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BACKGROUND: Obesity is well-established as a significant contributor to the development of insulin resistance (IR) and diabetes, partially due to elevated plasma saturated free fatty acids like palmitic acid (PA). Grb10-interacting GYF Protein 2 (GIGYF2), an RNA-binding protein, is widely expressed in various tissues including the liver, and has been implicated in diabetes-induced cognitive impairment. Whereas, its role in obesity-related IR remains uninvestigated. METHODS: In this study, we employed palmitic acid (PA) exposure to establish an in vitro IR model in the human liver cancer cell line HepG2 with high-dose chronic PA treatment. The cells were stained with fluorescent dye 2-NBDG to evaluate cell glucose uptake. The mRNA expression levels of genes were determined by real-time qRT-PCR (RT-qPCR). Western blotting was employed to examine the protein expression levels. The RNA immunoprecipitation (RIP) was used to investigate the binding between protein and mRNA. Lentivirus-mediated gene knockdown and overexpression were employed for gene manipulation. In mice, an IR model induced by a high-fat diet (HFD) was established to validate the role and action mechanisms of GIGYF2 in the modulation of HFD-induced IR in vivo. RESULTS: In hepatocytes, high levels of PA exposure strongly trigger the occurrence of hepatic IR evidenced by reduced glucose uptake and elevated extracellular glucose content, which is remarkably accompanied by up-regulation of GIGYF2. Silencing GIGYF2 ameliorated PA-induced IR and enhanced glucose uptake. Conversely, GIGYF2 overexpression promoted IR, PTEN upregulation, and AKT inactivation. Additionally, PA-induced hepatic IR caused a notable increase in STAU1, which was prevented by depleting GIGYF2. Notably, silencing STAU1 prevented GIGYF2-induced PTEN upregulation, PI3K/AKT pathway inactivation, and IR. STAU1 was found to stabilize PTEN mRNA by binding to its 3'UTR. In liver cells, tocopherol treatment inhibits GIGYF2 expression and mitigates PA-induced IR. In the in vivo mice model, GIGYF2 knockdown and tocopherol administration alleviate high-fat diet (HFD)-induced glucose intolerance and IR, along with the suppression of STAU1/PTEN and restoration of PI3K/AKT signaling. CONCLUSIONS: Our study discloses that GIGYF2 mediates obesity-related IR by disrupting the PI3K/AKT signaling axis through the up-regulation of STAU1/PTEN. Targeting GIGYF2 may offer a potential strategy for treating obesity-related metabolic diseases, including type 2 diabetes.
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Proteínas Portadoras , Resistencia a la Insulina , Hígado , Fosfohidrolasa PTEN , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Proteínas de Unión al ARN , Transducción de Señal , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Hígado/metabolismo , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Células Hep G2 , Ácido Palmítico , Masculino , Proteínas del Citoesqueleto/metabolismo , Proteínas del Citoesqueleto/genética , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversosRESUMEN
Plant pathogenic fungi elaborate numerous detoxification strategies to suppress host reactive oxygen species (ROS), but their coordination is not well-understood. Here, we show that Sirt5-mediated protein desuccinylation in Magnaporthe oryzae is central to host ROS detoxification. SIRT5 encodes a desuccinylase important for virulence via adaptation to host oxidative stress. Quantitative proteomics analysis identified a large number of succinylated proteins targeted by Sirt5, most of which were mitochondrial proteins involved in oxidative phosphorylation, TCA cycle, and fatty acid oxidation. Deletion of SIRT5 resulted in hypersuccinylation of detoxification-related enzymes, and significant reduction in NADPH : NADP+ and GSH : GSSG ratios, disrupting redox balance and impeding invasive growth. Sirt5 desuccinylated thioredoxin Trx2 and glutathione peroxidase Hyr1 to activate their enzyme activity, likely by affecting proper folding. Altogether, this work demonstrates the importance of Sirt5-mediated desuccinylation in controlling fungal process required for detoxifying host ROS during M. oryzae infection.
