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Background: Dandouchi polypeptide (DDCP) is derived from Semen Sojae Praeparatum (Dandouchi in Chinese), a fermented product of Glycine max (L.) Merr. Semen Sojae Praeparatum is widely used in the food industry for its unique flavor and nutritional value, and DDCP, as its derivative, also shows potential health benefits in food applications. However, the specific active substances responsible for Semen Sojae Praeparatum and the underlying mechanisms involved have not been fully elucidated. Methods: DDCP was extracted from Semen Sojae Praeparatum using enzymes, and its antidepressant effects were tested in chronic unpredictable mild stress (CUMS)-induced mice. Immunohistochemistry, immunofluorescence, and western blotting were used to analyze neurogenesis and the nuclear factor κB (NF-κB) pathway. Moreover, an adeno-associated virus (AAV) shRNA was used to induce tripartite motif-containing 67 (TRIM67) deficiency to examine the function of TRIM67 in the neuroprotective effects of DDCP in depressive disorders. Results: DDCP reduced depressive behaviors in CUMS mice and the expression of proinflammatory markers in the hippocampus. DDCP promoted neurogenesis and modulated the TRIM67/NF-κB pathway, with TRIM67 deficiency impairing its antidepressant effect. Conclusions: This research revealed that DDCP has a protective effect on countering depression triggered by CUMS. Notably, TRIM67 plays a crucial role in mitigating depression through DDCP, positioning DDCP as a potential therapeutic option for treating depressive disorders.
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Depresión , Hipocampo , FN-kappa B , Neurogénesis , Animales , Humanos , Masculino , Ratones , Antidepresivos/química , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/metabolismo , Depresión/tratamiento farmacológico , Depresión/genética , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Neurogénesis/efectos de los fármacos , FN-kappa B/metabolismo , FN-kappa B/genética , Péptidos/administración & dosificación , Péptidos/química , Péptidos/farmacología , Péptidos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
ABSTRACT: Arteriosclerosis (AS) is a chronic inflammatory disease and Buyang Huanwu decoction (BHD) has been identified as an anti-atherosclerosis effect, and the study is aimed to investigate the underlying mechanism. The E4 allele of Apolipoprotein E (ApoE) is associated with both metabolic dysfunction and an enhanced pro-inflammatory response, ApoE-knockout (ApoE-/-) mice were fed with a high-fat diet to establish an arteriosclerosis model and treated with BHD or atorvastatin (as a positive control). The atherosclerotic plaque in each mouse was evaluated using Oil red O Staining. Elisa kits were used to evaluate blood lipid, interleukin-6 (IL-6), IL-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), IL-4, IL-10, and tumor growth factor beta (TGF-ß) contents, while Western blot was applicated to measure inducible nitric oxide synthase (iNOS), arginase I (Arg-1) expression. Meanwhile, pyruvate kinase M2 (PKM2), hypoxia-inducible factor-1 alpha (HIF-1α) and its target genes glucose transporter type 1 (GLUT1), lactate dehydrogenase A (LDHA), and 3-phosphoinositide-dependent kinase 1 (PDK1), as well as IL-6, IL-1ß, TNF-α, IL-4, IL-10, and TGF-ß were evaluated by the quantitative reverse transcription-polymerase chain reaction. BHD treatment significantly reduced body weight and arteriosclerosis plaque area and blood lipid levels including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Meanwhile, BHD demonstrated a significant suppression of M1 polarization, by decreased secretion of iNOS and pro-inflammatory factors (IL-6, IL-1ß, and TNF-α) in ApoE-/- mice. The present study also revealed that BHD promotes the activation of M2 polarization, characterized by the expression of Arg-1 and anti-inflammatory factors (IL-4 and IL-10). In addition, PKM2/HIF-1α signaling was improved by M1/M2 macrophages polarization induced by BHD. The downstream target genes (GLUT1, LDHA, and PDK1) expression was significantly increased in high fat feeding ApoE-/- mice, and those of which were recused by BHD and Atorvastatin. These results suggested that M1/M2 macrophages polarization produce the inflammatory response against AS progress after BHD exposure.
