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Hypertensive heart disease (HHD) presents a substantial global health burden, spanning a spectrum from subtle cardiac functional alterations to overt heart failure. In this comprehensive review, we delved into the intricate pathophysiological mechanisms governing the onset and progression of HHD. We emphasized the significant role of neurohormonal activation, inflammation, and metabolic remodeling in HHD pathogenesis, offering insights into promising therapeutic avenues. Additionally, this review provided an overview of contemporary imaging diagnostic tools for precise HHD severity assessment. We discussed in detail the current potential treatments for HHD, including pharmacologic, lifestyle, and intervention devices. This review aimed to underscore the global importance of HHD and foster a deeper understanding of its pathophysiology, ultimately contributing to improved public health outcomes.
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Corneal injury leads to impaired normal structure of the cornea. Improving the wound healing process in epithelial cells significantly contributes to ocular damage treatments. Here, we aimed to investigate the potential mechanisms of nitric oxide (NO) and its mediator, inducible nitric oxide synthase (iNOS), in the process of corneal wound healing. We established a corneal injury model of iNOS-/- mice, and treated human corneal epithelial cell lines (HCE-2) with the iNOS inhibitor L-INL, with or without NO replenishment by supplying sodium nitroferricyanide dihydrate (SNP). Our findings showed that inhibition of NO/iNOS accelerated corneal repair, enhanced uPAR (a receptor protein indicating the migration ability), and improved epithelial cell migration. Furthermore, NO/iNOS ablation activated Akt phosphorylation, reduced neutrophil marker protein MPO expression, and downregulated the transcription of inflammation cytokines CXCL-1, CXCL-2, IL-1ß, IL-6, and TNF-α. However, the protective effects of NO/iNOS inhibition are significantly reduced by NO replenishment when treated with SNP. Therefore, we confirmed that inhibiting NO/iNOS improved the corneal wound healing by facilitating epithelial cell migration and reducing inflammatory reactions, which might be related to the activation of the Akt signaling pathway.
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Movimento Celular , Lesões da Córnea , Modelos Animais de Doenças , Epitélio Corneano , Óxido Nítrico Sintase Tipo II , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Cicatrização , Animais , Humanos , Masculino , Camundongos , Western Blotting , Movimento Celular/fisiologia , Lesões da Córnea/metabolismo , Lesões da Córnea/patologia , Epitélio Corneano/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Cicatrização/fisiologiaRESUMO
Skin aging is characterized by changes in its structural, cellular, and molecular components in both the epidermis and dermis. Dermal aging is distinguished by reduced dermal thickness, increased wrinkles, and a sagging appearance. Due to intrinsic or extrinsic factors, accumulation of excessive reactive oxygen species (ROS) triggers a series of aging events, including imbalanced extracellular matrix (ECM) homeostasis, accumulation of senescent fibroblasts, loss of cell identity, and chronic inflammation mediated by senescence-associated secretory phenotype (SASP). These events are regulated by signaling pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), mechanistic target of rapamycin (mTOR), transforming growth factor beta (TGF-ß), and insulin-like growth factor 1 (IGF-1). Senescent fibroblasts can induce and accelerate age-related dysfunction of other skin cells and may even cause systemic inflammation. In this review, we summarize the role of dermal fibroblasts in cutaneous aging and inflammation. Moreover, the underlying mechanisms by which dermal fibroblasts influence cutaneous aging and inflammation are also discussed.
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Senescência Celular , Envelhecimento da Pele , Humanos , Senescência Celular/fisiologia , Fibroblastos/metabolismo , Derme , Inflamação/metabolismoRESUMO
The ability of the adult mammalian heart to regenerate can save the cardiac muscle from a loss of function caused by injury. Cardiomyocyte regeneration is a key aspect of research for the treatment of cardiovascular diseases. The mouse heart shows temporary regeneration in the first week after birth; thus, the newborn mouse heart is an ideal model to study heart muscle regeneration. In this study, proteomic analysis was used to investigate the differences in protein expression in the hearts of neonatal mice at days 1 (P1 group), 4 (P4 group), and 7 (P7 group). Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed changes in several groups of proteins, including the protein kinase A (PKA) signaling pathway. Moreover, it was found that PKA inhibitors and agonists regulated cardiomyocyte replication in neonatal mouse hearts. These findings suggest that PKA may be a target for the regulation of the cardiomyocyte cell cycle.
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The repair of large-diameter corneal stroma defects is a major clinical problem. Although some studies have attempted to use hydrogels to repair corneal damage, most of these hydrogels can only be used for focal stromal defects that are ≤3.5 mm in diameter due to poor hydrogel adhesion. Here, a photocurable adhesive hydrogel that mimics the extracellular matrix (ECM) with regard to composition for repairing 6 mm-diameter corneal stromal defects in rabbits is investigated. This ECM-like adhesive can be rapidly cured after light exposure, with high light transmittance and good mechanical properties. More importantly, this hydrogel maintains the viability and adhesion of cornea-derived cells and promotes their migration in vitro in 2D and 3D culture environments. Proteomics analysis confirms that the hydrogel promotes cell proliferation and ECM synthesis. Furthermore, in rabbit corneal stromal defect repair experiments, it is proven by histological and proteomic analysis that this hydrogel can effectively promote corneal stroma repair, reduce scar formation, and increase corneal stromal-neural regeneration at the six months follow-up. This work demonstrates the great application of ECM-like adhesive hydrogels for the regeneration of large-diameter corneal defects.
