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Idiopathic pulmonary fibrosis treatments are limited, often with severe side effects, highlighting the need for novel options. Taraxerone has diverse biomedical properties, but its mechanism remains unclear. This study investigates taraxerone's impact and the mechanisms involved in bleomycin-induced pulmonary fibrosis in mice. After establishing a pulmonary fibrosis mouse model, taraxerone was intraperitoneally injected continuously for 14-28 days. The in vivo antifibrotic and antioxidative stress effects of taraxerone were assessed. In vitro, the influence of taraxerone on transforming growth factor-ß1-induced myofibroblast transformation and oxidative stress was investigated. Subsequently, quantitative polymerase chain reaction screened the histone deacetylase and Sirtuin family, and taraxerone's effects on SIRT1 were assessed. After SIRT1 siRNA treatment, changes in myofibroblast transformation and antioxidant capacity in response to taraxerone were observed. Acetylation and phosphorylation levels of Smad3 were evaluated. We also examined the binding levels of SIRT1 with Pho-Smad3 and Smad3, as well as the nuclear localization of Smad2/3. EX527 confirmed SIRT1's in vivo action in response to taraxerone. In vitro experiments suggested that taraxerone inhibited myofibroblast differentiation by activating SIRT1 and reducing oxidative stress. We also observed a new interaction between SIRT1 and the Smad complex. Taraxerone activates SIRT1, enabling it to bind directly to Smad3. This leads to reduced Smad complex phosphorylation and limited nuclear translocation. As a result, the transcription of fibrotic factors is reduced. In vivo validation confirms taraxerone's SIRT1-mediated antifibrotic effectiveness. This suggests that targeting SIRT1-mediated inhibition of myofibroblast differentiation could be a key strategy in taraxerone-based therapy for pulmonary fibrosis.
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Antioxidantes , Bleomicina , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Fibrose Pulmonar , Transdução de Sinais , Sirtuína 1 , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Animais , Sirtuína 1/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteína Smad3/metabolismo , Antioxidantes/farmacologia , Masculino , Fator de Crescimento Transformador beta1/metabolismo , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Modelos Animais de Doenças , Fosforilação , AcetilaçãoRESUMO
This study explored the feasibility of mineral element content and ratios of nitrogen isotopes to discriminate the cultivation mode of Dendrobium nobile in order to provide theoretical support for the discrimination of the cultivation mode of D. nobile. The content of 11 mineral elements(N, K, Ca, P, Mg, Na, Fe, Cu, Zn, Mn, and B) and nitrogen isotope ratios in D. nobile and its substrate samples in three cultivation methods(greenhouse cultivation, tree-attached cultivation, and stone-attached cultivation) were determined. According to the analysis of variance, principal component analysis, and stepwise discriminant analysis, the samples of different cultivation types were classified. The results showed that the nitrogen isotope ratios and the content of elements except for Zn were significantly different among different cultivation types of D. nobile(P<0.05). The results of correlation analysis showed that the nitrogen isotope ratios, mineral element content, and effective component content in D. nobile were correlated with the nitrogen isotope ratio and mineral element content in the corresponding substrate samples to varying degrees. Principal component analysis can preliminarily classify the samples of D. nobile, but some samples overlapped. Through stepwise discriminant analysis, six indicators, including δ~(15)N, K, Cu, P, Na, and Ca, were screened out, which could be used to establish the discriminant model of D. nobile cultivation methods, and the overall correct discrimination rates after back-substitution test, cross-check, and external validation were all 100%. Therefore, nitrogen isotope ratios and mineral element fingerprints combined with multivariate statistical analysis could effectively discriminate the cultivation types of D. nobile. The results of this study provide a new method for the identification of the cultivation type and production area of D. nobile and an experimental basis for the quality evaluation and quality control of D. nobile.
