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BACKGROUND: Postweaning is a pivotal period for brain development and individual growth. As an important chemical used in medicines, foods and beverages, sodium citrate (SC) is commonly available. Although some effects of SC exposure on individual physiology have been demonstrated, the potential long-lasting effects of postweaning dietary SC exposure on social behaviours are still elusive. METHODS: Both postweaning male and female C57BL/6 mice were exposed to SC through drinking water for a total of 3 weeks. A series of behavioural tests, including social dominance test (SDT), social interaction test (SIT), bedding preference test (BPT) and sexual preference test (SPT), were performed in adolescence and adulthood. After these tests, serum oxytocin (OT) levels and gut microbiota were detected. RESULTS: The behavioural results revealed that postweaning SC exposure decreased the social dominance of male mice in adulthood and female mice in both adolescence and adulthood. SC exposure also reduced the sexual preference rates of both males and females, while it had no effect on social interaction behaviour. ELISA results indicated that SC exposure decreased the serum OT levels of females but not males. 16S rRNA sequencing analysis revealed a significant difference in ß-diversity after SC exposure in both males and females. The correlation coefficient indicated the correlation between social behaviours, OT levels and dominant genera of gut microbiota. CONCLUSION: Our findings suggest that postweaning SC exposure may have enduring and sex-dependent effects on social behaviours, which may be correlated with altered serum OT levels and gut microbiota composition.
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Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Oxitocina , Conducta Social , Citrato de Sodio , Animales , Masculino , Femenino , Ratones , Oxitocina/sangre , Microbioma Gastrointestinal/efectos de los fármacos , Citrato de Sodio/farmacología , Destete , Conducta Animal/efectos de los fármacos , Predominio Social , Caracteres Sexuales , Factores SexualesRESUMEN
Yam is a dual-purpose crop as both medicine and food. However, the mechanism controlling the eating quality of yam remains to be elucidated. This study explored the influence of starch multiscale structure on the texture of yam. The results indicated that FS and RC yam have higher hardness and chewiness, while BZ, XM, and PL yam possess waxiness, Fineness, and Stickiness. Statistically, high amylose (AM) can increase hardness, chewiness, and compactness; and average molecular size (Rh) is positively correlated with stickiness, fineness, and waxiness. Specifically, medium- and long-chain amylose (1000â¯<â¯Xâ¯≤â¯10,000) and amylopectin (24â¯<â¯Xâ¯≤â¯100), particularly medium-chain amylose (1000â¯<â¯Xâ¯≤â¯5000) and long-chain amylopectin (24â¯<â¯Xâ¯≤â¯36), primarily affect sensory and rheological stickiness. The long chains of amylose form a straight chain interspersed in the crystalline and amorphous regions to support the entire lamellar structure. Higher proportion of amylose long chains, promoting the starch's structural rigidity, which in turn enhanced its hardness-related attributes. Moreover, a higher ratio of long chains within amylopectin results in tightly intertwined adjacent outer chains, forming double helix crystalline zones. This consequently augmenting the texture quality linked to stickiness-related attributes.
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Amilopectina , Amilosa , Dioscorea , Almidón , Almidón/química , Amilosa/química , Dioscorea/química , Amilopectina/química , Culinaria , Dureza , ReologíaRESUMEN
Exposure to cadmium (Cd), a toxic heavy metal classified as an environmental endocrine disruptor, can exert significant toxicity in both animals and humans. However, the potential effects of Cd exposure on socioemotional behaviors are still poorly understood, as are the underlying mechanisms. In the present study, employing a series of behavioral tests as well as 16â¯S rRNA sequencing analysis, we investigated the long-term effects of Cd exposure on socioemotional behaviors and their associated mechanisms in mice based on the brain-gut interaction theory. The results showed that postweaning exposure to Cd reduced the ability to resist depression, decreased social interaction, subtly altered sexual preference, and changed the composition of the gut microbiota in male mice during adolescence. These findings provided direct evidence for the deleterious effects of exposure to Cd in the postweaning period on socioemotional behaviors later in adolescence, and suggested that these effects of Cd exposure may be linked to changes in the gut microbiota.
