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TFE3 and TFEB, as the master regulators of lysosome biogenesis and autophagy, are well characterized to enhance the synaptic protein α-synuclein degradation in protecting against Parkinson's disease (PD) and their levels are significantly decreased in the brain of PD patients. However, how TFE3 and TFEB are regulated during PD pathogenesis remains largely vague. Herein, we identified that programmed cell death 4 (PDCD4) promoted pathologic α-synuclein accumulation to facilitate PD development via suppressing both TFE3 and TFEB translation. Conversely, PDCD4 deficiency significantly augmented global and nuclear TFE3 and TFEB distributions to alleviate neurodegeneration in a mouse model of PD with overexpressing α-synuclein in the striatum. Mechanistically, like TFEB as we reported before, PDCD4 also suppressed TFE3 translation, rather than influencing its transcription and protein stability, to restrain its nuclear translocation and lysosomal functions, eventually leading to α-synuclein aggregation. We proved that the two MA3 domains of PDCD4 mediated the translational suppression of TFE3 through binding to its 5'-UTR of mRNA in an eIF-4A dependent manner. Based on this, we developed a blood-brain barrier penetrating RVG polypeptide modified small RNA drug against pdcd4 to efficiently prevent α-synuclein neurodegeneration in improving PD symptoms by intraperitoneal injections. Together, we suggest PDCD4 as a PD-risk protein to facilitate α-synuclein neurodegeneration via suppressing TFE3 and TFEB translation and further provide a potential small RNA drug against pdcd4 to treat PD by intraperitoneal injections.
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This study employs Reflexive Thematic Analysis to explore youth expressions of suicide on Bilibili, a video platform popular among young audiences. By analyzing comments from three vloggers who died by suicide, the research identified 42 initial codes, leading to 19 themes and seven sub-themes, categorized into three main domains: Perspectives on Suicide, Perspectives on Life, and Perspectives on Death. The "Perspectives on Suicide" domain mainly includes individual assessments, attitudes toward suicide, and attributions of suicide behaviors. "Perspectives on Life" encompasses insights shaped by personal experiences, whereas discussions on death, less frequent, focus on perceptions of death and assumptions about the afterlife. The content reflects a blend of traditional Chinese views and a noticeable shift toward individualism, with the internet playing a significant role in stimulating discussions on suicide and facilitating the expression and exchange of related views. These findings provide critical insights for organizations developing effective suicide prevention strategies.
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PURPOSE: The purpose of this study was to study the effects of the severity of preoperative bone marrow oedema (BME) on the postoperative short-term outcomes following bone marrow stimulation (BMS) for osteochondral lesions of the talus (OLTs) and to propose a new metric that combines volume and signal density to evaluate BME. METHODS: Sixty-five patients with symptomatic OLTs (<100 mm2) and preoperative BME, who received BMS in our institution from April 2017 to July 2021 with follow-ups of 3, 6 and 12 months, were analysed retrospectively. The area, volume and signal value of the BME were collected on preoperative magnetic resonance imaging. The enroled patients were divided into two groups according to the BME index (BMEI), which was defined as the product of oedema relative signal intensity and the relation of oedema volume to total talar volume. Visual analogue scale, American Orthopedic Foot and Ankle Society (AOFAS), Tegner, Foot and Ankle Ability Measure (FAAM)-activities of daily living (ADL) and Sports scores were assessed before surgery and at each follow-up. The relationship between the scores and the volume, relative signal intensity and BMEI was explored. RESULTS: Sixty-five patients with preoperative BME were divided into the mild (n = 33) and severe (n = 32) groups based on the BMEI. A significant difference was found for each score with the general linear model for repeated measures through all follow-up time points (p < 0.001). For the preoperative and 12-month postoperative changes of the enroled patients, 53 patients (81.5%) exceeded the minimal clinically important difference of AOFAS and 26 (40.0%) exceeded that of FAAM-sports in this study. The mild group showed significantly more improvement in AOFAS scores at 12 months (89.6 ± 7.0 vs. 86.2 ± 6.2) and FAAM-ADL scores at 6 months (83.6 ± 7.6 vs. 79.7 ± 7.7) and 12 months (88.5 ± 8.5 vs. 84.4 ± 7.7) than the severe group (p < 0.05). No significant difference of all the scores between the groups was found at 3 months. No significant correlation was found in each group between BMEI and clinical outcomes. CONCLUSION: The severity of the preoperative BME negatively affected short-term clinical outcomes following arthroscopic BMS for OLTs. Worse clinical outcomes were shown at postoperative 6 and 12 months in patients with a high preoperative BMEI, which could be a favourable parameter for assessing the severity of BME and assist in developing personalised rehabilitation plans and determining the approach and timing of surgery. LEVEL OF EVIDENCE: Level III.
