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1.
J Exp Med ; 220(1)2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36350325

RESUMO

Marginal zone (MZ) B cells represent innate-like B cells that mediate a fast immune response. The adhesion of MZ B cells to the marginal sinus of the spleen is governed by integrins. Here, we address the question of whether ß1-integrin has additional functions by analyzing Itgb1fl/flCD21Cre mice in which the ß1-integrin gene is deleted in mature B cells. We find that integrin ß1-deficient mice have a defect in the differentiation of MZ B cells and plasma cells. We show that integrin ß1-deficient transitional B cells, representing the precursors of MZ B cells, have enhanced B cell receptor (BCR) signaling, altered PI3K and Ras/ERK pathways, and an enhanced interaction of integrin-linked kinase (ILK) with the adaptor protein Grb2. Moreover, the MZ B cell defect of integrin ß1-deficient mice could, at least in part, be restored by a pharmacological inhibition of the PI3K pathway. Thus, ß1-integrin has an unexpected function in the differentiation and function of MZ B cells.


Assuntos
Integrina beta1 , Fosfatidilinositol 3-Quinases , Camundongos , Animais , Integrina beta1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Diferenciação Celular , Integrinas
2.
Oncol Rep ; 49(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36367181

RESUMO

Astragalus membranaceus Bunge is widely used in Traditional Chinese Medicine to treat various cancers. Astragaloside­IV (AS­IV) is one of the major compounds isolated from A. membranaceus Bunge and has been demonstrated to have antitumor effects by inhibiting cell proliferation, invasion and metastasis in various cancer types. Numerous studies have used in vitro cell culture and in vivo animal models of cancer to explore the antitumor activities of AS­IV. In the present study, the antitumor effects and mechanisms of AS­IV reported in studies recorded in the PubMed database were reviewed. First, the antitumor effects of AS­IV on proliferation, cell cycle, apoptosis, autophagy, invasion, migration, metastasis and epithelial­mesenchymal transition processes in cancer cells and the tumor microenvironment, including angiogenesis, tumor immunity and macrophage­related immune responses to cancer cells, were comprehensively discussed. Subsequently, the molecular mechanisms and related signaling pathways associated with antitumor effects of AS­IV as indicated by in vitro and in vivo studies were summarized, including the Wnt/AKT/GSK-3ß (glycogen synthase kinase­3ß)/ß­catenin, TGF­ß/PI3K/AKT/mTOR, PI3K/MAPK/mTOR, PI3K/AKT/NF­κB, Rac family small GTPase 1/RAS/MAPK/ERK, TNF­α/protein kinase C/ERK1/2­NF­κB and Tregs (T­regulatory cells)/IL­11/STAT3 signaling pathways. Of note, several novel mechanisms of Toll­like receptor 4 (TLR4)/NF­κB/STAT3, pSmad3C/3L, nuclear factor erythroid 2­related factor (NrF2)/heme oxygenase 1, circDLST/microRNA­489­3p/eukaryotic translation initiation factor 4A1 and macrophage­related high­mobility group box 1­TLR4 signaling pathways associated with the anticancer activity of AS­IV were also included. Finally, the limitations of current studies that must be addressed in future studies were pointed out to facilitate the establishment of AS­IV as a potent therapeutic drug in cancer treatment.


Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Glicogênio Sintase Quinase 3 beta , NF-kappa B , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 4 Toll-Like , Serina-Treonina Quinases TOR/metabolismo
3.
Autoimmunity ; 56(1): 1-7, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36343159

RESUMO

Dexamethasone (Dex) is a type of glucocorticoid drug. Long term use can induce growth plate chondrocytes (GPCs) apoptosis, impair differentiation, and inhibit cell proliferation and bone growth. It has been reported that Krüppel-like factor 2 (KLF2) inhibits osteoblast damage induced by Dex, but the role in Dex-induced GPCs remains unclear. Dex was used to construct a model of growth plate injury in vitro. CCK-8 and TUNEL kits were used to determine cell viability and apoptosis. A model of growth plate injury was established by intraperitoneal injection of Dex. Immunohistochemistry was used to investigate the expression of KLF2 in rats. The results showed that KLF2 expression of rat tibial GPCs was down-regulated after Dex stimulation. Overexpression of KLF2 promoted cell viability and cell cycle, while inhibited apoptosis of growth plate Dex-induced chondrocytes. Moreover, KLF2 inhibited Runx2-mediated PI3K/AKT and ERK signalling pathways. And PI3K/AKT and ERK signalling pathways, which were involved in the regulation of KLF2 on GPCs. Further studies showed that KLF2 alleviated growth plate injury in vivo. In conclusion, our study found that KLF2 promoted proliferation and inhibited apoptosis of Dex-induced GPCs by targeting the Runx2-mediated PI3K/AKT and ERK signalling pathways.