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Dendrobium , Minerais , Análise Discriminante , Análise Multivariada , Isótopos de NitrogênioRESUMO
Diabetes mellitus has been a major public health problem worldwide, characterized by insulin resistance and dysfunction of ß-cells. A previous study showed that Kindlin-2 loss in ß-cells dramatically reduces insulin secretion and decreases ß-cell mass, resulting in severe diabetes-like phenotypes. It suggests that Kindlin-2 in ß-cells play an important role in regulating glucose homeostasis. However, the effect of Kindlin-2 on the function of ß-cells under chronic hyperglycemia in diabetes has not been explored. Here we report that Kindlin-2 overexpression ameliorates diabetes and improves insulin secretion in mice induced by streptozocin. In contrast, Kindlin-2 insufficiency exacerbates diabetes and promotes ß-cells dysfunction and inflammation in ß-cells induced by a high-fat diet (HFD). In vitro, Kindlin-2 overexpression prevented high-glucose (HG)-induced dysfunction in ß-cells. Kindlin-2 overexpression also decreased the expression of pro-inflammatory cytokines and NLRP3 inflammasome expression in ß-cells exposed to HG. Furthermore, the loss of Kindlin-2 aggravates the expression of inflammatory cytokines and NLRP3 induced by HG in ß-cells. Collectively, we demonstrate that Kindlin-2 protects against diabetes by inhibiting NLRP3 inflammasome activation.
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Proteínas do Citoesqueleto , Diabetes Mellitus Experimental , Inflamassomos , Células Secretoras de Insulina , Animais , Citocinas/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Inflamassomos/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
OBJECTIVES: The ß-cell dedifferentiation is one of the critical mechanisms in diabetic ß-cell loss. Long-term activation of N-methyl-D-aspartate (NMDA) receptors plays an essential role in the development of diabetes, but the underlying mechanisms have not been fully elucidated. This study aims to investigate the effect of prolonged activation of NMDA receptors on islet ß-cell dedifferentiation. METHODS: Male C57BL/6 mice were randomly divided into a normal control group (control group) and an NMDA group. The mice in the NMDA group were intraperitoneally injected with NMDA (8 mg/kg body weight) and those in the control group were injected with the same volume of saline every day for 6 months. At the end of the 6 th month, glucose tolerance and enzyme linked immunosorbent assay (ELISA) were used to detect the function of islets, and pancreatic tissues were taken for immunofluorescence staining to detect the expressions of insulin, glucagon, and proliferating cell nuclear antigen (PCNA). Real-time PCR was used to detect the mRNA expression of pancreatic ß cells, α cells, and islet progenitor cell markers.The primary islets were treated with NMDA to observe the effect of NMDA on the dedifferentiation of ß cells. The nuclear factor kappa-B (NF-κB) inhibitor BAY 11-7082 was used at the cellular level via detecting insulin secretion and the expression of endocrine cell markers. RESULTS: Compared with the control group, the mice in the NMDA group had higher blood glucose levels at each time point after glucose injection, and the area under the glucose tolerance curve was significantly increased ( P <0.05). The serum insulin content and insulin stimulatory index of the mice in the NMDA group were significantly lower than those in the control group at 30 min after glucose injection (both P <0.05). The double immunofluorescence staining for insulin and glucagon showed that the number of insulin-positive ß cells in the pancreatic tissues of mice was significantly decreased after intraperitoneal injection of NMDA in mice for 6 months, while the number of glucagon-positive α cells was significantly increased. Real-time PCR results showed that ß-cell markers ( Insulin , Pdx1 , Neurod1 , and Mafa ) were significantly down-regulated in mouse pancreatic tissues after intraperitoneal injection of NMDA for 6 months, while pancreatic progenitor cell markers ( Neurog3 , Gata6 , Hnf4a , Notch1, and Hes1 ) were significantly down-regulated; α-cell markers ( Glucagon , Arx , Irx2 , Mafb , Pou6f2 , Fev , Kcnj3, and Sv2b ) were significantly up-regulated. NMDA treatment of mouse primary islets for 48 h cause significant down-regulation of ß-cell marker gene expression ( P <0.05 or P <0.01), accompanied by significant up-regulation of pancreatic progenitor cell markers and α-cell markers ( P <0.05, P <0.01 or P <0.001). The NF-κB inhibitor BAY 11-7082 significantly blocked the down-regulation of ß-cell marker expression (all P <0.05) and the up-regulation of α-cell and pancreatic progenitor cell marker after NMDA treatment of islets for 48 h ( P <0.05 or P <0.01). CONCLUSIONS: Prolonged activation of NMDA receptors induces islet ß-cell dedifferentiation via regulating the NF-κB pathway.