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Artroscopía , Edema , Imagen por Resonancia Magnética , Índice de Severidad de la Enfermedad , Astrágalo , Humanos , Astrágalo/cirugía , Edema/etiología , Masculino , Femenino , Adulto , Estudios Retrospectivos , Enfermedades de la Médula Ósea/cirugía , Enfermedades de la Médula Ósea/etiología , Enfermedades de la Médula Ósea/diagnóstico por imagen , Persona de Mediana Edad , Resultado del Tratamiento , Médula Ósea , Adulto Joven , Periodo Preoperatorio , Cartílago Articular/cirugíaRESUMEN
Nervous system diseases are a global health problem, and with the increase in the elderly population around the world, their incidence will also increase. Harmful substances in the environment are closely related to the occurrence of nervous system diseases. China is a large agricultural country, and thus the insecticide cyfluthrin has been widely used. Cyfluthrin is neurotoxic, but the mechanism of this injury is not clear. Inflammation is an important mechanism for the occurrence of nervous system diseases. Mitochondria are the main regulators of the inflammatory response, and various cellular responses, including autophagy, directly affect the regulation of inflammatory processes. Mitochondrial damage is related to mitochondrial quality control (MQC) and PTEN-induced kinase 1 (PINK1). As an anti-inflammatory factor, stimulator of interferon genes (STING) participates in the regulation of inflammation. However, the relationship between STING and mitochondria in the process of cyfluthrin-induced nerve injury is unclear. This study established in vivo and in vitro models of cyfluthrin exposure to explore the role of MQC and to clarify the mechanism of action of STING and PINK1. Our results showed that cyfluthrin can increase the reactive oxygen species (ROS) level, resulting in mitochondrial damage and inflammation. In this process, an imbalance in MQC leads to the aggravation of mitochondrial damage, and high STING expression drives the occurrence of inflammation. We established a differential expression model of STING and PINK1 to further determine the underlying mechanism and found that the interaction between STING and PINK1 regulates MQC to affect the levels of mitochondrial damage and inflammation. When STING and PINK1 expression are downregulated, mitochondrial damage and STING-induced inflammation are significantly alleviated. In summary, a synergistic effect between STING and PINK1 on cyfluthrin-induced neuroinflammation may exist, which leads to an imbalance in MQC by inhibiting mitochondrial biogenesis and division/fusion, and PINK1 can reduce STING-driven inflammation.