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Aterosclerosis , Medicamentos Herbarios Chinos , Macrófagos , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ratones , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Aterosclerosis/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Apolipoproteínas E/genética , Apolipoproteínas E/deficiencia , Modelos Animales de Enfermedad , Ratones Noqueados para ApoE , Ratones Noqueados , Ratones Endogámicos C57BL , Citocinas/metabolismoRESUMEN
Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment.
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Glioblastoma , FN-kappa B , Células Madre Neoplásicas , Transducción de Señal , Macrófagos Asociados a Tumores , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Humanos , Animales , Ratones , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , FN-kappa B/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Microambiente TumoralRESUMEN
BACKGROUND: Osteoporosis and major depressive disorder (MDD) represent two significant health challenges globally, particularly among perimenopausal women. This study utilizes NHANES data and Mendelian randomization (MR) analysis to explore the link between them, aiming to provide a basis for intervention strategies for this group. METHODS: The study analyzed NHANES 2007-2018 data using weighted logistic regression in R software to evaluate the link between MDD and osteoporosis risk. Then, a two-sample MR analysis with GWAS summary statistics was performed, mainly using the IVW method. Additional validation included MR Egger, Weighted Median, Mode, and MR-PRESSO methods. RESULTS: The research analysis indicated a significant link between MDD and the risk of osteopenia/osteoporosis. Our analysis revealed a significant positive relationship between MDD and both femoral neck osteoporosis (OR = 6.942 [95 % CI, 1.692-28.485]) and trochanteric osteoporosis (OR = 4.140 [95 % CI, 1.699-10.089]). In analyses related to osteopenia, a significant positive correlation was observed between MDD and both total femoral osteopenia (OR = 3.309 [95 % CI, 1.577-6.942]) and trochanteric osteopenia (OR = 2.467 [95 % CI, 1.004-6.062]). Furthermore, in the MR analysis, genetically predicted MDD was causally associated with an increased risk of osteoporosis via the IVW method (P = 0.013). LIMITATIONS: Our study was limited by potential selection bias due to excluding subjects with missing data, and its applicability was primarily to European and American populations. CONCLUSION: Integrating NHANES and MR analyses, a robust correlation between MDD and osteoporosis was identified, emphasizing the significance of addressing this comorbidity within clinical practice and meriting further investigation.
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Trastorno Depresivo Mayor , Análisis de la Aleatorización Mendeliana , Osteoporosis , Perimenopausia , Humanos , Femenino , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/epidemiología , Persona de Mediana Edad , Osteoporosis/genética , Osteoporosis/epidemiología , Estudio de Asociación del Genoma Completo , Encuestas Nutricionales , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/epidemiología , Factores de Riesgo , AdultoRESUMEN
PANoptosis is a newly described inflammatory programmed cell death, that highlights coordination between pyroptosis, apoptosis and necroptosis. However, the functions of PANoptosis-related genes in glioma progression still remain to be explored. This study aims to identify PANoptosis-related predictors that may be utilized for prognosis prediction and development of new therapeutic targets. Firstly, bulk and single-cell RNA-seq (scRNA-seq) data of glioma patients were extracted from TCGA, CGGA and GEO database. Genetic analysis indicates a considerably high mutation frequency of PANoptosis-related genes (PANRGs) in glioma. Consensus clustering was applied to reveal different subtypes of glioma based on PANRGs. Two PANoptosis subtypes with distinct prognostic and TME characteristics were identified. Then, with LASSO-Cox regression analysis, four PANoptosis-related predictors (MYBL2, TUBA1C, C21orf62 and KCNIP2) were determined from bulk and scRNA-seq analysis. Predictive PANRG score model was established with these predictors and its correlation with tumor microenvironment (TME) was investigated. The results showed that patients with low PANRG score, had higher infiltration of anti-tumor immune cells, higher MSI score and lower TIDE score, which are more likely to benefit from immunotherapy. Further analysis identified 16 potential drugs associated with PANoptosis-related predictors. Moreover, the expression levels of four PANoptosis-related predictors were examined in clinical samples and the results were consistent with those analyzed in the database. Besides, we also confirmed the biological functions of two oncogenic predictors (MYBL2 and TUBA1C) by cell experiments, which revealed that knockdown of MYBL2 or TUBA1C could significantly inhibit the proliferation and migration of glioma cells. These findings highlight the prognostic value and biological functions of PANRGs in glioma, which may provide valuable insights for individualized treatment.
