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Few approaches have been conducted in the treatment of renal cell carcinoma (RCC) after nephrectomy, resulting in a high mortality rate in urological tumours. Mitophagy is a mechanism of mitochondrial quality control that enables selective degradation of damaged and unnecessary mitochondria. Previous studies have found that glycerol-3-phosphate dehydrogenase 1-like (GPD1L) is associated with the progression of tumours such as lung cancer, colorectal cancer and oropharyngeal cancer, but the potential mechanism in RCC is still unclear. In this study, microarrays from tumour databases were analysed. The expression of GPD1L was confirmed by RT-qPCR and western blotting. The effect and mechanism of GPD1L were explored using cell counting kit 8, wound healing, invasion, flow cytometry and mitophagy-related experiments. The role of GPD1L was further confirmed in vivo. The results showed that GPD1L expression was downregulated and positively correlated with prognosis in RCC. Functional experiments revealed that GPD1L prevented proliferation, migration and invasion while promoting apoptosis and mitochondrial injury in vitro. The mechanistic results indicated that GPD1L interacted with PINK1, promoting PINK1/Parkin-mediated mitophagy. However, inhibition of PINK1 reversed GPD1L-mediated mitochondrial injury and mitophagy. Moreover, GPD1L prevented tumour growth and promoted mitophagy by activating the PINK1/Parkin pathway in vivo. Our study shows that GPD1L has a positive correlation with the prognosis of RCC. The potential mechanism involves interacting with PINK1 and regulating the PINK1/Parkin pathway. In conclusion, these results reveal that GPD1L can act as a biomarker and target for RCC diagnosis and therapy.
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Carcinoma de Células Renais , Glicerolfosfato Desidrogenase , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mitofagia/genética , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Glicerolfosfato Desidrogenase/metabolismoRESUMO
BACKGROUND: Sepsis-induced acute lung injury (ALI) is associated with poor survival rates. The identification of potential therapeutic targets for preventing sepsis-induced ALI has clinical importance. This study aims to investigate the role of estrogen-related receptor alpha (ERRα) in sepsis-induced ALI. METHODS: Lipopolysaccharide (LPS) was used to simulate sepsis-induced ALI model in rat pulmonary microvascular endothelial cells (PMVECs). The effects of ERRα overexpression and knockdown on LPS-induced endothelial permeability, apoptosis and autophagy were determined by horseradish peroxidase permeability assay, TdT-mediated dUTP Nick End Labeling (TUNEL) assay, flow cytometry, immunofluorescence staining, RT-PCR and Western Blotting. The rat model with sepsis-induced ALI was established by cecal ligation and puncture in anesthetized rats to verify the results of in vitro experiments. Animals were randomly assigned to receive intraperitoneal injection of vehicle or ERRα agonist. Lung vascular permeability, pathological injury, apoptosis and autophagy were examined. RESULTS: Overexpression of ERRα ameliorated LPS-induced endothelial hyperpermeability, degradation of adherens junctional molecules, upregulation of bax, cleaved caspase 3 and cleaved caspase 9 levels, downregulation of anti-apoptotic protein Bcl-2 level, and promoted the formation of autophagic flux, while the knockdown of ERRα exacerbated LPS-induced apoptosis and inhibited the activation of autophagy. Administration of ERRα agonist alleviated the pathological damage of lung tissue, increased the levels of tight junction proteins and adherens junction proteins, and decreased the expression of apoptosis-related proteins. Promoting the expression of ERRα significantly enhanced the process of autophagy and reduced CLP-induced ALI. Mechanistically, ERRα is essential to regulate the balance between autophagy and apoptosis to maintain the adherens junctional integrity. CONCLUSION: ERRα protects against sepsis-induced ALI through ERRα-mediated apoptosis and autophagy. Activation of ERRα provides a new therapeutic opportunity to prevent sepsis-induced ALI.
