosis subtypes of LGG patients. Next, the prognostic model was constructed based on differentially expressed FRGs and validation in the validating datasets. The immune microenvironment, biological pathway, and hypoxia score were explored by single-sample gene set enrichment analysis. The potential response of chemotherapy and immune checkpoint blockade therapy was also estimated. In addition, the correlation between the risk score and autophagy-related genes was examined by the Pearson correlation coefficient. Results: A total of three ferroptosis subtypes were identified by consensus clustering for prognostic FRGs which exhibited different outcomes, clinicopathological characteristics, and immune microenvironment. Afterward, a prognostic model that performed great predictive ability based on nine prognostic FRGs has been constructed and validated. Moreover, the prognostic model had the potential to screen the sensitivity to chemotherapy and immunotherapy in LGG patients. Finally, we also found that the prognostic model has a great connection to autophagy and hypoxia. Conclusion: We developed a ferroptosis-related prognostic model which strongly linked to diagnosis, treatment, prognosis, and recurrence of LGG. This study also reveals the connection between ferroptosis and tumor immune microenvironment.
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5-Methylcytosine (m5C) methylation is an important RNA modification pattern that can participate in oncogenesis and progression of cancers by affecting RNA stability, expression of oncogenes, and the activity of cancer signaling pathways. Alterations in the expression pattern of long non-coding RNAs (lncRNAs) are potentially correlated with abnormalities in the m5C regulation features of cancers. Our aim was to reveal the mechanisms by which lncRNAs regulated the m5C process, to explore the impact of aberrant regulation of m5C on the biological properties of lower-grade gliomas (LGG), and to optimize current therapeutic. By searching 1017 LGG samples from the Cancer Genome Atlas and Chinese Glioma Genome Atlas, we first clarified the potential impact of m5C regulators on LGG prognosis in this study and used univariate Cox analysis and least absolute shrinkage and selection operator regression to explore clinically meaningful lncRNAs. Consequently, we identified four lncRNAs, including LINC00265, CIRBP-AS1, GDNF-AS1, and ZBTB20-AS4, and established a novel m5C-related lncRNAs signature (m5CrLS) that was effective in predicting prognosis. Notably, mutation rate, WHO class II, IDH mutation, 1p/19q co-deletion and MGMT promoter methylation were increased in the low m5CrLS score group. Patients with increased m5CrLS scores mostly showed activation of tumor malignancy-related pathways, increased immune infiltrating cells, and decreased anti-tumor immune function. Besides, the relatively high expression of immune checkpoints also revealed the immunosuppressed state of patients with high m5CrLS scores. In particular, m5CrLS stratification was sensitive to assess the efficacy of LGG to temozolomide and the responsiveness of immune checkpoint blockade. In conclusion, our results revealed the molecular basis of LGG, provided valuable clues for our understanding of m5C-related lncRNAs, and filled a gap between epigenetics and tumor microenvironment.
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Neoplasias Encefálicas , Glioma , RNA Longo não Codificante , 5-Metilcitosina , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Glioma/tratamento farmacológico , Glioma/terapia , Humanos , Prognóstico , RNA Longo não Codificante/genética , Resultado do Tratamento , Microambiente TumoralRESUMO
Recent research on altering threat memory has focused on a reconsolidation window. During reconsolidation, threat memories are retrieved and become labile. Reconsolidation of distinct threat memories is synapse dependent, whereas the underlying regulatory mechanism of the specificity of reconsolidation is poorly understood. We designed a unique behavioral paradigm in which a distinct threat memory can be retrieved through the associated conditioned stimulus. In addition, we proposed a regulatory mechanism by which the activation of acid-sensing ion channels (ASICs) strengthens the distinct memory trace associated with the memory reconsolidation to determine its specificity. The activation of ASICs by CO2 inhalation, when paired with memory retrieval, triggers the reactivation of the distinct memory trace, resulting in greater memory lability. ASICs potentiate the memory trace by altering the amygdala-dependent synaptic transmission and plasticity at selectively targeted synapses. Our results suggest that inhaling CO2 during the retrieval event increases the lability of a threat memory through a synapse-specific reconsolidation process.