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BACKGROUND: The incessant communication that takes place between microglia and neurons is essential the development, maintenance, and pathogenesis of the central nervous system (CNS). As mobile phagocytic cells, microglia serve a critical role in surveilling and scavenging the neuronal milieu to uphold homeostasis. AIM OF REVIEW: This review aims to discuss the various mechanisms that govern the interaction between microglia and neurons, from the molecular to the organ system level, and to highlight the importance of these interactions in the development, maintenance, and pathogenesis of the CNS. KEY SCIENTIFIC CONCEPTS OF REVIEW: Recent research has revealed that microglia-neuron interaction is vital for regulating fundamental neuronal functions, such as synaptic pruning, axonal remodeling, and neurogenesis. The review will elucidate the intricate signaling pathways involved in these interactions, both direct and indirect, to provide a better understanding of the fundamental mechanisms of brain function. Furthermore, gaining insights into these signals could lead to the development of innovative therapies for neural disorders.
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OBJECTIVE: Increasing evidence suggests that inflammation appears to play a role in the genesis of depression. Berberine has potent anti-inflammatory effects and potential antidepressant activity, although the mechanism by which it works is yet unclear. Our study aimed to investigate the molecular mechanisms through which berberine treats depression and reduces inflammation. METHODS: The CUMS model and behavioral evaluation were utilized in this study to evaluate the efficacy of berberine in the treatment of depression. Berberine's effect on the inflammatory response in CUMS mice was evaluated via ELISA assays and western blotting. Nissl staining was used to observe hippocampal neuronal functional damage. Western blotting, ELISA, ubiquitination tests, and immunoprecipitation were utilized in conjunction with in vitro experiments to study the involvement of Trim65 in the antidepressant effects of berberine. RESULTS: The results suggest that berberine effectively alleviates depressive symptoms, suppresses the expression of genes associated with the NLRP3 inflammasome (NLRP3, cleaved caspase-1, ASC, GSDMD-N, Pro-IL-1ß, IL-1ß, Pro-IL-18, and IL-18), and reduces hippocampal neuronal functional damage in CUMS mice. Further studies showed that knockdown of Trim65 reversed the effects of berberine and increased NLRP3 inflammasome activity. Finally, K285, an important site for Trim65 binding to NLRP3, was identified. CONCLUSION: Our study describes the mechanism of berberine limiting NLRP3 inflammasome activity by promoting the conjugation of Trim65 to NLRP3 and NLRP3 ubiquitination, and suggests NLRP3 inflammasome activation as a prospective target for treating inflammation-associated disorders such as depression.
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Berberina , Animales , Ratones , Berberina/farmacología , Berberina/uso terapéutico , Depresión/tratamiento farmacológico , Inflamasomas , Interleucina-18 , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Hipocampo , Inflamación/tratamiento farmacológicoRESUMEN
The development of natural membranes as coatings for nanoparticles to traverse the blood-brain barrier (BBB) presents an effective approach for treating central nervous system (CNS) disorders. In this study, we have designed a nanogel loaded with PACAP and estrogen (E2), sheathed with exosomes and responsive to reactive oxygen species (ROS), denoted as HA NGs@exosomes. The objective of this novel design is to serve as a potent drug carrier for the targeted treatment of perimenopausal depression. The efficient cellular uptake and BBB penetration of HA NGs@exosomes has been demonstrated in vitro and in vivo. Following intranasal intervention with HA NGs@exosomes, ovariectomized mice under chronic unpredictable mild stress (CUMS) have shown improved behavioral performance, indicating that HA NGs@exosomes produced a rapid-onset antidepressant effect. Moreover, HA NGs@exosomes exhibit notable antioxidant and anti-inflammatory properties and may regulate the expression of pivotal proteins in the PACAP/PAC1 pathway to promote synaptic plasticity. Our results serve as a proof-of-concept for the utility of exosome-sheathed ROS-responsive nanogel as a promising drug carrier for the treatment of perimenopausal depression.