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Cadmio , Microbioma Gastrointestinal , Humanos , Masculino , Animales , Ratones , Adolescente , Cadmio/toxicidadRESUMEN
Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs (lncRNAs) are associated with cardiac pathologies, but their functions in cardiac fibroblasts and contributions to cardiac fibrosis remain unclear. Here, we aimed to identify fibroblast-enriched lncRNAs essential in myocardial infarction (MI)-induced fibrosis and explore the molecular mechanisms responsible for their functions. Global lncRNA profiling was performed in post-MI mouse heart ventricles and transforming growth factor-ß (TGF-ß)-treated primary cardiac fibroblasts and confirmed in published data sets. We identified the cardiac fibroblast-enriched lncPostn, whose expression is stimulated in cardiac fibrosis induced by MI and the extracellular growth factor TGF-ß. The promoter of lncPostn contains a functional TGF-ß response element, and lncPostn knockdown suppresses TGF-ß-stimulated cardiac fibroblast activation and improves cardiac functions post-MI. LncPostn stabilizes and recruits EP300 to the profibrotic periostin's promoter, representing a major mechanism for its transcriptional activation. Moreover, both MI and TGF-ß enhance lncPostn expression while suppressing the cellular growth gatekeeper p53. TGF-ß and p53 knockdown-induced profibrotic gene expression and fibrosis occur mainly through lncPostn and show additive effects. Finally, levels of serum lncPostn are significantly increased in patients' postacute MI and show a strong correlation with fibrosis markers, revealing a potential biomarker of cardiac fibrosis. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor, providing a transcriptional link between TGF-ß and p53 signaling pathways to regulate fibrosis in cardiac fibroblasts.NEW & NOTEWORTHY Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs are functional and contribute to the biological processes of cardiovascular development and disorders. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor and demonstrate that serum lncPostn level may serve as a potential biomarker of human cardiac fibrosis postacute myocardial infarction.
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Cardiomiopatías , Infarto del Miocardio , ARN Largo no Codificante , Humanos , Ratones , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Fibrosis , Fibroblastos/metabolismo , Transducción de Señal , Biomarcadores/metabolismoRESUMEN
BACKGROUND: Despite considerable efforts, ischemic stroke (IS) remains a challenging clinical problem. Therefore, the discovery of effective therapeutic and targeted drugs based on the underlying molecular mechanism is crucial for effective IS treatment. METHODS: A cDNA-encoding peptide was cloned from RNA extracted from Rana limnocharis skin, and the mature amino acid sequence was predicted and synthesized. Hemolysis and acute toxicity of the peptide were tested. Furthermore, its neuroprotective properties were evaluated using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in neuron-like PC12 cells. The underlying molecular mechanisms were explored using microRNA (miRNA) sequencing, quantitative real-time polymerase chain reaction, dual-luciferase reporter gene assay, and western blotting. RESULTS: A new peptide (NP1) with an amino acid sequence of 'FLPAAICLVIKTC' was identified. NP1 showed no obvious toxicities in vivo and in vitro and was able to cross the blood-brain barrier. Intraperitoneal administration of NP1 (10 nmol/kg) effectively reduced the volume of cerebral infarction and relieved neurological dysfunction in MCAO/R model rats. Moreover, NP1 significantly alleviated the decrease in viability and increase in apoptosis of neuron-like PC12 cells induced by OGD/R. NP1 effectively suppressed inflammation by reducing interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) levels in vitro and in vivo. Furthermore, NP1 up-regulated the expression of miR-6328, which, in turn, down-regulated kappa B kinase ß (IKKß). IKKß reduced the phosphorylation of nuclear factor-kappa B p65 (NF-κB p65) and inhibitor of NF-κB (I-κB), thereby inhibiting activation of the NF-κB pathway. CONCLUSIONS: The newly discovered non-toxic peptide NP1 ('FLPAAICLVIKTC') exerted neuroprotective effects on cerebral ischemia-reperfusion injury by reducing inflammation via the miR-6328/IKKß/NF-κB axis. Our findings not only provide an exogenous peptide drug candidate and endogenous small nucleic acid drug candidate but also a new drug target for the treatment of IS. This study highlights the importance of peptides in the development of new drugs, elucidation of pathological mechanisms, and discovery of new drug targets.
