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The widespread use of emerging refractory organic contaminants poses a significant threat to human health, prompting the need for a cost-effective and efficient removal strategy. While the iron ions/PMS system effectively removes organic pollutants, slow Fe3+ to Fe2+ transformation hampers its efficiency, and the homogeneous distribution of iron ions complicates separation, resulting in secondary sludge pollution. Herein, we developed a novel submicron Fe-MoS2 (S-Fe-MoS2) catalyst with abundant surface cationic groups and sulfur vacancy through a cationic polyacrylamide aerogels (CPAMA) confined hydrothermal synthesis strategy. These features promote active site exposure, enhance reactant adsorption, and accelerate electron transfer between Mo and Fe sites, improving catalytic kinetics and promoting Fe3+/Fe2+ cycle for PMS activation. As a result, the S-Fe-MoS2/PMS system exhibited a high catalytic rate constant (kobs) of 0.32â min-1, in the degradation of 4-chlorophenol (4-CP), 1.5 times higher than that of the conventional Fe-MoS2/PMS system. It also achieved 82.9% total organic carbon (TOC) degradation within 60â min. Additionally, it possessed similar degradation performance for various organic pollutants, along with remarkable reusability (four cycles) and broad pH adaptability (2-8), indicating significant potential for widespread application. This study provided a new way for developing advanced heterogeneous catalysts with high efficiency for water treatment.
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Developing highly effective iron-based catalyst to selectively remove organic contaminants has garnered considerable attention. Herein, a magnetic Fe0/FeS2-doped carbon nanolayer (S-Fe@NC) was synthesized through a straightforward one-step pyrolysis method, pyrolyzing a mixture composed of 4,6-dihydroxypyrimidine, trithiocyanuric acid, and FeCl3·6H2O. With the presence of PMS, S-Fe@NC demonstrated the ability to remove almost 100% bisphenol-A (50 µM) within 3 min, attributed to its excellent graphitization degree and high FeS2/Fe0 content. Furthermore, the S-Fe@NC catalyst demonstrated an impressive kobs value of 1.476 min-1, which surpassed the traditional Fenton system by 77 times and even exceeded the commercial Fe0 catalyst by 127 times. More importantly, the S-Fe@NC/PMS system succeeded in selectively removing organic contaminants based on the hydrophobic interaction between catalyst and contaminants. Besides, the result of electron paramagnetic resonance and the radical quenching experiments indicated that ·OH, SO4·-, 1O2, and O2·- were involved in the organic contaminants removal. Interestingly, after adding ascorbic acid (AA) to the S-Fe@NC/PMS system, more ROS could be generated to result in the kobs augmenting by 4.16 times (6.133 min-1), completely different from the common sense that AA was usually used as a radical quencher. Additionally, the magnetically separable catalyst also exhibited excellent reusability and broad pH adaptability (2.0-12.0). This study provided a valuable insight for developing highly selective and effective Fe-based catalyst for practical wastewater treatment.
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Medicinal fungi Phellinus igniarius exhibited hypoglycemic effects; however, the protective mechanisms of P. igniarius on type 2 diabetes are not yet fully understood. Herein, the anti-diabetic effect of P. igniarius was investigated via gas chromatography-mass spectrometry (GC/MS)-based metabolome analysis. The rats were divided into normal group; model group; positive group; and groups treated with low, medium, and high dose of P. igniarius. After the treatments, a significant decrease in blood glucose concentration was observed. The levels of total cholesterol and triglyceride were dramatically decreased, whereas the level of insulin was increased. Multivariate statistical analysis revealed 31 differential endogenous metabolites between model group and normal group. A total of 14, 28, and 31 biomarkers were identified for low, medium, and high dose of P. igniarius treated groups, respectively. Twenty-one of the biomarkers were validated by using standard substances. The linear correlation coefficients ranged from 0.9990 to 1.0000. The methodology exhibited good repeatability, recoveries, and stability. The major intervened metabolic pathways covered glyoxylate and dicarboxylic acid metabolism; alanine, aspartate, and glutamate metabolism; and glycine, serine, and threonine metabolism. Our metabolome analysis has provided insights into the underlying mechanism of P. igniarius on type 2 diabetes.