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Canais Iônicos Sensíveis a Ácido/genética , Comportamento Animal , Condicionamento Clássico/fisiologia , Regulação da Expressão Gênica , Memória/fisiologia , RNA/genética , Canais Iônicos Sensíveis a Ácido/biossíntese , Estimulação Acústica , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos AnimaisRESUMO
Background: Cancer-associated fibroblasts (CAFs) are vital components of prominent cellular components in lower-grade gliomas (LGGs) that contribute to LGGs' progression, treatment resistance, and immunosuppression. Epigenetic modification and immunity have significant implications for tumorigenesis and development. Methods: We combined aberrant methylation and CAFs abundances to build a prognostic model and the impact on the biological properties of LGGs. Grouping based on the median CAFs abundances score of samples in the TCGA-LGGs dataset, differentially expressed genes and aberrantly methylated genes were combined for subsequent analysis. Results: We identified five differentially methylated and expressed genes (LAT32, SWAP70, GSAP, EMP3, and SLC2A10) and established a prognostic gene signature validated in the CGGA-LGGs dataset. Immunohistochemistry (IHC) and in vitro tests were performed to verify these expressions. The high-risk group increased in tumor-promoting immune cells and tumor mutational burden. Notably, risk stratification had different ICB sensitivities in LGGs, and there were also significant sensitivity differences for temozolomide and the other three novel chemotherapeutic agents. Conclusion: Our study reveals characteristics of CAFs in LGGs, refines the direct link between epigenetics and tumor stroma, and might provide clinical implications for guiding tailored anti-CAFs therapy in combination with immunotherapy for LGGs patients.
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Background: Although mRNA vaccines have been efficient for combating a variety of tumors, their effectiveness against glioma remains unclear. There is growing evidence that immunophenotyping can reflect the comprehensive immune status and microenvironment of the tumor, which correlates closely with treatment response and vaccination potency. The purpose of this research was to screen for effective antigens in glioma that could be used for developing mRNA vaccines and to further differentiate the immune subtypes of glioma to create an selection criteria for suitable patients for vaccination. Methods: Gene expression profiles and clinical data of 698 glioma samples were extracted from The Cancer Genome Atlas, and RNA_seq data of 1018 glioma samples was gathered from Chinese Glioma Genome Atlas. Gene Expression Profiling Interactive Analysis was used to determine differential expression genes and prognostic markers, cBioPortal software was used to verify gene alterations, and Tumor Immune Estimation Resource was used to investigate the relationships among genes and immune infiltrating cells. Consistency clustering was applied for consistent matrix construction and data aggregation, Gene oncology enrichment was performed for functional annotation, and a graph learning-based dimensionality reduction method was applied to describe the subtypes of immunity. Results: Four overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in glioma, including TP53, IDH1, C3, and TCF12. Besides, four immune subtypes of glioma (IS1-IS4) and 10 immune gene modules were identified consistently in the TCGA data. The immune subtypes had diverse molecular, cellular, and clinical features. IS1 and IS4 displayed an immune-activating phenotype and were associated with worse survival than the other two subtypes, while IS2 and IS3 had lower levels of tumor immune infiltration. Immunogenic cell death regulators and immune checkpoints were also diversely expressed in the four immune subtypes. Conclusion: TP53, IDH1, C3, and TCF12 are effective antigens for the development of anti-glioma mRNA vaccines. We found four stable and repeatable immune subtypes of human glioma, the classification of the immune subtypes of glioma may play a crucial role in the predicting mRNA vaccine outcome.