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Mitocondrias , Nitrilos , Proteínas Quinasas , Piretrinas , Piretrinas/toxicidad , Mitocondrias/efectos de los fármacos , Animales , Nitrilos/toxicidad , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Enfermedades Neuroinflamatorias/inducido químicamente , Insecticidas/toxicidad , Ratones , Especies Reactivas de Oxígeno/metabolismo , Inflamación/inducido químicamente , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genéticaRESUMEN
This study investigates the specific mechanisms of Huaier-induced mitochondrial apoptosis in colorectal cancer. HCT116 and SW480 cells were subjected to Huaier treatment. Cell proliferation and migration capabilities were examined through CCK-8 and scratch experiments, respectively. Apoptotic cells were clarified with Annexin-PE staining. DCFH-DA staining, malondialdehyde(MDA), and glutathione(GSH) were used to evaluate the oxidative stress damage level of cells. MitoSOX and JC-1 probes were used to selectively target mitochondria reactive oxygen species(mtROS) and mitochondria membrane potential(MMP) for the evaluation of mitochondria damage. Western blot(WB) experiment was performed to determine apoptosis proteins and PINK1/Parkin pathway. Experiments reveal that in different concentrations of Huaier treatment, the proliferation and migration capabilities of HCT116 and SW480 cells were both restrained. Additionally, mitochondrial apoptosis was activated. Compared with the control group, excessive ROS in colorectal cancer cells was generated in the Huaier group, while MDA increased, and GSH decreased, indicating oxidative stress damage. mtROS increased, and MMP decreased in colorectal cancer cells treated with Huaier, indicating mitochondrial damage. WB result revealed that Huaier suppressed the PINK1/Parkin pathway, hindered the clearance of impaired mitochondria, and subsequently facilitated apoptosis. In conclusion, Huaier impairs colorectal cancer cells through oxidative stress and mitochondria damage. Furthermore, it suppressed the PINK1/Parkin pathway, promoting mitochondria apoptosis in colorectal cancer cells.
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Apoptosis , Proliferación Celular , Neoplasias Colorrectales , Mitocondrias , Estrés Oxidativo , Especies Reactivas de Oxígeno , Humanos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/fisiopatología , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Medicamentos Herbarios Chinos/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Movimiento Celular/efectos de los fármacosRESUMEN
Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.
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Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.
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Hepatopatías Alcohólicas , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteína Homóloga de Ras Enriquecida en el Cerebro , Transducción de Señal , Proteína 2 del Complejo de la Esclerosis Tuberosa , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Proteína Homóloga de Ras Enriquecida en el Cerebro/metabolismo , Proteína Homóloga de Ras Enriquecida en el Cerebro/genética , Humanos , Animales , Ratones , Proteína 2 del Complejo de la Esclerosis Tuberosa/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/genética , Interleucina-1/metabolismo , Interleucina-1/genética , Ratones Endogámicos C57BL , Masculino , Células HEK293RESUMEN
Leptomeningeal metastasis (LM) is a lethal complication of malignant tumors, with an incidence rate of 3%-5% among patients with non-small cell lung cancer (NSCLC). LM poses significant challenges in diagnosis, has poor prognosis, limited treatment options, and lacks standardized criteria for evaluating therapeutic efficacy, making it a difficult aspect of NSCLC management. Circulating tumor DNA (ctDNA), shed from tumor cells and carrying cancer-related information, holds significant value in precision oncology. Cerebrospinal fluid (CSF), present in the subarachnoid space of the brain, the spinal cord, and the central canal, and in direct contact with meningeal tissues, serves as the fluid medium that best reflects the genetic characteristics of LM. In recent years, CSF ctDNA has become a focal point due to its multi-omics features, playing a crucial role in the management of central nervous system (CNS) metastatic tumors. Its applications span the entire continuum of care, including aiding in diagnosis, assessing treatment response, predicting prognosis, and analyzing resistance mechanisms. This article provides a concise overview of CSF ctDNA detection techniques and their clinical applications in patients with NSCLC-LM.â©.