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Singlet oxygen (1O2) is an essential reactive species responsible for selective oxidation of organic matter, especially in Fenton-like processes. However, due to the great limitations in synthesizing catalysts with well-defined active sites, the controllable production and practical application of 1O2 remain challenging. Herein, guided by theoretical simulations, a series of boron nitride-based single-atom catalysts (BvBN/M, M=Co, Fe, Cu, Ni and Mn) were synthesized to regulate 1O2 generation by activating peroxymonosulfate (PMS). All the fabricated BvBN/M catalysts with explicit M-N3 sites promoted the self-decomposition of the two PMS molecules to generate 1O2 with high selectivity, where BvBN/Co possessed moderate adsorption energy and d-band center exhibited superior catalytic activity. As an outcome, the BvBN/Co-PMS system coupled with membrane filtration technology could continuously transform aromatic alcohols to aldehydes with nearly 100 % selectivity and conversion rate under mild conditions, suggesting the potential of this novel catalytic system for green organic synthesis.
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AIMS: To investigate the association between mitochondrial events and immune response in periodontitis and related regulatory genes. MAIN METHODS: Gene expression profiles in gingival tissues were retrieved from the Gene Expression Omnibus. Mitochondria-immune response-related differentially expressed genes (MIR-DEGs) between the healthy and periodontitis samples were determined. WGCNA, GO, and KEGG were used to investigate the function and the enriched pathways of MIR-DEGs. The correlation between MIR-DEGs expression and clinical probing pocket depth was analyzed. The MIR-DEGs were further identified and verified in animal samples. A periodontitis model was established in C57BL/6 mice with silk ligation. Micro-computed tomography was used to assess alveolar bone loss. Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses further validated the differential expression of the MIR-DEGs. KEY FINDINGS: A total of ten MIR-DEGs (CYP24A1, PRDX4, GLDC, PDK1, BCL2A1, CBR3, ARMCX3, BNIP3, IFI27, and UNG) were identified, the expression of which could effectively distinguish patients with periodontitis from the healthy controls. Enhanced immune response was detected in the periodontitis group with that in the healthy controls, especially in B cells. PDK1 was a critical MIR-DEG correlated with B cell immune response and clinical periodontal probing pocket depth. Both animal and clinical periodontal samples presented higher gene and protein expression of PDK1 than the control samples. Additionally, PDK1 colocalized with B cells in both animal and clinical periodontal tissues. SIGNIFICANCE: Mitochondria participate in the regulation of the immune response in periodontitis. PDK1 may be the key mitochondria-related gene regulating B-cell immune response in periodontitis.
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Camundongos Endogâmicos C57BL , MicroRNAs , Mitocôndrias , Periodontite , Animais , Periodontite/genética , Periodontite/imunologia , Periodontite/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Gengiva/metabolismo , Gengiva/patologia , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Masculino , Linfócitos B/metabolismo , Linfócitos B/imunologia , Perfilação da Expressão Gênica , Feminino , Transcriptoma , Serina-Treonina Quinase 3 , Regulação da Expressão GênicaRESUMO
Neuronal cell damage is a major cause of cognitive impairment in Alzheimer's disease (AD). Multiple factors, such as amyloid deposition, tau hyperphosphorylation, and neuroinflammation, can lead to neuronal cell damage. Therefore, the development of multi-target drugs with broad neuroprotective effects may be an effective strategy for the treatment of AD. Natural products have become an important source of drug discovery because of their good pharmacological activity, multiple targets, and low toxicity. In this study, we screened a natural compound library and found that the fat-soluble sesquiterpene natural compound isolinderalactone (Iso) extracted from the dried root pieces of Lindera aggregata had the ability to alleviate cellular damage induced by ß-amyloid-1-42 (Aß1-42). The role and mechanism of Iso in AD have not yet been reported. Herein, we demonstrated that Iso significantly reduced the level of apoptosis in PC12 cells. Besides, Iso treatment reduced amyloid deposition, neuron apoptosis, and neuroinflammation, ultimately improving the cognitive dysfunction of APP/PS1 (APPswe/PSEN 1dE9) mice. Notably, Iso-10 mg/kg showed superior improved effects in APP/PS1 mice compared with the positive control drug donepezil-5 mg/kg. Mechanistically, the results of RNA sequencing combined with Western blots showed that Iso exerted its therapeutic effect by inhibiting the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our findings suggest that Iso is a potential drug candidate for the treatment of AD.