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Ascomicetos , Magnaporthe , Oryza , Especies Reactivas de Oxígeno/metabolismo , Lisina/metabolismo , Estrés Oxidativo , Ascomicetos/metabolismo , Proteínas Fúngicas/metabolismo , Oryza/metabolismo , Enfermedades de las Plantas/microbiologíaRESUMEN
In this study, the dual strategy of 1-butyl-3-vinylimidazolium bromide ionic liquid (IL) grafting and carbon nanotubes (CNTs) nanocomposition was applied to modify poly(vinylidene fluoride) (PVDF)-based membranes. The highly hydrophilic/oleophobic and fouling-resistant PVDF-g-IL/CNTs membranes with excellent separation efficiency were obtained by the nonsolvent-induced phase separation method with ethanol-water mixed solution as the coagulation bath. The grafted IL not only generated hydrophilic groups on PVDF chains but also acted together with the CNTs to induce the formation of hydrophilic ß-crystalline phase of PVDF, which significantly improved the hydrophilicity and pore structure of the modified PVDF membranes. As a result, the pure water flux of the optimal membrane increased up to 294.2 L m-2 h-1, which was 5.2 times greater than that of the pure PVDF membrane. Simultaneously, the electrostatic interaction of the positive IL and the integration of CNTs enhanced adsorption sites of the membranes, producing exceptional retention and adsorption of dye wastewater and oil-water emulsion. This study presents a straightforward and efficient approach for fabricating PVDF separation membranes, which have potential applications in the purification of various polluted wastewater.
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Retinal explant cultures provide a valuable system to study retinal function in vitro. This study established a new retinal explant culture method to prolong the survival of retinal ganglion cells (RGCs). Explants were prepared in two different ways: with or without optic nerve. Retinas from newborn mice that had received an injection of MitoTracker Red into the contralateral superior colliculus to label axonal mitochondria were cultured as organotypic culture for 7 days in vitro. At several time points during the culture, viability of RGCs was assessed by multi-electrode array recording, and morphology by immunohistochemical methods. During the culture, the thickness of the retinal tissue in both groups gradually decreased, however, the structure of the layers of the retina could be identified. Massive apoptosis in the retinal ganglion cell layer (GCL) appeared on the first day of culture, thereafter the number of apoptotic cells decreased. Glial activation was observed throughout the culture, and there was no difference in morphology between the two groups. RGCs loss was exacerbated on 3rdday of culture, and RGCs loss in retinal explants with preserved optic nerve was significantly lower than in retinas that did not preserve the optic nerve. More and longer-lasting mitochondrial signals were observed in the injured area of the optic nerve-preserving explants. Retinal explants provide an invaluable tool for studying retinal function and developing treatments for ocular diseases. The optic nerve-preserving culture helps preserve the integrity of RGCs. The higher number of mitochondria in the nerve-preserving cultures may help maintain viability of RGCs.
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Traumatismos del Nervio Óptico , Células Ganglionares de la Retina , Ratones , Animales , Células Ganglionares de la Retina/metabolismo , Retina/metabolismo , Axones/metabolismo , Nervio Óptico , Mitocondrias , Traumatismos del Nervio Óptico/metabolismoRESUMEN
Diosmetin (3',5,7 -trihydroxy-4'-methoxy flavone) is a natural flavonoid compound in the citrus species, it exhibits a variety of pharmacological activities, but little is known of its effects on colitis. In this study we evaluated the therapeutic effects of diosmetin on mouse models of chronic and acute colitis. Chronic colitis was induced in mice by drinking water containing 3% dextran sulfate sodium (DSS) from D0 to D8, followed by administration of diosmetin (25, 50 mg · kg-1 · d-1) for another 8 days. Acute colitis was induced by drinking water containing 5% DSS from D0 to D7, the mice concomitantly received diosmetin (25, 50 mg · kg-1 · d-1) from D1 to D7. During the experiments, body weight and disease activity index (DAI) were assessed daily. After the mice were sacrificed, colon tissue and feces samples were collected, and colon length was measured. We showed that in both models, diosmetin administration significantly decreased DAI score and ameliorated microscopic colon tissue damage; increased the expression of tight junction proteins (occludin, claudin-1, and zonula occludens-1), and reduced the secretion of proinflammatory cytokines IL-1ß, IL-6, TNF-α, and Cox-2 in colon tissue. We found that diosmetin administration remarkably inhibited colon oxidative damage by adjusting the levels of intracellular and mitochondrial reactive oxygen species, GSH-Px, SOD, MDA and GSH in colon tissue. The protection of diosmetin against intestinal epithelial barrier damage and oxidative stress were also observed in LPS-treated Caco-2 and IEC-6 cells in vitro. Furthermore, we demonstrated that diosmetin markedly increased the expression of Nrf2 and HO-1 and reduced the ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1 axis, which inhibited oxidative stress and inflammation in vivo and in vitro. Diosmetin reversed the effects of si-circSirt1 and si-Sirt1 in LPS-treated Caco-2 and IEC-6 cells. When the gut microbiota was analyzed in the mouse model of colitis, we found that diosmetin administration modulated the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were crucial for inflammatory bowel disease. Our results have linked colitis to the circ-Sirt1/Sirt1 signaling pathway, which is activated by diosmetin. The results imply that diosmetin may be a novel candidate to alleviate DSS-induced colitis and can be a lead compound for future optimization and modification.