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Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Neoplasias Meníngeas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/líquido cefalorraquídeo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/líquido cefalorraquídeo , Neoplasias Pulmonares/genética , Neoplasias Meníngeas/secundario , Neoplasias Meníngeas/líquido cefalorraquídeo , Neoplasias Meníngeas/genéticaRESUMEN
Inflammation assumes a pivotal role in the aortic remodeling of aortic dissection (AD). Asiatic acid (AA), a triterpene compound, is recognized for its strong anti-inflammatory properties. Yet, its effects on ß-aminopropionitrile (BAPN)-triggered AD have not been clearly established. The objective is to determine whether AA attenuates adverse aortic remodeling in BAPN-induced AD and clarify potential molecular mechanisms. In vitro studies, RAW264.7 cells pretreated with AA were challenged with lipopolysaccharide (LPS), and then the vascular smooth muscle cells (VSMCs)-macrophage coculture system was established to explore intercellular interactions. To induce AD, male C57BL/6J mice at three weeks of age were administered BAPN at a dosage of 1 g/kg/d for four weeks. To decipher the mechanism underlying the effects of AA, RNA sequencing analysis was conducted, with subsequent validation of these pathways through cellular experiments. AA exhibited significant suppression of M1 macrophage polarization. In the cell coculture system, AA facilitated the transformation of VSMCs into a contractile phenotype. In the mouse model of AD, AA strikingly prevented the BAPN-induced increases in inflammation cell infiltration and extracellular matrix degradation. Mechanistically, RNA sequencing analysis revealed a substantial upregulation of CX3CL1 expression in BAPN group but downregulation in AA-treated group. Additionally, it was observed that the upregulation of CX3CL1 negated the beneficial impact of AA on the polarization of macrophages and the phenotypic transformation of VSMCs. Crucially, our findings revealed that AA is capable of downregulating CX3CL1 expression, accomplishing this by obstructing the nuclear translocation of NF-κB p65. The findings indicate that AA holds promise as a prospective treatment for adverse aortic remodeling by suppressing the activity of NF-κB p65/CX3CL1 signaling pathway.
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Disección Aórtica , Quimiocina CX3CL1 , Ratones Endogámicos C57BL , Triterpenos Pentacíclicos , Transducción de Señal , Factor de Transcripción ReIA , Remodelación Vascular , Animales , Ratones , Masculino , Disección Aórtica/metabolismo , Disección Aórtica/patología , Disección Aórtica/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Remodelación Vascular/efectos de los fármacos , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Aminopropionitrilo/farmacología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacosRESUMEN
Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the neuropathologic progression of HAND. A recent study by our group found that gp120 mediates A1 astrocytes (neurotoxicity), which secrete proinflammatory factors and promote HAND disease progression. Here, by comparing the expression of A2 astrocyte (neuroprotective) markers in the brains of gp120 tgm mice and gp120+/α7nAChR-/- mice, we found that inhibition of alpha 7 nicotinic acetylcholine receptor (α7nAChR) promotes A2 astrocyte generation. Notably, kynurenine acid (KYNA) is an antagonist of α7nAChR, and is able to promote the formation of A2 astrocytes, the secretion of neurotrophic factors, and the enhancement of glutamate uptake through blocking the activation of α7nAChR/NF-κB signaling. In addition, learning, memory and mood disorders were significantly improved in gp120 tgm mice by intraperitoneal injection of kynurenine (KYN) and probenecid (PROB). Meanwhile, the number of A2 astrocytes in the mouse brain was significantly increased and glutamate toxicity was reduced. Taken together, KYNA was able to promote A2 astrocyte production and neurotrophic factor secretion, reduce glutamate toxicity, and ameliorate gp120-induced neuropathological deficits. These findings contribute to our understanding of the role that reactive astrocytes play in the development of HAND pathology and provide new evidence for the treatment of HAND via the tryptophan pathway.
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Astrocitos , Ácido Glutámico , Quinurenina , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Ácido Glutámico/metabolismo , Ácido Glutámico/toxicidad , Ratones , Quinurenina/metabolismo , Ácido Quinurénico/metabolismo , Ácido Quinurénico/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , Proteína gp120 de Envoltorio del VIH/toxicidad , Transducción de Señal/efectos de los fármacos , Ratones Noqueados , Probenecid/farmacología , Ratones Endogámicos C57BL , Masculino , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/efectos de los fármacos , FN-kappa B/metabolismoRESUMEN
ABSTRACT: Platelet α-granules are rich in transforming growth factor ß1 (TGF-ß1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-ß/Smad pathways in TPO-RA-corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-ß1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-ß1 induces the expansion and functional reprogramming of MDSCs via the TGF-ß/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.