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Lesão Pulmonar Aguda , Sepse , Ratos , Animais , Lipopolissacarídeos , Células Endoteliais/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Lesão Pulmonar Aguda/tratamento farmacológico , Pulmão/patologia , Sepse/metabolismo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
The silver coating is widely used in electronic device manufacturing due to its excellent conductivity and soldering properties. Conventional preparation of local silver coating often uses the preplated silver, mask high-speed silver plating, and deplated silver processes. In this paper, the laser-induced electrodeposition technique is used to perform maskless laser-induced localized electrodeposition on a copper substrate preplated with a layer of silver. After the deplated silver process, ultrathin silver coatings with high dimensional accuracy, good corrosion resistance, and good bonding were obtained. The spatial distribution of the transient temperature field under laser irradiation is studied, the variation pattern of cathode substrate current under laser irradiation is tested, and finally, the spatial distribution of the pressure field under laser irradiation is simulated by Comsol. The effect of different laser scanning methods on the coating morphology was investigated, and the experimental study of the different single pulse energy-induced localized silver coatings was systematically carried out. The results show that the localized coating obtained by cross-line scanning with a laser single pulse energy of 93 µJ is flat with a film thickness of 0.23 µm, high dimensional accuracy, and good bonding force and corrosion resistance properties. This method provides a new approach for the preparation of a localized silver coating.
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Renal fibrosis, which is characterized by excessive extracellular matrix (ECM) accumulation in the renal tubulointerstitium, can lead to chronic kidney disease (CKD). The role of microfiber-associated protein 4 (MFAP4), which is an ECM protein that interacts with elastin and collagen, in renal fibrosis has not been investigated. The aim of this study was to examine the role of MFAP4 in the pathogenesis of renal fibrosis and the underlying mechanism using in vivo and in vitro models. The MFAP4-/- mice were subjected to unilateral ureteral obstruction (UUO) to elucidate the role of MFAP4 in renal fibrosis in vivo. Compared to the wild-type mice, the MFAP4-/- mice exhibited decreased protein expression of p-p65 and p-IKBα and ECM deposition after UUO. The MFAP4-/- mice exhibited attenuated nuclear translocation of p65 (the hub subunit of nuclear factor (NF)-κB signaling pathway), suppressed activation of transforming growth factor (TGF)-ß/Smad pathways, and downregulated expression of fibronectin, collagen I, and plasminogen activator inhibitor-1. The knockdown of MFAP4 mitigated the TGF-ß-induced upregulated expression of fibronectin, collagen I, and plasminogen activator inhibitor-1 in the human proximal tubular epithelial cells (HK-2). Compared to the HK-2 cells transfected with sh-MFAP4, the HK-2 cells co-transfected with sh-MFAP4 and Ad-MFAP4 exhibited severe inflammatory response and increased fibrosis-related proteins expression. Mechanistically, the knockdown of MFAP4 inhibited the activation of NF-κB and TGF-ß/Smad signaling pathways and downregulated the expression of fibrosis-related proteins. The findings of this study indicate that MFAP4 is involved in UUO-induced renal fibrosis through regulation of NF-κB and TGF-ß/Smad pathways.
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Proteínas de Transporte/fisiologia , Proteínas da Matriz Extracelular/fisiologia , Fibrose/prevenção & controle , Glicoproteínas/fisiologia , Nefropatias/prevenção & controle , NF-kappa B/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Obstrução Ureteral/complicações , Animais , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
Locating nanomedicines at the active sites plays a pivotal role in the nanoparticle-based cancer therapy field. Herein, a multifunctional nanotherapeutic is designed by using graphene oxide (GO) nanosheets with rich carboxyl groups as the supporter for hyaluronic acid (HA)-methotrexate (MTX) prodrug modification via an adipicdihydrazide cross-linker, achieving synergistic multistage tumor-targeting and combined chemo-photothermal therapy. As a tumor-targeting biomaterial, HA can increase affinity of the nanocarrier toward CD44 receptor for enhanced cellular uptake. MTX, a chemotherapeutic agent, can also serve as a tumor-targeting enhancer toward folate receptor based on its similar structure with folic acid. The prepared nanosystems possess a sheet shape with a dynamic size of approximately 200 nm and pH-responsive drug release. Unexpectedly, the physiological stability of HA-MTX prodrug-decorated GO nanosystems in PBS, serum, and even plasma is more excellent than that of HA-decorated GO nanosystems, while both of them exhibit an enhanced photothermal effect than GO nanosheets. More importantly, because of good blood compatibility as well as reduced undesired interactions with blood components, HA-MTX prodrug-decorated GO nanosystems exhibited remarkably superior accumulation at the tumor sites by passive and active targeting mechanisms, achieving highly effective synergistic chemo-photothermal therapeutic effect upon near-infrared laser irradiation, efficient ablation of tumors, and negligible systemic toxicity. Hence, the HA-MTX prodrug-decorated hybrid nanosystems have a promising potential for synergistic multistage tumor-targeting therapy.