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Colitis , Microbioma Gastrointestinal , Animales , Células CACO-2 , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colon/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Flavonoides/metabolismo , Flavonoides/farmacología , Flavonoides/uso terapéutico , Humanos , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Sirtuina 1/metabolismoRESUMEN
Currently, the most effective way to improve the anti-fouling performance of water treatment separation membrane is to enhance the hydrophilicity of the membrane surface, but it can still cause contamination, leading to the occurrence of flux reduction. The construction of a strong hydration layer to resist wastewater contamination is still a challenging task. In this study, a defect-free hydration layer barrier was achieved by grafting chitosan polysaccharide derivatives (CS-SDAEM) on the membrane, which achieved in effective fouling prevention and low flux decline rate. A layer of tannic acid-coated carbon nanotubes (TA@CNTs) has been uniformly deposited on the commercial PVDF membrane so that the surface was rich in -COOH groups, providing sufficient reaction sites. These reactive groups facilitate the grafting of amphiphilic polymers onto the membrane. This modification strategy achieved in enhancing the antifouling performance. The modified membrane achieved low contamination rate with DR of 16.9 % for wastewater filtration, and the flux recovery rate was above 95 % with PWF of 1100 (L·m-2·h-1). The membrane had excellent anti-fouling performance, which provided a new route for the future development of water treatment membrane.
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Quitosano , Emulsiones , Membranas Artificiales , Nanotubos de Carbono , Polivinilos , Purificación del Agua , Purificación del Agua/métodos , Quitosano/química , Polivinilos/química , Nanotubos de Carbono/química , Taninos/química , Polisacáridos/química , Agua/química , Aguas Residuales/química , Aceites/química , Interacciones Hidrofóbicas e Hidrofílicas , Filtración/métodos , Polímeros de FluorocarbonoRESUMEN
Functional catalytic hydrogels were a promising catalyst carrier with the advantages of low cost, high efficiency and environmental friendliness. However, conventional hydrogels suffered from mechanical defects and brittleness. Acrylamide (AM) and lauryl methacrylate (LMA) were used as raw materials, SiO2-NH2 spheres as toughening agents, and chitosan (CS) as stabilizers to form hydrophobic binding networks. p(AM/LMA)/SiO2-NH2/CS hydrogels exhibited superior stretchability and withstood strains up to 14,000 %. In addition, these hydrogels exhibited exceptional mechanical properties, including a tensile strength of 213 kPa and a toughness of 13.1 MJ/m3. Surprisingly, the introduction of chitosan into hydrogels showed excellent antibacterial activity against S. aureus and E. coli. At the same time, the hydrogel served as a template for the formation of Au nanoparticles. This resulted in high catalytic activity for methylene blue (MB) and Congo red (CR) on p(AM/LMA)/SiO2-NH2/CS-8 %-Au hydrogels with Kapp of 1.038 and 0.76 min-1, respectively. The catalyst was also found to be reusable for 10 cycles while maintaining an efficiency of over 90 %. Therefore, innovative design strategies can be used to develop durable and scalable hydrogel materials for catalysis in the wastewater treatment industry.
