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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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Modelos Animais de Doenças , Terapia Genética , Optogenética , Síndromes da Apneia do Sono , Animais , Optogenética/métodos , Terapia Genética/métodos , Síndromes da Apneia do Sono/terapia , Síndromes da Apneia do Sono/genética , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Dependovirus/genética , Nervo Hipoglosso , Medições Luminescentes , Neurônios Motores/metabolismoRESUMO
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
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
Objective To investigate the distribution of abnormal karyotypes and their associations with clinical manifestations of the infertile patients in southern Sichuan Province.Methods A total of 4 157 infertile patients who attended the Reproductive Medicine Center of our hospital from July 2018 to June 2021 were included.The chromosome karyotype in peripheral blood was detected by G-banding,and their semen analysis results,uterine development and other clinical data were collected.Results Among the 4 157 patients,chromosomal polymorphisms were found in 239 cases(5.75%),and abnormal karyotypes wee found 137 cases(3.30%).The abnormal karyotypes included 57 cases(41.61%)of sex chromosome aneuploidy,6 cases(4.38%)of Robertsonian transloca-tions,32 cases(23.36%)of balanced translocations,21 cases(15.33%)of chromosomal inversions,9 cases(6.57%)of mosai-cism,8 cases(5.84%)of marker chromosomes,3 cases(2.19%)of sex reversal and 1 case(0.73%)of sex chromosome deletion.In male patients with abnormal karyotypes,91.58%showed abnormal semen parameters,while in those with polymorphic karyotypes,55%had abnormal semen parameters.The patients with Turner syndrome had significantly smaller uterine dimensions(longitudinal,transverse,and anteroposterior)compared to the normal control group(P<0.01).Conclusion Chromosomal abnormalities should be the important cause of infertility.Conducting karyotype analysis combining with clinical manifestations is crucial examination for the di-agnosis and reproductive guidance of infertile patients.
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The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving factor. Literature reports suggest that dual-specificity phosphatase 1 (DUSP1) plays a critical role in maintaining mitochondrial function and structural integrity. In this study, ischemic Acute Kidney Injury (AKI) and post-ischemic fibrosis models were established by clamping the renal pedicle with different reperfusion times. To investigate the role of DUSP1, constitutional Dusp1 knockout mice and tubular-specific Sting knockout mice were used. Mitochondrial damage was assessed through electron microscopy observation, measurements of mitochondrial membrane potential, mtDNA release, and BAX translocation. We found that Dusp1 expression was significantly upregulated in human transplant kidney tissue and mouse AKI tissue. Dusp1 gene deletion exacerbated acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in mice. Mechanistically, DUSP1 could directly bind to JNK, and DUSP1 deficiency could lead to aberrant phosphorylation of JNK and BAX mitochondria translocation. BAX translocation promoted mitochondrial DNA (mtDNA) leakage and activated the cGAS-STING pathway. Inhibition of JNK or BAX could inhibit mtDNA leakage. Furthermore, STING knockout or JNK inhibition could significantly mitigate the adverse effects of DUSP1 deficiency in ischemic AKI model. Collectively, our findings suggest that DUSP1 is a regulator for the protective response during AKI. DUSP1 protects against AKI by preventing BAX-induced mtDNA leakage and blocking excessive activation of the cGAS-STING signaling axis through JNK dephosphorylation.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Humanos , Camundongos , Injúria Renal Aguda/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Rim/metabolismo , Camundongos Knockout , Mitocôndrias/metabolismo , Nucleotidiltransferases/metabolismo , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismoRESUMO
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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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
Industrial park is an important emission sector of PM2.5 pollution. Previous studies have provided valuable information on the impact of PM2.5 from industrial parks on human health, but relevant studies at city scale are limited. In this study, the health burden of industrial parks was evaluated based on PM2.5-related premature deaths and economic contributions. The premature deaths were calculated in terms of a novel research model by integrating the Bayesian maximum entropy (BME) model, weighted concentration-weighted trajectory (WCWT), and integrated exposure-response function (IER). Take Tianjin City for example, it was found that since the main diffusion direction of PM2.5 in Tianjin is from south to north, the industrial parks in the south of Tianjin and close to the central city with high population density have high health burden. These industrial parks need to be focused on or even relocated in the future. The research model can provide scientific basis for the health burden evaluation of industrial parks at city scale, so as to help local governments optimize the layout of industrial parks and formulate environmental responsibility management policies for industrial parks.
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Poluentes Atmosféricos , Poluição do Ar , Humanos , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Material Particulado/análise , Teorema de Bayes , Poluição Ambiental , China/epidemiologia , Monitoramento AmbientalRESUMO
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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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
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: 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.