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Depresión , Exosomas , Ratones , Animales , Nanogeles , Depresión/tratamiento farmacológico , Depresión/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Exosomas/metabolismo , Perimenopausia/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Portadores de Fármacos/metabolismoRESUMEN
PURPOSE: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of GSC populations and reprogramming the TIME to an immunosuppressive state. EXPERIMENTAL DESIGN: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and a xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. RESULTS: We identified that CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. CONCLUSIONS: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/patología , Macrófagos Asociados a Tumores/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Células Madre Neoplásicas/metabolismo , Proliferación Celular , Microambiente Tumoral/genéticaRESUMEN
The pathogenesis of coronary heart disease is a highly complex process, with lipid metabolism disorders being closely linked to its development. Therefore, this paper analyzes the various factors that influence lipid metabolism, including obesity, genes, intestinal microflora, and ferroptosis, through a comprehensive review of basic and clinical studies. Additionally, this paper delves deeply into the pathways and patterns of coronary heart disease. Based on these findings, it proposes various intervention pathways and therapeutic methods, such as the regulation of lipoprotein enzymes, lipid metabolites, and lipoprotein regulatory factors, as well as the modulation of intestinal microflora and the inhibition of ferroptosis. Ultimately, this paper aims to offer new ideas for the prevention and treatment of coronary heart disease.
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Enfermedad Coronaria , Metabolismo de los Lípidos , Humanos , Enfermedad Coronaria/prevención & control , Enfermedad Coronaria/etiología , Enfermedad Coronaria/metabolismo , Obesidad , Lipoproteínas/metabolismoRESUMEN
Yueju pill, a classic Chinese Medicine formulated, was recently found to produce rapid antidepressant-like effects in a PKA-CREB signaling-dependent manner. In our study, we found that the Yueju pill induced a remarkable increase in PACAP. The intracerebroventricular injection of PACAP agonist induced a rapid antidepressant-like effect; conversely, the intrahippocampal infusion of a PACAP antagonist reversed the antidepressant response of the Yueju pill. Mice with hippocampal PACAP knockdown via viral-mediated RNAi displayed depression-like behavior. PACAP knockdown also blunted the antidepressant effect of the Yueju pill. PACAP knockdown resulted in down-regulated CREB and expression of the synaptic protein PSD95 at both baselines and after administration of the Yueju pill. However, administration of the Yueju pill in the knockdown mice promoted PACAP and PKA levels. Chronically stressed mice showed deficient hippocampal PACAP-PKA-CREB signaling and depression-like behavior, which were reversed by a single dose of the Yueju pill. In this study, we demonstrated that the up-regulation of PACAP induced activating of PKA-CREB signaling would play a part in the rapid antidepressant-like effects of the Yueju pill. We also identified iridoids fraction of Gardenia jasminoides Ellis (GJ-IF), a vital component of the Yueju pill, was identified to recapitulate rapid antidepressant-like behavior through increased hippocampal PACAP expression of the Yueju pill. The promotion of hippocampal PACAP may collectively represent a novel mechanism of rapid antidepressant-like effect.