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Antígenos de Neoplasias/genética , Neoplasias Encefálicas/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Glioma/tratamento farmacológico , Desenvolvimento de Vacinas , Vacinas de mRNA/uso terapêutico , Antígenos de Neoplasias/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Tomada de Decisão Clínica , Complemento C3/genética , Complemento C3/imunologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Glioma/genética , Glioma/imunologia , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Mutação , Medicina de Precisão , Transcriptoma , Microambiente Tumoral , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia , Vacinas de mRNA/imunologiaRESUMO
BACKGROUND: Caffeine is broadly present in tea, coffee, and cocoa, and is commonly consumed. The bone microenvironment might be damaged by excessive caffeine, which has been shown to exert negative effects on human health. In this study, we sought to determine whether excessive caffeine could damage the biological functions of bone marrow mesenchymal stem cells (BMSCs) and induce bone loss in mice, and further investigate effective therapeutic methods. METHODS: BMSCs were treated with different concentrations of caffeine (0.01, 0.05, 0.1, 0.5, and 1.0 mM) for 48 h. Cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were performed to detect the cell viability, proliferation, migration, and pluripotency of BMSCs, respectively. Alizarin red S (ARS) staining, alkaline phosphatase (ALP) staining, oil red O (ORO) staining, and qRT-PCR assay were applied to assess the osteogenic and adipogenic differentiation of BMSCs. BMSCs were treated with caffeine and further exposed to different concentrations of psoralidin (PL) (0.01, 0.1, 1, and 10 µM) for 48 h. Micro-computed tomography (µCT) scanning was used to evaluate the bone mass of mice. 7α-(7-((4,4,5,5,5-Pentafluoropentyl)-sulfiny)nonyl)estra-1,3,5(10)-triene-3,17ß-diol (ICI 182,780, ICI) was applied to examine whether the classical estrogen receptor (ER) pathway was involved. RESULTS: The CCK-8 assay, colony formation assay, wound healing assay, and qRT-PCR analysis indicated that caffeine (0.01, 0.05, 0.1, 0.5, 1.0 mM) attenuated the cell viability, proliferation, migration and pluripotency of BMSCs, respectively, in a concentration-dependent manner. Caffeine treatment inhibited osteogenic differentiation but promoted adipogenic differentiation of BMSCs in a dose-dependent manner. Furthermore, ARS staining, ALP staining, ORO staining, and qRT-PCR assay showed that excessive caffeine induced bone loss and osteoporosis (OP) in mice by regulating the osteogenesis and adipogenesis of BMSCs. Also, PL treatment could reverse the caffeine-induced dysfunctions and aberrant differentiation of BMSCs via the ER pathway. CONCLUSIONS: Our results revealed a novel molecular mechanism for the therapeutic effects of PL in treating excessive caffeine-induced OP, which might shed new light on the clinical application of PL for caffeine-related OP.
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Osteosarcoma (OS) is a type of malignant primary bone cancer, which is highly aggressive and occurs more commonly in children and adolescents. Thus, novel potential drugs and therapeutic methods are urgently needed. In the present study, we aimed to elucidate the effects and mechanism of melatonin on OS cells to provide a potential treatment strategy for OS. The cell survival rate, cell viability, proliferation, migration, invasion and metastasis were examined by trypan blue assay, MTT, colony formation, wound healing, transwell invasion and attachment/detachment assay, respectively. The expression of relevant lncRNAs in OS cells was determined by real-time qPCR analysis. The functional roles of lncRNA JPX in OS cells were further examined by gain and loss of function assays. The protein expression was measured by western blot assay. Melatonin inhibited the cell viability, proliferation, migration, invasion and metastasis of OS cells (Saos-2, MG63 and U2OS) in a dose-dependent manner. Melatonin treatment significantly downregulated the expression of lncRNA JPX in Saos-2, MG63 and U2OS cells. Overexpression of lncRNA JPX into OS cell lines elevated the cell viability and proliferation, which was accompanied by the increased metastasis. We also found that melatonin inhibited the OS progression by suppressing the expression of lncRNA JPX via regulating the Wnt/ß-catenin pathway. Our results suggested that melatonin inhibited the biological functions of OS cells by repressing the expression of lncRNA JPX through regulating the Wnt/ß-catenin signalling pathway, which indicated that melatonin might be applied as a potentially useful and effective natural agent in the treatment of OS.