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Plaquetas , Células Supresoras de Origen Mieloide , Púrpura Trombocitopénica Idiopática , Factor de Crecimiento Transformador beta1 , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Plaquetas/metabolismo , Plaquetas/inmunología , Reprogramación Celular , Ratones SCID , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/patología , Púrpura Trombocitopénica Idiopática/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The hybridization chain reaction (HCR), as one of the nucleic acid amplification technologies, is combined with fluorescence signal output with excellent sensitivity, simplicity, and stability. However, current HCR-based fluorescence sensing methods still have some defects such as the blocking effect of the HCR combination with fluorophores and the aggregation-caused quenching (ACQ) phenomenon of traditional fluorophores. Herein, a triplex DNA-based aggregation-induced emission probe (AIE-P) was designed as the fluorescent signal transduction, which is able to provide a new platform for HCR-based sensing assay. The AIE-P was synthesized by attaching the AIE fluorophores to terminus of the oligonucleotide through amido bond, and captured the products of HCR to form triplex DNA. In this case, the AIE fluorophores were located in close proximity to generate fluorescence. This assay provided turn-on fluorescence efficiency with a high signal-to-noise ratio and excellent amplification capability to solve the shortcoming of HCR-based fluorescence sensing methods. It enabled sensitive detection of Vibrio parahaemolyticus in the range of 102-106 CFU mL-1, and with a low limit of detection down to 39 CFU mL-1. In addition, this assay expressed good specificity and practicability. The triplex DNA-based AIE probe forms a universal molecular tool for developing HCR-based fluorescence sensing methods.
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Técnicas Biosensibles , ADN , ADN/genética , ADN/química , Hibridación de Ácido Nucleico/métodos , Colorantes Fluorescentes/química , Técnicas de Amplificación de Ácido Nucleico/métodos , Técnicas Biosensibles/métodos , Límite de DetecciónRESUMEN
The appropriate transcriptional activity of PPARγ is indispensable for controlling inflammation, tumor and obesity. Therefore, the identification of key switch that couples PPARγ activation with degradation to sustain its activity homeostasis is extremely important. Unexpectedly, we here show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) critically controls PPARγ activity homeostasis via SIRT1 to enhance adipose plasticity via promoting white adipose tissues beiging and brown adipose tissues thermogenesis. Mechanistically, ACSS2 binds directly acetylated PPARγ in the presence of ligand and recruits SIRT1 and PRDM16 to activate UCP1 expression. In turn, SIRT1 triggers ACSS2 translocation from deacetylated PPARγ to P300 and thereafter induces PPARγ polyubiquitination and degradation. Interestingly, D-mannose rapidly activates ACSS2-PPARγ-UCP1 axis to resist high fat diet induced obesity in mice. We thus reveal a novel ACSS2 function in coupling PPARγ activation with degradation via SIRT1 and suggest D-mannose as a novel adipose plasticity regulator via ACSS2 to prevent obesity.
