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Hepatocellular carcinoma (HCC) is a malignancy worldwide with one of the worst prognoses. Emerging studies have revealed that long noncoding RNAs (lncRNAs) contribute to HCC progression. This research probes the expression and regulatory effect of lncRNA SATB2-AS1 on HCC development. Reverse transcription-polymerase chain reaction (RT-PCR) was applied to measure the SATB2-AS1 profile in HCC tissues and adjacent non-tumor tissues. The impact of SATB2-AS1, miR-3678-3p, or GRIM-19 on HCC cell proliferation, growth, migration, invasion, and apoptosis was determined by gain- and loss-of-function experiments. The results revealed that SATB2-AS1 was downregulated in HCC tissues, and its lower levels were related to higher tumor staging and poorer prognosis of HCC patients. SATB2-AS1 overexpression repressed HCC cell proliferation, induced G1 arrest, and apoptosis, and inhibited migration, invasion, and epithelial-mesenchymal transition (EMT). Mechanistically, SATB2-AS1 inactivated STAT3/HIF-1α and strengthened GRIM-19 expression. After knocking down GRIM-19 with small interfering RNA (siRNA), the malignant phenotypes of HCC cells were enhanced. Further bioinformatics analysis showed that miR-3678-3p was targeted by SATB2-AS1. The dual-luciferase reporter assay, RNA immunoprecipitation (RIP) experiment, and Fluorescence in situ Hybridization (FISH) test confirmed that SATB2-AS1 sponged miR-3678-3p and the latter targeted GRIM-19. The rescue experiments showed that miR-3678-3p aggravated the malignant behaviors of HCC cells, whereas SATB2-AS1 overexpression reversed miR-3678-3p-mediated effects. Inhibition STAT3 promoted SATB2-AS1 and GRIM-19 expression, and reduced miR-3678-3p level. Activation STAT3 exerted opposite effects. Overall, this study confirmed that SATB2-AS1 is a potential prognostic biomarker for HCC and regulates HCC devolvement by regulating the miR-3678-3p/GRIM-19/STAT3/HIF-1α pathway.
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PURPOSE: To investigate the molecular mechanism of Croci stigma (CS) in the treatment of melasma by network pharmacology and molecular docking. METHODS: TCMSP, CTD, STITCH, SymMap, GeneCard, GenBank, OMIM and DrugBank databases were used to obtain the components and targets of CS and the targets of chloasma. STRING was used to build a protein-protein interaction (PPI) network of intersecting targets between drugs and diseases. Cytoscape was used to establish drug-compounds-targets-disease network and analyze PPI network. R was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and visualization. AutoDock was used for molecular docking and R was used to visualize docking results. RESULTS: Four active compounds were screened out from CS, and 31 target genes intersecting with melasma were found after further analysis. The top 10 hub genes were found after analysis of the PPI network, including TYR, TYRP1, DCT, CREB1, KITLG, MITF, ESR1, EDNRB, CD4, and PTGS2. In the enrichment analysis, melanogenesis was considered as the core pathway through which CS exerts its therapeutic effect on melasma. Molecular docking results showed that the core genes in the regulatory network had high binding activity with related active components, especially crocetin. CONCLUSION: CS may treat melasma by regulating core targets, such as TYR, TYRP1, DCT, CREB1, KITLG, MITF, EDNRB, and PTGS2, and acting on melanogenesis. And crocetin may be the core compound worthy of further study.
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Melanose , Farmacologia em Rede , Humanos , Simulação de Acoplamento Molecular , Ciclo-Oxigenase 2 , Melanose/tratamento farmacológico , Melanose/genéticaRESUMO
Erianin, a phytoestrogen with therapeutic potential, is one of the major active components of Dendrobll caulis. Erianin has a variety of pharmacological effects, such as anti-tumor, anti-inflammatory, anti-diabetic retinopathy, anti-psoriasis, and antibacterial effects. Especially, in regard to the anti-tumor effect of erianin, the underlying molecular mechanism has been partly clarified. In fact, the numerous pharmacological actions of erianin are complex and interrelated, mainly including ERK1/2, PI3K/Akt, JAK2/STAT3, HIF-1α/PD-L1, PPT1/mTOR, JNK/c-Jun, and p38 MAPK signal pathway. However, on account of the poor water solubility and the low bioavailability of erianin, greatly affected and limited its further development and application. And it is worthwhile and meaningful to explore more extensive pharmacological effects and mechanisms, clarify pharmacokinetics, and synthesize the derivatives of erianin. Conclusively, in this paper, the pharmacological effects of erianin and its mechanism, pharmacokinetics, and derivatives studies were reviewed, in order to provide a reference for the development and application of erianin.
