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BACKGROUND: Hyperlipidemia, inadequate diet, and excessive medication increase the risk of cardiovascular disease. Paeonl (Pae), a phenolic compound found in Peony and Angelica dahurica, can alleviate lipid metabolism disorders and lipotoxicity. However, the molecular mechanism of Pae alleviating hyperlipidemia remains unclear and needs to be further explored. PURPOSE: In this study, we explored whether Pae can prevent hyperlipidemia and investigated the molecular mechanisms. METHODS: The effects of Pae (30, 45, 60mg·kg-1) on hyperlipidemia in Tyloapol-induced WT mice and Nrf2 knockout mice (Pae: 60mg·kg-1) were detected by oil red O staining, HE staining, TG, TC and other indexes. The expression levels of proinflammatory mediators, key lipid proteins and autophagy signaling pathway proteins were analyzed by enzyme-linked immunosorbent assay, western blot and immunofluorescence. The molecular mechanism of Pae alleviating hyperlipidemia was explored through molecular docking technique and in vivo and in vitro experiments. RESULTS: Several studies indicated that Pae effectively improved tyloxapol (Ty)-induced lipid metabolism disorder, as evidenced by decreased triglyceride content, increased carnitine palmitoyltransferase 1 (CPT1), and Sirtuin 1 (Sirt1) protein expression. In addition, Pae ameliorated hyperlipidemia by activating the AMPK/ACC and PI3K/mTOR pathways. Interestingly, the therapeutic effect of Pae on hyperlipidemia was markedly reduced in Nrf2-/- mice. Molecular docking results indicated that Pae and Nrf2 exhibited good binding ability, suggesting that Nrf2 is a core target mediating the effects of Pae in the treatment of hyperlipidemia. Taken together, Pae alleviated hyperlipidemia in vivo and ameliorated lipid accumulation in vitro by activating AMPK/ACC and PI3K/mTOR signaling pathways via Nrf2 binding. CONCLUSION: Our data suggest that paeonol can ameliorate hyperlipidemia and autophagy in mice by regulating Nrf2 and AMPK/mTOR pathways, and it has potential therapeutic value in the occurrence and development of hyperlipidemia.
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Proteínas Quinases Ativadas por AMP , Acetofenonas , Autofagia , Hiperlipidemias , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Serina-Treonina Quinases TOR/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Hiperlipidemias/tratamento farmacológico , Autofagia/efeitos dos fármacos , Acetofenonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Simulação de Acoplamento MolecularRESUMO
Ketosis, a commonly observed energy metabolism disorder in dairy cows during the peripartal period, is distinguished by increased concentrations of BHB in the blood. This condition has a negative impact on milk production and quality, causing financial losses. An untargeted metabolomics approach was performed on plasma samples from cows between 5 and 7 DIM diagnosed as controls (CON; BHB <1.2 mM, n = 30), subclinically ketotic (SCK; 1.2 < BHB <3.0 mM, n = 30), or clinically ketotic (CK; BHB >3.0 mM, n = 30). Cows were selected from a commercial farm of 214 Holstein cows (average 305-d yield in the previous lactation of 35.42 ± 7.23 kg/d; parity, 2.41 ± 1.12; BCS, 3.1 ± 0.45). All plasma and milk samples (n = 90) were subjected to liquid chromatography-MS-based metabolomic analysis. Statistical analyses were performed using GraphPad Prism 8.0, MetaboAnalyst 4.0, and R version 4.1.3. Compared with the CON group, both SCK and CK groups had greater milk fat, freezing point, and fat-to-protein ratio, as well as lower milk protein, lactose, solids-not-fat, and milk density. Within 21 d after calving, compared with CON, the SCK group experienced a reduction of 2.65 kg/d in milk yield, while the CK group experienced a decrease of 7.7 kg/d. Untargeted metabolomics analysis facilitated the annotation of a total of 5,259 and 8,423 metabolites in plasma and milk. Differentially affected metabolites were screened in CON versus SCK, CON versus CK, and SCK versus CK (unpaired t-test, false discovery rate <0.05; and absolute value of log(2)-fold change >1.5). A total of 1,544 and 1,888 differentially affected metabolites were detected in plasma and milk. In plasma, glycerophospholipid metabolism, pyrimidine metabolism, tryptophan metabolism, sphingolipid metabolism, amino sugar and nucleotide sugar metabolism, phenylalanine metabolism, and steroid hormone biosynthesis were identified as important pathways. Weighted gene co-expression network analysis (WGCNA) indicated that tryptophan metabolism is a key pathway associated with the occurrence and development of ketosis. Increases in 5-hydroxytryptophan and decreases in kynurenine and 3-indoleacetic acid in SCK and CK were suggestive of an impact at the gut level. The decrease of most glycerophospholipids indicated that ketosis is associated with disordered lipid metabolism. For milk, pyrimidine metabolism, purine metabolism, pantothenate and CoA biosynthesis, amino sugar and nucleotide sugar metabolism, nicotinate and nicotinamide metabolism, sphingolipid metabolism, and fatty acid degradation were identified as important pathways. The WGCNA indicated that purine and pyrimidine metabolism in plasma was highly correlated with milk yield during the peripartal period. Alterations in purine and pyrimidine metabolism characterized ketosis, with lower levels of these metabolites in both milk and blood underscoring reduced efficiency in nitrogen metabolism. Our results may help to establish a foundation for future research investigating mechanisms responsible for the occurrence and development of ketosis in peripartal cows.