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Medicamentos Herbarios Chinos , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Ratones , Animales , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Antidepresivos/farmacología , Transducción de Señal , Medicamentos Herbarios Chinos/farmacología , HipocampoRESUMEN
BACKGROUND: Zhi-Zi-Chi-Tang (ZZCT) is an effective traditional Chinese medicinal formula. ZZCT has been used for the treatment of depression for centuries. Its clinical efficacy in relieving depression has been confirmed. However, the molecular mechanisms of ZZCT regarding neuroplasticity in the pathogenesis of depression have not yet been elucidated. PURPOSE: The present study aimed to examine the effects of ZZCT on neuroplasticity in mice exposed to chronic unpredictable mild stress (CUMS), and to explore the underlying molecular mechanisms. METHODS: For this purpose, a murine model of depression was established using the CUMS procedure. Following the intragastric administration of ZZCT or fluoxetine, classic behavioral experiments were performed to observe the efficacy of ZZCT as an antidepressant. Immunofluorescence was used to label and quantify microtubule-associated protein (MAP2) and postsynaptic density protein (PSD95) in the hippocampus. Golgi staining was applied to visualize the dendritic spine density of neurons in the hippocampi. Isolated hippocampal slices were prepared to induce long-term potentiation (LTP) in the CA1 area. The hippocampal protein expression levels of glycogen synthase kinase-3ß (GSK-3ß), p-GSK-3ß (Ser9), cAMP response element binding protein (CREB), p-CREB (Ser133), brain-derived neurotrophic factor (BDNF) and 14-3-3ζ were detected using western blot analysis. The interaction of 14-3-3ζ and p-GSK-3ß (Ser9) was examined using co-immunoprecipitation. LV-shRNA was used to knockdown 14-3-3ζ by an intracerebroventricular injection. RESULTS: ZZCT (6 g/kg) and fluoxetine (20 mg/kg) alleviated depressive-like behavior, restored hippocampal MAP2+ PSD95+ intensity, and reversed the dendritic spine density of hippocampal neurons and LTP in the CA1 region of mice exposed to CUMS. Both low and high doses of ZZCT (3 and 6 g/kg) significantly promoted the binding of 14-3-3ζ to p-GSK-3ß (Ser9) in the hippocampus, and ZZCT (6 g/kg) significantly promoted the phosphorylation of GSK-3ß Ser9 and CREB Ser133 in the hippocampus. ZZCT (3 and 6 g/kg) upregulated hippocampal BDNF expression in mice exposed to CUMS. LV-sh14-3-3ξ reduced the antidepressant effects of ZZCT. CONCLUSION: ZZCT exerted antidepressant effects against CUMS-stimulated depressive-like behavior mice. The knockdown of 14-3-3ζ using lentivirus confirmed that 14-3-3ζ was involved in the ZZCT-mediated antidepressant effects through GSK-3ß/CREB/BDNF signaling. On the whole, these results suggest that the antidepressant effects of ZZCT are attributed to restoring damage by neuroplasticity enhancement via the 14-3-3ζ/GSK-3ß/CREB/BDNF signaling pathway.
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Factor Neurotrófico Derivado del Encéfalo , Fluoxetina , Ratones , Animales , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Fluoxetina/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas 14-3-3/metabolismo , Proteínas 14-3-3/farmacología , Antidepresivos/farmacología , Plasticidad Neuronal/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hipocampo , Estrés Psicológico/tratamiento farmacológico , Depresión/tratamiento farmacológico , Depresión/metabolismo , Modelos Animales de EnfermedadRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Zuojinwan (ZJW) is a traditional Chinese medicine compound, which is often used clinically to treat gastritis and has anti-inflammatory activity. It was found that ZJW is involved in suppressing the expression of inflammatory factors, and neuroinflammation is thought to be associated with the development of depression. AIM OF THE STUDY: In this study, we investigated whether ZJW could exert antidepressant effects by regulating MyD88 ubiquitination in depressed mice and attempted to elucidate the possible mechanisms. MATERIALS AND METHODS: Six active compounds of Zuojinwan (ZJW) were identified by HPLC. Then, the effects of ZJW on depression-like behavior in mice were investigated by constructing a chronic unpredictable mild stimulation (CUMS) mouse model. Meanwhile, the effect of ZJW on hippocampal neurons was investigated by Nissl staining. In addition, western blotting, PCR, ELISA, co-immunoprecipitation and immunostaining were used to explore whether ZJW could inhibit neuroinflammation through SPOP/MyD88/NF-κB pathway and thus produce antidepressant effects. Finally, we constructed the AAV-Sh-SPOP virus vector to silence SPOP and verify the mechanism of ZJW's antidepressant action. RESULTS: ZJW could dramatically ameliorate the depressive behavior induced by CUMS stimulation and alleviate hippocampal neuronal damage. CUMS stimulation resulted in decreased SPOP expression, impaired MyD88 ubiquitination, and activation of downstream NF-κB signaling, which could be reversed by ZJW. In addition, ZJW could significantly ameliorate the abnormal activation of microglia, and the excessive levels of pro-inflammatory factors were inhibited. By blocking the expression of SPOP, we found that ZJW exerted anti-inflammatory and antidepressant effects mainly by promoting the ubiquitination of MyD88 and inhibiting the activation of downstream inflammatory signals. CONCLUSION: In conclusion, ZJW possesses alleviating effects on depression induced by CUMS stimulation. ZJW can inhibit neuroinflammation and improve neuroinflammation-induced depression-like behaviors through SPOP/MyD88/NF-κB pathway.