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Homeostasis , PPAR gamma , Sirtuina 1 , Animales , PPAR gamma/metabolismo , Ratones , Sirtuina 1/metabolismo , Sirtuina 1/genética , Acetato CoA Ligasa/metabolismo , Acetato CoA Ligasa/genética , Ratones Endogámicos C57BL , Humanos , Obesidad/metabolismo , Obesidad/patología , Factores de Transcripción/metabolismo , Dieta Alta en Grasa , Masculino , Tejido Adiposo Pardo/metabolismo , Termogénesis , Manosa/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Tejido Adiposo Blanco/metabolismo , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genética , Tejido Adiposo/metabolismoRESUMEN
OBJECTIVE: Scutellaria baicalensis (SB) and Polygonatum Rhizoma (PR), two traditional Chinese medicines, are both known to suppress cancer. However, the mechanism and effect of combined treatment of them for lung cancer are rarely known. Investigating the combined effect of SB and PR (hereafter referred to as SP) in potential mechanism of lung cancer is required. This study was to evaluate the inhibitory effects of SP on A549 cell growth and to explore the underlying molecular mechanisms. METHODS: According to the theory of Chinese medicine and network pharmacology, in the in vivo experiment, a mouse model of carcinoma in situ was constructed, and lung carcinoma in situ tissues were collected for proteomics analysis, hematoxylin-eosin staining, and CK19 immunohistochemistry. In the in vitro experiment, lung cancer A549 cells at logarithmic growth stage were taken, and the inhibitory effect of SP on the proliferation of A549 cells was detected by CCK8 method. The expression of PON3 was detected by quantitative polymerase chain reaction and western blot. In addition, the effect of SP on the induction of apoptosis in A549 cells and the changes of membrane potential and reactive oxygen species (ROS) content were detected by flow cytometry. The changes of PON3 content in endoplasmic reticulum (ER) are observed by laser confocal microscopy, whereas the effects of SP on the expression of apoptosis-related proteins and ER stress-related proteins in A549 cells were examined by western blot. RESULT: By searching the Traditional Chinese Medicines of Systems Pharmacology (TCMSP) (https://www.tcmspe.com/index.php) database and SymMap database, the respective target genes of PR and SB were mapped into protein network interactions, and using Venn diagrams to show 38 genes in common between PR and SB and lung cancer, SP was found to play a role in the treatment of lung cancer. In vivo experiments showed that in a lung carcinoma in situ model, lung tumor tissue was significantly lower in the SP group compared with the control group, and PON3 was shown to be downregulated by lung tissue proteomics analysis. The combination of SP was able to inhibit the proliferation of A549 cells in a concentration-dependent manner (p < .0001). The expression levels of apoptosis-related proteins and ER stress proteins were significantly increased and the expression levels of PON3 and anti-apoptosis-related proteins were decreased in A549 cells. At the same time, knockdown of PON3 could inhibit tumor cell proliferation (p < .0001). The combination of different concentrations of SP significantly induced apoptosis in A549 cells (p < .05; p < .0001), increased ROS content (p < .01), and damaged mitochondrial membrane potential of A549 cells (p < .05; p < .0001), and significantly increased the expression levels of apoptosis-related proteins and ER stress proteins in lung cancer A549 cells. CONCLUSION: SP inhibits proliferation of lung cancer A549 cells by downregulating PON3-induced apoptosis in the mitochondrial and ER pathways.
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Carcinoma in Situ , Neoplasias Pulmonares , Polygonatum , Animales , Ratones , Humanos , Células A549 , Polygonatum/metabolismo , Scutellaria baicalensis/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Abajo , Neoplasias Pulmonares/patología , Apoptosis , Proliferación Celular , Estrés del Retículo Endoplásmico , Proteínas de Choque Térmico/metabolismo , Línea Celular TumoralRESUMEN
The spontaneous migration of bone marrow neutrophils (BMNs) is typically induced by distant tumor cells during the early stage of the tumor and critically controls tumor progression and metastases. Therefore, identifying the key molecule that prevents this process is extremely important for suppressing tumors. Interleukin-37 (IL-37) can suppress pro-inflammatory cytokine generation via an IL-1R8- or Smad3-mediated pathway. Here, we demonstrate that human neutrophil IL-37 is responsively reduced by tumor cells and the recombinant IL-37 isoform d (IL-37d) significantly inhibits spontaneous BMN migration and tumor lesion formation in the lung by negatively modulating CCAAT/enhancer binding protein beta (C/EBPß) in a Lewis lung carcinoma (LLC)-inducing lung cancer mouse model. Mechanistically, IL-37d promotes C/EBPß ubiquitination degradation by facilitating ubiquitin ligase COP1 recruitment and disrupts C/EBPß DNA binding abilities, thereby reducing neutrophil ATP generation and migration. Our work reveals an anti-tumor mechanism for IL-37 via destabilization of C/EBPß to prevent spontaneous BMN migration and tumor progression.