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Doenças dos Bovinos , Cetose , Lactação , Metabolômica , Leite , Animais , Bovinos , Leite/química , Leite/metabolismo , Feminino , Cetose/veterinária , Cetose/metabolismo , Cetose/sangue , Doenças dos Bovinos/metabolismo , Doenças dos Bovinos/sangueRESUMO
BACKGROUNDS: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. The leaves of Broussonetia papyrifera contain a large number of flavonoids, which have a variety of biological functions. METHODS: In vitro experiments, free fatty acids were used to stimulate HepG2 cells. NAFLD model was established in vivo in mice fed with high fat diet (HFD) or intraperitoneally injected with Tyloxapol (Ty). At the same time, Total flavonoids of Broussonetia papyrifera (TFBP) was used to interfere with HepG2 cells or mice. RESULTS: The results showed that TFBP significantly decreased the lipid accumulation induced by oil acid (OA) with palmitic acid (PA) in HepG2 cells. TFBP decreased the total cholesterol (TC), the triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDLC) in serum. TFBP could also effectively inhibit the generation of reactive oxygen species (ROS) and restrained the level of myeloperoxidase (MPO), and enhance the activity of superoxide dismutase (SOD) to alleviate the injury from oxidative stress in the liver. Additionally, TFBP activated nuclear factor erythroid-2-related factor 2 (Nrf2) pathway to increasing the phosphorylation of AMP-activated protein kinase (AMPK). Meanwhile, protein levels of mTORC signaling pathway were evidently restrained with the treatment of TFBP. CONCLUSION: Our experiments proved that TFBP has the therapeutic effect in NAFLD, and the activation of Nrf2 and AMPK signaling pathways should make sense.
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Proteínas Quinases Ativadas por AMP , Broussonetia , Flavonoides , Fator 2 Relacionado a NF-E2 , Hepatopatia Gordurosa não Alcoólica , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Humanos , Camundongos , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Broussonetia/química , Dieta Hiperlipídica/efeitos adversos , Flavonoides/farmacologia , Células Hep G2/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismoRESUMO
Chromium propionate (Cr-Pro) and calcium propionate (Ca-Pro) are widely applied in dairy production, especially in the alleviation of heat stress (HS). HS can reduce the abundance of rumen microbiota and the lactation performance of dairy cows. The present work mainly focused on evaluating the effects of Cr-Pro and Ca-Pro on the performance, ruminal bacterial community, and stress of postpartum HS dairy cows as well as identifying the differences in their mechanisms. Fifteen multiparous postpartum Holstein cows with equivalent weights (694 ± 28 kg) and milk yields (41.2 ± 1.21 kg/day) were randomly divided into three groups: control (CON), Cr-Pro (CRPR), and Ca-Pro (CAPR). The control cows received the basal total mixed ration (TMR) diet, while the CRPR group received TMR with 3.13 g/day of Cr-Pro, and the CAPR group received TMR with 200 g/day of Ca-Pro. The rumen microbial 16S rRNA was sequenced using the Illumina NovaSeq platform along with the measurement of ruminal volatile fatty acids (VFAs) and milking performance. Cr-Pro and Ca-Pro improved lactation performance, increased the rumen VFA concentration, and altered the rumen microbiota of the HS dairy cows. Cr-Pro significantly improved the milk yield (p < 0.01). The richness and diversity of the microbial species significantly increased after feeding on Ca-Pro (p < 0.05). Gene function prediction revealed increased metabolic pathways and biological-synthesis-related function in the groups supplemented with Cr-Pro and Ca-Pro. Our results indicate that the application of Cr-Pro or Ca-Pro can provide relief for heat stress in dairy cows through different mechanisms, and a combination of both is recommended for optimal results in production.