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Glucagon , Receptores de N-Metil-D-Aspartato , Animais , Masculino , Camundongos , Glucagon/metabolismo , N-Metilaspartato , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Insulina , Glucose/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
Hepatitis B, one of the most common contagious viral hepatitis with high infection rate, is challenging to treat. Although the treatment for hepatitis B has been improved over the years, many therapeutic drugs still have either severe adverse effects or insufficient effectiveness via systemic administration. In this study, we confirmed that glycyrrhetinic acid can enhance the accumulation of entecavir in HepaRG cell and liver. Then we constructed a novel albumin nanoparticle co-loading entecavir and glycyrrhetinic acid (ETV-GA-AN) to improve liver accumulation of entecavir and investigated its ability to deliver both drugs to liver. In vitro cellular uptake study and in vivo tissue distribution experiment showed that these negatively charged ETV-GA-AN (112 ± 2 nm in diameter) can increase the accumulation of entecavir in hepatic HepaRG cells and improve entecavir distribution in liver. We also revealed the mechanism that glycyrrhetinic acid enhances intracellular accumulation of entecavir by inhibiting the activity of specific efflux transporters. Our delivery system is the first liver-targeted albumin nanoparticle that utilizes the site-specific co-delivery strategy to delivery entecavir and glycyrrhetinic acid. As it combines high efficiency and low toxicity, it possess great potential for treating hepatitis B.
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Albuminas/química , Antivirais/farmacocinética , Guanina/análogos & derivados , Fígado/metabolismo , Nanopartículas/química , Animais , Antivirais/uso terapêutico , Western Blotting , Cromatografia Líquida , Ácido Glicirretínico/administração & dosagem , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/uso terapêutico , Guanina/administração & dosagem , Guanina/farmacocinética , Guanina/uso terapêutico , Células Hep G2 , Hepatite B , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas em TandemRESUMO
This study presents an efficient strategy for separation of three phenolic compounds with high molecular weight from the crude extract of Terminalia chebula Retz. by ultrasound-assisted extraction and high-speed counter-current chromatography. The ultrasound-assisted extraction conditions were optimized by response surface methodology and the results showed the target compounds could be well enriched under the optimized extraction conditions. Then the crude extract was directly separated by high-speed counter-current chromatography without any pretreatment using n-hexane/ethyl acetate/methanol/water (1:7:0.5:3, v/v/v/v) as the solvent system. In 180 min, 13 mg of A, 18 mg of B, and 9 mg of C were obtained from 200 mg of crude sample. Their structures were identified as Chebulagic acid (A, 954 Da), Chebulinic acid (B, 956 Da), and Ellagic acid (C) by (1) H NMR spectroscopy.
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Fenóis/química , Fenóis/isolamento & purificação , Extratos Vegetais/química , Terminalia/química , Distribuição Contracorrente , Peso Molecular , UltrassomRESUMO
Barley seedlings are rich in flavones that can have positive effects on people with antihypoxia and antifatigue. Lutonarin and saponarin are two major flavonoid glycosides that have unique structures in barley seedlings. This study presents a new approach for the preparation of lutonarin and saponarin from barely seedlings by membrane separation technology and preparative high-performance liquid chromatography. Preparative conditions of these two flavonoid glycosides by membrane separation technology were studied using response surface methodology. Under the optimized conditions, the total contents of these two flavonoid glycosides amounts to 17.0%.