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Doença de Alzheimer , Sesquiterpenos , Ratos , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Doenças Neuroinflamatórias , Camundongos Transgênicos , Peptídeos beta-Amiloides , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/metabolismoRESUMO
Recently, targeted protein degradation technologies based on lysosomal pathways have been developed. Lysosome-based targeted protein degradation technology has a broad range of substrates and the potential to degrade intracellular and extracellular proteins, protein aggregates, damaged organelles and non-protein molecules. Thus, they hold great promise for drug R&D. This study has focused on the biogenesis of lysosomes, their basic functions, lysosome-associated diseases and targeted protein degradation technologies through the lysosomal pathway. In addition, we thoroughly examine the potential applications and limitations of this technology and engage in insightful discussions on potential avenues for future research. Our primary objective is to foster preclinical research on this technology and facilitate its successful clinical implementation.
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Lisossomos , Proteínas , Proteólise , Lisossomos/metabolismo , Proteínas/metabolismo , AutofagiaRESUMO
Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.
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Neoplasias , Exaustão das Células T , Humanos , Ratos , Animais , Linfócitos T , Proteínas Serina-Treonina Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/metabolismo , Pirimidinas/farmacologia , Pirimidinas/metabolismoRESUMO
We aimed to screen specific genes in liver tissue samples of patients with nonalcoholic steatohepatitis (NASH) with clinical diagnostic value based on bioinformatics analysis. The datasets of liver tissue samples from healthy individuals and NASH patients were retrieved for consistency cluster analysis to obtain the NASH sample typing, followed by verification of the diagnostic value of sample genotyping-specific genes. All samples were subjected to logistic regression analysis, followed by the establishment of the risk model, and then, the diagnostic value was determined by receiver operating characteristic curve analysis. NASH samples could be divided into cluster 1, cluster 2, and cluster 3, which could predict the nonalcoholic fatty liver disease activity score of patients. A total of 162 sample genotyping-specific genes were extracted from patient clinical parameters, and the top 20 core genes in the protein interaction network were obtained for logistic regression analysis. Five sample genotyping-specific genes (WD repeat and HMG-box DNA-binding protein 1 [WDHD1], GINS complex subunit 2 [GINS2], replication factor C subunit 3 (RFC3), secreted phosphoprotein 1 [SPP1], and spleen tyrosine kinase [SYK]) were extracted to construct the risk models with high diagnostic value in NASH. Compared with the low-risk group, the high-risk group of the model showed increased lipoproduction and decreased lipolysis and lipid ß oxidation. The risk models based on WDHD1, GINS2, RFC3, SPP1, and SYK have high diagnostic value in NASH, and this risk model is closely related to lipid metabolism pathways.
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OBJECTIVE: The traditional She medicine is a notable type of traditional Chinese medicine, which has been applied for a long history despite the lack of sufficient mechanistic understanding. Our study revealed the possible molecular mechanism of sesquiterpene 5α-Hydroxycostic acid, active ingredient of traditional She medicine Artemisia lavandulaefolia DC., in the treatment of rheumatoid arthritis (RA). METHODS: RA-fibroblast like synoviocytes (RA-FLSs) were treated with 5α-Hydroxycostic acid, Anthemidin, and methotrexate (MTX). CCK-8 and ELISA were used to measure the resultant viability of RA-FLSs and to quantify pro-inflammatory cytokines. Target genes of 5α-Hydroxycostic acid and Anthemidin, RA-related differentially expressed genes, and RA-related genes were retrieved by bioinformatics analyses, results of which were further intersected to identify candidate genes. The protein-protein interaction network was constructed to develop the pharmacophore model. The molecular docking was simulated to determine the core target androgen receptor (AR) for subsequent molecular mechanism investigation in vitro. RESULTS: The 5É-Hydroxycostic acid, Anthemidin, or MTX of different concentrations inhibited the viability of RA-FLSs, and downregulated the levels of proinflammatory cytokines. The pharmacophore model and molecular docking of 10 candidate targets with 5α-Hydroxycostic acid were successfully established. In vitro experiments provided evidence confirming that 5α-Hydroxycostic acid elevated AR expression to inhibit inflammatory responses of RA-FLSs and degradation of extracellular matrix. CONCLUSION: Therefore, this study reveals the active ingredient sesquiterpene 5α-Hydroxycostic acid of traditional She medicine Artemisia lavandulaefolia DC., and illustrates potential molecular mechanism in RA treatment by upregulating AR expression. This study is the first to report the effect of the active ingredient sesquiterpenes in traditional She medicine A.lavandulaefolia DC on RA and elucidate the underlying molecular mechanism associated with up-regulated AR expression. This study provides new insights into the mechanistic understanding of traditional She medicine in the treatment of RA.