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PANoptosis is an intricate programmed death pathway that involves the interaction between pyroptosis, apoptosis, and necroptosis. We systematically explored the protective effect of Echinacea polyphenols (EPP) against the lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the underlying mechanisms both in vitro and in vivo. We noted that EPP pretreatment could significantly alleviate LPS-induced lung tissue injury and pulmonary edema. EPP inhibited the PANoptosis by regulating the expression of nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, gasdermin D, caspase-8, caspase-3, and mixed lineage kinase domain-like protein. Meanwhile, a comparative study of EPP and inducible nitric oxide synthase inhibitor S-methylisothiourea sulfate indicated that EPP may play a preprotective role in inhibiting PANoptosis via reducing the activity of inducible nitric oxide synthase and the production of nitric oxide (NO) during ALI. Our results clearly indicated that PANoptosis existed in LPS-induced ALI, and EPP pretreatment could provide obvious protective effects to LPS-induced ALI by inhibiting PANoptosis, which may be related to NO production.
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Lesão Pulmonar Aguda , Echinacea , Piroptose , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipopolissacarídeos/efeitos adversos , Óxido Nítrico/metabolismo , Polifenóis , Necroptose , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Inflamassomos/metabolismo , Apoptose , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/genéticaRESUMO
Subclinical hyperketonemia (SCHK) is the major metabolic disease observed during the transition period in dairy goats, and is characterized by high plasma levels of nonesterified fatty acids (NEFA) and ß-hydroxybutyrate (BHB). However, no prior study has comprehensively assessed metabolomic profiles of dairy goats with SCHK. Plasma samples were collected within 1 h after kidding from SCHK goats (BHB concentration >0.8 mM, n = 7) and clinically healthy goats (BHB concentration <0.8 mM, n = 7) with similar body condition score (2.75 ± 0.15, mean ± standard error of the mean) and parity (primiparous). A combination of targeted and untargeted mass spectrometric approaches was employed for analyzing the various changes in the plasma lipidome and metabolome. Statistical analyses were performed using the GraphPad Prism 8.0, SIMCA-P software (version 14.1), and R packages (version 4.1.3). Plasma aminotransferase, nonesterified fatty acids, and BHB concentrations were greater in the SCHK group, but plasma glucose concentrations were lower. A total of 156 metabolites and 466 lipids were identified. The analysis of untargeted metabolomics data by principal component analysis and orthogonal partial least squares discriminant analysis revealed a separation between SCHK and clinically healthy goats. According to the screening criteria (unpaired t-test, P < 0.05), 30 differentially altered metabolites and 115 differentially altered lipids were detected. Pathway enrichment analysis identified citrate cycle, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine metabolism as significantly altered pathways. A greater concentration of plasma isocitric acid and cis-aconitic acid levels was observed in SCHK goats. In addition, AA such as lysine and isoleucine were greater, whereas alanine and phenylacetylglycine were lower in SCHK dairy goats. Dairy goats with SCHK also exhibited greater oleic acid, acylcarnitine, and phosphatidylcholine and lower choline and sphingomyelins. Acylcarnitines, oleic acid, and tridecanoic acid displayed positive correlations with several lipid species. Alanine, hippuric acid, and histidinyl-phenylalanine were negatively correlated with several lipids. Overall, altered metabolites in SCHK dairy goats indicated a more severe degree of negative energy balance. Data also indicated an imbalance in the tricarboxylic acid (TCA) cycle, lipid metabolism, and AA metabolism. The findings provide a more comprehensive understanding of the pathogenesis of SCHK in dairy goats.
