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The escalating incidence of nonalcoholic fatty liver disease (NAFLD) is closely associated with a high-fat diet, leading to a decline in quality of life and significant health impairment. 7-Hydroxyflavone (7-HY) is a flavonoid known for its anti-inflammatory, anticarcinogenic, and antioxidant effects. This study aims to assess the ameliorative effects of 7-HY on NAFLD induced by a high-fat diet and elucidate underlying mechanisms. Oleic acid/palmitic acid-induced HepG2 cells and C57BL/6 mice on a high-fat diet were utilized as in vitro and in vivo models. In animal experiments, 7-HY was utilized as a dietary supplement. The 15-week in vivo experiment monitored body weight, body fat percentage, glucose tolerance, insulin tolerance, and metabolic indexes. Commercial kits assessed triglyceride (TG) and total cholesterol levels in cells, liver tissue, and blood. Discovery Studio identified potential targets of 7-HY, compared with NAFLD-associated targets in the GeneCards database. Results indicated 7-HY mitigated fat accumulation, hepatic steatosis, and oxidative stress induced by a high-fat diet. Furthermore, 7-HY showed potential efficacy in ameliorating abnormal glucose metabolism and promoting energy metabolism. Reverse target finding and molecular docking demonstrated a robust interaction between 7-HY and serine/threonine kinase 24 (STK24). Subsequent experimental results confirmed 7-HY's ability to inhibit TG deposition in HepG2 cells through interaction with STK24. In conclusion, 7-HY demonstrated the capacity to alleviate high-fat diet-induced NAFLD, presenting a novel strategy for the prevention and treatment of NAFLD.
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Dieta Alta en Grasa , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Proteínas Serina-Treonina Quinasas , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Humanos , Células Hep G2 , Ratones , Dieta Alta en Grasa/efectos adversos , Masculino , Proteínas Serina-Treonina Quinasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Flavonas/farmacología , Flavonas/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Simulación del Acoplamiento Molecular , Triglicéridos/sangre , Flavonoides/farmacologíaRESUMEN
OBJECTIVE: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue. METHODS: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet. RESULTS: We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity. CONCLUSIONS: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.
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Canales de Calcio , Resistencia a la Insulina , Animales , Ratones , Tejido Adiposo/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Lípidos , Ratones Endogámicos C57BL , Obesidad/metabolismoRESUMEN
Single-shot optical imaging based on ultrashort lasers has revealed nonrepetitive processes in subnanosecond timescales beyond the recording range of conventional high-speed cameras. However, nanosecond photography without sacrificing short exposure time and image quality is still missing because of the gap in recordable timescales between ultrafast optical imaging and high-speed electronic cameras. Here, we demonstrate nanosecond photography and ultrawide time-range high-speed photography using a spectrum circuit that produces interval-tunable pulse trains while keeping short pulse durations. We capture a shock wave propagating through a biological cell with a 1.5-ns frame interval and 44-ps exposure time while suppressing image blur. Furthermore, we observe femtosecond laser processing over multiple timescales (25-ps, 2.0-ns, and 1-ms frame intervals), showing that the plasma generated at the picosecond timescale affects subsequent shock wave formation at the nanosecond timescale. Our technique contributes to accumulating data of various fast processes for analysis and to analyzing multi-timescale phenomena as a series of physical processes.
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Non-alcoholic fatty liver disease (NAFLD) is a potentially serious disease that affects 30 % of the global population and poses a significant risk to human health. However, to date, no safe, effective and appropriate treatment modalities are available. In recent years, ferroptosis has emerged as a significant mode of cell death and has been found to play a key regulatory role in the development of NAFLD. In this study, we found that arbutin (ARB), a natural antioxidant derived from Arctostaphylos uva-ursi (L.), inhibits the onset of ferroptosis and ameliorates high-fat diet-induced NAFLD in vivo and in vitro. Using reverse docking, we identified the demethylase fat mass and obesity-related protein (FTO) as a potential target of ARB. Subsequent mechanistic studies revealed that ARB plays a role in controlling methylation of the SLC7A11 gene through inhibition of FTO. In addition, we demonstrated that SLC7A11 could alleviate the development of NAFLD in vivo and in vitro. Our findings identify the FTO/SLC7A11 axis as a potential therapeutic target for the treatment of NAFLD. Specifically, we show that ARB alleviates NAFLD by acting on the FTO/SLC7A11 pathway to inhibit ferroptosis.