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Apigenina/síntese química , Apigenina/isolamento & purificação , Flavonoides/isolamento & purificação , Glucosídeos/síntese química , Glucosídeos/isolamento & purificação , Glicosídeos/isolamento & purificação , Hordeum/química , Plântula/química , Apigenina/química , Cromatografia Líquida de Alta Pressão , Flavonoides/síntese química , Flavonoides/química , Glucosídeos/química , Glicosídeos/síntese química , Glicosídeos/química , Estrutura MolecularRESUMO
The senescence of alveolar epithelial cells (AECs) and fibroblasts plays a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a condition lacking specific therapeutic interventions. Curculigoside (CCG), a prominent bioactive constituent of Curculigo, exhibits anti-osteoporotic and antioxidant activities. Our investigation aimed to elucidate the anti-senescence and anti-fibrotic effects of CCG in experimental pulmonary fibrosis and delineate its underlying molecular mechanisms. Our findings demonstrate that CCG attenuates bleomycin-induced pulmonary fibrosis and lung senescence in murine models, concomitantly ameliorating lung function impairment. Immunofluorescence staining for senescence marker p21, alongside SPC or α-SMA, suggested that CCG's mitigation of lung senescence correlates closely with the deceleration of senescence in AECs and fibroblasts. In vitro, CCG mitigated H2O2-induced senescence in AECs and the natural senescence of primary mouse fibroblasts. Mechanistically, CCG can upregulate SIRT1 expression, downregulating P300 expression, enhancing Trim72 expression to facilitate P300 ubiquitination and degradation, reducing the acetylation levels of antioxidant enzymes, and upregulating their expression levels. These actions collectively inhibited endoplasmic reticulum stress (ERS) and alleviated senescence. Furthermore, the anti-senescence effects and mechanisms of CCG were validated in a D-galactose (D-gal)-induced progeroid model. This study provides novel insights into the mechanisms underlying the action of CCG in cellular senescence and chronic diseases, offering potential avenues for the development of innovative drugs or therapeutic strategies.
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BACKGROUND: Extended contact with silica particles can lead to Silicosis, a chronic lung condition lacking established treatment protocols or clear mechanisms of development. The urgency for innovative treatments arises from the unavailability of effective treatment methodologies. The origin of silica-induced pulmonary fibrosis includes essential processes such as macrophage activation and the conversion of fibroblasts into myofibroblasts, with oxidative stress playing a pivotal role. Shionone (SHI), a triterpenoid extracted from the Aster tataricus plant, is recognized for its extensive health benefits. This study explores the capability of SHI to alleviate the effects of silica-induced lung fibrosis in mice. METHODS: This investigation explored the impact of SHI on lung inflammation and fibrosis at different stages (early and late) triggered by silica in mice, focusing specifically on the initial and more developed phases. It comprised an analysis of isolated peritoneal macrophages and fibroblasts extracted from mice to elucidate SHI's therapeutic potential and its underlying mechanism. The methodology employed encompassed quantitative PCR, immunofluorescence, flow cytometry, and western blotting to examine macrophage activity and their transition into myofibroblasts. The activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by SHI was confirmed via immunofluorescence and western blot studies. SHI's antioxidative properties were evidenced by the measurement of reactive oxygen species (ROS) and mitochondrial ROS within both macrophages and fibroblasts, using 2', 7'-dichlorodihydrofluorescein diacetate and MitoSOX, respectively. The relevance of SHI was further underscored by applying ML385 and Nrf2 siRNA to gauge its effectiveness. RESULTS: Starting SHI treatment early countered the harmful effects of lung inflammation and fibrosis caused by silica, while initiating SHI at a later phase decelerated the advancement of fibrosis. SHI's action was linked to the activation of the Nrf2 signaling pathway, a boost in antioxidant enzyme levels, and a decrease in oxidative stress and inflammation in macrophages affected by silica. Furthermore, SHI prevented the conversion of fibroblasts into myofibroblasts prompted by TGF-ß, along with the resultant oxidative stress. The beneficial outcomes of SHI were negated when ML385 and Nrf2 siRNA were applied, highlighting the pivotal role of the Nrf2 pathway in SHI's efficacy. CONCLUSION: SHI plays a significant role in stimulating the Nrf2 pathway, thereby defending against silica-induced oxidative stress and inflammatory reactions in macrophages, and inhibiting the conversion of fibroblasts to myofibroblasts due to TGF-ß. This suggests that SHI is a viable option for treating lung inflammation and fibrosis in mice suffering from silicosis.