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Doenças das Cabras , Cetose , Gravidez , Feminino , Animais , Lactação , Lipidômica , Ácidos Graxos não Esterificados , Metabolômica , Cetose/veterinária , Ácido 3-Hidroxibutírico , Alanina , Cabras , Fenilalanina , Ácidos OleicosRESUMO
Baicalin is an active ingredient extracted from the Chinese medicine Scutellaria and has many beneficial effects. Pulmonary interstitial and alveolar edema are common symptoms of an acute lung injury (ALI). We investigated the effects of baicalin on LPS-induced inflammation and the underlying mechanisms in mice and cells. The protein contents and mRNA expression of TNF-α, IL-1ß, and IL-6 in RAW264.7 cells and mice were detected using ELISA and qRT-PCR. Baicalin significantly suppressed TNF-α, IL-1ß, and IL-6 levels and expression, both in vitro and in vivo, compared with the LPS group. Baicalin inhibits the expression of TLR4 and MyD88, resulting in significant decreases in p-p65, p-p38, p-ERK, and p-JNK, as measured by the Western blotting of RAW264.7 cells. A baicalin treatment for 12 h resulted in a rapid increasing of the white blood cell number and significantly improved the pathological changes in the lung. We also found that the baicalin pretreatment for 12 h could decrease the MPO content and wet/dry (W/D) weight ratio, which indicates that baicalin can significantly reduce pulmonary edema. Furthermore, the baicalin pretreatment also resulted in the recovery of TGF-ß protein levels and decreased iNOS. Baicalin inhibits ALI inflammation in mice and cells and is a potential candidate for the treatment of ALI.
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Lesão Pulmonar Aguda , Flavonoides , Pneumonia , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Inflamação/patologia , Interleucina-6/metabolismo , Lipopolissacarídeos , Pulmão , NF-kappa B/metabolismo , Pneumonia/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Flavonoides/farmacologia , Células RAW 264.7RESUMO
BACKGROUND: NAFLD is a liver disease that is caused by liver damage or extreme lipid deposition but not alcohol. Nrf2 could mediate resistance to oxidative stress injury. Autophagy can degrade metabolic waste and accumulated toxic endogenous substances. Pterostilbene (PTE) is an active compound extracted from blueberry, and grape, that exhibits many biological effects, such as antiinflammation and antitumor. PURPOSE: This study provides a mechanism of PTE affecting on oxidative stress and autophagy in NAFLD mice. Tyloxapol, oil acid (OA) and palmitic acid (PA) were used to induce lipid accumulation in mice and HepG2 cells. METHODS: Western blotting, CRISPR/Cas 9 and other molecular biological approaches were applied to explore the mechanisms of PTE effected on NAFLD. RESULTS: PTE pretreatment effectively reduced the lipid accumulation in OA and PA induced HepG2 cells and tyloxapol induced mice, and significantly promoted the expression of nNrf2, PPAR-α and HO-1, and AMPK activity, but inhibited the expression of mTORC 1 and SREBP-1c. PTE activated phosphatidylinositide 3-kinase (PI3K) and proteins in the autophagy-related gene (ATG) family, and promoted the transformation of LC3â to LC3â ¡ which indicated the activation of autophagy, however, these effects were abolished after Nrf2 knockout. CONCLUSION: PTE effectively alleviated oxidative stress damage induced by excessive lipid accumulation in hepatocytes, thus promoting the metabolism and decomposition of fatty acids to improve NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Estresse Oxidativo , Autofagia , Ácidos Graxos , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BLRESUMO
