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Ferroptosis, a key factor in tumor progression, is poorly understood at the molecular level. This study investigates how ELK4 and CHMP6 regulate skin cutaneous melanoma (SKCM) cell proliferation and ferroptosis. Analysis of TCGA data reveals high expression of ELK4 and CHMP6 in SKCM. Overexpression of ELK4 or CHMP6 enhances cell proliferation, invasion, and migration while reducing ROS and Fe2 + levels. It also increases GPX4 and xCT expression and decreases ACSL4 levels in SKCM cells. The opposite effects are observed with ELK4 or CHMP6 knockdown. ELK4 binds to the CHMP6 promoter, promoting CHMP6 transcription. Knockdown of CHMP6 reverses the oncogenic effects of ELK4 overexpression. In conclusion, ELK4 enhances proliferation, invasion, and migration while inhibiting ferroptosis in SKCM cells by upregulating CHMP6 transcription. This study sheds light on the intricate mechanisms involved in SKCM progression and identifies potential therapeutic targets in melanoma treatment.
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Movimiento Celular , Proliferación Celular , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Melanoma , Neoplasias Cutáneas , Humanos , Ferroptosis/genética , Melanoma/patología , Melanoma/genética , Melanoma/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Movimiento Celular/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Coenzima A Ligasas/metabolismo , Coenzima A Ligasas/genética , Melanoma Cutáneo Maligno , Invasividad Neoplásica/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genéticaRESUMEN
AIM: Disulfidptosis is a new metabolic-related regulated cell death associated with cancer growth. This study aimed to investigate the molecular mechanisms associated with disulfidptosis in skin cutaneous melanoma (SKCM) and establish a disulfidptosis-related gene signature for prognostic prediction in SKCM. METHODS: Disulfidptosis-associated genes were identified from RNA-seq data of SKCM. A risk score signature was developed and validated through univariate Cox and LASSO analyses. Additionally, the immune microenvironment related to the risk score signature was investigated. Finally, a disulfidptosis-related genes-transcription factor -miRNA network was developed, and the expression levels of five disulfidptosis-related genes were initially verified in SKCM cell lines. RESULTS: A total of 107 disulfidptosis-related differentially expressed genes in SKCM samples were identified. A ten-disulfidptosis-gene signature was established, including BIN2, CCL3L3, CCL8, CD79A, CIITA, CXCR3, DEFB1, GPR171, IL2RB, and SOCS1. The SKCM samples were divided into high- and low-risk groups, of which samples in the low-risk group showed better survival performance. The receiver operating characteristic curve analysis confirmed the good potency of the disulfidptosis-related gene prognostic model. Except for DEFB1, the other nine genes were positively related with T cell CD8+, T cell CD4+ memory activated, T cell gamma delta, NK cell activated, and macrophage M1, and they were all negatively related with NK cell resting, macrophage M0, macrophage M2, and mast cell activated. Finally, we verified downregulated levels of SOCS1 and DEFB1 and upregulated CXCR3, BIN2, and CCL3L3 in A875 and A375. CONCLUSION: We successfully established ten disulfidptosis-related genes' prediction prognostic signatures for SKCM patients.
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BACKGROUND: Some studies indicated an association between fatty acids (FA) and psoriasis. While definitive correlation between FA and psoriasis is still unclear. Therefore, our objective is to ascertain whether fatty acid levels are causally related to psoriasis using a Mendelian randomization approach. METHOD: We investigated the causal relationship between psoriasis and multiple types of FA by mendelian randomization. All data were acquired from Genome-Wide Association Study. We also performed additional analysis to assess the validity of the causal connection. RESULTS: Our mendelian analysis suggests that n-3 fatty acid levels are associated with a lower risk of psoriasis. [IVW, OR/95% CI: 0.998/(0.997, 0.999), p (2.479 × 10-4)] Complementary analyses returned similar results, indicating consistency in our findings. No horizontal pleiotropy was found in our analysis. There was no indication of causal effects from other varieties of FA on psoriasis. CONCLUSION: Our studies found that n-3 FA may lower the likelihood of developing psoriasis. We also need well-designed prospective studies and related large-scale, multicenter RCTs to confirm our findings.