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Carcinoma Pulmonar de Lewis , Neutrófilos , Ratones , Animales , Humanos , Neutrófilos/metabolismo , Citocinas/metabolismo , Pulmón/metabolismoRESUMEN
OBJECTIVE: [18F] AV-45 can be produced in a simple, stable, and repeatable manner on the Tracerlab FXF-N platform using a self-editing synthetic procedure and solid-phase extraction purification method. This technique is applied to positron emission tomography (PET) imaging of Alzheimer's disease (AD) to observe its distribution and characteristics in various brain regions and its diagnostic efficiency for the disease. METHODS: The precursor was subjected to nucleophilic radiofluorination at 120°C in anhydrous dimethyl sulfoxide, followed by acid hydrolysis of the protecting groups. The neutralized reaction mixture was purified by solid phase extraction to obtain a relatively pure [18F] AV-45 product with a high specific activity. A total of 10 participants who were diagnosed with Alzheimer's disease (AD group) and 10 healthy controls (HC group) were included retrospectively. All of them underwent [18F] AV-45 brain PET/CT imaging. The distribution of [18F] AV-45 in the AD group was analyzed visually and semi-quantitatively. RESULTS: Six consecutive radiochemical syntheses were performed in this experiment. The average production time of [18F] AV-45 was 52 minutes, the radiochemical yield was 14.2 % ± 2.7% (n = 6), and the radiochemical purity was greater than 95%. When used with PET/CT imaging, the results of the visual analysis indicated increased [18F] AV-45 radioactivity uptake in the frontal, temporal, and parietal lobes in AD patients. Semiquantitative analysis showed the highest diagnostic efficacy in the posterior cingulate gyrus compared with other brain regions (P < 0.001). CONCLUSION: Intravenous [18F] AV-45 was successfully prepared on the Tracerlab FXF-N platform by solid-phase extraction of crude product and automated radiochemical synthesis. PET/CT imaging can be used to diagnose and evaluate AD patients and provide a more robust basis for clinicians to diagnose AD.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Retrospectivos , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , RadiofármacosRESUMEN
BACKGROUND: Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) is a promising stroke biomarker. However, a large study of human serum ASC has not yet to be reported; additionally, the diagnostic value of prehospital concentration and practicality of ASC remains unknown. METHODS: We recruited 774 Chinese stroke patients, including 523 with ischemic stroke (IS) and 251 with hemorrhagic stroke (HS) within 14 days following symptom onset in the emergency department, alongside 481 healthy individuals and 64 cognitive impairment patients as controls. Serum ASC concentrations were determined using automated chemiluminescence immunoassay, exploring the relationship between serum ASC concentration and subtypes, severity, and sampling timepoints of stroke. RESULTS: ASC concentrations were significantly higher in stroke patients compared with all controls (P < 0.001). HS patients had greater ASC concentrations than IS patients (P < 0.05). With increasing ASC concentration, the proportion of severe cases increased. The area under the receiver operating characteristic curve (AUC) for differentiating between healthy individuals and stroke patients in the hyperacute phase was 0.78; this markedly improved (0.90) when considering samples from healthy individuals and patients with subarachnoid hemorrhage (SAH) ≤ 3 h from last-known-well (LKW). CONCLUSIONS: Serum ASC is a valuable biomarker for stroke differentiation and aids in the clinical diagnosis of stroke severity and subtypes.