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Factor 88 de Diferenciación Mieloide , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Enfermedades Neuroinflamatorias , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ubiquitinación , Depresión/tratamiento farmacológico , Depresión/etiología , Hipocampo/metabolismo , Estrés Psicológico/complicaciones , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptors. Here, we investigate adaptive behavior of GSCs under different cholesterol supplies. METHODS: In silico analysis of patient tumors demonstrated enrichment of cholesterol synthesis associated with decreased angiogenesis. Comparative gene expression of cholesterol biosynthesis enzymes in paired GBM specimens and GSCs were performed. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of SREBP2 on GBM cholesterol biosynthesis, proliferation, and self-renewal. Chromatin immunoprecipitation quantitative real-time PCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptors in GSCs. RESULTS: Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than in invasive margins. SREBP2 promoted cholesterol biosynthesis in GSCs, especially under starvation, as well as proliferation, self-renewal, and tumor growth. SREBP2 governed the balance between cholesterol biosynthesis and uptake in different nutrient conditions. CONCLUSIONS: SREBP2 displays context-specific regulation of cholesterol biology based on its availability in the microenvironment with induction of cholesterol biosynthesis in the tumor core and uptake in the margin, informing a novel treatment strategy for GBM.
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Glioblastoma , Humanos , Línea Celular Tumoral , Colesterol/metabolismo , Regulación de la Expresión Génica , Glioblastoma/patología , Células Madre Neoplásicas/metabolismo , Células Madre/metabolismo , Células Madre/patología , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Microambiente TumoralRESUMEN
The liver lipid metabolism of older individuals canbecome impaired and the circadian rhythm of genes involved in lipid metabolism is also disturbed. Although the link between metabolism and circadian rhythms is already recognized, how these processes are decoupled in liver during aging is still largely unknown. Here, we show that the circadian rhythm for the transcription factor Egr-1 expression is shifted forward with age in male mice. Egr-1 deletion accelerates liver age-related metabolic dysfunction, which associates with increased triglyceride accumulation, disruption of the opposite rhythmic coupling of Egr-1 and Cidea (Cell Death Inducing DFFA Like Effector A) at the transcriptional level and large lipid droplet formation. Importantly, adjustment of the central clock with light via a 4-hour forward shift in 6-month-old mice, leads to recovery the rhythm shift of Egr-1 during aging and largely ameliorated liver metabolic dysfunction. All our collected data suggest that liver Egr-1 might integrate the central and peripheral rhythms and regulate metabolic homeostasis in the liver.