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Ferroptosis , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Arbutina , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina , Sistema de Transporte de Aminoácidos y+/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genéticaRESUMEN
Stimulus-responsive polymer materials are an attractive alternative to conventional supramolecular and polymer assemblies for applications in sensing, imaging, and drug-delivery systems. Herein, we synthesized a series of pyrene-labeled α- and ε-poly-l-lysine conjugates with varying degrees of substitution (DSs). Hydrostatic-pressure-UV/vis, fluorescence, and excitation spectroscopies and fluorescence lifetime measurements revealed ground-state conformers and excited-state ensembles emitting fluorescence with variable intensities. The polylysine-based chemosensors demonstrated diverse ratiometric responses to hydrostatic pressure through adjustments in polar solvents, DSs, and polymer backbones. Additionally, the fluorescence chemosensor exhibited a promising glum value of 3.2 × 10-3, indicating potential applications in chiral fluorescent materials. This study offers valuable insights into the development of smart hydrostatic-pressure-responsive polymer materials.
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Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1-21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.
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Alcaloides , Melanoma , Ratones , Animales , Humanos , Pez Cebra , Neovascularización Patológica/patología , Ratones Endogámicos C57BL , Células Endoteliales de la Vena Umbilical Humana , Inhibidores de la Angiogénesis/química , Alcaloides/farmacología , Alcaloides/uso terapéutico , Melanoma/tratamiento farmacológico , Proliferación CelularRESUMEN
Obesity is of public concern worldwide, and it increases the probability of developing a number of comorbid diseases, including NAFLD. Recent research on obesity drugs and health demands have shown the potential of natural plant extracts for preventing and treating obesity and their lack of toxicity and treatment-related side effects. We have demonstrated that tuberostemonine (TS), an alkaloid extracted from the traditional Chinese medicine Stemona tuberosa Lour can inhibit intracellular fat deposition, reduce oxidative stress, increase cellular adenosine triphosphate (ATP), and increase mitochondrial membrane potential. It effectively reduced weight gain and fat accumulation caused by a high-fat diet, and regulated liver function and blood lipid levels. Moreover, it regulate glucose metabolism and improved energy metabolism in mice. TS also decreased high-fat diet-induced obesity and improved lipid and glucose metabolism disorders in mice, with no significant side effects. In conclusion, TS was shown to be a safe alternative for obese patients and might be developed as an antiobesity and anti-nonalcoholic fatty liver drug.
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Alcaloides , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Obesidad/etiología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Alcaloides/farmacología , Lípidos , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Hígado/metabolismoRESUMEN
Many non-nucleoside human cytomegalovirus (HCMV) inhibitors have been reported in patent and scientific literature, however, none have reached commercialization despite the urgent need for new HCMV treatments. Herein we report select compounds from different templates that all had low micromolar human ether-à-go-go (hERG) ion channel IC50 values. We also describe a series of pyrroloquinoline derivatives that were designed and synthesized to understand the effect of various substitution on human cytomegalovirus (HCMV) polymerase activity, antiviral activity, and hERG inhibition. These results demonstrated that hERG inhibition can be significantly altered based on the substitution on this template. An HCMV inhibitor with low hERG inhibition and reduced cytotoxicity is also described. The results suggest substitution can be fine tuned for the non-nucleoside polymerase inhibitors to reduce hERG inhibition and maintain HCMV antiviral potency.