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MicroARNs , Fármacos Neuroprotectores , Daño por Reperfusión , Animales , Ratas , FN-kappa B , Quinasa I-kappa B , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Proteínas Serina-Treonina Quinasas , Péptidos/farmacología , Péptidos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Objective: To evaluate the quality of surgical guidelines on bariatric/metabolic surgery. Methods: Four independent reviewers used the AGREE II (The Appraisal of Guidelines for Research and Evaluation II) tool to assess the methodological quality of the included guidelines and conducted a comparative analysis of the main recommendations for surgical methods of these guidelines. Results: Nine surgical guidelines were included in this study. Five articles with AGREE II scores over 60% are worthy of clinical recommendation. The field of rigor of development was relatively low, with an average score of 50.82%. Among 15 key recommendations and the corresponding best evidence in the guidelines, only 4 key recommendations were grade A recommendations. Conclusions: The quality of metabolic and bariatric guidelines is uneven, and there is much room for improvement.
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Cirugía Bariátrica , Guías de Práctica Clínica como Asunto , Cirugía Bariátrica/normas , Guías de Práctica Clínica como Asunto/normasRESUMEN
Diabetic nephropathy (DN) is one of the most common complications of diabetes. Gradual loss of podocytes is a sign of DN and pyroptosis mechanistically correlates with podocyte injury in DN; however, the mechanism(s) involved remain unknown. Here we reveal that TRIM29 is overexpressed in high glucose (HG)-treated murine podocytes cells and that TRIM29 silencing significantly inhibits podocyte damage due to HG treatment, as evidenced by lower desmin expression and greater nephrin expression. Additionally, flow cytometry analysis showed that TRIM29 silencing significantly inhibited HG treatment-induced pyroptosis, which was confirmed by immunoblotting for NLRP3, active Caspase-1, GSDMD-N, and phosphorylated NF-κB-p65. Conversely, overexpression of TRIM29 could trigger pyroptosis that was attenuated by NF-κB inhibition, indicating that TRIM29 promotes pyroptosis through the NF-κB pathway. Mechanistic studies revealed that TRIM29 interacts with IκBα to mediate its ubiquitination-dependent degradation, which in turn leads to NF-κB activation. Taken together, our data demonstrate that TRIM29 can promote podocyte pyroptosis by activating the NF-κB/NLRP3 pathway. Thus, TRIM29 represents a potentially novel therapeutic target that may also be clinically relevant in the management of DN.
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Nefropatías Diabéticas , Podocitos , Animales , Ratones , Nefropatías Diabéticas/metabolismo , Proteínas de Unión al ADN/metabolismo , Inflamasomas/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Podocitos/metabolismo , Piroptosis , Factores de Transcripción/metabolismoRESUMEN
Microglia are widely distributed in the central nervous system (CNS), where they aid in the maintenance of neuronal function and perform key auxiliary roles in phagocytosis, neural repair, immunological control, and nutrition delivery. Microglia in the undamaged spinal cord is in a stable state and serve as immune monitors. In the event of spinal cord injury (SCI), severe changes in the microenvironment and glial scar formation lead to axonal regeneration failure. Microglia participates in a series of pathophysiological processes and behave both positive and negative consequences during this period. A deep understanding of the characteristics and functions of microglia can better identify therapeutic targets for SCI. Technological innovations such as single-cell RNA sequencing (Sc-RNAseq) have led to new advances in the study of microglia heterogeneity throughout the lifespan. Here,We review the updated studies searching for heterogeneity of microglia from the developmental and pathological state, survey the activity and function of microglia in SCI and explore the recent therapeutic strategies targeting microglia in the CNS injury.