Assuntos
Condrócitos , Fraturas Salter-Harris , Ratos , Animais , Condrócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt , Lâmina de Crescimento/metabolismo , Fraturas Salter-Harris/metabolismo , Dexametasona/efeitos adversos , Fatores de Transcrição/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo
4.
J Ethnopharmacol ; 301: 115805, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36216195

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shenkang injection (SKI), a Chinese patent medicine injection, has been approved for the treatment of chronic kidney disease (CKD) due to its definite clinical therapeutic efficacy. However, the effect and associated underlying mechanism of Shenkang injection against cisplatin (CDDP)-induced acute kidney injury (AKI) has not yet been well elucidated. AIM OF THE STUDY: This study aims to investigate the therapeutic effect and associated underlying mechanism of Shenkang injection against CDDP-induced AKI. MATERIALS AND METHODS: We established a CDDP-induced AKI mouse model to evaluate renal function by biochemical markers measurement and to observe histopathological alterations by haemotoxylin and eosin (HE)-staining sections of renal. In addition, the distribution of representative components of SKI in the kidneys of mice was evaluated by liquid chromatography tandem mass spectrometry (LC-MS/MS). Furthermore, the degree of oxidative stress and inflammation were assessed by detecting the levels of inflammatory cytokines and oxidants, while the related mechanisms were elucidated by network pharmacology. RESULTS: CDDP could induce excessive inflammation and severe injury to the kidneys of mice. However, SKI significantly ameliorated the kidney damages and improved the renal function by reducing the levels of renal function markers (SCr, BUN and urine protein), and inhibiting the production of inflammatory cytokines IL-34, IL-6 and TNF-α. SKI repaired oxidative balance through up-regulation of antioxidants SOD and GSH and down-regulated oxidants MDA. Moreover, 4 components from SKI were detected in the kidney by LC-MS/MS quantification. In addition, pharmacology network indicated the PI3K/AKT, TNF, MAPK, and p53 were the possible signaling pathways for the therapeutic effect of SKI against CDDP-induced AKI, which were related to inflammation, oxidative stress and apoptosis. CONCLUSION: In the present study, we for the first time demonstrated that SKI alleviates CDDP-induced nephrotoxicity by antioxidant and anti-inflammation via regulating PI3K/AKT, MAPK, TNF, and p53 signaling pathways. The study may provide a scientific rationale for the clinical indication of SKI.


Assuntos
Injúria Renal Aguda , Cisplatino , Camundongos , Animais , Cisplatino/toxicidade , Cromatografia Líquida , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Espectrometria de Massas em Tandem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Rim , Estresse Oxidativo , Apoptose , Inflamação/patologia , Antioxidantes/farmacologia , Oxidantes/metabolismo , Citocinas/metabolismo
5.
J Ethnopharmacol ; 301: 115820, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36220511

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Yangshe granule is a characteristic Chinese preparation against cervical cancer used at Fudan University Shanghai Cancer Center, and it consists of Hedyotis Diffusae Herba, Solani Lyrati Herba, Rubiae Radix et Rhizoma, Echinopsis Radix, Angelicae Sinensis Radix, Codonopsis Radix and Atractylodis Macrocephalae Rhizoma. AIM OF THE STUDY: The objective of the current study was to investigate the preclinical efficacy of compound Yangshe granule against cervical cancer and elucidate the underlying mechanisms. MATERIALS AND METHODS: Antitumor effect of the preparation was investigated in U14 cells in vitro and subcutaneous xenograft mice in vivo. The underlying mechanisms were investigated by through network pharmacological analysis and identified by in vitro study. The components of compound Yangshe granule were collected from the Traditional Chinese Medicine Systems Pharmacology database, and the corresponding targets were predicted by the SwissTargetPrediction database. The targets involved in cervical cancer were collected from the GeneCards, Online Mendelian Inheritance in Man and DrugBank databases. A protein‒protein interaction network was constructed by using the String platform. The drug-disease-target network was plotted by Cytoscape software. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were performed to investigate hub targets. RESULTS: After treatment with 0.5-10 mg/mL compound Yangshe granule, the survival rates of U14 cells gradually declined to 53.32% for 24 h, 23.62% for 48 h, and 12.81% for 72 h. The apoptosis rates of U14 cells gradually increased to 15.52% for 24 h, 23.87% for 48 h, and 65.01% for 72 h after treatment with 2-10 mg/mL compound Yangshe granule. After oral administration of compound Yangshe granule by xenograft mice, the tumor inhibition rates reached 52.27%, 74.62%, and 82.70% in the low, middle, and high dose groups, respectively. According to the network pharmacological analysis, quercetin, luteolin and naringenin were the most bioactive ingredients of the preparation. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that compound Yangshe granule may combat cervical cancer through the PI3K/AKT pathway. CONCLUSION: In summary, network pharmacology combined with biological experiments demonstrated that the main bioactive components including quercetin, luteolin and naringenin could inhibit the tumor growth by regulating the PI3K/AKT pathway and Bcl-2 family. Thus, compound Yangshe granule may be a promising adjuvant therapy for cervical cancer.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias do Colo do Útero , Feminino , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Quercetina/farmacologia , Luteolina/farmacologia , Farmacologia em Rede , Transdução de Sinais , China , Medicina Tradicional Chinesa , Neoplasias do Colo do Útero/tratamento farmacológico , Simulação de Acoplamento Molecular
6.
J Ethnopharmacol ; 301: 115804, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36228892