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Antivirales , Citomegalovirus , Humanos , Antivirales/farmacología , Éter/farmacología , Canales de Potasio Éter-A-Go-Go , Cardiotoxicidad , Éteres de Etila/farmacología , Nucleotidiltransferasas , Éteres/farmacología , Canal de Potasio ERG1 , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
Hepatic fat metabolism may be altered in the context of overnutrition and obesity, often resulting in the accumulation of triglycerides in hepatocytes and leading to nonalcoholic fatty liver disease (NAFLD). Natural plant alkaloids have demonstrated great potential for the prevention and treatment of NAFLD. However, the role of rhynchophylline (RHY) in lipid metabolism is not clear. We explored the role of RHY in lipid metabolism in cells treated with oleic and palmitic acids to mimic high-fat diet (HFD) conditions. RHY attenuated oleic and palmitic acid-induced increases in triglyceride accumulation in HepG2, AML12, and LMH cells. RHY also increased energy metabolism and reduced oxidative stress. We further investigated the effect of RHY on hepatic lipid metabolism in mice fed an HFD including 40 mg/kg RHY. RHY alleviated hepatic steatosis, reduced fat deposition, promoted energy metabolism, and improved glucose metabolism. We investigated the mechanism responsible for this activity by docking with key proteins of lipid metabolism disorders using Discovery Studio software, which showed that RHY interacted well with lipases. Finally, we found that adding RHY promoted lipase activity and lipolysis. In conclusion, RHY ameliorated HFD-induced NAFLD and its complications by increasing lipase activity.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Lipasa , Hígado , Metabolismo de los Lípidos , Triglicéridos , Oxidación-Reducción , Dieta Alta en Grasa , Ratones Endogámicos C57BLRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a major health problem. However, no effective treatments are currently available. Thus, there is a critical need to develop novel drugs that can prevent and treat NAFLD with few side effects. In this study, Tussilagone (TUS), a natural sesquiterpene isolated from Tussilago farfara L, was explored in vitro and in vivo for its potential to treat NAFLD. Our results showed that in vitro TUS reduced oleic acid palmitate acid-induced triglyceride and cholesterol synthesis in HepG2 cells, reduced intracellular lipid droplet accumulation, improved glucose metabolism disorders and increased energy metabolism and reduced oxidative stress levels. In vivo, TUS significantly reduced fat accumulation and improved liver injury in high-fat diet (HFD)-induced mice. TUS treatment significantly increased liver mitochondrial counts and antioxidant levels compared to the HFD group of mice. In addition, TUS was found to reduce the expression of genes involved in lipid synthesis sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FASN), and stearoy-CoA desaturase 1 (SCD1) in vitro and in vivo. Our results suggest that TUS may be helpful in the treatment of NAFLD, suggesting that TUS is a promising compound for the treatment of NAFLD. Our findings provided novel insights into the application of TUS in regulating lipid metabolism.
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BACKGROUND: Central post-stroke pain (CPSP) is an intractable and disabling central neuropathic pain that severely affects patients' lives, well-being, and socialization abilities. However, CPSP has been poorly studied mechanistically and its treatment remains challenging. Here, we used a rat model of CPSP induced by thalamic hemorrhage to investigate its underlying mechanisms and the effect of stellate ganglion block (SGB) on CPSP and emotional comorbidities. METHODS: Thalamic hemorrhage was produced by injecting collagenase IV into the ventral-posterolateral nucleus (VPL) of the right thalamus. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Behavioral tests were carried out to examine depressive and anxiety-like behaviors including the open field test (OFT), elevated plus maze test (EPMT), novelty-suppressed feeding test (NSFT), and forced swim test (FST). The peri-thalamic lesion tissues were collected for immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA). Genetic knockdown of thalamic hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) with microinjection of HIF-1α siRNA and NLRP3 siRNA into the VPL of thalamus were performed 3 days before collagenase injection into the same regions. Microinjection of lificiguat (YC-1) and MCC950 into the VPL of thalamus were administrated 30 min before the collagenase injection in order to inhibited HIF-1α and NLRP3 pharmacologically. Repetitive right SGB was performed daily for 5 days and laser speckle contrast imaging (LSCI) was conducted to examine cerebral blood flow. RESULTS: Thalamic hemorrhage caused persistent mechanical allodynia and anxiety- and depression-like behaviors. Accompanying the persistent mechanical allodynia, the expression of HIF-1α and NLRP3, as well as the activities of microglia and astrocytes in the peri-thalamic lesion sites, were significantly increased. Genetic knockdown of thalamic HIF-1α and NLRP3 significantly attenuated mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Further studies revealed that intra-thalamic injection of YC-1, or MCC950 significantly suppressed the activation of microglia and astrocytes, the release of pro-inflammatory cytokines, the upregulation of malondialdehyde (MDA), and the downregulation of superoxide dismutase (SOD), as well as mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. In addition, repetitive ipsilateral SGB significantly restored the upregulated HIF-1α/NLRP3 signaling and the hyperactivated microglia and astrocytes following thalamic hemorrhage. The enhanced expression of pro-inflammatory cytokines and the oxidative stress in the peri-thalamic lesion sites were also reversed by SGB. Moreover, LSCI showed that repetitive SGB significantly increased cerebral blood flow following thalamic hemorrhage. Most strikingly, SGB not only prevented, but also reversed the development of mechanical allodynia and anxiety- and depression-like behaviors induced by thalamic hemorrhage. However, pharmacological activation of thalamic HIF-1α and NLRP3 with specific agonists significantly eliminated the therapeutic effects of SGB on mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. CONCLUSION: This study demonstrated for the first time that SGB could improve CPSP with comorbid anxiety and depression by increasing cerebral blood flow and inhibiting HIF-1α/NLRP3 inflammatory signaling.