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Artrite Reumatoide , Farmacologia em Rede , Humanos , China , Simulação de Acoplamento Molecular , Etnicidade , Artrite Reumatoide/metabolismo , Metotrexato/uso terapêutico , Citocinas/metabolismo , Fibroblastos/metabolismo , Células Cultivadas , Proliferação de CélulasRESUMO
Increased level of Angiotensin II (Ang II) contributes to hypertensive heart failure via -hemodynamic and non-hemodynamic actions. Ginsenoside Rg5 (Rg5) occurs naturally in ginseng, which has shown various benefits for cardiovascular diseases. This study evaluated Rg5's effects on Ang II-caused cardiac remodeling and heart failure. C57BL/6 mice developed hypertensive cardiac failure after four weeks of Ang II infusion. The mice were administered Rg5 via oral gavage for the last two weeks to investigate the potential mechanism of Rg5. RNA sequencing of heart tissues was performed for mechanistic studies. It was discovered that Rg5 inhibited cardiac inflammation, myocardial fibrosis, and hypertrophy, and prevented cardiac malfunction in mice challenged with Ang II, without altering blood pressure. RNA sequencing showed that Rg5's cardioprotective effect involves the JNK/AP-1 signaling pathway. Rg5 diminished inflammation in mice hearts and cultured cardiomyocytes by blocking Ang II-activated JNK/AP-1 pathway. In the absence of JNK or AP-1 in cardiomyocytes, the anti-inflammatory effects of Rg5 were nullified. The study found that Rg5 preserved the hearts of Ang II-induced mice by reducing JNK-mediated inflammatory responses, suggesting that Rg5 is an effective therapy for hypertensive heart failure.
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Insuficiência Cardíaca , Hipertensão , Camundongos , Animais , Fator de Transcrição AP-1/metabolismo , Angiotensina II , Camundongos Endogâmicos C57BL , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Arritmias CardíacasRESUMO
Liver fibrosis, a compensatory repair response to chronic liver injury, is caused by various pathogenic factors, and hepatic stellate cell (HSC) activation and phenotypic transformation are regarded as key events in its progression. Ferroptosis, a novel form of programmed cell death, is also closely related to different pathological processes, including those associated with liver diseases. Here, we investigated the effect of doxofylline (DOX), a xanthine derivative with potent anti-inflammatory activity, on liver fibrosis as well as the associated mechanism. Our results indicated that in mice with CCl4-induced liver fibrosis, DOX attenuated hepatocellular injury and the levels of liver fibrosis indicators, inhibited the TGF-ß/Smad signaling pathway, and significantly downregulated the expression of HSC activation markers, both in vitro and in vivo. Furthermore, inducing ferroptosis in activated HSCs was found to be critical for its anti-liver fibrosis effect. More importantly, ferroptosis inhibition using the specific inhibitor, deferoxamine (DFO) not only abolished DOX-induced ferroptosis, but also led to resistance to the anti-liver fibrosis effect of DOX in HSCs. In summary, our results showed an association between the protective effect of DOX against liver fibrosis and HSC ferroptosis. Thus, DOX may be a promising anti-hepatic fibrosis agent.