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The ancient Chinese medicine book "Huangdi Neijing" reports that "the brain is the sea of marrow" and that the kidney "mainly induces bones to produce marrow". Therefore, Chinese medicine has a "kidney-brain axis" theory, but supporting evidence is lacking. In this study, curculigoside, the main component of the kidney-tonifying drug Rhizoma Curculiginis, was used to explore whether a kidney-tonifying drug could regulate the pathological state of the brain. AIM OF THE STUDY: To explore the efficacy of curculigoside in protecting against ischemic brain injury (IBI) through the regulation of oxidative stress and NF-κB and PI3K/Akt expression. MATERIALS AND METHODS: Middle cerebral artery occlusion (MCAO) was used to induce IBI in rats, and curculigoside was administered. The degree of IBI, morphological changes and severity of nerve injury (using neurological severity scores; NSSs) in the rats were assessed. Enzyme-linked immunosorbent assays (ELISAs), Western blotting, and immunohistochemistry were used to evaluate changes in hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), TNF-α, IL-1ß, catalase (CAT), superoxide dismutase (SOD), nitric oxide synthase (NOS), NF-κB, PI3K and Akt levels. RESULTS: Curculigoside significantly alleviated behavioral deficits and reduced the degree of cerebral ischemia in the rats. After curculigoside treatment, the levels of H2O2, NO, MDA, NOS, iNOS, TNF-α, IL-1ß, intercellular adhesion molecule-1 (ICAM-1) and NF-κB in the ischemic area of the brain were significantly reduced. The activities of CAT, SOD, PI3K and Akt were significantly increased. CONCLUSION: Curculigoside is a potentially effective drug for the treatment of IBI.


Assuntos
Lesões Encefálicas , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Peróxido de Hidrogênio/farmacologia , Transdução de Sinais , Estresse Oxidativo , Infarto da Artéria Cerebral Média/patologia , Superóxido Dismutase/metabolismo
7.
J Ethnopharmacol ; 301: 115825, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36240978

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Biejiajian pill (BJJP) is a canonical formula that is clinically used to treat chronic liver disease, especially to decrease the incidence of hepatocellular carcinoma (HCC). However, the mechanisms underlying the prevention of HCC progression by BJJP remain unclear. AIM OF THE STUDY: This study aimed to determine whether BJJP inhibits HCC progression by downregulating platelet-derived growth factor receptor beta (PDGFRß) signaling in cancer-associated fibroblasts (CAFs) in a mouse model of diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced HCC. MATERIALS AND METHODS: C57BL/6 male mice were intraperitoneally injected with DEN 2 weeks after birth, followed by repeated injections of CCl4 weekly from 6 weeks of age onwards, to recapitulate features of HCC. At week 14, BJJP was orally administered to mice. The effects of BJJP on HCC progression were evaluated using histology, immunohistochemistry, and serum biochemical marker levels. Transcriptome analysis, molecular docking, quantitative real-time PCR, and Western blot were used to study the genes targeted by BJJP and the associated signaling pathway. The effects of BJJP on PDGFRß signaling in CAFs and the underlying mechanism were demonstrated. RESULTS: BJJP treatment significantly suppressed carcinogenesis and cancer progression, and it ameliorated liver inflammation in mice with HCC. A total of 176 genes, including PDGFRß, were significantly downregulated after BJJP treatment and five components of BJJP with high binding affinity to PDGFRß were identified. BJJP inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK3ß) by suppressing PDGFRß expression in CAFs, and it also downregulated the expression of the downstream proteins hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A). Furthermore, BJJP-containing serum consistently reduced PDGFRß, HGF, and VEGF-A expression levels in HSC-derived CAFs in vitro. Importantly, PDGF-BB induced PDGFRß activation in CAFs and both BJJP and sunitinib (a kinase inhibitor) inhibited PDGF-BB/PDGFRß signaling. CONCLUSION: BJJP inhibits the progression of HCC through suppressing VEGF-A and HGF expression in CAFs by downregulating PDGFRß signaling.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Camundongos , Animais , Carcinoma Hepatocelular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Becaplermina , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos Endogâmicos C57BL , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia
8.
J Ethnopharmacol ; 301: 115835, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36252878

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Er-Xian decoction (EXD) is a traditional Chinese medicine (TCM) formula used to treat osteoporosis (OP). However, the anti-OP mechanism of EXD has not yet been fully elucidated. AIM OF THE STUDY: The study aimed to verify the anti-OP effect of EXD and to explore its underlying mechanism. METHODS: The anti-OP targets and mechanisms of EXD were predicted by network pharmacological analysis. Then, an ovariectomized (OVX) rat model was established to validate the key anti-OP mechanism of EXD. Firstly, the therapeutic effect of EXD on OP was confirmed using micro-CT bone analysis, pathological observation, and ELISA detection. Secondly, serum metabolites related to key biological processes were detected using an automatic biochemical analyzer and GC-MS. Finally, ELISA, qRT-PCR, and western blot were utilized to further explore the potential key anti-OP pathway of EXD. RESULTS: A total of 159 anti-OP targets of EXD were identified. Functional annotation revealed that OP treatment using EXD was associated with lipid metabolism, fatty acid (FA) metabolism, and PI3K/AKT signaling pathway. Experimental studies confirmed that EXD ameliorated ovariectomy-induced bone loss and bone microstructure deterioration. EXD treatment also upregulated the level of serum estrogen and downregulated the level of OC, PⅠNP, CTX-1, TC, and LDL-C. Besides, principal component analysis (PCA) and heat map of serum FAs distinguished OVX rats from the SHAM and EXD groups. Serum concentrations of important n-3 FAs, including C20:3N3, C20:5N3, and C22:5N3, were significantly increased in the EXD group. The increased stearoyl-CoA desaturase 1 (SCD1) index 1 and index 2 in the OVX group were reversed by EXD administration. Additionally, EXD reversed the decreased serum IGF1 level and tibia IGF1R, PI3K, and AKT expression in OVX rats. CONCLUSION: EXD ameliorated ovariectomy-induced bone loss by modulating lipid metabolism, FA metabolism, and IGF1/PI3K/AKT pathway.