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Ácidos Grasos Omega-3 , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Psoriasis , Psoriasis/genética , Humanos , Ácidos Grasos , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Astragalus polysaccharide (APS) is a major bioactive component of the Chinese herb astragalus, with well-established protective effects on the kidney. However, the effect of APS on diabetic nephropathy (DN) is unclear. METHODS: Long non-coding RNA (lncRNA) expression profiles in kidney samples from control, db/db, and APS-treated db/db mice were evaluated using RNA high-throughput sequencing techniques. Additionally, rat renal tubular epithelial (NRK-52E) cells were cultured in high glucose (HG) media. We inhibited the expression of Gm41268 and prolactin receptor (PRLR) by transfecting NRK-52E cells with Gm41268-targeting antisense oligonucleotides and PRLR siRNA. RESULTS: We found that APS treatment reduced 24-h urinary protein levels and fasting blood glucose and improved glucose intolerance and pathological renal damage in db/db mice. Furthermore, APS treatment enhanced autophagy and alleviated fibrosis in the db/db mice. We identified a novel lncRNA, Gm41268, which was differentially expressed in the three groups, and the cis-regulatory target gene PRLR. APS treatment induced autophagy by reducing p62 and p-mammalian target of rapamycin (mTOR) protein levels and increasing the LC3 II/I ratio. Furthermore, APS alleviated fibrosis by downregulating fibronectin (FN), transforming growth factor-ß (TGF-ß), and collagen IV levels. In addition, APS reversed the HG-induced overexpression of Gm41268 and PRLR. Reduction of Gm41268 decreased PRLR expression, restored autophagy, and ameliorated renal fibrosis in vitro. Inhibition of PRLR could enhance the protective effect of APS. CONCLUSIONS: In summary, we demonstrated that the therapeutic effect of APS on DN is mediated via the Gm41268/PRLR pathway. This information contributes to the exploration of bioactive constituents in Chinese herbs as potential treatments for DN.
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Diabetes Mellitus , Nefropatías Diabéticas , ARN Largo no Codificante , Ratones , Ratas , Animales , Nefropatías Diabéticas/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Receptores de Prolactina , Autofagia , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Fibrosis , Mamíferos/genética , Mamíferos/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Hypertensive nephropathy (HN) is a complication of hypertension. Taohongsiwu decoction (THSWD) is used clinically but its application in the prevention and treatment of HN remains unelucidated. AIM OF STUDY: This study aims to explore the potential targets and molecular mechanisms of THSWD in the treatment of HN. MATERIALS AND METHODS: A network pharmacology approach was used to predict the components and targets of THSWD for treating HN. Animal experiments were performed to verify the network pharmacology findings. RESULTS: 205 targets were identified and regarded as potential targets of THSWD in HN treatment. Subsequently, we screened 17 hub genes and identified TP53 as the most critical one. KEGG enrichment analysis showed that p53 signaling pathway might play a significant role. In vivo experiments indicated that high-salt diets can lead to high blood pressure, kidney injury, inflammation, and fibrosis. Furthermore, the altered levels of biomarkers (Iron, malondialdehyde, catalase, ferritin, transferrin, Superoxide dismutase and Glutathione Peroxidase 4) provided evidence of ferroptosis. We found that the ferroptosis inhibitor ferrostatin-1 (Fer-1) and THSWD could significantly alleviate HN by suppressing ferroptosis. THSWD and Fer-1 treatment downregulated the protein and mRNA expression of p53, p21, RB, and CTNNB1, which were upregulated by high salt. Meanwhile, THSWD and Fer-1 reversed the downregulation of Nrf2 caused by high-salt diet. CONCLUSIONS: Our results suggested that THSWD attenuate HN induced by a high-salt diet through inhibiting ferroptosis via the p53/Nrf2/p21 pathway.