The present study evaluated the effects of strontium (Sr) on proliferation and differentiation of chondrocytes isolated from dairy cows, and whether Sr exerts its effects via transforming growth factor ß (TGFß) signaling. The chondrocytes were isolated from patellar cartilage from newborn Holstein bull calves (n = 3, 1 day old, 38.0 ± 2.8 kg, fasting) within 15 min after euthanasia, and treated with different concentrations of Sr (0, 0.1, 1, and 10 µg/ml, as SrCl2·6H2O). After pretreatment with or without activin receptor-like kinase 5 (ALK5) inhibitor (10 µM SB-505124) for 4 h, chondrocytes were incubated with Sr for another 4 h. Overall effects of Sr were evaluated relative to NaCl as the control. In contrast, the 1 µg/ml Sr-treated group served as the control to determine effects of preincubating with SB-505124. Western blot and qRT-PCR were used for measuring expression of proliferation-, differentiation-, and TGFß1-responsive factors. Data were analyzed using one-way ANOVA in GraphPad Prism 7.0. Incubation with all doses of Sr increased TGFß1/ALK5-induced SMAD3 phosphorylation, and at 10 µg/ml it inhibited ALK1-induced SMAD1/5/9 phosphorylation. Expression of mRNA and protein of the proliferation-responsive factors type â ¡ Collagen α1 (COL2A1) and aggrecan (ACAN) was induced by Sr at 1 µg/ml. In contrast, Sr at 10 µg/ml inhibited the expression of differentiation-responsive factors type â © Collagen α1 (COL10A1) and secreted phosphoprotein 1 (SPP1), and at 1 µg/ml it had the same effect on alkaline phosphatase (ALPL) mRNA and protein levels. Cells were stained with PI/RNase Staining buffer to assess cell cycle activity using flow-cytometry. Incubation with Sr at 1 and 10 µg/ml induced an increase in the number of cells in the S-phase, leading to an increase in the proliferation index. Incubation with SB-505124 inhibited phosphorylation of SMAD3. Abundance of ACAN and COL2A1 mRNA and protein was lower when cells were pre-incubated with SB-505124. Overall, data indicated that Sr promotes proliferation and inhibits differentiation of primary chondrocytes by directing TGFß1 signaling towards SMAD3 phosphorylation rather than SMAD1/5/9 phosphorylation. Whether these effects occur in vivo remains to be determined and could impact future application of Sr as an experimental tool in livestock.
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In this paper, we consider how to incorporate psychophysical measurements of human visual perception into the loss function of a deep neural network being trained for a recognition task, under the assumption that such information can reduce errors. As a case study to assess the viability of this approach, we look at the problem of handwritten document transcription. While good progress has been made towards automatically transcribing modern handwriting, significant challenges remain in transcribing historical documents. Here we describe a general enhancement strategy, underpinned by the new loss formulation, which can be applied to the training regime of any deep learning-based document transcription system. Through experimentation, reliable performance improvement is demonstrated for the standard IAM and RIMES datasets for three different network architectures. Further, we go on to show feasibility for our approach on a new dataset of digitized Latin manuscripts, originally produced by scribes in the Cloister of St. Gall in the the 9th century.
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Algoritmos , Redes Neurais de Computação , Escrita Manual , Humanos , PercepçãoRESUMO
The present study was conducted regarding four acute-phase proteins (APPs) including C-reactive protein (CRP), ceruloplasmin (CP), serum amyloid A (SAA), and haptoglobin (HP) in dairy goats during the periparturient period. The aim of this study was to detect the changes in APPs in plasma during the periparturient period of healthy dairy goats. Guanzhong dairy goats with no other symptoms (n = 15) were selected on the basis of their blood calcium (Ca) and ß-hydroxybutyrate (BHBA) concentration. The plasma was collected once a week for ±3 weeks delivery. The concentrations of the four APPs mentioned above were determined using goat-specific ELISA kits. The results showed the CRP level in plasma decreased from 3 weeks to 1 week antepartum and increased later until 1 week postpartum and then decreased to a similar level with antepartum between 1 and 3 weeks postpartum. The content of CP showed a decline in 3 weeks before parturition and an upward trend between 1 week antepartum and 3 weeks postpartum. The SAA concentration decreased from 3 weeks antepartum to 2 weeks postpartum and rebounded later. The level of HP decreased during 3 weeks before parturition and increased until 1 week postpartum, then reached a stable value. Clear variation range and rules of APPs contribute to perinatal health monitoring of dairy goats.