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Interferon Tipo I , Miosite , Humanos , Autoanticorpos , Monócitos/metabolismo , Leucócitos Mononucleares/metabolismo , Interferon Tipo I/genética , CitocinasRESUMO
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
Objective. Chronic hepatitis B liver fibrosis is an important intermediate link in the development of liver cirrhosis. A retrospective cohort study was conducted in Longhua Hospital affiliated to the Shanghai University of Traditional Chinese Medicine in order to prove whether integrated traditional Chinese and Western medicine could improve the incidence of CHB complications and clinical prognosis. There are 130 patients with hepatitis B liver fibrosis (being treated from 2011-2021) included in the study, and the patients were divided into 64 TCM users (NAs combined with TCM) and 66 TCM nonusers (NAs antiviral therapy). The serum noninvasive diagnostic model (APRI, FIB-4) and LSM value were used to classify the stages of fibrosis. The results showed that the LSM value was decreased significantly in TCM users compared with TCM nonusers (40.63% versus 28.79%). Indicators of FIB-4 and APRI of TCM users have improved significantly compared with that of TCM nonusers (32.81% versus 10.61% and 35.94% versus 24.24%). The AST, TBIL, and HBsAg levels in TCM users were lower than those in TCM nonusers, and the HBsAg level was inversely correlated with the CD3+, CD4+, and CD8+ in TCM users. The PLT and spleen thickness of TCM users also were improved considerably. The incidence rate of end-point events (decompensated cirrhosis/liver cancer) in TCM nonusers was higher than that of TCM users (16.67% versus 1.56%). The long course of the disease and a family history of hepatitis B were the risk factors for disease progression, and long-term oral administration of TCM was the protective factor. As a result, the serum noninvasive fibrosis index and imaging parameters in TCM users were lower than those of TCM nonusers. Patients in the treatment of NAs combined with TCM had better prognoses such as a lower HBsAg level, a more stable lymphocyte function, and a lower incidence of end-point events. The present findings suggest the effect of TCM combined with NAs in the treatment of chronic hepatitis B liver fibrosis is better than that of single drug treatment.
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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.
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Fibrose Pulmonar , Masculino , Animais , Camundongos , Fibrose Pulmonar/induzido quimicamente , Bleomicina/toxicidade , Camundongos Endogâmicos C57BL , Hipóxia/metabolismo , Ansiedade , Modelos Animais de DoençasRESUMO
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
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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OBJECTIVE@#To investigate the influence and mechanism of atorvastatin on glycolysis of adriamycin resistant acute promyelocytic leukemia (APL) cell line HL-60/ADM.@*METHODS@#HL-60/ADM cells in logarithmic growth phase were treated with different concentrations of atorvastatin, then the cell proliferation activity was measured by CCK-8 assay, the apoptosis was detected by flow cytometry, the glycolytic activity was checked by glucose consumption test, and the protein expressions of PTEN, p-mTOR, PKM2, HK2, P-gp and MRP1 were detected by Western blot. After transfection of PTEN-siRNA into HL-60/ADM cells, the effects of low expression of PTEN on atorvastatin regulating the behaviors of apoptosis and glycolytic metabolism in HL-60/ADM cells were further detected.@*RESULTS@#CCK-8 results showed that atorvastatin could inhibit the proliferation of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.872, r=0.936), and the proliferation activity was inhibited most significantly when treated with 10 μmol/L atorvastatin for 24 h, which was decreased to (32.3±2.18)%. Flow cytometry results showed that atorvastatin induced the apoptosis of HL-60/ADM cells in a concentration-dependent manner (r=0.796), and the apoptosis was induced most notably when treated with 10 μmol/L atorvastatin for 24 h, which reached to (48.78±2.95)%. The results of glucose consumption test showed that atorvastatin significantly inhibited the glycolytic activity of HL-60/ADM cells in a concentration-dependent and time-dependent manner (r=0.915, r=0.748), and this inhibition was most strikingly when treated with 10 μmol/L atorvastatin for 24 h, reducing the relative glucose consumption to (46.53±1.71)%. Western blot indicated that the expressions of p-mTOR, PKM2, HK2, P-gp and MRP1 protein were decreased in a concentration-dependent manner (r=0.737, r=0.695, r=0.829, r=0.781, r=0.632), while the expression of PTEN protein was increased in a concentration-dependent manner (r=0.531), when treated with different concentrations of atorvastatin for 24 h. After PTEN-siRNA transfected into HL-60/ADM cells, it showed that low expression of PTEN had weakened the promoting effect of atorvastatin on apoptosis and inhibitory effect on glycolysis and multidrug resistance.@*CONCLUSION@#Atorvastatin can inhibit the proliferation, glycolysis, and induce apoptosis of HL-60/ADM cells. It may be related to the mechanism of increasing the expression of PTEN, inhibiting mTOR activation, and decreasing the expressions of PKM2 and HK2, thus reverse drug resistance.