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Microglía , Traumatismos de la Médula Espinal , Humanos , Microglía/patología , Médula Espinal/patología , Sistema Nervioso Central/patología , Gliosis/patologíaRESUMEN
Zhejiang Rosy Vinegar (ZRV) is a traditional condiment in Southeast China. This study aimed to track the physicochemical, microbiological, sensory changes, and metabolomic profiles of ZRV during fermentation and aging. The increase of acidity and decrease of reducing sugar were associated with the dominant growth of Lactobacillus and Acetobacter. The total 35 volatile compounds were identified in ZRV, mainly containing alcohols, esters, acids, aldehydes, ketones acids, phenols and nitrogen-containing. Compared to phenethyl acetate with sweet aroma in fresh vinegar, the compound with high odor activity values was isoamyl acetate with fruity aromas in aged vinegar. Furthermore, 1309 types of non-volatile components were identified, and histidine metabolism and arginine biosynthesis were revealed as main pathways during fermenting and aging. Concurrently, various bioactive substances in ZRV were identified. This study enriched the knowledge on the components and flavor of ZRV, and assist to improve the production quality of vinegar.
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Acetobacter , Compuestos Orgánicos Volátiles , Ácido Acético/química , Fermentación , Compuestos Orgánicos Volátiles/metabolismo , Acetobacter/metabolismo , OdorantesRESUMEN
Industrial applications and environmental awareness recently prompted vanadium recovery spell from secondary resources. In this work, a polymer inclusion membrane containing trioctylmethylammonium chloride as carrier was successfully employed in electrodialysis for vanadium recovery from acidic sulfate solutions. The permeability coefficient of V(V) increased from 0.29 µm·s-1 (without electric field) to 4.10 µm·s-1 (with the 20 mA·cm-2 current density). The transport performance of VO2SO4-, which was the predominant species containing V(V) in the acidic region (pH <3), was influenced by the aqueous pH value and sulfate concentration. Under an electric field, a low concentrated H2SO4 solution (0.2 M) effectively stripped V(V) from the membranes, avoiding the requirement of a highly concentrated H2SO4 without electric field. Under the optimum conditions, the permeability coefficient and flux reached 6.80 µm·s-1 and 13.34 µmol·m-2·s-1, respectively. High selectivity was observed for the separation of V(V) and Mo(VI) from mixed solutions of Co (II), Ni (II), Mn (II), and Al (III). Additionally, the separation between Mo(VI) and V(V) was further improved by adjusting the acidity of the stripping solution. The V(V) selectivity for the resulting membrane was higher than that of commercial anion exchange membranes.
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Polímeros , Vanadio , Ácidos , Membranas Artificiales , Sulfatos , AguaRESUMEN
Testicular seminoma is a relatively rare tumor which is mostly detected in male population aged from 15 to 35â years old. Although several molecular biomarkers have been identified to be associated with testicular seminoma pathogenesis, the exact mechanism for testicular seminoma progression remains largely unknown. CDKN2A interacting protein (CDKN2AIP) has previously been identified as a tumor suppressor in multiple malignant diseases. In this study, we aimed to further explore its role in testicular seminoma as well as the underlying molecular mechanisms. Retrospective testicular seminoma clinical samples, normal tissues, NTERA-2 cell line, and mouse xenograft models were used in this study. RT-qPCR, western blot analysis, immunofluorescence microscopy, Co-IP and IP-MS experiments were performed to detect the expression of CDKN2AIP and its interaction with CARM1 and eIF4ß. SA-ß-gal staining assay and H3K9me3 activity experiments were used to subsequently evaluate the cell senescence and apoptosis. Mouse xenograft animal model was used for in vivo study. The results showed that CDKN2AIP is highly expressed in normal testis samples, and is significantly suppressed in testicular seminoma clinical samples and cell line model. Up-regulation of CDKN2AIP is significantly associated with the inhibition of testicular seminoma tumor growth and the increase of cell senescence and apoptosis. CDKN2AIP exhibits anti-tumor activity by interacting with CARM1 and eIF4ß. CDKN2AIP induces testicular seminoma cell senescence by suppressing CARM1 expression and eIF4ß phosphorylation. The CDKN2AIP-CARM1 and CDKN2AIP-eIF4ß interactions, which induce tumor cell senescence and apoptosis, may be the potential druggable molecular pathways in testicular seminoma tumor pathogenesis and progression.