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The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is closely related to the alleviation of nonalcoholic fatty liver disease (NAFLD) by regulating oxidative stress and lipid homeostasis. Gentiopicroside (GPS), an iridoid glycoside found in the Gentianaceae, possesses anti-inflammatory and antioxidant effects. However, the protective effects of GPS on lipid accumulation and oxidative damage have not been investigated thoroughly in free fatty acid- (FFA-) induced HepG2 cells and tyloxapol- (Ty-) induced hyperlipidemia mice. Cell counting kit-8 assays, Oil Red O staining, Western blotting analysis, extraction of nuclear and cytosolic proteins, and biochemical index assay were employed to explore the mechanisms by which GPS exerts a protective effect on FFA-induced HepG2 cells and Ty-induced hyperlipidemia mouse model. This paper demonstrates that GPS could effectively alleviate NAFLD by elevating cell viability, reducing fatty deposition, downregulating TG, and activating nucleus Nrf2 in FFA-induced HepG2 cells. Meanwhile, GPS significantly regulated the activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, Nrf2 antioxidant pathway, peroxisome proliferator-activated receptor α (PPARα), and GPS-inhibited sterol regulatory element-binding protein-1c (SREBP-1c) expression in FFA-stimulated lipid accumulation of HepG2 cells and Ty-treated mice. Interestingly, we highlight that PI3K/AKT inhibitor (LY294002) markedly increased the expression of Nrf2 antioxidant pathway, PPARα, and downregulated SREBP-1c in FFA-stimulated HepG2 cells. For these reasons, we found that the deletion of Nrf2 could lose the protective effects of GPS on the Nrf2 antioxidant pathway and PPARα activation and SREBP-1c inactivation in FFA-stimulated HepG2 cells and Ty-treated mice. GPS treatment had no effect on abnormal lipogenesis and antioxidant enzymes in Ty-induced Nrf2-/- mice. This work gives a new explanation that GPS may be a useful therapeutic strategy for NAFLD through upregulation of the Nrf2 antioxidant pathway, which can alleviate oxidative damage and lipid accumulation.
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Antioxidantes/farmacologia , Glucosídeos Iridoides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos não Esterificados/farmacologia , Células Hep G2 , Humanos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Lipogênese/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Non-alcohol fatty liver disease (NAFLD) is a common disease which causes serious liver damage. Geniposide (GEN), a kind of iridoid glycoside extracted from Gardenia jasminoides fruit, has many biological effects, such as resistance to cell damage and anti-neurodegenerative disorder. Lipid accumulation was obvious in tyloxapol-induced liver and oil acid (OA) with palmitic acid (PA)-induced HepG2 cells compared with the control groups while GEN improved the increasing conditions. GEN significantly lessened the total cholesterol (TC), the triglyceride (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), myeloperoxidase (MPO), reactive oxygen species (ROS) and increased high-density lipoprotein (HDL), superoxide dismutase (SOD) to response the oxidative stress via activating nuclear factor erythroid-2-related factor 2 (Nrf2), haeme oxygenase (HO)-1 and peroxisome proliferator-activated receptor (PPAR)α which may influence the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway in mice and cells. Additionally, GEN evidently decreased the contents of sterol regulatory element-binding proteins (SREBP)-1c, phosphorylation (P)-mechanistic target of rapamycin complex (mTORC), P-S6K, P-S6 and high mobility group protein (HMGB) 1 via inhibiting the expression of phosphoinositide 3-kinase (PI3K), and these were totally abrogated in Nrf2-/- mice. Our study firstly proved the protective effect of GEN on lipid accumulation via enhancing the ability of antioxidative stress and anti-inflammation which were mostly depend on up-regulating the protein expression of Nrf2/HO-1 and AMPK signalling pathways, thereby suppressed the phosphorylation of mTORC and its related protein.
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Proteínas Quinases Ativadas por AMP/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Iridoides/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Células Hep G2 , Humanos , Inflamação , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Ácido Palmítico/química , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Polietilenoglicóis , Transdução de SinaisRESUMO
Chicoric acid is polyphenol of natural plant and has a variety of bioactivity. Caused by various kinds of stimulating factors, acute liver injury has high fatality rate. The effect of chicoric acid in acute liver injury induced by Lipopolysaccharide (LPS) and d-galactosamine (d-GalN) was investigated in this study. The results showed that CA decreased the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum and reduced the mortality induced by LPS/d-GalN. CA can restrain mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) to alleviate inflammation. Meanwhile, the results indicated CA can active nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway with increasing the level of AMP-activated protein kinase (AMPK). And with the treatment of CA, protein levels of autophagy genes were obvious improved. The results of experiments indicate that CA has protective effect in liver injury, and the activation of AMPK and autophagy may make sense.