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BACKGROUND: The relationship between hepatitis B surface antigen (HBsAg)-positive carrier status and liver cancer has been extensively studied. However, the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown. The epigenetic modification of DNA hydroxymethylation is critical in tumor development. Further, 5-hydroxymethylcytosine (5hmC) is an important base for DNA demethylation and epigenetic regulation. It is also involved in the assembly of chromosomes and the regulation of gene expression. However, the mechanism of action of 5hmC in HBsAg-positive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated. AIM: To investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma (HCC) progression from cirrhosis. METHODS: Forty HBsAg-positive carriers, forty patients with liver cirrhosis, and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants. Free DNA was extracted using a cf-DNA kit. cfDNA was extracted by 5hmC DNA sequencing for principal component analysis, the expression profiles of the three groups of samples were detected, and the differentially expressed genes (DEGs) modified by hydroxymethylation were screened. Bioinformatic analysis was used to enrich DEGs, such as in biological pathways. RESULTS: A total of 16455 hydroxymethylated genes were identified. Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients, of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers. Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes, of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis. These genes may have potential loci that are undiscovered or unelucidated, which contribute to the development and progression of liver cancer. Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion. The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2. CONCLUSION: The occurrence and development of liver cancer involves multiple genes and pathways, which may be potential targets for preventing hepatitis B carriers from developing liver cancer.
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BACKGROUND: Acute tubular necrosis (ATN) is a common type of acute renal failure. Recent studies have shown that NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in macrophages plays a crucial role in the progression of ATN. Previously, we synthesized an anti-inflammatory compound 15a based on Tanshinone IIA (Tan IIA). In the present study, we found that compound 15a exhibited a greater inhibitory effect on NLRP3-mediated pyroptosis than Tan IIA in vitro. METHODS: C57BL/6 and NLRP3-knockout (NLRP3-KO) mice were intraperitoneally injected with LPS or folic acid (FA) to develop ATN. In vitro, bone marrow-derived macrophages (BMDMs) were treated with LPS for 3 h and then treated with ATP for 0.5 h. RESULTS: We explored the mechanism by which compound 15a inhibited NLRP3 inflammasome in BMDMs as well as its renal protective effect against ATN in mice. We found that compound 15a exhibited a protective effect on mitochondria and reduced the production of mitochondrial reactive oxygen species (mtROS). Moreover, we revealed that compound 15a remarkably reduced the production of mtROS by promoting mitophagy, which resulted in the inhibition of NLRP3 inflammasome to alleviates ATN in mice. CONCLUSION: In summary, compound 15a inhibited NLRP3-mediated inflammation by activating mitophagy in macrophages to alleviate ATN. Our results identified compound 15a as a promising candidate for the treatment of NLRP3-driven ATN.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Mitofagia , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Macrófagos , Espécies Reativas de Oxigênio , Camundongos Knockout , Inflamação/tratamento farmacológico , Necrose/tratamento farmacológicoRESUMO
Background: The incidence and mortality of hepatocellular carcinoma (HCC) are globally on the rise. Dihydrotanshinone I, a natural product isolated from Salvia miltiorrhiza Bunge, has attracted extensive attention in recent years for its anti-tumour proliferation efficiency. Methods: Cell proliferations in hepatoma cells (Huh-7 and HepG2) were evaluated by MTT and colony formation assays. Immunofluorescence (IF) of 53BP1 and flow cytometry analysis were performed to detect DNA damage and cell apoptosis. Furthermore, network pharmacological analysis was applied to explore the potential therapeutic targets and pathway of dihydrotanshinone I. Results: The results showed that dihydrotanshinone I effectively inhibited the proliferation of Huh-7 and HepG2 cells. Moreover, dihydrotanshinone I dose-dependently induced DNA-damage and apoptosis in vitro. Network pharmacological analysis and molecular simulation results indicated that EGFR might be a potential therapeutic target of dihydrotanshinone I in HCC. Collectively, our findings suggested that dihydrotanshinone I is a novel candidate therapeutic agent for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Dano ao DNA/genética , Proliferação de Células , Receptores ErbB/genéticaRESUMO
Objective: Herbal medicine discovery is a complex and time-consuming process, while pharmacophore modeling and molecular docking methods enable simple and economic studies. The pharmacophore model provides an abstract description of essential intermolecular interactions between chemical structures, and the molecular docking technology can identify novel compounds of therapeutic interests and predict the ligand-target interaction at the molecular level. This study was based on the two methods to elucidate the mechanism of dehydrovomifoliol, an active ingredient extracted from Artemisia frigida willd, in nonalcoholic fatty liver disease (NAFLD). Methods: Bioinformatics analysis was performed to screen target genes of dehydrovomifoliol in NAFLD treatment, which were thus intersected with NAFLD-related differentially expressed genes (DEGs) and NAFLD-related genes. Venn diagram was used to identify candidate DEGs. A pharmacophore model was then generated, and molecular docking was performed. A protein-protein interaction (PPI) network was constructed to identify core genes, which were evaluated using GO and the KEGG enrichment analyses. Results: Seven target genes of dehydrovomifoliol in NAFLD treatment were screened out, namely E2F1, MERTK, SOX17, MMP9, SULT2A1, VEGFA, and BLVRA. The pharmacophore model and molecular docking of candidate DEGs and dehydrovomifoliol were successfully constructed. E2F1 was identified as a core gene of dehydrovomifoliol in NAFLD treatment. Further enrichment analysis indicated the regulatory role of E2F1 in fat metabolism was associated with the regulation of the AKT/mTOR signaling pathway. Conclusion: Overall, this study illustrates the anti-NAFLD mechanism of dehydrovomifoliol, which could be a useful compound for developing novel drugs in the treatment of NAFLD.