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Accidente Cerebrovascular Hemorrágico , Neuralgia , Accidente Cerebrovascular , Ratas , Animales , Hiperalgesia/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Accidente Cerebrovascular Hemorrágico/complicaciones , Accidente Cerebrovascular Hemorrágico/patología , Depresión/etiología , Depresión/terapia , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ganglio Estrellado/metabolismo , Ganglio Estrellado/patología , Ratas Sprague-Dawley , Accidente Cerebrovascular/patología , Tálamo/metabolismo , Hemorragia Cerebral/patología , Neuralgia/metabolismo , Ansiedad , Colagenasas/metabolismo , Citocinas/metabolismoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent liver disease that is closely related to obesity and metabolic disorders. 5-methoxyflavone (5-MF) is a flavonoid with DNA polymerase-ß inhibitory properties. In this study, we explored the effects of 5-MF on NAFLD and its potential mechanisms using oleic acid/palmitic acid-treated HepG2 cells and high-fat diet-fed C57BL/6J mice. Our results showed that 5-MF not only alleviated fat deposition and hepatic steatosis, but also improved oxidative damage. In addition, 5-MF has the effect of alleviating disorders of glucose metabolism and enhancing energy expenditure in HFD-induced obese mice. Mechanistically, reverse screening methods and molecular docking analysis were used in combination, and revealed that cytochrome P450 1A1 (CYP1A1) is the target for 5-MF. Further experiments showed that 5-MF ameliorated triglycerides deposition by inhibiting the enzyme activity and protein expression of CYP1A1. In conclusion, 5-MF provides a novel strategy for the prevention and treatment of high-fat-induced NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Hígado/metabolismo , Citocromo P-450 CYP1A1/genética , Simulación del Acoplamiento Molecular , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Metabolismo de los LípidosRESUMEN
Chemoinformatic and bioassay-guided fractionation of a gorgonian coral Junceella juncea resulted in the isolation of 45 briarane-type diterpenoids, of which 16 new analogues were characterized. Their structures were identified by extensive analyses of the spectroscopic data. Most isolated briaranes showed significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow-derived macrophages cells (BMMs). Praelolide, one of the active analogues, significantly activates nuclear factor erythroid-2-related factor 2 (Nrf2) nucleus translocation, induces the expression of Nrf2-targeted genes, suppresses reactive oxygen species (ROS) production, abrogates the activation of downstream mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NFκB) signaling, and subsequently attenuates osteoclast differentiation. Mechanically, praelolide interacts with Kelch-like ECH-associated protein 1 (Keap1) protein by non-covalent interaction to interrupt the interaction between Keap1 and Nrf2 and thereby to activate the Nrf2 signaling pathway. In addition, praelolide rescues the bone loss in prednisone-induced zebrafish. The present study provided praelolide as a new natural scaffold to remedy osteoclastogenic bone disease.
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Diterpenos , Osteoclastos , Animales , Diterpenos/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Osteoclastos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Pez Cebra/metabolismo , MacrófagosRESUMEN
Treg cells acquire distinct transcriptional properties to suppress specific inflammatory responses. Transcription characteristics of Treg cells are regulated by epigenetic modifications, the mechanism of which remains obscure. Here, we report that Setd2, a histone H3K36 methyltransferase, is important for the survival and suppressive function of Treg cells, especially those from the intestine. Setd2 supports GATA3+ST2+ intestinal thymic-derived Treg (tTreg) cells by facilitating the expression and reciprocal relationship of GATA3 and ST2 in tTreg cells. IL-33 preferentially boosts Th2 cells rather than GATA3+ Treg cells in Foxp3Cre-YFPSetd2 flox/flox mice, corroborating the constraint of Th2 responses by Setd2 expression in Treg cells. SETD2 sustains GATA3 expression in human Treg cells, and SETD2 expression is increased in Treg cells from human colorectal cancer tissues. Epigenetically, Setd2 regulates the transcription of target genes (including Il1rl1) by modulating the activity of promoters and intragenic enhancers where H3K36me3 is typically deposited. Our findings provide mechanistic insights into the regulation of Treg cells and intestinal immunity by Setd2.