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Circular RNAs (circRNAs), a novel type of single-stranded noncoding RNAs with a covalently closed loop structure, are generated in a circular conformation via non-canonical splicing or back-splicing events. Functionally, circRNAs have been elucidated to soak up microRNAs (miRNAs) and RNA binding proteins (RBPs), serve as protein scaffolds, maintain mRNA stability, and regulate gene transcription and translation. Notably, circRNAs are strongly implicated in the regulation of ß-cell functions, insulin resistance, adipocyte functions, inflammation as well as oxidative stress via acting as miRNA sponges and RBP sponges. Basic and clinical studies have demonstrated that aberrant alterations of circRNAs expressions are strongly associated with the initiation and progression of diabetes mellitus (DM) and its complications. Here in this review, we present a summary of the biogenesis, transportation, degradation and functions of circRNAs, and highlight the recent findings on circRNAs and their action mechanisms in DM and its complications. Overall, this review should contribute greatly to our understanding of circRNAs in DM pathogenesis, offering insights into the further perspectives of circRNAs for DM diagnosis and therapy.
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Diabetes Mellitus , MicroARNs , Humanos , ARN Circular/genética , ARN Circular/metabolismo , MicroARNs/genética , Empalme del ARN , Estabilidad del ARN , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/genéticaRESUMEN
In the process of removing dye wastewater, the membrane surface is susceptible to contamination, resulting in reduced performance and limited dye separation efficiency. A single hydrophilic modification layer is not enough to achieve effective separation of different types of dyes. The present research designed a "double layer protection" method in order to overcome the above deficiencies. A solution of dopamine (DA) coated carbon nanotubes (CNTs-COOH) was covered on the surface of the polyvinylidene fluoride (PVDF) membrane by deposition, followed by grafting a layer of chitosan (CS) polymer brushes on its surface. The spatial double layer structure provides an excellent barrier effect and effectively reduces the contamination of dyes. When filtering different types of dyes, effective filtration of anionic and cationic dyes through the electrostatic effect of the first layer, the adsorption of CNTs in the second layer and the hydration layer of both layers. All membranes have excellent rejection properties. More importantly, the membranes also had good chemical and mechanical stability and their serviceability was not degraded. Therefore, the prepared PVDF-based multi-layer composite membranes behave a potential application prospect in the wastewater purification field.
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Excessive free fatty acids (FFAs) accumulation is a leading risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine-phosphate phospho-lyase (ETNPPL), a newly identified metabolic enzyme, catalyzes phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde and is highly expressed in hepatic tissue. Whether it plays a role in regulating FFA-induced IR in hepatocytes has yet to be understood. In this study, we established an in vitro palmitic acid (PA)-induced IR model in human HepG2 cells and mouse AML12 cells with chronic treatment of PA. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without PA stimulation. We show that ETNPPL expression is significantly elevated in PA-induced IR and that silencing ETNPPL ameliorates this IR in hepatocytes. Inversely, overexpressing ETNPPL under normal conditions without PA promotes IR, reactive oxygen species generation, and ARG2 activation in both HepG2 and AML12 cells. Moreover, ETNPPL depletion markedly down-regulates ARG2 expression in hepatocytes. Besides, silencing ARG2 prevents ETNPPL-induced ROS accumulation and inhibition of autophagic flux and IR in hepatocytes. Finally, we found that phytopharmaceutical disruption of ETNPPL by quercetin ameliorates PA-induced IR in hepatocytes. Our study discloses that ETNPPL inhibiting autophagic flux mediates insulin resistance triggered by PA in hepatocytes via ARG2/ROS signaling cascade. Our findings provide novel insights into elucidating the pathogenesis of obesity-associated hepatic IR, suggesting that targeting ETNPPL might represent a potential approach for T2DM therapy.
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Resistencia a la Insulina , Humanos , Ratones , Animales , Resistencia a la Insulina/genética , Especies Reactivas de Oxígeno/metabolismo , Ácido Palmítico/toxicidad , Hígado/metabolismo , Hepatocitos/metabolismo , Autofagia/genéticaRESUMEN
In the past three decades, nuclear energy has gained much attention as carbon-free electricity. Due to the supply of cooling water in nuclear power plant, large amount of waste heat will increase the water temperature, promote the microalgae and cyanobacteria propagation and increase the chance of red tide. Excess phytoplankton of cool source will result in abnormal operation of cooling system, even core overheating and nuclear leakage. Consequently, it is very important to remove microalgae and cyanobacteria from cold source of nuclear power plants. This review summarizes the formation mechanism and monitoring methods of red tide, compares the advantages and disadvantages of traditional microalgae removal technology including physical, chemical and biological methods. Furthermore, the improved electrochemical method and micro-nano bubble method are introduced in detail. Their combination is considered to be a low-cost, efficient and environmentally-friendly technology to prevent and control red tides for cold source of nuclear power plant.