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In this study, we used a serum metabolomics methodology based on GC coupled with MS (GC-MS) to investigate the liver-protective effects of raw and stir-fried semen of Hovenia dulcis in rats models of carbon tetrachloride-induced liver injury. Multivariate statistical analysis, such as principal component analysis and orthogonal partial least squares discriminant analysis, were performed to examine changes in the metabolic state of rats with carbon tetrachloride-induced liver injury, as well as the recovery pattern of rats pretreated with the raw and stir-fried semen of H. dulcis. Liver tissues were subjected to histopathological examination. A total of 47 biomarkers were predicted to contribute to the dynamic pathological processes in the liver injury, such as phenylalanine, glutamic acid, glycine, arachidonic acid and linoleic acid. Further analysis revealed that pathways associated with phenylalanine, tyrosine and tryptophan biosynthesis, and linoleic acid metabolism were altered in the injured liver, and that pretreatment with raw and stir-fried semen of H. dulcis abolished the changes in the aforementioned metabolic pathways.
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Tetracloreto de Carbono , Doença Hepática Crônica Induzida por Substâncias e Drogas , Ratos , Animais , Cromatografia Gasosa-Espectrometria de Massas , Ácido Linoleico , Quimiometria , Sementes , Metabolômica/métodos , Biomarcadores , Fenilalanina , MetabolomaRESUMO
Two new prenylated flavonoid glycosides (1-2), together with five known compounds (3-7) were isolated from the EtOAc-soluble extract of the stems of Celastrus orbiculatus. The structures of new compounds were elucidated with spectroscopic and physico-chemical analyses. All isolates were evaluated for in vitro cytotoxic activities against HepG2, MCF-7, A549, and A2780 cancer cells. Among them, compound 1 showed potential antiproliferative activity on A2780 cells with IC50 value of 10.76 µM. In addition, compound 2 exhibited selective cytotoxic activity on A2780 cells with IC50 value of 26.30 µM.
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Antineoplásicos , Celastrus , Neoplasias Ovarianas , Feminino , Humanos , Celastrus/química , Linhagem Celular Tumoral , Glicosídeos/farmacologia , Flavonoides/farmacologia , Estrutura MolecularRESUMO
A series of novel paclitaxel derivatives modified by boronic acid according to the characteristics of the interaction between RB(OH)2 and different strapping agents of intraliposomal aqueous phase were designed and synthesized, which were then used to develop remote poorly water-soluble drugs loading into liposomes. Meanwhile, we screened nineteen paclitaxel boronic acid derivatives for their cytotoxic activities against three cancer cell lines (A549, HCT-116 and 4T1) and one normal cell line (LO2), and performed liposome formulation screening of active compounds. Among all the compounds, the liposome of 4d, with excellent drug-encapsulated efficiency (>95% for drug-to-lipid ratio of 0.1 w/w), was the most stable. Furthermore, the liposomes of compound 4d (8 mg/kg, 4 times) and higher dose of compound 4d (24 mg/kg, 4 times) showed better therapeutic effect than paclitaxel (8 mg/kg, 4 times) in the 4T1 tumor model in vivo, and the rates of tumor inhibition were 74.3%, 81.9% and 58.5%, respectively. This study provided a reasonable design strategy for the insoluble drugs to improve their drug loading into liposomes and anti-tumor effect in vivo.