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Relojes Circadianos , Hígado , Ratones , Masculino , Animales , Hígado/metabolismo , Ritmo Circadiano/genética , Regulación de la Expresión Génica , Metabolismo de los Lípidos/genética , Envejecimiento/metabolismo , Relojes Circadianos/genética , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
INTRODUCTION: Adult hippocampal neurogenesis (AHN) is acknowledged to play a critical role in depression. Emerging evidence suggests that the Wnt/ß-catenin pathway can modulate hippocampal neurogenesis. Crocin, a natural carotenoid, possesses antidepressant property. Yet, how it affects neurogenesis and exerts antidepressant response remains unknown. OBJECTIVE: To explore the role of AHN and Wnt/ß-catenin in the antidepressant action of crocin. METHODS: Depressive-related behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and sexual behaviors were performed following crocin treatment. Neurogenesis was characterized via immunohistochemistry, immunofluorescence, Golgi staining and electrophysiology approach. Wnt/ß-catenin signaling was examined with western blot analysis. The role of AHN Wnt/ß-catenin cascade in crocin's antidepressant response was assessed by conditional removal of glial fibrillary acidic protein (GFAP)-expressing newborn neural cells, temozolomide administration, microinfusion of Dkk1 or viral-mediated shRNA of Wnt3a. RESULTS: Crocin decreased the immobility duration in TST and FST without impairing the performance in sexual behaviors. Crocin boosted the proliferation and differentiation of progenitors, and promoted dendritic maturation and functional integration of hippocampal newborn neurons. Conditional removal of GFAP-expressing neural cells or temozolomide administration impaired the antidepressant response of crocin. Additionally, Wnt/ß-catenin signaling was promoted following crocin treatment. In chronic unpredictable mild stress (CUMS) murine model, crocin treatment displayed antidepressant response in SPT, FST and TST, and restored the neurogenesis levels and Wnt/ß-catenin signaling impaired by CUMS. Infusion of Dickkopf-1 (DKK1) or knockdown of Wnt3a in the hippocampus impaired the antidepressant response of crocin. CONCLUSION: Crocin exerted antidepressant response, which was dependent on enhancement of AHN and activation of the Wnt/ß-catenin pathway.
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Carotenoides , Hipocampo , Neurogénesis , Animales , Ratones , Antidepresivos/farmacología , Antidepresivos/metabolismo , beta Catenina/efectos de los fármacos , beta Catenina/metabolismo , beta Catenina/farmacología , Carotenoides/metabolismo , Carotenoides/farmacología , Carotenoides/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Temozolomida/metabolismo , Temozolomida/farmacologíaRESUMEN
BACKGROUND: Cancer cells including cancer stem cells exhibit a higher rate of ribosome biogenesis than normal cells to support rapid cell proliferation in tumors. However, the molecular mechanisms governing the preferential ribosome biogenesis in glioma stem cells (GSCs) remain unclear. In this work, we show that the novel INHAT repressor (NIR) promotes ribosomal DNA (rDNA) transcription to support GSC proliferation and glioblastoma (GBM) growth, suggesting that NIR is a potential therapeutic target for GBM. METHODS: Immunoblotting, immunohistochemical and immunofluorescent analysis were used to determine NIR expression in GSCs and human GBMs. Using shRNA-mediated knockdown, we assessed the role and functional significance of NIR in GSCs and GSC-derived orthotopic GBM xenografts. We further performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which NIR promotes GBM progression. RESULTS: Our results show that high expression of NIR predicts poor survival in GBM patients. NIR is enriched in the nucleoli of GSCs in human GBMs. Disrupting NIR markedly suppresses GSC proliferation and tumor growth by inhibiting rDNA transcription and pre-ribosomal RNA synthesis. In mechanistic studies, we find that NIR activates rDNA transcription to promote GSC proliferation by cooperating with Nucleolin (NCL) and Nucleophosmin 1 (NPM1), 2 important nucleolar transcription factors. CONCLUSIONS: Our study uncovers a critical role of NIR-mediated rDNA transcription in the malignant progression of GBM, indicating that targeting this axis may provide a novel therapeutic strategy for GBM.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/patología , ADN Ribosómico/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Glioma/patología , Células Madre Neoplásicas/metabolismo , Proliferación CelularRESUMEN
INTRODUCTION: The mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a matrilineal hereditary multisystem disease caused by mutations in the mitochondrial DNA. Although the initial diagnostic criteria correlate with a range of clinical phenotypes, including clinical onset after the age of 40, there is still lack of a unified single diagnostic standard for MELAS. CASE REPORT: A 71-year-old female patient with recurrent stroke was reported. Magnetic resonance imaging showed a cerebral gyrus-like diffusion weighted imaging high signal lesion in the parietal-occipital lobe and the area of this lesion expanded with disease progression. The MRS result showed significantly inverted Lac/Lip peaks. The nucleic acid sequencing result displayed a MT-TWm.5541C>T mutation, and a 12.86% mutation rate in the blood sample. The patient had a 6-year history of type 2 diabetes. CONCLUSION: Patients with the MELAS syndrome may present with a variety of clinical manifestations. Our data demonstrated that, for patients with atypical cerebral infarction and suspected MELAS syndrome, gene sequencing and muscle biopsy should be performed in time. This case provides a reference for the diagnostic criteria of MELAS syndrome.