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Apoptosis , Senescencia Celular , Seminoma , Neoplasias Testiculares , Animales , Humanos , Masculino , Ratones , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Senescencia Celular/genética , Estudios Retrospectivos , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Seminoma/genética , Seminoma/metabolismo , Seminoma/patología , Neoplasias Testiculares/genética , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologíaRESUMEN
BACKGROUND: Shift work is associated with increased risk of acute myocardial infarction (AMI) and worsened prognosis. However, the mechanisms linking shift work and worsened prognosis in AMI remain unclear. OBJECTIVES: This study sought to investigate the impact of shift work on reperfusion injury, a major determinant of clinical outcomes in AMI. METHODS: Study patient data were obtained from the database of the EARLY-MYO-CMR (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI) registry, which was a prospective, multicenter registry of patients with ST-segment elevation myocardial infarction (STEMI) undergoing cardiac magnetic resonance (CMR) imaging after reperfusion therapy. The primary endpoint was CMR-defined post-reperfusion infarct size. A secondary clinical endpoint was the composite of major adverse cardiac events (MACE) during follow-up. Potential mechanisms were explored with the use of preclinical animal AMI models. RESULTS: Of 706 patients enrolled in the EARLY-MYO-CMR registry, 412 patients with STEMI were ultimately included. Shift work was associated with increased CMR-defined infarct size (ß = 5.94%; 95% CI: 2.94-8.94; P < 0.0001). During a median follow-up of 5.0 years, shift work was associated with increased risks of MACE (adjusted HR: 1.92; 95% CI: 1.12-3.29; P = 0.017). Consistent with clinical findings, shift work simulation in mice and sheep significantly augmented reperfusion injury in AMI. Mechanism studies identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that played a crucial role in mediating the detrimental effects of shift work on myocardial injury. CONCLUSIONS: The current study provided novel findings that shift work increases myocardial infarction reperfusion injury. It identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that might play a crucial role in mediating this process. (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI [EARLY-MYO-CMR] registry; NCT03768453).
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Infarto del Miocardio , Daño por Reperfusión Miocárdica , Infarto del Miocardio con Elevación del ST , Horario de Trabajo por Turnos , Animales , Ritmo Circadiano , Humanos , Imagen por Resonancia Cinemagnética , Ratones , Infarto del Miocardio/terapia , Estudios Prospectivos , Receptores Citoplasmáticos y Nucleares , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/cirugía , OvinosRESUMEN
CD147, also known as EMMPRIN or basigin, is a transmembrane glycoprotein receptor that activates matrix metalloproteinases and promotes inflammation. CD147 function is regulated by posttranslational modifications of which glycosylation has attracted the most attention. In this study, we demonstrated that glycosylated CD147 was the dominant form in heart tissue, and its levels were markedly elevated in response to transverse aortic constriction (TAC). Adeno-associated virus 9-mediated, cardiac-specific overexpression of wild-type CD147 in mice significantly promoted pressure overload-induced pathological cardiac remodeling accompanied by augmented oxidative stress and ferroptosis. By contrast, mutations of CD147 glycosylation sites notably weakened these detrimental effects of CD147. Mechanistically, CD147 exacerbated TAC-induced pathological cardiac remodeling via direct binding with the adaptor molecule TRAF2 and subsequent activation of TAK1 signalling, which was dependent on glycosylation of CD147. Collectively, our findings provide the first evidence that CD147 promoted pathological cardiac remodeling and dysfunction in a glycosylation-dependent manner through binding the adaptor protein TRAF2 and activating the downstream TRAF2-TAK1 signalling pathway. Thus, glycosylation of CD147 may be a potent interventional target for heart failure treatment.