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Ferroptosis , Hipertensión , Animales , Factor 2 Relacionado con NF-E2/genética , Farmacología en Red , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Arsenate (AsV) is one of the most common forms of arsenic (As) in environment and plant high-affinity phosphate transporters (PHT1s) are the primary plant AsV transporters. However, few PHT1s involved in AsV absorption have been identified in crops. In our previous study, TaPHT1;3, TaPHT1;6 and TaPHT1;9 were identified to function in phosphate absorption. Here, their AsV absorption capacities were evaluated using several experiments. Ectopic expression in yeast mutants indicated that TaPHT1;9 had the highest AsV absorption rates, followed by TaPHT1;6, while not for TaPHT1;3. Under AsV stress, further, BSMV-VIGS-mediated TaPHT1;9-silencing wheat plants exhibited higher AsV tolerance and lower As concentrations than TaPHT1;6-silenced plants, whereas TaPHT1;3-silencing plants had similar phenotype and AsV concentrations to control. These suggested that TaPHT1;9 and TaPHT1;6 possessed AsV absorption capacity with the former showing higher activities. Under hydroponic condition, furthermore, CRISPR-edited TaPHT1;9 wheat mutants showed the enhanced tolerance to AsV with decreased As distributions and concentrations, whereas TaPHT1;9 ectopic expression transgenic rice plants had the opposite results. Also, under AsV-contaminated soil condition, TaPHT1;9 transgenic rice plants exhibited depressed AsV tolerance with increased As concentrations in roots, straws and grains. Moreover, Pi addition alleviated the AsV toxicity. These suggested that TaPHT1;9 should be a candidate target gene for AsV phytoremediation.
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Arseniatos , Arsénico , Arseniatos/toxicidad , Arseniatos/metabolismo , Triticum/genética , Triticum/metabolismo , Biodegradación Ambiental , Arsénico/toxicidad , Arsénico/metabolismo , Raíces de Plantas/metabolismoRESUMEN
Dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), is a new type of oral hypoglycemic drugs which can promote glucose excretion in the kidney. Studies have shown that dapagliflozin has renoprotective effect in the treatment of type 2 diabetes. However, the underlying mechanism remains unclear. Here, we combined integrated RNA sequencing and network pharmacology approach to investigate the molecular mechanism of dapagliflozin for diabetic nephropathy (DN). Dapagliflozin significantly relieved glucose intolerance, urinary albumin/creatinine ratio (UACR) and renal pathological injuries of db/db mice. The LncRNA and mRNA expression in kidney tissues from control group (CR), db/db group (DN) and dapagliflozin group (DG) were assessed by RNA sequencing. We identified 7 LncRNAs and 64 mRNAs common differentially expressed in CR vs DN and DN vs DG, which were used to construct co-expression network to reveal significantly correlated expression patterns in DN. In addition, network pharmacology was used to predict the therapeutic targets of dapagliflozin and we constructed component-target-pathway network according to the results of RNA sequencing and network pharmacology. We found that SMAD9, PPARG, CD36, CYP4A12A, CYP4A12B, CASP3, H2-DMB2, MAPK1, MAPK3, C3 and IL-10 might be the pivotal targets of dapagliflozin for treating DN and these genes were mainly enriched in pathways including TGF-ß signaling pathway, PPAR signaling pathway, Chemokine signaling pathway, etc. Our results have important implication and provide novel insights into the protective mechanism of dapagliflozin for treating DN.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , ARN Largo no Codificante , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Albúminas/genética , Albúminas/metabolismo , Albúminas/uso terapéutico , Animales , Compuestos de Bencidrilo , Caspasa 3/genética , Caspasa 3/metabolismo , Caspasa 3/uso terapéutico , Quimiocinas/metabolismo , Creatinina , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Glucosa/metabolismo , Glucósidos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-10/uso terapéutico , Ratones , Farmacología en Red , PPAR gamma/metabolismo , ARN Largo no Codificante/genética , ARN Mensajero/genética , Análisis de Secuencia de ARN , Sodio/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Factor de Crecimiento Transformador betaRESUMEN
A hydrothermal method was used to synthesise (Ce,La)CO3F grain simulated minerals, in accordance with the Ce-La ratio of bastnaesite in the mineralogy of the Bayan Ebo process. The NH3-SCR catalytic activity of the synthesised (Ce,La)CO3F was improved by loading transition metals Mn and Fe and sulphuric acid acidification treatments. The activity test results showed that the catalysts which were simultaneously acidified with sulphuric acid and loaded with transition metals Mn and Fe had a NO x conversion of 92% at 250 °C. XRD, SEM, XPS and in situ Fourier transform infrared spectroscopy (FTIR) were used to investigate the physical phase structure, surface morphology, reaction performance and mechanism of the catalysts, to provide theoretical guidance for the specific reaction path of cerium fluorocarbon ore in the NH3-SCR reaction. The results showed that the introduction of transition metals and sulphuric acid greatly increases the proportion of adsorbed oxygen (Oα) and facilitates the adsorption of NH3 and NO. The catalyst surface metal sulphate and metal oxide species act as the main active components on the catalyst surface to promoted the reaction, and cracks and pores appear on the surface to facilitate the adsorption of reactive gases. The reaction mechanism of the SO4 2--Mn-Fe/(Ce,La)CO3F catalyst, and characterisation of the adsorption and conversion behaviour of the reactive species on the catalyst surface, were investigated by Fourier transform infrared spectroscopy (FTIR). The results showed that the catalyst follows the E-R and L-H mechanisms throughout the reaction, with the E-R mechanism being the main reaction. The reaction species were NH4 +/NH3 species in the adsorbed state and NO. The NH3(ad) species on the Lewis acidic site is the main NH3(g) adsorbed species for the reaction, bonded to Ce4+ in the carrier (Ce,La)CO3F to participate in the acid cycle reaction, and undergo a redox reaction on the catalyst surface to produce N2 and H2O. The SO4 2- present on the catalyst surface can also act as an acidic site for the adsorption of NH3. The above results indicated the excellent performance of the SO4 2--Mn-Fe/(Ce,La)CO3F catalyst, which provided a theoretical basis for the high value utilization of bastnaesite.