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Sistemas de Liberação de Medicamentos/métodos , Grafite/química , Nanoconjugados/química , Fotoquimioterapia/métodos , Neoplasias do Colo do Útero/terapia , Adipatos/química , Adipatos/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Feminino , Grafite/metabolismo , Células HeLa , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Células MCF-7 , Metotrexato/química , Metotrexato/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To study the expression of CLAUDIN-11 in the testis tissue of non-obstructive azoospermia (NOA) patients with different severities and investigate its clinical significance. METHODS: Sixty-two NOA patients were divided into a hypospermatogenesis (HS) group (n = 30) and a Sertoli cell only syndrome (SCO) group (n =32). The expression of CLAUDIN-11 in the testicular tissue of the patients was detected by immunohistochemistry, that of CLAUDIN-11 mRNA determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), and the levels of serum reproductive hormones measured by chemiluminescent immunoassay. RESULTS: Immunohistochemistry showed that the expression of CLAUDIN-11 was mainly in the cytoplasm of the Sertoli cells around the seminiferous tubule wall in the HS group, but diffusely distributed in the membrane of the Sertoli cells in the SCO group. RT-qPCR revealed a significantly lower expression of CLAUDIN-11 mRNA in the HS than in the SCO group (0.008 ± 0.001 vs 0.013 ± 0.002, t = 10.616, P<0.01). The level of serum luteotropic hormone (LH) was also markedly lower in the HS than in the SCO group (ï¼»3.62 ± 1.34ï¼½ vs ï¼»4.96 ± 3.10ï¼½ IU/L, P<0.05) and so was that of follicle-stimulating hormone (FSH) (ï¼»5.36 ± 2.80ï¼½ vs ï¼»10.65 ± 9.18ï¼½ IU/L, P<0.05). CONCLUSIONS: The up-regulated expression of CLAUDIN-11 in Sertoli cells may play an important role in the development and progression of spermatogenic dysfunction in NOA patients.
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Azoospermia/metabolismo , Claudinas/metabolismo , Oligospermia/metabolismo , Síndrome de Células de Sertoli/metabolismo , Testículo/metabolismo , Azoospermia/genética , Hormônio Foliculoestimulante/metabolismo , Humanos , Masculino , Oligospermia/genética , RNA Mensageiro/metabolismo , Túbulos Seminíferos/metabolismo , Síndrome de Células de Sertoli/genética , Células de Sertoli/metabolismo , EspermatogêneseRESUMO
Notch pathway has played a significant role in the pathophysiology of pulmonary hypertension (PH). However, the role of Jagged 2 (Jag2), one ligand of Notch, remains to be elucidated.Therefore, determining the contribution of Jag2 to PH and its impact on pulmonary artery smooth muscle cells (PASMCs) was the aim of this investigation. Adeno-associated virus-mediated Jag2 inhibition was used to explore the role of Jag2 in peripheral pulmonary vascular remodeling assessed in a rat model of chronic hypoxia (10% O2, 4 weeks) induced pulmonary hypertension. In vitro, the effect of Jag2 silencing on hypoxia (1% O2, 24h) induced rat PASMCs was determined. Group differences were assessed using a 2-sided unpaired Student's t-test for two groups and one-way ANOVA for multiple groups. Jag2 upregulation was first confirmed in rats with sustained hypoxia-induced PH using publicly available gene expression data, experimental PH rat models and hypoxia induced rat PASMCs. Jag2 deficiency decreased oxidative stress injury, peripheral pulmonary vascular remodeling (0.276±0.020 vs. 0.451±0.033 µm, P<0.001, <50µm), and right ventricular systolic pressure (36.8±3.033 vs. 51.8±4.245 mmHg, P<0.001) in the chronic hypoxia-induced rat model of PH. Moreover, Jag2 knockdown decreased proliferation (1.227±0.051 vs. 1.45±0.07, P = 0.012), increased apoptosis (16.733%±0.724% vs. 6.56%±0.668%, P<0.001), and suppressed mitochondrial injury in hypoxia-treated rat PASMCs. Jag2 inhibition restored the activity of the Nrf2/HO-1 pathway, which was abolished by Sirtuin 1 deficiency. These findings show that Jag2 is essential for modulating pulmonary vascular dysfunction and accelerating PH, and that inhibition of Jag2 expression suppresses the progression and development of PH.