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Ácidos Cafeicos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Succinatos/farmacologia , Quinases Proteína-Quinases Ativadas por AMP , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Autofagia/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Galactosamina/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação/sangue , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Proteínas Quinases/genéticaRESUMO
Subacute ruminal acidosis (SARA) can increase the level of inflammation and induce rumenitis in dairy cows. Berberine (BBR) is the major active component of Rhizoma Coptidis, which is a type of Chinese anti-inflammatory drug for gastrointestinal diseases. The purpose of this study was to investigate the anti-inflammatory effects of BBR on lipopolysaccharide (LPS)-stimulated rumen epithelial cells (REC) and the underlying molecular mechanisms. REC were cultured and stimulated with LPS in the presence or absence of different concentrations of BBR. The results showed that cell viability was not affected by BBR. Moreover, BBR markedly decreased the concentrations and mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in the LPS-treated REC in a dose-dependent manner. Importantly, Western blotting analysis showed that BBR significantly suppressed the protein expression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein (MyD88) and the phosphorylation of nuclear factor-κB (NF-κB), inhibitory kappa B (IκBα), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) in LPS-treated REC. Furthermore, the results of immunocytofluorescence showed that BBR significantly inhibited the nuclear translocation of NF-κB p65 induced by LPS treatment. In conclusion, the protective effects of BBR on LPS-induced inflammatory responses in REC may be due to its ability to suppress the TLR4-mediated NF-κB and MAPK signaling pathways. These findings suggest that BBR can be used as an anti-inflammatory drug to treat inflammation induced by SARA.
Assuntos
Berberina/farmacologia , Citocinas/metabolismo , Lipopolissacarídeos/toxicidade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Bovinos , Citocinas/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , NF-kappa B/genética , Rúmen , Receptor 4 Toll-Like/genéticaRESUMO
Aucubin (AU) is the main active ingredient of Aucuba japonica which has showed many positive effects such as anti-inflammation and liver protection. Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. In this research, we explored the effects of AU on the tyloxapol-induced NAFLD in mice and apolipoprotein C-III (apoC-III) induced-3T3L1 cells. Tyloxapol (300 mg/kg) was injected to C57BL/6 mice with aucubin. The differentiated 3T3-L1 cells were treated with or without aucubin after stimulation of apoC-III (100 µg/mL). In results, aucubin inhibited hyperlipidaemia, oxidative stress and inflammation by influencing the content of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL), myeloperoxidase (MPO), superoxide dismutase (SOD), tumour necrosis factor receptor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 in blood. AU activated NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor α (PPARα), PPARγ and hemeoxygenase-1 (HO-1) and promoted the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPKα), AMPKß, acetyl-CoA carboxylase (ACC) and protein kinase B (AKT). In conclusion, AU performed the function of hypolipidaemic by its obvious anti-inflammation and antioxidant activity, which may become a kind of new drug targeting at NAFLD.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Heme Oxigenase-1/metabolismo , Glucosídeos Iridoides/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Colesterol/metabolismo , Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/metabolismoRESUMO
Morin (MO), a natural bioflavinoid, exists in many herbs. Previous studies have acclaimed MO's anti-inflammatory, antidiabetic, antioxidant, antifibrotic, anticancer, and antihyperglycemic biological effects. This study aimed to assess the molecular mechanism of MO involved in the oleic acid (OA)-induced inflammatory damage and lipid accumulation in HepG2 cell and tyloxapol (Ty)-induced hyperlipidemia in mice. We found that MO can efficaciously mitigate reactive tumor necrosis factor-α (TNF-α) level and triglyceride (TG) accumulation in OA-induced HepG2 cell and in tyloxapol-induced mice. Next, the study testified that MO apparently suppressed OA-excited nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways in HepG2 cell. In addition, MO distinctly upregulated the expression of peroxisome proliferator-activated receptor α (PPARα) and decreased the expression of sterol regulatory element-binding protein 1c (SREBP-1c) in OA-induced HepG2 cell and in tyloxapol-induced mice, both of which are dependent upon the phosphorylation of acetyl-CoA carboxylase (ACC), adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and protein kinase B (AKT). In conclusion, these results suggest that MO has protective potential against hyperlipidemia and steatosis, and the potential mechanism may have a close relation with activation of PPARα and inhibition of SREBP-1c.