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Cianobacterias , Microalgas , Plantas de Energía Nuclear , Fitoplancton , Tecnología , AguaRESUMEN
Arginase, a binuclear manganese metalloenzyme in the urea, catalyzes the hydrolysis of L-arginine to urea and L-ornithine. Both isoforms, arginase 1 and arginase 2 perform significant roles in the regulation of cellular functions in cardiovascular system, such as senescence, apoptosis, proliferation, inflammation, and autophagy, via a variety of mechanisms, including regulating L-arginine metabolism and activating multiple signal pathways. Furthermore, abnormal arginase activity contributes to the initiation and progression of a variety of CVDs. Therefore, targeting arginase may be a novel and promising approach for CVDs treatment. In this review, we give a comprehensive overview of the physiological and biological roles of arginase in a variety of CVDs, revealing the underlying mechanisms of arginase mediating vascular and cardiac function, as well as shedding light on the novel and promising therapeutic approaches for CVDs therapy in individuals.
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The calcium/calcineurin signaling pathway plays a key role in the development and virulence of plant pathogenic fungi, but the regulation of this signaling pathway is still not clear. In this study, we identified a calcineurin regulator MoRCN1 in the plant pathogenic fungus Magnaporthe oryzae and found it is important for virulence by regulating the calcineurin pathway. MoRCN1 deletion mutants were severely decreased in colony growth and conidia formation. More importantly, the deletion of MoRCN1 led to a significant reduction in virulence due to defects in appressorium formation and invasive growth. The ΔMorcn1 mutants were more sensitive to different stresses and induced host ROS accumulation, suggesting a role of MoRCN1 in stress adaptation. We found that MoRCN1 directly interacted with the calcineurin catalytic subunit MoCNA and affected its protein stability, which was therefore important for regulating the calcineurin pathway. Transcriptome analysis showed that MoRCN1 significantly activated 491 genes and suppressed 337 genes in response to calcium ion, partially overlapped with the MoCRZ1-bound genes. Gene Ontology and KEGG pathway analyses indicated that MoRCN1-regulated genes were enriched in stress adaptation, lipid metabolism, and secondary metabolite biosynthesis, reflecting a function of MoRCN1 in host cell adaptation. Altogether, these results suggest MoRCN1 functions as a regulator of the calcium/calcineurin signaling pathway for fungal development and infection of host cells.
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OBJECTIVES: Anlotinib hydrochloride (AL3818) is a novel multitarget tyrosine kinase inhibitor which has the same targets as nintedanib, an effective drug has been approved for the treatment of idiopathic pulmonary fibrosis. Here, we examined whether anlotinib could also attenuate bleomycin-induced pulmonary fibrosis in mice and explored the antifibrosis mechanism. METHODS: We have evaluated the effect of anlotinib on bleomycin-induced pulmonary fibrosis in mice. Inflammatory cytokines in alveolar lavage fluid including IL-1ß, IL-4, IL-6 and TNF-α were determined by ELISA. Biomarkers of oxidative stress were measured by corresponding kit. Histopathologic examination was analysed by H&E staining and immunohistochemistry. In vitro, we investigated whether anlotinib inhibited TGFß/Smad3 and non-Smad pathways by luciferase assay or Western blotting. We also evaluated whether anlotinib inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and promoted myofibroblast apoptosis in order to explore the possible molecular mechanism. KEY FINDINGS: The results indicated that anlotinib treatment remarkably attenuated inflammation, oxidative stress and pulmonary fibrosis in mouse lungs. Anlotinib could inhibit the TGF-ß1 signalling pathway. Additionally, anlotinib not only profoundly inhibited TGF-ß1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and promoted the apoptosis in fibroblasts. CONCLUSIONS: In summary, the results suggest that anlotinib-mediated suppression of pulmonary fibrosis is related to the inhibition of TGF-ß1 signalling pathway.