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Acute lung injury (ALI) remains a high mortality rate with dramatic lung inflammation and alveolar epithelial cell death. Although fatty acid ß-oxidation (FAO) impairment has been implicated in the pathogenesis of ALI, whether Carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme for FAO, plays roles in lipopolysaccharide (LPS)-induced ALI remains unclear. Accordingly, we focused on exploring the effect of CPT1A in the context of ALI and the underlying mechanisms. We found that overexpression of CPT1A (AAV-CPT1A) effectively alleviated lung injury by reduction of lung wet-to-dry ratio, inflammatory cell infiltration, and protein levels in the BALF of ALI mice. Meanwhile, AAV-CPT1A significantly lessened histopathological changes and several cytokines' secretions. In contrast, blocking CPT1A with etomoxir augmented inflammatory responses and lung injury in ALI mice. Furthermore, we found that overexpression of CPT1A with lentivirus reduced the apoptosis rates of alveolar epithelial cells and the expression of apoptosis-related proteins induced by LPS in MLE12 cells, while etomoxir increased the apoptosis of MLE12 cells. Overexpression of CPT1A prevented the drop in bioenergetics, palmitate oxidation, and ATP levels. In conclusion, the results rendered CPT1A worthy of further development into a pharmaceutical drug for the treatment of ALI.
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Lesão Pulmonar Aguda , Compostos de Epóxi , Lipopolissacarídeos , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/genética , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Lipopolissacarídeos/metabolismo , Pulmão/patologiaRESUMO
The modulation of vascular smooth muscle cell (VSMC) phenotype during cellular proliferation and migration may represent a potential therapeutic approach for vascular intimal hyperplasia prevention. However, the precise role of this process in VSMC biology and remodeling remains unclear. In the present study, western blotting, PCR, MTT and Transwell assays were used to analyze related protein and mRNA expression, cell viability and cell migration, respectively. It was demonstrated that miR92a modulated VSMCs into a synthetic phenotype via the Kruppellike factor 4 (KLF4) pathway. Targeting microRNA (miRNA/miR)92a in VSMCs using a KLF4 inhibitor suppressed the synthetic phenotype and inhibited VSMC proliferation and migration. To further confirm this finding, the expression levels of miR92a were measured in patients undergoing coronary artery intervention. The serum miR92a expression levels were significantly higher in patients with instent restenosis (ISR) compared with those in patients without ISR, whereas KLF4 expression was significantly reduced in the nonISR group. Bioinformatic analysis and promoterluciferase reporter assays were used to examine the regulatory mechanisms underlying KLF4 expression. KLF4 was demonstrated to be transcriptionally upregulated by miR92a in VSMCs. miRNA transfection was also performed to regulate the level of miR92a expression. miR92a overexpression inhibited VSMC proliferation and migration, and also increased the mRNA and protein expression levels of certain differentiated VSMCrelated genes. Finally, miR92a inhibition promoted the proliferation and migration of VSMCs, which could be reversed using a KLF4 inhibitor. Collectively, these results indicated that the local delivery of a KLF4 inhibitor may act as a novel therapeutic option for the prevention of ISR.
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Reestenose Coronária , MicroRNAs , Humanos , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Reestenose Coronária/genética , Reestenose Coronária/prevenção & controle , Reestenose Coronária/metabolismo , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , FenótipoRESUMO
Currently, the treatment for sepsis-induced acute lung injury mainly involves mechanical ventilation with limited use of drugs, highlighting the urgent need for new therapeutic options. As a pivotal aspect of acute lung injury, the pathologic activation and apoptosis of endothelial cells related to oxidative stress play a crucial role in disease progression, with NOX4 and Nrf2 being important targets in regulating ROS production and clearance. Echinacoside, extracted from the traditional Chinese herbal plant Cistanche deserticola, possesses diverse biological activities. However, its role in sepsis-induced acute lung injury remains unexplored. Moreover, although some studies have demonstrated the regulation of NOX4 expression by SIRT1, the specific mechanisms are yet to be elucidated. Therefore, this study aimed to investigate the effects of echinacoside on sepsis-induced acute lung injury and oxidative stress in mice and to explore the intricate regulatory mechanism of SIRT1 on NOX4. We found that echinacoside inhibited sepsis-induced acute lung injury and oxidative stress while preserving endothelial function. In vitro experiments demonstrated that echinacoside activated SIRT1 and promoted its expression. The activated SIRT1 was competitively bound to p22 phox, inhibiting the activation of NOX4 and facilitating the ubiquitination and degradation of NOX4. Additionally, SIRT1 deacetylated Nrf2, promoting the downstream expression of antioxidant enzymes, thus enhancing the NOX4-Nrf2 axis and mitigating oxidative stress-induced endothelial cell pathologic activation and mitochondrial pathway apoptosis. The SIRT1-mediated anti-inflammatory and antioxidant effects of echinacoside were validated in vivo. Consequently, the SIRT1-regulated NOX4-Nrf2 axis may represent a crucial target for echinacoside in the treatment of sepsis-induced acute lung injury.