Assuntos
Flavonoides/farmacologia , Hiperlipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Quinases Proteína-Quinases Ativadas por AMP , Acetil-CoA Carboxilase/genética , Animais , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Inflamação/induzido quimicamente , Inflamação/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Ácido Oleico/toxicidade , PPAR alfa/genética , Fosforilação/efeitos dos fármacos , Polietilenoglicóis/toxicidade , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismoRESUMO
Rosmarinic acid (RA) has antioxidation, anticancer, antibacterial, anti-inflammatory and various biological functions. In our study, we aim to evaluate effects of RA on acute liver injury caused by LPS and d-galactosamine (d-GalN) and its underlying molecular mechanism in mice. Our findings showed that RA could protect C57BL/6 mice from LPS/d-GalN-induced acute liver injury, which not only reflected on declining aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of the serum, but also restrained the phosphorylation of nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK1/2) and p38 protein expression and the content of tissue myeloperoxidase (MPO) elevation. Moreover, RA could enhance the level of glutathione-dependent peroxidase (GSH-PX). Furthermore, RA promoted that nuclear factor erythroid-2-related factor 2 (Nrf2) transported into nucleus, and then up-regulated heme oxygenase 1 (HO-1), glutamate-cysteine ligase catalytic (GCLC), glutamate cysteine ligase modifier (GCLM) and quinone oxidoreductase (NQO1). These results indicated that RA could protect the mice from acute liver injury induced by LPS/d-GalN.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cinamatos/farmacologia , Depsídeos/farmacologia , Galactosamina/toxicidade , Lipopolissacarídeos/toxicidade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ácido RosmarínicoRESUMO
Magnolol (MG) is a kind of lignin isolated from Magnolia officinalis, which serves several different biological functions, such as antifungal, anticancer, antioxidant, and hepatoprotective functions. This study aimed to evaluate the protective effect of MG against oleic acid (OA)-induced hepatic steatosis and inflammatory damage in HepG2 cells and in a tyloxapol (Ty)-induced hyperlipidemia mouse model. Our findings indicated that MG can effectively inhibit OA-stimulated tumor necrosis factor α (TNF-α) secretion, reactive oxygen species generation, and triglyceride (TG) accumulation. Further study manifested that MG significantly suppressed OA-activated mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways and that these inflammatory responses can be negated by pretreatment with inhibitors of extracellular regulated protein kinase and c-Jun N-terminal kinase (U0126 and SP600125, respectively). In addition, MG dramatically upregulated peroxisome proliferator-activated receptor α (PPARα) translocation and reduced sterol regulatory element-binding protein 1c (SREBP-1c) protein synthesis and excretion, both of which are dependent upon the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), acetyl-CoA carboxylase, and AKT kinase (AKT). However, MG suspended the activation of PPARα expression and was thus blocked by pretreatment with LY294002 and compound c (specific inhibitors of AKT and AMPK). Furthermore, MG clearly alleviated serum TG and total cholesterol release; upregulated AKT, AMPK, and PPARα expression; suppressed SREBP-1c generation; and alleviated hepatic steatosis and dyslipidemia in Ty-induced hyperlipidemia mice. Taken together, these results suggest that MG exerts protective effects against steatosis, hyperlipidemia, and the underlying mechanism, which may be closely associated with AKT/AMPK/PPARα activation and MAPK/NF-κB/SREBP-1c inhibition.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Anti-Inflamatórios/farmacologia , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR alfa/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Lignanas/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ácido OleicoRESUMO
Morin, a bioactive flavonoid extracted from the bark of Moraceae plants and many medicinal herbs, has anti-inflammatory and antioxidative effects. In this research, we explored the protective effects of morin against lipopolysaccharide (LPS) and d-galactosamine (D-GalN) induced acute liver injury in mice. Mice were given an intraperitoneal injection of morin before LPS and D-GalN treatment and the HepG2 cells were only given morin to investigate its effects. The results showed that morin markedly inhibited the production of serum alanine transaminase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and hepatic TNF-α, IL-6, and myeloperoxidase (MPO) induced by LPS/D-GalN. In order to evaluate morin effect in the future, we investigated the expression of nuclear factor E2 related factor 2 (Nrf2), nuclear factor-kappaB (NF-κB), toll like receptor 4 (TLR4) on liver injury. Taken together, these results suggested that morin could exert the anti-inflammatory and anti-oxidative effects against LPS/D-GalN-induced acute liver injury by activating Nrf2 signal pathways and inhibiting NF-κB activation.