Assuntos
Medicamentos de Ervas Chinesas , Osteoporose , Humanos , Feminino , Ratos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ovariectomia/efeitos adversos , Transdução de Sinais , Metabolismo dos Lipídeos , Ácidos Graxos/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo
9.
J Ethnopharmacol ; 301: 115842, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36265674

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Wu-Tang (SWT) has become a common basic prescription for supplementing blood and regulating menstruation, and enjoys the reputation of "the first prescription in gynecology". It is often reported in the treatment of premature ovarian failure (POF). However, knowledge of its specific mechanism is still limited. AIM OF THE STUDY: This study aimed to identify the potential effects and underlying mechanisms of SWT on POF. MATERIALS AND METHODS: After confirming the therapeutic effect of SWT on POF mice induced by cyclophosphamide, we further clarified the promoting effect of SWT on ovarian follicle development by detecting the expression of key factors related to follicle development in the ovary in different ways.Then, network pharmacology and gene expression profiling of POF from the GEO database were used to clarify the underlying mechanisms. Molecular biology and molecular docking analysis were applied for final mechanism verification. RESULTS: Our results showed that SWT increased body weight, ovarian index, reversed disordered serum hormone levels, and menstrual cycle in POF mice. After SWT treatment, the number of follicles at all levels in mice with POF also recovered. Using molecular biology techniques, it was proven that SWT can improve follicle development and angiogenesis in the microenvironment. The network pharmacology and gene expression profiling from the GEO database indicated that the PI3K/Akt signaling pathway may be the reason why SWT improves ovarian function in mice with POF. Subsequently, further Western blot and immunoprecipitation indicated that SWT indeed inhibited the PI3K/Akt signaling pathway in mice with POF. In addition, this conclusion was further confirmed by molecular docking experiments. CONCLUSIONS: SWT can improve ovarian function in POF mice induced by cyclophosphamide, and its mechanism is related to the inhibition of the PI3K/Akt signaling pathway.


Assuntos
Menopausa Precoce , Insuficiência Ovariana Primária , Humanos , Feminino , Camundongos , Animais , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simulação de Acoplamento Molecular , Ciclofosfamida/toxicidade , Modelos Animais de Doenças
10.
J Ethnopharmacol ; 301: 115834, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36270558

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mume Fructus (MF) is processed from the near-ripe fruit of Prunus mume (Siebold) Siebold & Zucc by drying at low temperature until the color turns black. MF is often used in Chinese medicine for the treatment of chronic diarrhea and dysentery. Previous studies have shown that the active components of MF against Crohn's disease (CD) are mainly citrate and hydroxycinnamate derivatives, which can alleviate the CD-induced inflammatory response and intestinal barrier damage. However, their molecular mechanisms on CD still need further elucidation. AIM OF THE STUDY: To investigate the protective effects and underlying mechanisms of citrate and hydroxycinnamate derivatives in MF on intestinal epithelial injury. MATERIALS AND METHODS: Network pharmacology technology was used to predict the anti-CD targets and molecular mechanisms of 4 citrate and 11 hydroxycinnamate derivative prototypes and 5 hydroxycinnamate derivative metabolites in the 40% ethanol fraction of MF (MFE40), the active anti-CD ingredient group of MF. Lipopolysaccharide (LPS)-treated IEC-6 cells were used to investigate the effects of the above components on the proliferation of damaged IEC-6 cells and to verify the molecular mechanism of their regulation on the FAK/PI3K/AKT signaling pathways for the promotion of the proliferation of IEC-6 cells. RESULTS: A "compound-target-pathway" network was constructed based on network pharmacology analysis, including 20 citrate and hydroxycinnamate derivatives that target 316 core proteins and 36 CD-related pathways, of which PI3K-AKT pathway and focal adhesion were the most enriched pathways. Further cell validation experiments showed that 1 citric acid (CA) compound and 10 hydroxycinnamate derivatives, including 3-O-caffeoylquinic acid (3CQA), 4-O-caffeoylquinic acid (4CQA), 5-O-caffeoylquinic acid (5CQA), caffeic acid (CFA), p-coumaric acid (PCMA), m-coumaric acid (MCMA), ferulic acid (FUA), isoferulic acid (IFUA), 3-hydroxyphenylpropionic acid (3HPPA) and hippuric acid (HPP), could promote the proliferation of IEC-6 cells and inhibit the damage of LPS to IEC-6 cells. Ethyl caffeate (ECFA), a hydroxycinnamic acid derivative, had no effect on promoting the proliferation of IEC-6 cells and was weak in inhibiting the damage of IEC-6 cells caused by LPS. Further mechanistic verification experiments showed that 7 citrate and hydroxycinnamate derivatives (CA, CFA, 3CQA, MCMA, FUA, 3HPPA, and HPP) could upregulate the expression of p-FAK, p-PI3K, and p-AKT proteins. Among them, CA had the better effect on activating the FAK-PI3K-AKT signaling pathway. CONCLUSIONS: Citrate and hydroxycinnamate derivatives in MF can ameliorate LPS-induced intestinal epithelial cell injury to demonstrate potential for Crohn's disease alleviation. This protective effect can be achieved by upregulating FAK/PI3K/AKT pathway.