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Acidosis Láctica , Diabetes Mellitus Tipo 2 , Síndrome MELAS , Accidente Cerebrovascular , Femenino , Humanos , Anciano , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Mutación/genética , ADN Mitocondrial/genética , Infarto CerebralRESUMEN
Euryale (Euryale ferox Salisb.) is an aquatic crop used as both food and drug in Asia, but its utilization is seriously limited due to low yield. Previously, we hypothesized that Euryale small auxin up RNAs (EuSAURs) regulate seed size, but the underlying biological functions and molecular mechanisms remain unclear. Here, we observed that the hybrid Euryale lines (HL) generate larger seeds with higher indole-3-acetic acid (IAA) concentrations than those in the North Gordon Euryale (WT). Histological analysis suggested that a larger ovary in HL is attributed to longer cells around. Overexpression of EuSAUR62 in rice (Oryza sativa L.) resulted in larger glumes and grains and increased the length of glume cells. Immunofluorescence and protein interaction assays revealed that EuSAUR62 modulates IAA accumulation around the rice ovary by interacting with the rice PIN-FORMED 9, an auxin efflux carrier protein. Euryale basic region/leucine zipper 55 (EubZIP55), which was highly expressed in HL, directly binds to the EuSAUR62 promoter and activated the expression of EuSAUR62. Constant light increased the expression of both EubZIP55 and EuSAUR62 with auxin-mediated hook curvature in HL seedlings. Overall, we proposed that EuSAUR62 is a molecular bridge between light and IAA and plays a crucial role in regulating the size of the Euryale seed.
RESUMEN
Background: Xiao-Yao-San (XYS) is a traditional Chinese prescription that regulates gastrointestinal function, improves mental and psychological abnormalities, and enhances liver function. However, the underlying mechanism of XYS for relieving anti-tuberculosis (AT) drug-induced liver injury is not clear. Objective: The current study examined whether XYS alleviated the symptoms of AT drug-induced liver injury in mice via the mitochondrial oxidative stress pathway. Methods: BALB/c male mice were randomly divided into four groups of 12 animals, including a control group, a model group, a 0.32 g/kg XYS group, and a 0.64 g/kg XYS group. The effect of XYS on the degree of liver injury was observed using haematoxylin and eosin staining (HE) and oil red O staining of pathological sections, biochemical parameters, and reactive oxygen species (ROS) levels. The protein expression of mitochondrial synthesis-related proteins and ferroptosis-related proteins was examined using Western blotting. Results: XYS improved the pathological changes in liver tissue and reduced the level of oxidative stress in liver-injured mice. XYS increased the expression of mitochondrial synthesis-related proteins and reversed the expression of ferroptosis-related proteins. Knockdown of G-rich RNA sequence binding factor 1 (Grsf1) expression with Grsf1 shRNA blocked the protective effects of XYS in liver injury. Conclusion: Our findings suggest that XYS alleviates AT drug-induced liver injury by mediating Grsf1 in the mitochondrial oxidative stress pathway.