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Basigina/efectos adversos , Cardiomegalia/fisiopatología , Animales , Glicosilación , Humanos , Masculino , RatonesRESUMEN
Acute myocardial ischemia/reperfusion (MI/R) is a major determinant of prognosis in myocardial infarction patients, while effective therapies are currently lacking. Nuclear receptor co-repressor 1 (NCoR1) is emerging as a critical regulator of cell survival and death signaling in mammals. However, the role of NCoR1 in the pathogenesis of acute MI/R injury remains unknown. Here, we observed that NCoR1 was highly expressed in the mouse heart and significantly downregulated after acute MI/R injury. Cardiomyocyte-specific NCoR1 deletion led to significantly increased infarct size and exacerbated cardiac dysfunction compared to wild-type littermates. Moreover, cardiomyocyte-specific NCoR1 deficiency exacerbated MI/R-induced mitochondrial dysfunction and apoptotic pathway activation. Transcriptomic profiling results indicated that cardiomyocyte-specific NCoR1 deficiency pivotally promoted activation of inflammatory pathways. Through integrated omics analysis, signal transducer and activator of transcription 1 (STAT1) was identified as a downstream target trans-repressed by NCoR1. STAT1 activation played a key mediating role in the detrimental effects of NCoR1 deficiency in MI/R injury. Collectively, our findings provided the first evidence that cardiomyocyte-expressed NCoR1 functioned as a crucial cardioprotective factor against acute MI/R injury by targeting the STAT1 pathway in heart.
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Infarto del Miocardio , Daño por Reperfusión Miocárdica , Animales , Apoptosis , Humanos , Mamíferos , Ratones , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Co-Represor 1 de Receptor Nuclear/genéticaRESUMEN
BACKGROUND AND AIMS: NASH, which is a common clinical condition predisposing to advanced liver diseases, has become a worldwide epidemic. A large and growing unmet therapeutic need for this condition reflects incomplete understanding of its pathogenesis. In the current study, we identified a transcription factor, zinc fingers and homeoboxes 2 (ZHX2), in hepatocytes as a protective factor against steatohepatitis. APPROACH AND RESULTS: We found that hepatic ZHX2 was significantly suppressed in NASH models and steatotic hepatic cells. Hepatocyte-specific ablation of ZHX2 exacerbated NASH-related phenotypes in mice, including lipid accumulation, enhanced inflammation, and hepatic fibrosis. Conversely, hepatocyte-specific overexpression of ZHX2 significantly alleviated the progression of NASH in an experimental setting. Integrated analysis of transcriptomic profiling and chromatin immunoprecipitation sequencing data demonstrated that the phosphatase and tensin homolog (PTEN) was a target gene of ZHX2 in hepatocyte. ZHX2 bound to the promoter of PTEN gene and subsequently promoted the transcription of PTEN, which mediated the beneficial role of ZHX2 against NASH. CONCLUSIONS: The current findings demonstrate a protective role of ZHX2 against NASH progression by transcriptionally activating PTEN. These findings shed light on the therapeutic potential of targeting ZHX2 for treating NASH and related metabolic disorders.