Assuntos
Doença de Crohn , Lipopolissacarídeos , Lipopolissacarídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Frutas/metabolismo , Ácido Cítrico , Doença de Crohn/metabolismo , Doença de Crohn/terapia , Transdução de Sinais , Células Epiteliais
11.
J Ethnopharmacol ; 301: 115855, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36280019

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Myrrh is an aromatic oleo-gum resin extracted from the stem of Commiphora myrrha (Nees) Engl., and has the efficacies to promote blood circulation and remove blood stasis. Myrrh is mainly used for the treatment of chronic diseases including cancer. Guggulsterone, a major active steroid extracted from myrrh, has been found to inhibit cancer cell growth. Glioblastoma is the most common malignancy of central nervous system, and its prognosis remains very poor mainly due to chemotherapeutic resistance. The active status of EGFR/PI3K/Akt and NF-κB signaling in glioblastoma contributed to poor response for chemotherapy, and blocking this signaling with antagonists sensitized glioblastoma cells to chemotherapy. AIM OF THE STUDY: The present study will investigate whether guggulsterone potentiates the anti-glioblastoma efficacy of temozolomide by down-regulating EGFR/PI3K/Akt signaling and NF-κB activation. MATERIALS AND METHODS: Cell viability and proliferation was determined by cell counting Kit-8 and colony formation assays. Cell apoptosis was evaluated by Annexin V/PI and hoechst 33342 staining assays. Molecular techniques such as western blotting and real-time quantitative PCR were used to demonstrate guggulsterone in vitro effect on EGFR/PI3K/Akt signaling and NF-κB activation. Finally, in vivo studies were performed in orthotopic mouse models of glioblastoma. RESULTS: The results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-κB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-кB activity. CONCLUSIONS: The present study suggested that guggulsterone potentiated anti-glioblastoma efficacy of temozolomide through down-regulating EGFR/PI3K/Akt signaling pathway and NF-кB activation.


Assuntos
Glioblastoma , NF-kappa B , Camundongos , Animais , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , NF-kappa B/metabolismo , Commiphora , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Glioblastoma/tratamento farmacológico , Apoptose , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Proliferação de Células
12.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1868(1): 159236, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36179802

RESUMO

Diet-induced obesity (OB) is usually accompanied by hypertriglyceridemia, which is characterized by the accumulation of triglyceride (TG)-rich lipoprotein (TRL) particles in the circulation. We previously found that postprandial TRL combined with insulin induced the adipogenic differentiation of 3T3-L1 preadipocytes, which may represent a key mechanism underlying obesity. However, the specific mechanism and signaling pathway involved in this process remain to be fully elucidated. In this study, we found that, in the postprandial state, patients with obesity had significantly higher levels of TG and remnant cholesterol (RC) than normal-weight controls. In vitro, we found that postprandial TRL, together with insulin, promoted the adipogenic differentiation of adipose-derived mesenchymal stem cells (AMSCs), as evidenced by the increased expression of lipogenesis-related genes and their protein products, including low-density lipoprotein related protein 1 (LRP1). Besides, caveolin-1 (Cav-1) expression was also significantly upregulated under this condition. Cav-1 and LRP1 were observed to interact, and then led to the activation of the PI3K/AKT1 signaling pathway. Meanwhile, the inhibition of LRP1 or Cav-1 significantly attenuated the adipogenic differentiation of AMSCs and downregulated AKT1 phosphorylation levels. Moreover, treatment with a selective AKT1 inhibitor significantly suppressed postprandial TRL and insulin-induced adipogenesis in AMSCs. Combined, our results demonstrated that, in association with insulin, postprandial TRL can promote the adipogenic differentiation of AMSCs in a manner that is dependent on the LRP1/Cav-1-mediated activation of the PI3K/AKT1 signaling pathway. Our findings indicated that a postprandial increase in TRL content is a critical factor in the pathogenesis of hypertriglyceridemia and diet-induced obesity.


Assuntos
Hipertrigliceridemia , Células-Tronco Mesenquimais , Humanos , Adipogenia , Caveolina 1/metabolismo , Triglicerídeos/metabolismo , Lipoproteínas/metabolismo , Hipertrigliceridemia/complicações , Insulina/metabolismo , Obesidade/metabolismo , Lipoproteínas LDL/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
13.
Mol Med Rep ; 27(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36382656