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Hipertensão Pulmonar , Animais , Ratos , Proliferação de Células/fisiologia , Células Cultivadas , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar , Sirtuína 1/metabolismo , Remodelação VascularRESUMO
Obstructive sleep apnea (OSA) incurs a huge individual, societal, and economic burden. Specific and selective targeting of hypoglossal motor neurons could be an effective means to treat OSA. Bioluminescent-optogenetics (BL-OG) is a novel genetic regulatory approach in which luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels, increase neuronal excitability when exposed to a suitable substrate. Here we develop and validate the feasibility of BL-OG for sleep-disordered breathing (SDB). Upon confirming that diet-induced obese mice represent an excellent SDB model, we employed a method of targeting the hypoglossal nucleus (12â¯N) by peripherally injecting retrogradely transported rAAV2/Retro. With AAV transduction, the eLMO3 protein is expressed in hypoglossal motor neurons (HMN); administration of CTZ results in production of bioluminescence that in turn activates the tethered channelrhodopsin, leading to an increase in the firing of HMN and a 2.7 ± 0.8-fold increase in phasic activity of the genioglossus muscle, a 7.6 ± 1.8-fold increase in tonic activity, and improvements in hypoventilation and apnea index without impacting sleep structure. This is therefore the first study to leverage the rAAV2/Retro vector to execute the BL-OG approach in SDB, which amplified genioglossus muscle discharge activity and increased airflow in mice after activation. This study marks the pioneering utilization of BL-OG in SDB research.
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Idiopathic inflammatory myopathies (IIM) are a group of myopathies that present with muscle weakness and multiple extra-muscular manifestations, in which lymphocytes play central roles in myositis pathogenesis. This study aimed to explore the clinical characteristics of lymphocyte subsets, especially B cell subsets, in patients with IIM. Our study included 176 patients with active IIM and 210 gender/age-matched healthy controls (HCs). Compared to HCs, patients have reduced counts of T cells, B cells, and natural killer cells. In addition, B cell subsets from 153 patients with IIM and 92 HCs were characterized. Patients had a lower percentage of memory B cells and translational memory B cells, while those patients were with an elevated percentage of CD19+ B cells, plasmablast and naïve B cells compared with HCs. Moreover, to further explore the heterogeneity of B cells in IIM, patients were categorized into three clusters based on clustering analysis. Cluster 1 was dominated by CD19+ B cells, Bregs and naïve B cells, cluster 3 was dominated by memory B cells and plasmablast, and cluster 2 had the highest proportion of translational memory B cells. Notably, patients in cluster 1 presented with higher CK levels, indicating muscle damage, whereas patients in cluster 3 showed a higher incidence of chest tightness. Our study indicated that lymphopenia is a common manifestation in patients with IIM. B cell subsets are abnormally expressed and showed high heterogeneity in patients with IIM. The patients with IIM were divided into three different clusters with different percentages of chest tightness and distinct CK levels.
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Background: Talaromycosis is a serious opportunistic infectious disease caused by Talaromyces marneffei, which mostly occurs in immunocompromised patients. The disease is mainly prevalent in tropical countries and regions of Southeast Asia and South Asia, but non-endemic areas also have patients with Talaromycosis. The disease has no characteristic clinical manifestations and is difficult to diagnose. Delayed diagnosis often leads to death. Case presentation: Both patients had cellular immunodeficiency. Case 1 had a history of acquired immune deficiency syndrome, and case 2 had a history of renal transplantation and glucose-6-phosphate dehydrogenase deficiency. They all had fever, anemia, fatigue, and skin lesions. Case 1 had gastrointestinal bleeding, enlarged lymph nodes, and hepatosplenomegaly. Case 2 had cough and dyspnea. Both patients had thrombocytopenia and hypoalbuminemia; an increased neutrophil ratio, procalcitonin, and C-reactive protein; and abnormal liver function and coagulation dysfunction. Case 1 sputum culture, blood culture, and bronchoalveolar lavage fluid were positive for T. marneffei. T. marneffei was detected in the blood culture of case 2, with infection of Candida parapsilosis and Pneumocystis jirovecii. Chest computed tomography scan mainly showed pulmonary exudative lesions. Although these two patients were actively treated, they died of poor efficacy. Conclusion: Talaromycosis has an insidious onset, long course, atypical clinical symptoms, imaging performance and laboratory results, difficult diagnosis, and high mortality. Therefore, it is important to promptly consider and treat Talaromycosis in immunocompromised patients upon infection in order to reduce mortality.