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Inhibition of apoptosis signal-regulating kinase 1 (ASK1) activation has emerged as a promising target for the treatment of nonalcoholic steatohepatitis (NASH). Multiple forms of posttranslational modifications determine the activity of ASK1. In addition to phosphorylation, recent studies revealed that ubiquitination is essential for ASK1 activation. However, the endogenous factor that regulates ASK1 ubiquitination and activation remains poorly defined. In this study, we identified the E3 ligase Skp1-Cul1-F-box (SCF) protein F-box/WD repeat-containing protein 5 (FBXW5) as a key endogenous activator of ASK1 ubiquitination. FBXW5 is the central component of the SCF complex (SCFFbxw5 ) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development. An in vivo study showed that hepatocyte-specific overexpression of FBXW5 exacerbated diet-induced systemic and hepatic metabolic disorders, as well as the activation of ASK1-related mitogen-activated protein kinase (MAPK) signaling in the liver. Conversely, hepatocyte-specific deletion of FBXW5 significantly prevented the progression of these abnormalities. Mechanically, FBXW5 facilitated the addition of Lys63-linked ubiquitin to ASK1 and thus exacerbated ASK1-c-Jun N-terminal kinase/p38 MAPK signaling, inflammation, and lipid accumulation. Furthermore, we demonstrated that the N-terminus (S1) and C-terminus (S3) of FBXW5 respectively and competitively ablate the function of FBXW5 on ASK1 activation and served as effective inhibitors of NASH progression. Conclusion: This evidence strongly suggests that SCFFbxw5 is an important activator of ASK1 ubiquitination in the context of NASH. The development of FBXW5(S1) or FBXW5(S3)-mimicking drugs and screening of small-molecular inhibitors specifically abrogating ASK1 ubiquitination-dependent activation are viable approaches for NASH treatment.
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Proteínas F-Box/fisiología , MAP Quinasa Quinasa Quinasa 5/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Ubiquitinación , Animales , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Repeticiones WD40 , Proteínas Quinasas p38 Activadas por Mitógenos/fisiologíaRESUMEN
Inactivated Sendai virus (HVJ-E) directly kills cancer cells by inducing apoptosis through a mechanism mediated by Janus kinases/signal transducers and activators of transcription (JAK/STAT) signaling pathways. However, whether other signaling pathways are involved remain largely unknown. This study aimed to investigate the mechanism underlying HVJ-E-induced apoptosis in murine B16F10 melanoma cells. We found that HVJ-E induced B16F10 cell apoptosis via the caspase pathway, particularly caspase-9, which mediates the intrinsic apoptotic pathway. Mitogen-activated protein kinase (MAPK) pathway activation also contributed to HVJ-E-induced apoptosis. Whereas caspase pathway involvement depended on both IFN-ß promoter stimulator-1 (IPS-1) and type I interferon (IFN), MAPK pathway activation was independent of type I IFN but involved IPS-1. In addition, intratumoral HVJ-E treatment displayed a direct oncolytic effect in an in vivo BALB/c nude mouse melanoma model. Collectively, our data provides new insights into the mechanism underlying HVJ-E-induced apoptosis in tumor cells.