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BACKGROUND: Acute lung injury (ALI) is a severe disease that can lead to acute respiratory distress syndrome (ARDS), characterized by intractable hypoxemia, poor lung compliance, and respiratory failure, severely affecting patients' quality of life. The pathogenesis of ALI has not been fully elucidated yet, and sepsis is an important cause of ALI. Among the organ injuries caused by sepsis, the lungs are the earliest damaged ones. Radix cyathulae is reported to have analgesic, anti-inflammatory, and anti-aging effects. Cyasterone is extracted from Radix cyathulae. However, it is not known whether cyasterone has protective effects for ALI. This study aims to investigate the effect of cyasterone on sepsis-related ALI and its mechanism. METHODS: We used the cecal ligation peferation (CLP) method to establish a mouse sepsis model, and cyasterone was given intraperitoneally on days 1-3 to observe its preventive effect on sepsis-related acute lung injury. Primary murine peritoneal macrophages were used to investigate the molecular mechanism of cyasterone in vitro. RESULTS: Cyasterone pretreatment inhibits pro-inflammatory cytokine production, NLRP3 inflammasome activation, and oxidative stress in vivo and in vitro. In addition, cyasterone attenuates sepsis-induced ALI by activating nuclear factor erythroid2-related factor (Nrf2), which may be associated with AKT(Ser473)/GSK3ß(Ser9) pathway activation. CONCLUSIONS: Cyasterone defends against sepsis-induced ALI by inhibiting inflammatory responses and oxidative stress, which depends heavily on the upregulation of the Nrf2 pathway through phosphorylation of AKT(Ser473)/GSK3ß(Ser9). These results suggest cyasterone may be a valuable drug candidate for preventing sepsis-related ALI.
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Adverse male reproduction caused by phthalate ester (PAE) exposure has been well documented in vivo. However, existing evidence from population studies remains inadequate to demonstrate the impact of PAE exposure on spermatogenesis and underlying mechanisms. Our present study aimed to explore the potential link between PAE exposure and sperm quality and the possible mediation by sperm mitochondrial and telomere in healthy male adults recruited from the Hubei Province Human Sperm Bank, China. Nine PAEs were determined in one pooled urine sample prepared from multiple collections during the spermatogenesis period from the same participant. Sperm telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined in sperm samples. The sperm concentration and count per quartile increment in mixture concentrations were -4.10 million/mL (-7.12, -1.08) and -13.52% (-21.62%, -4.59%), respectively. We found one quartile increase in PAE mixture concentrations to be marginally associated with sperm mtDNAcn (ß = 0.09, 95% CI: -0.01, 0.19). Mediation analysis showed that sperm mtDNAcn significantly explained 24.6% and 32.5% of the relationships of mono-2-ethylhexyl phthalate (MEHP) with sperm concentration and sperm count (ß = -0.44 million/mL, 95% CI: -0.82, -0.08; ß = -1.35, 95% CI: -2.54, -0.26, respectively). Our study provided a novel insight into the mixed effect of PAEs on adverse semen quality and the potential mediation role of sperm mtDNAcn.