RESUMO

Colorectal cancer (CRC) is one of the deadliest malignant tumors worldwide and its prevalence is increasing in South Korea. The efficacy of combined treatment with natural product­derived and chemotherapy agents including curcumin combined with 5­fluorouracil, resveratrol combined with cisplatin and epigallocatechin­3­gallate (EGCG) combined with cisplatin in preventing cancer progression and killing cancer cells has emerged. The Akt and Hippo signaling pathways serve a key role in colorectal tumor growth; however, the exact role of the crosstalk between Akt and Hippo signaling pathways in CRC remains poorly elucidated. The combined effect of UA and DOX on the cell proliferation, apoptosis, migration and cell cycle of CRC cells were investigated by performing Cell proliferation assay, a soft agar colony formation assay, flow cytometry, wound healing assay and western blotting assay. Subsequently, the expression of AKT and Hippo signaling pathway­associated proteins were also assessed by western blot assay. Moreover, a xenograft nude mouse model was constructed to verify the effects of UA and DOX on the tumorigenesis of HCT116 cell in vivo. The present study reported that ursolic acid (UA) strongly enhanced the antitumor action of doxorubicin (DOX) via blocking the Akt/glycogen synthase kinase­3ß (Gsk3ß) signaling pathway and activating tumor­suppressive Hippo signaling (mammalian Ste20­like kinase 1 and 2, salvador family WW domain containing protein 1 and MOB kinase activator 1), thereby downregulating downstream effector yes­associated protein 1 (Yap) and connective tissue growth factor (CTGF) protein expression levels in CRC cells. Furthermore, The PI3K inhibitor LY294002 further suppressed Akt activity and enhance the function of Hippo pathway­associated proteins in DOX + UA treated cells; this effect led to subsequent oncogenic Yap and CTGF inhibition following combined treatment, whereas Akt activator SC79 exerted an opposite effect in CTGF expression. In vivo, treatment with UA combined with DOX markedly suppressed the progression of CRC without any toxic effects on a xenograft mouse model by disrupting Akt signaling and activating the Hippo signaling pathway. These results demonstrated that UA and DOX treatment successfully induced Akt/Gsk3ß inactivation via Hippo signaling pathway activation to promote Yap degradation, resulting in the inhibition of colorectal tumorigenesis. In conclusion, these findings suggested that combination therapy with UA and DOX may be more effective than DOX alone. UA may be a novel anticancer strategy and could be considered for investigation as a complementary chemotherapy agent in the future.


Assuntos
Neoplasias Colorretais , Fosfatidilinositol 3-Quinases , Humanos , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Via de Sinalização Hippo , Cisplatino/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais , Carcinogênese , Proliferação de Células , Apoptose , Doxorrubicina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Mamíferos/metabolismo
14.
Theriogenology ; 195: 138-148, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332373

RESUMO

Damage to Sertoli cell junction proteins caused by inflammation can lead to male infertility. Nerve growth factor (NGF) plays an important role in reproductive and inflammatory disease; however, whether and how NGF regulates Sertoli cell function remains unclear. Here, we aimed to assess the effect of NGF on the growth of Sertoli cells isolated from the testes of dairy goats and evaluate if NGF has a protective effect on these cells. We confirmed that Sertoli cell viability, proliferation, and ATP content increased following NGF treatment. In addition, qPCR results suggested that Sertoli cell apoptosis was inhibited after NGF treatment. To investigate the protective effect of NGF on Sertoli cells under pathological inflammatory conditions, LPS was used to induce inflammatory response in Sertoli cells. Post-treatment, the entangled filamentous pseudopodia of the cells loosened and no longer spanned adjacent cells. The expression of several junction proteins (ZO-1, occludin, CX-43, ß-catenin, and N-cadherin), which was down-regulated after inflammatory response induction, was restored following NGF treatment. LPS-induced changes in cytotoxicity and transepithelial electrical resistance were reversed and the intercellular connections became tighter after NGF treatment. We further demonstrated that NGF prevented the inflammatory response of Sertoli cells via the PI3K/AKT/NFκB signaling pathway, similar to the effect of the PI3K-inhibitor, LY294002, which is modified by the PI3K activator, 740Y-P. These results provide insights for devising strategies for protecting the male reproductive system and curing or preventing associated pathological conditions.


Assuntos
Fator de Crescimento Neural , Células de Sertoli , Masculino , Animais , Fator de Crescimento Neural/farmacologia , Fosfatidilinositol 3-Quinases , Lipopolissacarídeos/toxicidade , Proteínas Proto-Oncogênicas c-akt , NF-kappa B , Proliferação de Células , Transdução de Sinais
15.
Artigo em Inglês | MEDLINE | ID: mdl-36261108

RESUMO

The lead (Pb) contamination is considered a lethal threat to birds. However, Pb-induced hepatotoxicology especially its impacts on metabolic processes in the liver of birds is not yet fully understood. Therefore, we tried to determine the toxicological effects of Pb exposure on hepatic carbohydrate and lipid metabolism via Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway by using an animal model- Japanese quail (Coturnix japonica). One-week old female Japanese quails were randomly allocated into four groups and fed with 0, 50 ppm, 500 ppm and 1000 ppm Pb drinking water respectively for 49 days. The results showed that Pb accumulated in the liver as a dose-dependent manner. Exposure to high dose of Pb (500 and 1000 ppm Pb) led to severe histopathological damages characterized by irregularity and dilation of liver sinusoids, hepatic lipid vacuolization and hepatocellular cytoplasm hyalinization. Meanwhile, Pb exposure caused glycogen increase and lipid droplets decrease in the liver. Pb exposure was also attributable to a decreased triglyceride level in the plasma. In addition, the transcriptional levels of PI3K and Akt in the liver were downregulated by Pb exposure. Subsequently, the mRNA expressions of genes related with glycometabolism in the liver were remarkably altered and the mRNA levels of genes involved in fat synthesis and oxidation in the liver were also markedly changed. it seems that Pb could lead to liver metabolic disorder through structural damages and PI3K/Akt signaling pathway disruption.