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Proteínas de Homeodominio , Enfermedad del Hígado Graso no Alcohólico , Factores de Transcripción , Animales , Genes Homeobox , Hepatocitos/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Tensinas/genética , Tensinas/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Dedos de ZincRESUMEN
Forkhead box M1 (FOXM1) has been reported to play a protective role against acute kidney injury by driving tubular regeneration. This study aims to probe the function of FOXM1 in diabetic nephropathy (DN) and the molecules involved. FOXM1 was poorly expressed in DN-diseased kidney tissues. A murine model of DN was established, and podocytes cells (MPC5) were treated with high-glucose (HG) for in vitro studies. FOXM1 overexpression improved kidney function and reduced pathological changes in mice, and it increased the expression of the podocyte marker Nephrin in kidney tissues. In vitro, FOXM1 increased viability and reduced pyroptosis of the HG-treated MPC5 cells, and it elevated the expression of the podocyte marker Nephrin whereas reduced the expression of pyroptosis-related NLRP3 inflammasome and cleaved caspase 1. FOXM1 bound to the promoter of sirtuin 4 (SIRT4) to induce transcriptional activation. Downregulation of SIRT4 blocked the protective roles of FOXM1 both in vivo and in vitro. Phosphorylation of nuclear factor-kappa B (NF-κB) in HG-treated cells was suppressed by FOXM1 but restored after SIRT4 inhibition. In conclusion, this study suggested that FOXM1 transcriptionally activates SIRT4 and inhibits NF-κB signaling and the NLRP3 inflammasome to alleviate kidney injury and podocyte pyroptosis in DN.
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Lesión Renal Aguda/genética , Nefropatías Diabéticas/genética , Proteína Forkhead Box M1/genética , Proteínas Mitocondriales/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Sirtuinas/genética , Lesión Renal Aguda/patología , Animales , Nefropatías Diabéticas/patología , Regulación de la Expresión Génica/genética , Humanos , Inflamasomas/genética , Riñón/lesiones , Riñón/metabolismo , Riñón/patología , Ratones , FN-kappa B/genética , Podocitos/metabolismo , Podocitos/patología , Piroptosis/genética , Transducción de SeñalRESUMEN
Diesel particulate filter is used to reduce particulate matter (PM) emission due to the stringent emission standards. The accumulated PM has been oxidized by the periodical regeneration method to avoid pressure buildup. The innovation of this study is to explore the oxidation performance of Printex-U (PU), which is mixed with ash and soluble organic fractions, under different operating conditions. Different aspects of operating parameters, such as the oxygen ratio in an O2/N2 atmosphere, total flow rate, initial PU mass, and heating rate, on PU oxidation properties have been critically discussed using a thermogravimetric analyzer. The oxygen ratio in the O2/N2 atmosphere is positively correlated with the oxidation characteristics of PU. The comprehensive oxidation index (S ) of PU under the 20% O2/80% N2 atmosphere increases by 184% compared with the 10% O2/90% N2 atmosphere. When the initial PU mass is 3 mg, the combustion stability coefficient (R w) and S reach the best values, which are 55.53 × 105 and 2.03 × 107 %2min-2 ° C-3, respectively. With the increase in the heating rate, the oxidation properties of PU become sensible and deflagration occurs easily, so that 10 °C/min heating rate is the best option. This study provides a theoretical basis for the optimization design of diesel particulates during the regeneration process.
RESUMEN
Diesel particulates are deposited in the diesel particulate filter and removed by the regeneration process. The Printex-U (PU) particles are simulated as the diesel soot to investigate the influence of thermal aging conditions on soot combustion performance with the addition of catalysts. The comprehensive combustion index S, combustion stability index Rw and peak temperature Tp are obtained to evaluate the combustion performance. Compared with the PU/Pt mixtures of different Pt contents (2 g/ft3, 3.5 g/ft3, and 5 g/ft3), the 10 g/ft3 Pt contents improve soot combustion with the outstanding oxygen absorption ability. When the weight ratio of PU/Pt mixture is 1:1, the promoted effect achieves the maximum degree. The S and Rw increase to 8.90 × 10-8 %2min-2°C-3 and 39.11 × 105, respectively, compared with pure PU. After the thermal aging process, the PU/Pt mixture with a 350 °C aging temperature for 10 h promotes the soot combustion the best when compared to pure PU particles. It is not good as the PU/Pt mixture without aging, because the inner properties of soot and Pt/Al2O3 catalyst may have been changed. The S and Rw are 9.07 × 10-8 %2min-2°C-3 and 38.39 × 105, respectively, which are close to the no aging mixture. This work plays a crucial role in understanding the mechanism of the comprehensive effect of soot and catalyst on soot combustion after the thermal aging process.