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Proteínas Adaptadoras de Señalización CARD , Accidente Cerebrovascular , Humanos , Apoptosis , Biomarcadores , Caspasas , Accidente Cerebrovascular/diagnósticoRESUMEN
The potentiation of synaptic plasticity and serotonin generation by brain-derived neurotrophic factor (BDNF) and tryptophan hydroxylase 2 (TPH2) is well characterized to facilitate rapid and long-lasting antidepressant actions. Therefore, the identification of the key protein that simultaneously controls both BDNF and TPH2 is important for the treatment of depression. We show here that a lack of acetyl-CoA synthetase short-chain family member 2 (ACSS2) causes impairments in BDNF-dependent synaptic plasticity and tryptophan hydroxylase 2 (TPH2)-mediated serotonin generation, thereby contributing to spontaneous and chronic restraint stress (CRS)-induced depressive-like behavior in mice. Conversely, D-mannose is identified as a rapid ACSS2 inducer and thus mediates rapid and long-lasting antidepressant-like effects. Mechanistically, acute and chronic D-mannose administration inhibits the phosphorylation of EF2 to increase BDNF levels and reverse the reduction of TPH2 histone acetylation and transcription. We reveal that ACSS2 promotes TPH2 histone acetylation and transcription with the requirement of AMPK activation. To elevate nuclear ACSS2 levels, D-mannose can rapidly and persistently activate AMPK via Ca2+-CAMKK2 and the lysosomal AXIN-LKB1 pathway to facilitate its fast-acting and persistent antidepressant responses. Taken together, the results presented here reveal that ACSS2 functions as a novel target to link rapid and persistent antidepressant actions and further suggest that D-mannose is a potential therapeutic agent to resist depression through its augmentation of the ACSS2 dependent BDNF and TPH2 pathways.
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Factor Neurotrófico Derivado del Encéfalo , Histonas , Ratones , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Manosa , Serotonina/metabolismo , Triptófano Hidroxilasa , Proteínas Quinasas Activadas por AMP/metabolismo , Antidepresivos/farmacología , Antidepresivos/uso terapéuticoRESUMEN
Spirulina, an herbal supplement and popular ingredient in health foods, is a potent stimulant of the immune system. Spirulina use is temporally associated with the onset or exacerbation of Dermatomyositis (DM), an autoimmune connective tissue disease that frequently affects the skin and muscle. In this study, we investigated the effect of Spirulina on peripheral blood mononuclear cells (PBMCs) in DM and Healthy Controls (HCs), showing that Spirulina stimulates Interferon ß (IFNß), Tumor necrosis factor α (TNFα), and Interferon γ (IFNγ) production of DM PBMCs primarily via Toll-Like Receptor 4 (TLR4) activation using ELISA (enzyme linked immunosorbent assay) and flow cytometry. We show that classical monocytes and monocyte-derived dendritic cells are stimulated by Spirulina and are activated via TLR4. Skin from patients with Spirulina-associated DM exhibits an inflammatory milieu similar to that of idiopathic DM but with a stronger correlation of TLR4 and IFNγ.
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To give consideration to both chip density and device performance, an In0.53Ga0.47As vertical electron-hole bilayer tunnel field effect transistor (EHBTFET) with a P+-pocket and an In0.52Al0.48As-block (VPB-EHBTFET) is introduced and systematically studied by TCAD simulation. The introduction of the P+-pocket can reduce the line tunneling distance, thereby enhancing the on-state current. This can also effectively address the challenge of forming a hole inversion layer in an undoped InGaAs channel during device fabrication. Moreover, the point tunneling can be significantly suppressed by the In0.52Al0.48As-block, resulting in a substantial decrease in the off-state current. By optimizing the width and doping concentration of the P+-pocket as well as the length and width of the In0.52Al0.48As-block, VPB-EHBTFET can obtain an off-state current of 1.83 × 10-19 A/µm, on-state current of 1.04 × 10-4 A/µm, and an average subthreshold swing of 5.5 mV/dec. Compared with traditional InGaAs vertical EHBTFET, the proposed VPB-EHBTFET has a three orders of magnitude decrease in the off-state current, about six times increase in the on-state current, 81.8% reduction in the average subthreshold swing, and stronger inhibitory ability on the drain-induced barrier-lowering effect (7.5 mV/V); these benefits enhance the practical application of EHBTFETs.