Assuntos
Coturnix , Metabolismo dos Lipídeos , Animais , Feminino , Coturnix/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Chumbo/toxicidade , Fosfatidilinositol 3-Quinase/metabolismo , Fígado/metabolismo , Transdução de Sinais , RNA Mensageiro/metabolismo
16.
J Ethnopharmacol ; 300: 115724, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36115599

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI) is a renowned traditional Chinese medicine often used clinically to treat cardiovascular and cerebrovascular diseases. Studies have shown that DHI can significantly alter microRNA (miRNA) expression in the brain tissue. Therefore, exploring specific miRNAs' regulatory mechanisms during treatment with DHI is essential. AIM OF THE STUDY: To investigate DHI's regulatory mechanism on cerebral autophagy in rats with cerebral ischemia-reperfusion injury (CIRI). MATERIAL AND METHODS: Rats were randomly divided into the sham, middle cerebral artery occlusion (MCAO) model, and DHI-treatment groups. The extent of brain damage was evaluated using triphenyl tetrazolium chloride and hematoxylin-eosin staining. Hippocampal cell autophagy was observed using transmission electron microscopy. Autophagy-related proteins were analyzed using western blotting. Differentially expressed miRNAs were screened using high-throughput and real-time quantitative reverse transcription PCR. The relationship between miR-132-3p and ATG12 was confirmed using a dual-luciferase assay. The miR-132-3p mimics and inhibitors were transfected into PC12 cells subjected to oxygen-glucose deprivation (OGD) in vitro and MCAO model rats in vivo. RESULTS: DHI significantly altered the miRNA expression profile in rat brain tissues. The pathological changes in the brain tissues were improved, and the autophagic hippocampal cell vehicles were significantly reduced after DHI treatment. miRNA-132-3p, one of the miRNAs with a significantly different expression, was screened. Kyoto Encyclopedia of Genes and Genomes signal pathway analysis showed that its target genes were closely related to autophagy. Western blotting revealed that the p-PI3K, p-AKT, and mTOR expression increased significantly; AMPK, ULK1, ATG12, ATG16L1, and LC3II/I were downregulated in the DHI group. Dual-luciferase reporter gene experiments showed that miRNA-132-3p could target the ATG12 3'-UTR region directly. In vitro, miRNA-132-3p had a protective effect on OGD/R-induced oxidative stress injury in PC12 cells, improving cell viability, and affecting the expression of autophagy pathway-related proteins. In vivo transfection experiments showed that miR-132-3p could regulate ATG12 expression in CIRI rats' lateral brain tissue, affecting the autophagy signaling pathway. miR-132-3p overexpression reduces CIRI-induced autophagy and protects neurons. CONCLUSION: This study showed that DHI inhibits neuronal autophagy after cerebral ischemia-reperfusion. This may have resulted from miR-132-3p targeting ATG12 and regulating the autophagy signaling pathway protein expression.


Assuntos
Isquemia Encefálica , MicroRNAs , Traumatismo por Reperfusão , Proteínas Quinases Ativadas por AMP , Animais , Apoptose , Autofagia , Proteína 12 Relacionada à Autofagia/metabolismo , Proteínas Relacionadas à Autofagia/genética , Isquemia Encefálica/metabolismo , Cloretos , Medicamentos de Ervas Chinesas , Amarelo de Eosina-(YS)/farmacologia , Amarelo de Eosina-(YS)/uso terapêutico , Glucose/farmacologia , Hematoxilina/farmacologia , Hematoxilina/uso terapêutico , Infarto da Artéria Cerebral Média/patologia , MicroRNAs/metabolismo , Oxigênio/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Traumatismo por Reperfusão/metabolismo , Serina-Treonina Quinases TOR
17.
Food Chem ; 399: 133799, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35998490

RESUMO

Flesh quality is evaluated according to nutritional value and sensory quality. Cinnamaldehyde (CIN) improves mammalian meat quality, but research relating this to aquaculture is scarce. In this study, five doses of CIN (0, 36, 72, 108, 144 mg/kg diet) were fed to grass carp (Ctenopharyngodon idella) for 60 days. The results show that CIN supplementation increased nutritional value by increasing crude protein content. CIN also improved the sensory quality by increasing the pH and collagen content, decreasing shear force, lactate, and cooking loss. These changes may be related to changes in muscle fiber growth by increasing myofiber diameter. The increased myofiber diameter induced by CIN is associated with TOR mRNA and protein levels, and down-regulated FOXO3a mRNA levels, which might be associated with PTP1B/IGF1/PI3K/AKTs-TOR/FOXO3a signaling. Based on muscle crude protein content, optimal CIN supplementation dosage was 88.01 mg/kg.


Assuntos
Carpas , Doenças dos Peixes , Acroleína/análogos & derivados , Ração Animal/análise , Animais , Carpas/genética , Carpas/metabolismo , Dieta , Suplementos Nutricionais , Doenças dos Peixes/genética , Proteínas de Peixes/metabolismo , Imunidade Inata , Mamíferos/genética , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/genética , Transdução de Sinais
18.
Curr Top Microbiol Immunol ; 438: 75-84, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35624345

RESUMO

Host-pathogen interactions involve complex inside-out and outside-in signal transmission through critical cellular networks that dictate disease outcomes. The phosphoinositide 3-kinase (PI3K)/Akt pathway is a pivotal junction that regulates several cell functions, and phospho-Akt (pAkt) is often found to be constitutively active in cancer cells, similar to phospho-STAT3. In this chapter, we discuss the regulation of PI3K/Akt pathway in VZV infected cells and of other pathways including p53 which, unlike pAkt and pSTAT3, directs cells towards apoptosis. The fine spatio-temporal balance of activation of pro- and anti-apoptotic factors during VZV infection likely provides an optimum environment for the virus to replicate and cause disease in the human host.