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Cholestatic fibrogenesis is a pathobiological process in which cumulative injury to the bile ducts coincides with progressive liver fibrosis. The pathobiologic mechanisms underlying fibrogenesis and disease progression remain poorly understood. Currently, there is no effective treatment for liver fibrosis. In this study, we discovered that components of the coagulation cascade were associated with the advanced progression of obstructive cholestasis, and anticoagulant therapy could improve liver cholestasis-induced fibrosis. In a mouse model of common bile duct ligation (BDL), which mimics cholestatic liver injury, RNA sequencing analysis revealed an increased expression of coagulation factors in endothelial cells. Pharmacological targeting of the coagulation signaling by hirudin, an anticoagulatory antagonist of thrombin, ameliorated obstructive cholestasis, and attenuated liver fibrosis symptoms. Hirudin attenuated fibrosis-associated angiogenesis, endothelial-to-mesenchymal transition (EndMT), and tissue hypoxia and reduced liver inflammation after BDL. Furthermore, hirudin suppressed YAP (Yes-associated protein) signaling and its downstream effectors in vascular endothelial cells, which are considered with profibrotic characteristics. In conclusion, we demonstrated that pharmacological targeting of coagulation signaling by hirudin has the potential to alleviate liver obstructive cholestasis and fibrosis.
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Colestase , Células Endoteliais , Camundongos , Animais , Células Endoteliais/metabolismo , Hirudinas/metabolismo , Hirudinas/farmacologia , Fígado/metabolismo , Colestase/complicações , Colestase/tratamento farmacológico , Ductos Biliares , Cirrose Hepática/complicações , LigaduraRESUMO
Organ fibrosis is accompanied by pathological angiogenesis. Discovering new ways to ameliorate pathological angiogenesis may bypass organ fibrosis. The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. Currently, a controversy exists as to whether cGAS/STING activation exacerbates inflammation and tissue injury or mitigates damage, and whether one of these effects predominates under specific context. This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis in liver and kidney fibrosis. We showed that cGAS expression was induced in fibrotic liver and kidney, but suppressed in endothelial cells. cGAS genetic deletion promoted liver and kidney fibrosis and pathological angiogenesis, including occurrence of endothelial-to-mesenchymal transition. Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial cells, which was evidenced by the attenuation of organ fibrosis in mice specifically lacking endothelial YAP. Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, and a G protein-coupled receptor (GPCR)-based antagonist that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses pathological angiogenesis. Further, pharmacological targeting of cGAS/STING-YAP axis exhibits the potential to alleviate liver and kidney fibrosis.
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Células Endoteliais , Proteínas de Sinalização YAP , Monofosfato de Adenosina , Animais , Células Endoteliais/metabolismo , Fibrose , Guanosina Monofosfato , Interferons , Proteínas de Membrana/metabolismo , Camundongos , Neovascularização Patológica , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismoRESUMO
Chronic or overwhelming liver injury is frequently associated with fibrosis, which is the main histological characteristic of non-alcoholic steatohepatitis (NASH). Currently, there is no effective treatment for liver fibrosis. Adaptive immunity is one of the perpetrators of liver inflammation and involves the antigen-specific activation of lymphocytes. Targeting adaptive immunity has been proposed as a novel therapeutic approach for NASH. In this study, we demonstrated that liver endothelial cells contribute to MHC class II (MHC-II) antigen presentation to CD4+ T cells after chronic liver injury. In human cirrhotic liver samples, we observed an increased expression of endothelial MHC-II and of the antigen presentation-associated protein LMP7, which is one of the proteolytically active subunits of the immunoproteasome. In a CCl4-induced chronic injury model or a diet- and chemical-induced NASH model, endothelial MHC-II and LMP7 expression was induced to increase. PR-957, a selective inhibitor of the immunoproteasome, inhibited MHC-II expression in endothelial cells and CD4+ T cell response after chronic liver injury. In vitro experiment demonstrated PR-957 also reversed IFN-γ-induced upregulation of MHC-II in endothelial cells. Furthermore, PR-957 treatment or CD4+ T cell depletion in chronic liver injury alleviated liver fibrosis and reduced inflammation, as indicated by the downregulation of inflammatory response markers (F4/80, IL-1, IL-6 and IL-18). In conclusion, targeted inhibition of the immunoproteasome blocks endothelial MHC-II antigen presentation to CD4+ T cells in chronic liver injury. In this regard, the PR-957 inhibitor is a promising candidate for the development of future therapies against NASH.
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Doença Enxerto-Hospedeiro , Hepatopatia Gordurosa não Alcoólica , Apresentação de Antígeno , Linfócitos T CD4-Positivos , Células Endoteliais , Antígenos de Histocompatibilidade Classe II , Humanos , Inflamação , Cirrose Hepática , Linfócitos TRESUMO
The present work investigated the antioxidative, anti-inflammatory and pulmonary protective effects of enzymatic- and acid- hydrolysed mycelia polysaccharides (En-MPS and Ac-MPS) from Oudemansiella radicata on LPS-induced acute lung injury (ALI) mice. The results demonstrated that both En-MPS and Ac-MPS showed potential pulmonary protective effects by decreasing serum levels of hs-CRP and C3, increasing pulmonary enzyme values of SOD, GSH-Px, CAT and the level of T-AOC; reducing the activity of MPO; and down-regulating the contents of MDA and LPO. In addition, the levels of TNF-É, IL-1ß, and IL-6 in BALF of mice treated with En-MPS at a dosage of 400 mg/kg/d were significantly lower than those in the ALI mice. The in vitro antioxidant effects also showed that the En-MPS was more effective than Ac-MPS. Furthermore, the physical properties of polysaccharides were also investigated by GC, HPGPC, FT-IR and NMR. These results indicated that both En-MPS and Ac-MPS possessed potent antioxidant and anti-inflammatory activities, which could be used as an ingestible drug in preventing lung injury.