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Síndrome da Imunodeficiência Adquirida , Hepatopatias , Micoses , Humanos , Micoses/diagnóstico , Tomografia Computadorizada por Raios X , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Antifúngicos/uso terapêuticoRESUMO
Proliferation of smooth muscle cells, oxidative stress, and pulmonary vasoconstriction resulting from intermittent hypoxia (IH) facilitate pulmonary hypertension (PH) in patients with obstructive sleep apnea. The role of Phosphodiesterase 4 B (PDE4B) in PH has not yet been established. Herein, we investigated whether PDE4B inhibition ameliorates experimental PH by modulating cAMP signaling. We performed an integrative analysis of PDE4B expression in Gene Expression Omnibus datasets, experimental IH-induced rat PH samples, and IH-induced pulmonary arterial smooth muscle cells (PASMCs). PDE4B expression was modulated using siRNA in vitro and a specific adeno-associated virus serotype 1 in vivo. In the databases of mouse models of IH-induced and sustained hypoxia-induced PH and in a rat model of six weeks of IH, the expression of PDE4B was up-regulated. Inhibition of PDE4B attenuated IH-induced pulmonary vascular remodeling and right ventricular hypertrophy. Our results also showed that PDE4B deficiency inhibited IH-induced proliferation of PASMCs with less mitochondrial reactive oxygen species and mitochondrial damage. Meanwhile, IH induced an increase in ATF4, which positively regulated the expression of PDE4B through transcription, and inhibition of ATF4 exerted effects similar to those of PDE4B inhibition. Mechanistically, downregulating the expression of PDE4B resulted in the activation of the cAMP/PKA/p-CREB/PGC-1α pathway in PASMCs after IH. Taken together, our present study provides evidence that inhibition of PDE4B attenuates IH-induced PH by regulating cAMP signaling.
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Hipertensão Pulmonar , Camundongos , Ratos , Animais , Hipertensão Pulmonar/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Transdução de Sinais , Hipóxia/metabolismo , Mitocôndrias/metabolismo , Artéria Pulmonar , Miócitos de Músculo Liso/metabolismo , Proliferação de CélulasRESUMO
Background: Circadian rhythm disruption and immune infiltration are both closely associated with the development of Obstructive sleep apnea (OSA) disease and a variety of cardiovascular and neurological complications, but their interactions with OSA disease are not clear. In this study, we used bioinformatics to investigate the roles of circadian rhythm disruption and immune microenvironments in OSA. Methods: We analyzed differential genes and their associated functional pathways in the circadian rhythm-associated OSA dataset, then regrouped OSA samples using the differential genes and explored differences in immune cell infiltration between the two different subgroups. Meanwhile, we used two machine learning algorithms to further define circadian rhythm-related signature genes and to explore the relationship between key genes and immune cell infiltration. Finally, we searched for the transcription factors of the key differential gene JUN. Results: We screened 15 circadian rhythm-related differential genes in the OSA-related dataset and further defined 3 signature genes by machine learning algorithms. Immunoassays showed a significant increase in resting mast cell infiltration and a decrease in monocyte infiltration in the OSA group. The results of our animal experiments also confirmed that the expression of these 3 key genes, as well as the immune cell infiltration, showed a trend consistent with the results of the bioinformatics analysis. Conclusions: In conclusion, this study reveals the interaction between circadian rhythm disruption and immune infiltration in OSA, providing new insights into the potential pathogenesis of OSA.