Assuntos
Herpesvirus Humano 3 , Fosfatidilinositol 3-Quinases , Humanos , Herpesvirus Humano 3/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Interações Hospedeiro-Patógeno
19.
Sci Total Environ ; 855: 158918, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36169023

RESUMO

Concerns are raised over the risk to digestive system's tumors from the N-nitrosamines (NAs) exposure in drinking water. Albeit considerable studies are conducted to explore the underlying mechanism responsible for NAs-induced esophageal squamous cell carcinoma (ESCC), the exact molecular mechanisms remain largely unknown, especially at the epigenetic regulation level. In this study, it is revealed that the urinary concentration of N-Nitrosodiethylamine is higher in high incidence area of ESCC, and the lncRNA-UCA1(UCA1) is significantly decreased in ESCC tissues. In vitro and in vivo experiments further show that UCA1 is involved in the malignant transformation of Het-1A cells and precancerous lesions of the rat esophagus induced by N-nitrosomethylbenzylamine (NMBzA). Functional gain and loss experiments verify UCA1 can affect the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Mechanically, through binding to heterogeneous nuclear ribonucleoprotein F (hnRNP F) protein, UCA1 regulates alternative splicing of fibroblast growth factor receptor 2 (FGFR2), which promotes the FGFR2IIIb isoform switching to FGFR2 IIIc isoform, and the latter activates epithelial-mesenchymal transition via PI3K-AKT signaling pathways impacting tumorigenesis. Therefore, NAs-mediated downregulation of UCA1 promotes ESCC progression through targeting hnRNP F/FGFR2/PI3k-AKT axis, which provides a new chemical carcinogenic target and establishes a previously unknown mechanism for NAs-induced ESCC.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , MicroRNAs , Nitrosaminas , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/metabolismo , Carcinoma de Células Escamosas do Esôfago/induzido quimicamente , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/metabolismo , Regulação para Baixo , Neoplasias Esofágicas/induzido quimicamente , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Processamento Alternativo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Epigênese Genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Regulação Neoplásica da Expressão Gênica , Movimento Celular , Proliferação de Células , Linhagem Celular Tumoral , Carcinogênese/induzido quimicamente , Nitrosaminas/toxicidade , MicroRNAs/metabolismo
20.
J Surg Res ; 281: 245-255, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36209683

RESUMO

INTRODUCTION: Heme oxygenase-1 (HO-1) is a protective protein in oxidative stress response. LXA4 is an "inflammatory braking signal" that is widely studied at present. The purpose of this study was to elucidate that LXA4 can protect cells by inducing HO-1 in human pulmonary microvascular endothelial cells (HPMECs) as in vitro model to explain acute lung injury after severe acute pancreatitis. METHODS: This study was performed in two parts: (1) To investigate the mechanisms of lipoxin A4-induced HO-1 expression in vitro, the study subjects were divided into four groups: a control group, LXA4 group (50 ng/mL LXA4), inhibitor group (50 ng/mL LXA4 + 20 µM LY294002 or 50 ng/mL LXA4 + 2 nmol/mL Bis II), and agonist group (50 ng/mL insulin-like growth factor 1, PMA). Western blotting was used to detect the expression of p-Akt, Akt, protein kinase C (PKC), p-Nrf2, Nrf2, and Keap1, and the location of Nrf2 was detected using immunofluorescence. The activation of antioxidant responsive element induced by Nrf2 was detected using Electrophoretic Mobility Shift Assay and (2) to investigate the cytoprotection of HO-1 induced by LXA4 in vitro, the subjects were divided into four groups: a control group, tumor necrosis factor α (TNF-α) group (50 ng/mL), LXA4 group (50 ng/mL TNF-α + 50 ng/mL LXA4), and Zinc protoporphyrin IX group (pretreated with 0.5 µM Zinc protoporphyrin IXfor 12 h, followed by 50 ng/mL TNF-α + 50 ng/mL LXA4). BCECF/AM-labeled THP-1 cells were used to analyze the adhesion of HPMECs, and a mitochondrial membrane potential assay kit with JC-1 was used to analyze the apoptosis of HPMECs. RESULTS: In part one, (1) LXA4 upregulated the expression of HO-1 in a dose-dependent manner and (2) LXA4 activated the PI3K/Akt and PKC pathways and modulated the phosphorylation and subsequent depolymerization of Nrf2 from Keap1, promoting the translocation of Nrf2 to the nucleus. In part two, (1) LXA4 reversed the changes in mitochondrial membrane potential to alleviate apoptosis in HPMECs and (2) LXA4 attenuated the adhesion of HPMECs induced by TNF-α. CONCLUSIONS: LXA4 can activate the PI3K/Akt and PKC pathways and induce the phosphorylation of Nrf2, resulting in the upregulation of HO-1. In addition, LXA4 alleviates adhesion and protects mitochondrial function by upregulating the expression of HO-1, which exerts cytoprotection in severe acute pancreatitis-induced lung injury.


Assuntos
Lesão Pulmonar Aguda , Pancreatite , Humanos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Citoproteção , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença Aguda , Células Endoteliais/metabolismo , Estresse Oxidativo , Lesão Pulmonar Aguda/prevenção & controle
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