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Ácidos Ftálicos , Análise do Sêmen , Humanos , Masculino , Adulto , Sêmen , População do Leste Asiático , Exposição Ambiental/análise , Espermatozoides , Ácidos Ftálicos/urina , DNA Mitocondrial , ChinaRESUMO
This study aimed to promote the separation of photogenerated carriers and improve the redox performance of graphite carbon nitride (g-C3N4) by synthesizing a double-heterojunction-structure photocatalyst, g-C3N4/(101)-(001)-TiO2, through the solvothermal method. The photocatalyst comprised a Z-system formed from g-C3N4 and the (101) plane of TiO2, as well as a surface heterojunction formed from the (101) and (001) planes of TiO2. The results showed that g-C3N4/(101)-(001)-TiO2 had strong photocatalytic activity and stable performance in the photodegradation of paracetamol. The active species ·O2 - and ·OH were found to play important roles in the photocatalytic degradation of paracetamol through a radical-quenching experiment. The charge-transfer mechanism was also described in detail. Overall, this work provided a new strategy for the Z-system heterojunction and opened up the application of this structure in the degradation of organic pollutants.
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Parabens are widely used as preservatives, which have been found to affect thyroid function in toxicological studies. However, population studies on whether they are associated with thyroid tumors remain unclear. This study aims to investigate the relationship between environmental paraben exposure and thyroid cancer and benign nodules. We recruited participants from the Department of Thyroid and Breast Surgery at Wuhan Central Hospital, Wuhan, China. The detectable percentages of methyl paraben, ethyl paraben, and propyl paraben in the urinary samples of 425 study subjects were 99.1%, 95.3%, and 92.0%, respectively. All uncorrected and creatinine-corrected parabens were moderately correlated with one another. After adjusting for possible confounders, all three parabens were associated with an increased risk of thyroid cancer. Furthermore, the mixture pollutant analysis of parabens found positive associations with risk of thyroid cancer (OR = 0.24, 95% CI: 0.18, 0.31) and benign nodules (OR = 1.33, 95% CI: 0.86, 1.80). We observed that individual exposure to paraben mixtures may be associated with the risk of thyroid cancer and benign nodules.
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Poluentes Ambientais , Neoplasias da Glândula Tireoide , Adulto , Creatinina/análise , Exposição Ambiental/análise , Poluentes Ambientais/análise , Humanos , Parabenos/análise , Neoplasias da Glândula Tireoide/induzido quimicamente , Neoplasias da Glândula Tireoide/epidemiologiaRESUMO
Idiopathic pulmonary fibrosis (IPF) can severely disrupt lung function, leading to fatal consequences, and there is currently a lack of specific therapeutic drugs. Bergenin is an isocoumarin compound with lots of biological functions including antioxidant activity. This study evaluated the potential beneficial effects of bergenin on pulmonary fibrosis and investigated the possible mechanisms. We found that bergenin alleviated bleomycin-induced pulmonary fibrosis by relieving oxidative stress, reducing the deposition of the extracellular matrix (ECM) and inhibiting the formation of myofibroblasts. Furthermore, we showed that bergenin could induce phosphorylation and expression of p62 and activation of Nrf2, Nrf2 was required for bergenin-induced p62 upregulation, and p62 knockdown reduced bergenin-induced Nrf2 activity. More importantly, knockdown of Nrf2 or p62 could abrogate the antioxidant activity of bergenin and the inhibition effect of bergenin on TGF-ß-induced ECM deposition and myofibroblast differentiation. Thereby, a regulatory loop is formed between p62 and Nrf2, which is an important target for bergenin aimed at treating pulmonary fibrosis.