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Apneia Obstrutiva do Sono , Animais , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/complicações , Ritmo Circadiano/genética , CoraçãoRESUMO
Background: By 2020, the prevalence of Obstructive Sleep Apnea Syndrome (OSAS) in the US has reached 26. 6-43.2% in men and 8.7-27.8% in women. OSAS promotes hypertension, diabetes, and tumor growth through unknown means. Chronic intermittent hypoxia (CIH), sleep fragmentation, and increased pleural pressure are central mechanisms of OSAS complications. CIH exacerbates ferroptosis, which is closely related to malignancies. The mechanism of ferroptosis in OSAS disease progression remains unknown. Methods: OSAS-related datasets (GSE135917 and GSE38792) were obtained from the GEO. Differentially expressed genes (DEGs) were screened using the R software and intersected with the ferroptosis database (FerrDb V2) to get ferroptosis-related DEGs (f-DEGs). GO, DO, KEGG, and GSEA enrichment were performed, a PPI network was constructed and hub genes were screened. The TCGA database was used to obtain the thyroid cancer (THCA) gene expression profile, and hub genes were analyzed for differential and survival analysis. The mechanism was investigated using GSEA and immune infiltration. The hub genes were validated with RT-qPCR, IHC, and other datasets. Sprague-Dawley rats were randomly separated into normoxia and CIH groups. ROS, MDA, and GSH methods were used to detect CIH-induced ferroptosis and oxidative stress. Results: GSEA revealed a statistically significant difference in ferroptosis in OSAS (FDR < 0.05). HIF1A, ATM, HSPA5, MAPK8, MAPK14, TLR4, and CREB1 were identified as hub genes among 3,144 DEGs and 74 f-DEGs. HIF1A and ATM were the only two validated genes. F-DEGs were mainly enriched in THCA. HIF1A overexpression in THCA promotes its development. HIF1A is associated with CD8 T cells and macrophages, which may affect the immunological milieu. The result found CIH increased ROS and MDA while lowering GSH indicating that it could cause ferroptosis. In OSAS patients, non-invasive ventilation did not affect HIF1A and ATM expression. Carvedilol, hydralazine, and caffeine may be important in the treatment of OSAS since they suppress HIF1A and ATM. Conclusions: Our findings revealed that the genes HIF1A and ATM are highly expressed in OSAS, and can serve as biomarkers and targets for OSAS.
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BACKGROUND: We aimed to investigate whether Taraxacum officinale (T. officinale)-derived exosome-like nanovesicles (ELNs) exerted hypotensive effects in intermittent hypoxia (IH)-induced hypertensive disorders and their potential mechanisms. RESULTS: In this study, we developed T. officinale-derived natural nanoparticles with ideal size and stable negative surface charge, containing large amount of lipids and some functional proteins. We found that ELNs effectively reduced IH-induced hypertension, exhibited local anti-inflammatory effects on intestinal tissues in a rat model of IH-induced hypertension, and reduced intestinal tissue damage, including loss of goblet cells and barrier integrity damage, and ultimately inhibited the systemic inflammatory response. In addition, we evaluated intestinal microbial composition and SCFAs content and found significant changes in the structure and diversity of intestinal microbes, where butyrate was identified as the most important cause of the overall differences in the flora. Therefore, we further evaluated whether butyrate was a key target for ELNs to exert their effects in IH-induced hypertensive disease. We found that butyrate intervention further inhibited systemic inflammatory response and vascular wall remodeling by improving the intestinal microenvironment in IH rats, thereby attenuating IH-induced hypertension. CONCLUSIONS: T. officinale-derived ELNs were effective in the treatment of IH-induced hypertensive disease, whereas butyrate played a major role in mediating the effects of ELNs in anti-IH-induced hypertensive disease.
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Exossomos , Hipertensão , Taraxacum , Ratos , Animais , Exossomos/metabolismo , Hipóxia/complicações , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Hipertensão/metabolismo , Butiratos , Síndrome de Resposta Inflamatória SistêmicaRESUMO
It is of great significance to identify the critical influential factors of pollutant emissions for emission mitigation. However, city disparity implies different priorities for regional mitigation. This study aims to estimate the consumption-based emissions of 309 prefecture-level cities in China based on the multi-region input-output table and the sectoral NOx emission inventory and investigate the emission transfer phenomenon among cities and sectors. In addition, a geographically weighted regression method is used to analyze the spatial heterogeneity in the driving factors of regional consumption-based emissions. The results reveal that the top 10 cities in consumption-based emissions account for 25.2% of emissions and contribute 22.6% to GDP. The consumption-based emissions are mainly driven by local demand (72.79%) at the regional level and by construction activities (94.43%) at the sectoral level. Besides, the results also show the spatial variances in contributions of driving forces to consumption-based emissions. Economic growth has been identified as the most important factor which promotes consumption-based emissions. However, disposable personal income, per capita road area, urbanization, and percentage of tertiary industry GDP are conducive to reduce consumption-based emissions in some cities of China. It could be concluded that policies without consideration of the emissions from a consumption perspective are difficult to achieve effective emission reduction.