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Agaricales/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Micélio/química , Polissacarídeos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/toxicidade , Antioxidantes/química , Antioxidantes/toxicidade , Celulase/química , Glucuronidase/química , Hidrólise , Interleucina-1alfa/metabolismo , Interleucina-6/metabolismo , Pulmão/patologia , Lesão Pulmonar/patologia , Masculino , Camundongos , Complexos Multienzimáticos/química , Poligalacturonase/química , Polissacarídeos/química , Polissacarídeos/toxicidade , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Substâncias Protetoras/toxicidade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The present study aimed to investigate candidate genes involved in the development and metastasis of osteosarcoma. Candidate genes were screened preliminarily from the Gene Expression Omnibus database and then validated using actual tumor tissues collected from patients with osteosarcoma. The cells were prepared and transfected with specific gene-targeted small interfering RNA followed by an MTS assay for cell viability detection and Transwell assays for cell migration and invasion capacity detection. The cell apoptosis was determined by flow cytometry and the protein level of the genes was detected by western blot analysis. An in vivo nude model was used and injected with cells to detect the functions of the genes. Transcriptome sequencing was performed to verify the regulation network, followed by reverse transcription-quantitative polymerase chain reaction and western blot analyses for validation. Increased tripartite motif-containing protein 2 (TRIM2) was detected in the osteosarcoma tumor tissues compared with normal tissues. The inhibition of TRIM2 induced lower cell viability and cell invasion capacity, and increased the rate of cell apoptosis. Decreased TRIM2 also inhibited the development and metastasis of osteosarcoma in the nude mouse models. The transcriptome sequencing revealed that the regulation of TRIM2 may be correlated with genes, Sirtuin 4, DNA damage inducible transcript 3, cAMP responsive element binding protein 5, G protein-coupled receptor 65 (GPR65) and ADP-ribosyltransferase 5. Western blot analysis indicated that TRIM2 regulated the development and metastasis of osteosarcoma via the phosphoinositide 3-kinase/protein kinase B signaling pathway. Therefore, TRIM2 performs important functions in regulating the development and metastasis of osteosarcoma.
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Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/metabolismo , Osteossarcoma/genética , Adulto , Animais , Neoplasias Ósseas/mortalidade , Osso e Ossos/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Proteínas Nucleares/genética , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Prognóstico , Análise de Sequência de RNA , Taxa de Sobrevida , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
The aim of this work was to characterize spent mushroom substrate polysaccharides (MSP) from Pleurotus eryngii and their antioxidant and organ protective effects in streptozotocin- (STZ-) induced diabetic mice. The enzymatic-, acidic-, and alkalic- (En-, Ac-, and Al-) MSP were extracted from P. eryngii with snailase (4%), hydrochloric acid (1 mol/l), and sodium hydroxide (1 mol/l), respectively. The characterizations were evaluated by spectral analysis. In animal experiments, the enzymatic activities, lipid peroxide contents, and serum lipid parameters were measured, and histological observations of the liver, kidney, pancreas, and heart were conducted. The results demonstrated that treatment with En-, Ac-, and Al-MSP increased the organ enzymatic activities, decreased the organ lipid peroxide contents, mitigated the serum biochemistry values, and ameliorated the histopathology of diabetic mice, indicating that En-, Ac-, and Al-MSP could potentially be used as functional foods for the prevention of diabetes.
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Agaricales/química , Diabetes Mellitus Experimental/tratamento farmacológico , Especificidade de Órgãos , Polissacarídeos/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Glucose/metabolismo , Lipídeos/sangue , Camundongos , Monossacarídeos/análise , Polissacarídeos/química , Polissacarídeos/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Estreptozocina , Testes de Toxicidade AgudaRESUMO
The antioxidant and multiple organ protection effects of acid- extracted mycelia polysaccharides (Ac-MPS) from Pleurotus eryngii var. tuoliensis on HFE-induced hypertriglyceridemic mice were investigated. The results showed that Ac-MPS have potential ability to relieve the hypertriglyceridemia and preventing oxidative stress by decreasing levels of TG, TC LDL-C, elevating contents of HDL-C in serum, increasing the activities of SOD, GSH-Px, CAT and T-AOC, and the down regulating MDA and LPO contents in liver, heart, kidney and spleen. And the histopathological observations also displayed that Ac-MPS could alleviate organ damage. Moreover, the GC, HPGPC, FT-IR and AFM analyses revealed the Ac-MPS possessed the typical polysaccharides structure with the molecular weights (Mw) of 2.712 × 105 Da. These conclusions indicated that the Ac-MPS had the potential to develop new drugs for hypertriglyceridemia-induced multiple organ failure.