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Earlier studies have suggested that exposure to phthalates (PAEs) may induce spermatozoa apoptosis. Sperm protamine as a molecular biomarker during spermatozoa apoptotic processes may mediate the association between PAE exposure and spermatozoa apoptosis. This study aimed to explore whether sperm protamine mediates the association of PAE exposure with spermatozoa apoptosis. We determined sperm protamine levels, 8 PAE metabolite concentrations in seminal plasma, and 3 spermatozoa apoptosis parameters among 111 men from an infertility clinic. The associations of PAEs as individual chemicals and mixtures with sperm protamine were determined. The mediating roles of protamine in the associations between PAEs and spermatozoa apoptosis parameters were examined by mediation analysis. After adjusting for confounders, we observed positive correlations between seminal plasma concentrations of mono(2-ethylhexyl) phthalate (MEHP) and sperm protamine-1 and protamine ratio. Estimates comparing highest vs. lowest quartiles of MEHP concentration were 4.65% (95% CI: 1.47%, 7.82%) for protamine-1 and 25.86% (95% CI: 3.05%, 53.73%) for protamine ratio. The quantile g-computation models showed that the adjusted protamine-1 per quartile increase in PAE mixture was 9.42% (95% CI: 1.00, 20.92) with MEHP being the major contributor. Although the joint association between PAE mixture and protamine ratio was negligible, MEHP was still identified as the main contributor. Furthermore, we found that protamine-2 and protamine ratio levels in the highest quartiles exhibited a decrease of 43.45% (95% CI: 60.54%, -19.75%) and an increase of 122.55% (95% CI: 60.00%, 209.57%) in Annexin V+/PI- spermatozoa relative to the lowest quartiles, respectively. Mediation analysis revealed that protamine ratio significantly mediated 55.6% of the association between MEHP and Annexin V+/PI- spermatozoa elevation (5.13%; 95% CI: 0.04%, 10.52%). Our findings provided evidence that human exposure to PAEs was associated with increased protamine levels which may mediate the process of spermatozoa apoptosis.
Assuntos
Análise de Mediação , Ácidos Ftálicos , Apoptose , Humanos , Masculino , Ácidos Ftálicos/análise , Protaminas/metabolismo , Espermatozoides/metabolismoRESUMO
Pancreatic carcinoma elevates quickly and thus has a high mortality rate. Therefore, early treatment is essential for treating pancreatic carcinoma. KRAS is the most frequently identified and one of the earliest mutations in pancreatic tumorigenesis. Thus, the KRAS-mutant cell is an ideal target for the treatment of pancreatic carcinoma, especially at the early stage. KRAS mutation increases macropinocytosis in pancreatic cancer cells, enhancing the internalization of exosomes. Because acquiring natural exosomes could be laborious and their encapsulation efficiency is often unsatisfactory, we aimed to develop a delivery system that mimics the Kras-mutant cell targeting capability of exosomes but is easier to generate and has better loading efficiency. For this purpose, we constructed a hybrid nanoplatform by fusing CLT (Celastrol)-Loaded PEGylated lipids with the DC2.4 cell membrane (M-LIP-CLT) to achieve targeted treatment of Kras-mutant pancreatic cancer. This hybrid nanoplatform improved CLT tumor accumulation and showed excellent anti-cancer efficiency both in vitro and in vivo with increased safety. These results suggest that M-LIP-CLT is an effective drug delivery system for targeted therapy against pancreatic carcinoma, and the fusion strategy showed attractive potential for further development.
Assuntos
Exossomos , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Exossomos/genética , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias PancreáticasRESUMO
The ubiquitous interactions between tumor cells and the surrounding microenvironment contribute to tumor metastasis, interrupting these communications has, therefore, a great potential for antimetastasis therapy. Here, we describe an in situ self-assembly strategy that limits direct contact between tumor cells and the tumor microenvironment (TME). In this strategy, the Lys-Leu-Val-Phe-Phe (KLVFF) peptide motifs are targeted to the tumor by hyaluronic acid (HA) functionalized liposomes and spontaneously undergo self-assembly to form nanofibers with a net-like structure wrapping around tumor cells. The fibrous nanostructures bury the membrane protrusions and thus hinder the migration and invasion of tumor cells, especially the transmigration through the fenestrated endothelium. The nanofibril coatings on tumor cells significantly block tumor cells induced platelet aggregation in vitro and prevent the adhesion of platelet around circulating tumor cells (CTCs) in vivo, thus limit the pro-metastasis effect of platelets and prevent the early metastasis. Furthermore, the nano-nets stably retain in the primary tumor site for over 72 h and effectively prevent the activation of intratumoral platelet, which suppress tumor progression and the spontaneous lung metastasis in 4T1 breast cancer mice model. Our study paves a promising avenue to combat tumor metastasis by regulating the interactions between tumor cells and the TME.