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Monitoramento Ambiental , Poluentes Ambientais , Cidades , China , Urbanização , Poluentes Ambientais/análise , Desenvolvimento Econômico , Dióxido de Carbono/análise , Carbono/análiseRESUMO
Autophagy has been increasingly recognized as a critical regulatory mechanism in the maintenance of cellular homeostasis. A previous study showed that phospholipase C-like protein 1 (PLCL1) is associated with lipid metabolism in renal cell carcinoma (RCC). However, it is unclear whether PLCL1 regulates autophagy, thereby influencing the progression of RCC. Bioinformatics analysis of five microarray datasets revealed that expression of PLCL1 is decreased in tumours and is positively correlated with prognosis in RCC patients. Three independent public datasets, clinical RCC tissues and RCC cell lines, were validated using real-time qPCR, western blotting and immunohistochemistry. Using wound healing and transwell assays, we observed that elevated PLCL1 levels decreased the migratory distance and the invasive number of 786-O and ACHN cells, but PLCL1 knockdown reversed these changes in 769P cell lines compared to those in controls. The results of flow cytometry analysis indicated that PLCL1 promotes apoptosis. Moreover, transcriptional analysis based on stable overexpression of PLCL1 in 786-O cells revealed that PLCL1 is related to autophagy, and western blotting and autophagic experimental results further verified these findings. Mechanistic investigations confirmed that PLCL1 activates the AMPK/mTOR pathway and interacts with decidual protein induced by progesterone (DEPP). Collectively, our data suggest that PLCL1 functions as a suppressor of RCC progression by activating the AMPK/mTOR pathway, interacting with DEPP, initiating autophagy and inducing apoptosis. PLCL1 may be a promising therapeutic target for the diagnosis and treatment of ccRCC patients.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Autofagia/genética , Proliferação de Células/fisiologia , Linhagem Celular Tumoral , Apoptose/genéticaRESUMO
Objective: To evaluate the efficacy and safety of leflunomide for the treatment of acute, symptomatic COVID-19. Methods: A single-center, open-label, randomized controlled trial was performed during an outbreak of SARS-CoV-2 Omicron variant in December 2022. Symptomatic patients within 5 days of COVID-19 onset were randomly allocated to receive 5 days of either symptomatic treatment with leflunomide or symptomatic treatment alone. The primary endpoint was time to sustained clinical recovery. Results: Fifty-seven participants were randomized into two groups: 27 received leflunomide plus symptomatic treatment and 30 were assigned to symptomatic treatment alone. Participants treated with leflunomide had a shorter fever duration [3.0 interquartile range (IQR, 2.0-4.0) days and 4.0 (IQR, 3.0-6.0) days, respectively (p = 0.027)] and reduced viral shedding [7 (IQR, 6-9.5) days and 9.0 (IQR, 7.5-12.0) days, respectively (p = 0.044)] compared with individuals treated with symptomatic treatment alone. However, there were no significant differences in time to sustained clinical recovery between the two groups [hazard ratio, 1.329 (95% confidence interval, 0.878-2.529); p = 0.207]. Conclusion: In acute adult COVID-19 patients presenting within 5 days of symptom onset, leflunomide combined with symptomatic treatment reduced fever duration and viral shedding time. Clinical Trial Registration: https://www.chictr.org.cn/about.html, ChiCTR2100051684.
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Epigenetic modifications are implicated in the onset and progression of obstructive sleep apnea (OSA) and its complications through their bidirectional relationship with long-term chronic intermittent hypoxia (IH). However, the exact role of epigenetic acetylation in OSA is unclear. Here we explored the relevance and impact of acetylation-related genes in OSA by identifying molecular subtypes modified by acetylation in OSA patients. Twenty-nine significantly differentially expressed acetylation-related genes were screened in a training dataset (GSE135917). Six common signature genes were identified using the lasso and support vector machine algorithms, with the powerful SHAP algorithm used to judge the importance of each identified feature. DSCC1, ACTL6A, and SHCBP1 were best calibrated and discriminated OSA patients from normal in both training and validation (GSE38792) datasets. Decision curve analysis showed that patients could benefit from a nomogram model developed using these variables. Finally, a consensus clustering approach characterized OSA patients and analyzed the immune signatures of each subgroup. OSA patients were divided into two acetylation patterns (higher acetylation scores in Group B than in Group A) that differed significantly in terms of immune microenvironment infiltration. This is the first study to reveal the expression patterns and key role played by acetylation in OSA, laying the foundation for OSA epitherapy and refined clinical decision-making.