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BACKGROUND: Adiponectin is an adipocytokine that plays a key regulatory role in glucose and lipid metabolism in obesity. The prevalence of obesity has led to an increase in the incidence of obesity-related glomerulopathy (ORG). This study aimed to identify the protective role of adiponectin in ORG. METHODS: Small-interfering RNA (siRNA) against the gene encoding adiponectin was transfected into podocytes. The oxidative stress level was determined using a fluorometric assay. Apoptosis was analyzed by flow cytometry. The expressions of podocyte markers and pyrin domain containing protein 3 (NLRP3) inflammasome-related proteins were measured by qRT-PCR, immunohistochemistry, and Western blot. RESULTS: Podocytes treated with palmitic acid (PA) showed downregulated expressions of podocyte markers, increased apoptosis, upregulated levels of NLRP3 inflammasome-related proteins, increased production of inflammatory cytokines (IL-18 and IL-1ß), and induced activation of NF-κB as compared to the vehicle-treated controls. Decreased adiponectin expression was observed in the serum samples from high fat diet (HFD)-fed mice. Decreased podocin expression and upregulated NLRP3 expression were observed in the kidney samples from high fat diet (HFD)-fed mice. Treatment with adiponectin or the NLRP3 inflammasome inhibitor, MCC950, protected cultured podocytes against podocyte apoptosis and inflammation. Treatment with adiponectin protected mouse kidney tissues against decreased podocin expression and upregulated NLRP3 expression. The knockout of adiponectin gene by siRNA increased ROS production, resulting in the activation of NLRP3 inflammasome and the phosphorylation of NF-κB in podocytes. Pyrrolidine dithiocarbamate, an NF-κB inhibitor, prevented adiponectin from ameliorating FFA-induced podocyte injury and NLRP3 activation. CONCLUSIONS: Our study showed that adiponectin ameliorated PA-induced podocyte injury in vitro and HFD-induced injury in vivo via inhibiting the ROS/NF-κB/NLRP3 pathway. These data suggest the potential use of adiponectin for the prevention and treatment of ORG.
Asunto(s)
Adiponectina/farmacología , Adiponectina/fisiología , Glomerulonefritis/prevención & control , Glomerulonefritis/fisiopatología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas Mitocondriales/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Obesidad/complicaciones , Animales , Apoptosis , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Glomerulonefritis/patología , Humanos , Inflamasomas/metabolismo , Metabolismo de los Lípidos , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Proteínas Mitocondriales/metabolismo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Podocitos/metabolismo , Podocitos/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Diesel particulate filter is an effective device to reduce diesel particulate emission. The particles in diesel particulate filter are usually affected by the aging of high-temperature exhaust gas before the regeneration process. In order to investigate the effect of aging conditions on the soot oxidation process, the effect of aging temperature and aging time on the oxidation process of carbon black (Printex-U, PU) and the PU/catalyst/ash mixture are studied by thermogravimetric analysis. The aging PU particles have lower starting temperature, peaking temperature, ending temperature, and activation energy. Compared with the particles without aging, the PU particles with a 400 °C aging temperature and 20 h aging time are able to reduce the activation energy from 191.2 to 158 kJ/mol. Low aging temperatures (200-300 °C) and the catalyst have a certain synergistic effect on the improvement of PU oxidation activity. The PU/CeO2 mixture with a 300 °C aging temperature and 20 h aging time decreases the activation energy from 178.4 to the lowest 113.6 kJ/mol. The addition of CaSO4 in PU particles cannot stop the improvement of its oxidation activity by aging, but it reduces the effect of aging. This work is helpful to reveal the mechanism of aging on PU and the PU/catalyst/ash mixture in air environment.