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N-Metiltransferasa de Histona-Lisina , Proteína 1 Similar al Receptor de Interleucina-1 , Intestinos , Linfocitos T Reguladores , Animales , Humanos , Ratones , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/inmunología , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/inmunología , Inflamación/genética , Inflamación/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/genética , Proteína 1 Similar al Receptor de Interleucina-1/inmunología , Linfocitos T Reguladores/inmunología , Timo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Intestinos/inmunologíaRESUMEN
In the title compound, [NiCl2(C20H18N4)2] n , the Ni2+ cation is situated on an inversion center and is coordinated by two chloride ions and four imidazole N atoms of four different 4,4'-bis-[(1H-imidazol-1-yl)meth-yl]-1,1'-biphenyl (BIMB), forming a slightly distorted octa-hedral geometry. Each BIMB ligand adopts a linear linker to connect Ni2+ ions, forming a two-dimensional layer with an sql network. In the crystal, neighboring layers repeat in an ABAB stacking mode, and weak inter-molecular C-Hâ¯Cl hydrogen bonds between alternate layers lead to a three-dimensional, twofold inter-penetrated, supra-molecular framework with a pcu topology net.
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Excessive formation and function of osteoclasts cause various osteolytic bone diseases. Natural products are a potential source for the discovery of new therapeutic candidates to treat bone destruction diseases. In this study, chemical informatics and bioassay guided examination of the marine-derived Aspergillus versicolor F77 fungus chemically resulted in the isolation of seven cyclopeptides, of which versicotides G-J (1-4) are new cyclohexapeptides. Their structures were identified by spectroscopic data in association with Marfey method and single crystal X-ray diffraction data for configurational assignments. Bioassay revealed that versicotide G (1, VG) is the most active among the analogs to suppress the receptor activator of nuclear factor-KB ligand (RANKL)-induced osteoclastogenesis in bone marrow derived monocytes (BMMs) without affecting BMMs viability. VG also suppressed RANKL-induced actin-ring formation and resorbing function of osteoclast dose-dependently. Mechanistically, VG attenuated RANKL-induced intracellular calcium elevation by inhibiting PLCγ1 phosphorylation and blocking the activation of downstream phosphatase calcineurin. In addition, VG abrogated the expression and translocation of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), leading to the downregulation of the expression of osteoclast-specific genes and the abolishment of the osteoclast formation. In the in vivo test, VG suppressed osteoclast formation and bone loss in Ti-induced calvarial osteolytic mouse model.These findings imply that VG is a promising candidate for the remedy of bone destruction-related diseases.
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Osteogénesis , Osteólisis , Ratones , Animales , Osteólisis/inducido químicamente , Osteólisis/metabolismo , Ligando RANK/farmacología , Ligando RANK/metabolismo , Osteoclastos/metabolismo , Diferenciación Celular , Ratones Endogámicos C57BLRESUMEN
Lipid metabolism disorders affect the growth and jeopardize the health of poultry, thus, decreasing economic benefits. Perillartine, a sweetener derived from Perilla frutescens, has excellent potential in regulating lipid metabolism. In this study, we explored the effects of perillartine on lipid metabolism in broiler chickens by establishing a nonalcoholic fatty liver model induced by a high-fat diet. By using network pharmacology and molecular docking, we analyzed the potential molecular targets and pathways through which perillartine regulates lipid metabolism and alleviates fatty liver. Perillartine was found to regulate the expression of genes associated with lipogenesis, lipolysis, and lipid transport, including FASN, PPARα, CPT-1, ACCα, APOB, and APOA1 in the liver, and to decrease lipid accumulation in the liver and blood in broilers without affecting growth performance. In addition, we discovered 24 candidate targets of perillartine, including SRD5A2 and XDH, through network pharmacology analysis and successfully constructed a compound-target-pathway-disease network. Our results suggested that perillartine may be a promising, long-lasting therapeutic molecule for modulating lipid metabolism disorders in broilers.