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Medicina de Precisão , Apneia Obstrutiva do Sono , Humanos , Acetilação , Polissonografia , Apneia Obstrutiva do Sono/genética , Aprendizado de Máquina , Actinas , Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA , Proteínas Adaptadoras da Sinalização ShcRESUMO
Depression and anxiety are prevalent in patients with idiopathic pulmonary fibrosis (IPF). Recent researchers reveal that intermittent hypoxia (IH) increases the severity of bleomycin (BLM)-induced lung injury. However, experimental studies dealing with anxiety- and depression-like behavior in animal models of BLM-induced pulmonary fibrosis in a combination of IH are lacking, hence, this study aimed to investigate that. In this study, 80 C57BL/6J male mice were intratracheally injected with BLM or normal saline at day0 and then exposed to IH (alternating cycles of FiO2 21 % for 60 s and FiO2 10 % for 30 s, 40 cycles/hour, 8 h/day) or intermittent air (IA) for 21 days. Behavioral tests, including open field test (OFT), sucrose preference test (SPT) and tail suspension test (TST), were detected from day22 to day26. This study found that pulmonary fibrosis developed and lung inflammation were activated in BLM-induced mice, which were potentiated by IH. Significant less time in center and less frequency of entries in the centre arena in OFT were observed in BLM treated mice, and IH exposure further decreased that. Marked decreased percent of sucrose preference in SPT, and significant increased immobility time of the TST were detected in BLM treated mice and IH widen the gaps. The expression of ionized calcium-binding adaptor molecule (Iba1) was activated in the hippocampus of BLM instillation mice and IH enlarged it. Moreover, a positive correlation between hippocampal microglia activation and inflammatory factors was observed. Our results demonstrated that IH exacerbated depressive and anxiety-like behaviors in the BLM-induced pulmonary fibrosis mice. The changes in pulmonary inflammation-hippocampal microglia activation may be a potential mechanism in this phenomenon, which can be researched in future.
Assuntos
Fibrose Pulmonar , Masculino , Animais , Camundongos , Fibrose Pulmonar/induzido quimicamente , Bleomicina/toxicidade , Camundongos Endogâmicos C57BL , Hipóxia/metabolismo , Ansiedade , Modelos Animais de DoençasRESUMO
Background: Myositis-specific autoantibodies (MSAs) are clinically used to diagnose and define idiopathic inflammatory myopathy (IIM) subsets. However, the underlying pathogenic mechanisms of patients with different MSAs remain unclear. Methods: A total of 158 Chinese patients with IIM and 167 gender- and age-matched healthy controls (HCs) were enrolled. Transcriptome sequencing (RNA-Seq) was performed with peripheral blood mononuclear cells (PBMCs), followed by the identification of differentially expressed genes (DEGs) and analysis of gene set enrichment analysis, immune cell infiltration, and WGCNA. Monocyte subsets and related cytokines/chemokines were quantified. The expressions of interferon (IFN)-related genes were validated using qRT-PCR and Western blot in both PBMCs and monocytes. We also performed correlation analysis and ROC analysis to explore the potential clinical significance of the IFN-related genes. Results: There were 1,364 genes altered in patients with IIM, including 952 upregulated and 412 downregulated genes. The type I interferon (IFN-I) pathway was remarkably activated in patients with IIM. Compared with patients with other MSAs, IFN-I signatures were significantly activated in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. In total, 1,288 hub genes associated with IIM onset were identified using WGCNA, including 29 key DEGs associated with IFN signaling. The patients had more CD14brightCD16- classical, CD14brightCD16+ intermediate, and fewer CD14dimCD16+ non-classical monocyte subsets. Plasma cytokines like IL-6 and TNF and chemokines including CCL3 and MCPs increased. The validation of IFN-I-related gene expressions was consistent with the findings from RNA-Seq. The IFN-related genes were correlated with laboratory parameters and helpful for IIM diagnosis. Conclusion: Gene expressions were remarkably altered in the PBMCs of IIM patients. Anti-MDA5+ IIM patients had a more pronounced activated IFN signature than others. Monocytes exhibited a proinflammatory feature and contributed to the IFN signature of IIM patients.