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Pollos , Trastornos del Metabolismo de los Lípidos , Animales , Pollos/metabolismo , Ciclohexenos , Dieta , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Metabolismo de los Lípidos , Trastornos del Metabolismo de los Lípidos/metabolismo , Lípidos , Hígado/metabolismo , Simulación del Acoplamiento Molecular , Monoterpenos , OximasRESUMEN
BACKGROUND: The distribution of allergens has geographic characteristics. Local epidemiological data provides evidence-based strategies for the prevention and management of allergic diseases. Age and sex differences may exist in the prevalence of sensitivity to various allergens. We investigated the distribution of common allergens in allergic children in Shanghai, southeastern China. METHODS: 39,926 children 1 month to 18 years of age diagnosed with allergic diseases were tested for the presence of serum-specific Immunoglobulins E (sIgE) to 17 allergens common to this region, using a reversed enzyme allergosorbent test. RESULTS: 25,757 (64.5%) of the subjects showed elevated sIgE to at least one of the tested allergens. House mite and dust mite were the most common aeroallergens, while egg and milk were the most common food allergens. The most common aeroallergens and food allergens were similar among each allergic disease. By age-group analysis, the positive rates of aeroallergens were higher at older age. Several peaks of sensitization to food allergens were observed in children between 1 and 3 years of age for eggs, milk, nut, crab and shrimp. In addition, the sensitization to beef and mango was highest in children 3-6 years of age. The rate of positive sIgE detection was higher in males than females for all the tested allergens except cockroach, trees and beef. Considering the interplay between sex and ages and other related components (including season, monthly temperature, humidity, air quality index, test rate of patients), the sIgE positive rates of the main aeroallergens increased with age, while the main food allergens decreased; males are more sensitive to several aeroallergens (including dust mite, house mite, cat epithelium, dog epithelium and mulberry). CONCLUSIONS: House mite, dust mite, milk, and egg are major allergens in Shanghai. Children at younger age are more sensitive to food allergens, while increasing overall prevalence of sensitization can be found with increasing age. Boys have higher positive rates of sIgE responses than girls. Knowledge of the prevalence of allergen sensitization in different age groups and sex may help facilitate diagnosis and intervention efforts to mitigate the impact of allergic diseases in this large geographical region. This approach may be extrapolated to other regions.
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Alérgenos , Hipersensibilidad a los Alimentos , Alérgenos/análisis , Niño , Preescolar , China/epidemiología , Femenino , Hipersensibilidad a los Alimentos/epidemiología , Humanos , Inmunoglobulina E , Masculino , Caracteres SexualesRESUMEN
Objectives: This study aimed to assess the associations of caesarean delivery (CD) with risk of wheezing diseases and changes of immune cells in children. Design: The cross-sectional study was conducted between May, 2020 and April, 2021. Setting and participants: The study was conducted in Shanghai Children's Medical Center, Shanghai, China. A total of 2079 children with a mean age of 36.97 ± 40.27 months and their guardians were included in the present study via face-to-face inquiry and physical examination by clinicians. Methods: Logistic regression was applied to estimate odds ratio (ORs) and 95% confidence intervals (CIs) for the association between CD and first episode of wheezing (FEW) or asthma. Models were adjusted for premature or full-term delivery, exclusive breastfeeding (at least 4 months) or not. Results: Among the 2079 children, 987 children (47.47%) were born by CD and 1092 (52.53%) by vaginal delivery (VD). Children delivered by caesarean had significantly lower gestational age (P<0.01) compared with those who delivered vaginally. Our results also showed that CD was related to increased risk of FEW by the age of 3(adjusted OR 1.50, 95%CI 1.06, 2.12) and increased tendency to develop asthma by the age of 4 (adjusted OR 3.16, 95%CI 1.25, 9.01). The subgroup analysis revealed that the negative effects of CD on asthma were more obvious in children without exclusive breastfeeding (adjusted OR 4.93, 95%CI 1.53, 21.96) or without postnatal smoking exposure (adjusted OR 3.58, 95%CI 1.20, 13.13). Furthermore, compared with children born through VD, a significant change of the T cells (increased proportion of CD4+ T cells and decreased number and proportion of CD8+ T cells) were observed before the age of one in the CD group. However, the changes were insignificant in children over 1 year old. Conclusions: This study showed age-dependent associations of CD with asthma and FEW in offspring. Moreover, CD appeared to have an effect on the cellular immunity in infants, the disorder of which may contribute to the development of asthma in children.