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Substância Própria , Regeneração , Animais , Coelhos , Adesivos , Hidrogéis/farmacologia , Proteômica , Matriz Extracelular , Regeneração NervosaRESUMO
Enamel hypoplasia is a tooth development defection due to the disruption of enamel matrix mineralization, manifesting as chalky white phenotype. Multiple genes may be involved in this tooth agenesis. It has been proved that ablation of coactivator Mediator1 (Med1) switches the cell fate of dental epithelia, resulting in abnormal tooth development via Notch1 signaling. Smad3 (-/-) mice displays the similar chalky white incisors. However, the expression of Smad3 in Med1 ablation mice and the impact of Med1 on functional integration between Smad3 and Notch1 remains unclear. Cre-loxP-based C57/BL6 mice with epithelial-specific Med1 knockout (Med1 KO) backgrounds were generated. Mandibles and dental epithelial stem cells (DE-SCs) from incisors cervical loop (CL) were isolated from wild-type (CON) mice and Med1 KO mice. Transcriptome sequencing was used to analyze the differences of CL tissue between KO and CON mice. The results revealed the enrichment of TGF-ß signaling pathway. qRT-PCR and western blot were performed to show the gene and protein expression of Smad3, pSmad3, Notch1 and NICD, the key regulators of TGF-ß and Notch1 signaling pathway. Expression of Notch1 and Smad3 was confirmed to be down-regulated in Med1 KO cells. Using activators of Smad3 and Notch1 on Med1 KO cells, both pSmad3 and NICD were rescued. Moreover, adding inhibitors and activators of Smad3 and Notch1 to cells of CON groups respectively, the protein expressions of Smad3, pSmad3, Notch1 and NICD were synergistically affected. In summary, Med1 participates in the functional integration of Smad3 and Notch1, thus promoting enamel mineralization.
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Transdução de Sinais , Calcificação de Dente , Camundongos , Animais , Epitélio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Diferenciação Celular , Camundongos Knockout , Proteína Smad3/genética , Proteína Smad3/metabolismoRESUMO
BACKGROUND: Psoriasis is a common, chronic and relapsing immune-related inflammatory dermal disease. Patients with psoriasis suffering from the recurrences is mainly caused by immune response disorder. Thus, our study is aimed to identify novel immune subtypes and select targeted drugs for the precision therapy in different subtypes of psoriasis. METHODS: Differentially expressed genes of psoriasis were identified from the Gene Expression Omnibus database. Functional and disease enrichment were performed by Gene Set Enrichment Analysis and Disease Ontology Semantic and Enrichment analysis. Hub genes of psoriasis were selected from protein-protein interaction networks using Metascape database. The expression of hub genes was validated in human psoriasis samples by RT-qPCR and immunohistochemistry. Further, novel immune subtypes of psoriasis were identified by ConsensusClusterPlus package and its association with hub genes were calculated. Immune infiltration analysis was performed, and its candidate drugs were evaluated by Connectivity Map analysis. RESULTS: 182 differentially expressed genes of psoriasis were identified from GSE14905 cohort, in which 99 genes were significantly up-regulated and 83 genes were down-regulated. We then conducted functional and disease enrichment in up-regulated genes of psoriasis. Five potential hub genes of psoriasis were obtained, including SOD2, PGD, PPIF, GYS1 and AHCY. The high expression of hub genes was validated in human psoriasis samples. Notably, two novel immune subtypes of psoriasis were determined and defined as C1 and C2. Bioinformatic analysis showed C1 and C2 had different enrichment in immune cells. Further, candidate drugs and mechanism of action that applicable to different subtypes were evaluated. CONCLUSIONS: Our study identified two novel immune subtypes and five potential hub genes of psoriasis. These findings might give insight into the pathogenesis of psoriasis and provide effective immunotherapy regimens for the precise treatment of psoriasis.
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Psoríase , Humanos , Psoríase/genética , Biologia Computacional , Bases de Dados Factuais , Sistemas de Liberação de Medicamentos , Imunoterapia , Perfilação da Expressão GênicaRESUMO
Mitochondrial dysfunctions underlie the pathogenesis in glioblastoma multiforme (GBM). Comprehensive proteomic profiling of mitochondria-specific changes in human GBM is still insufficient. This study carried out a DIA-MS based proteomic analysis on the mitochondria isolated from human primary GBM and peritumoral tissue (as paired control), and further compared those findings with the transcriptomic datasets. A total of 538 mitochondrion-specific proteins were rigorously confirmed, among which 190 differentially expressed proteins were identified. Co-regulations of the mitochondrial dysfunction pathway networks were observed, including significant up-regulations of mitochondrial translation and apoptosis, as well as down-regulations of OXPHOS and mitochondrial dynamics. Proteins related to FA, AA metabolism and ROS also showed significant variations. Most of these alterations were consistent in trend when compared the proteomics findings with the RNA-Seq datasets, while the changes at protein levels appeared to be more dramatic. Potentially key proteins in GBM were identified, including up-regulated pro-apoptotic protein CASP3, BAX, fatty acid oxidation enzymes CPT1A, CPT2, ACADM, serine-glycine enzymes SHMT2, GATM, ROS-related protein SOD2, GPX1, and CAT; and down-regulated dynamin-related protein MFN1, MFN2, OPA1, and OXPHOS components; and also several differentially expressed ALDH isoforms. This study systematically profiled the mitochondrial dysfunctions by combining proteomic findings and mRNA datasets, which would be a valuable resource to the community for further thorough analyses.
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Glioblastoma , Humanos , Glioblastoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , RNA-Seq , Proteômica , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismoRESUMO
Mediator complex subunit 1 (MED1) is a coactivator of multiple transcription factors and plays a key role in regulating epidermal homeostasis as well as skin wound healing. It is unknown, however, whether it plays a role in healing oral mucosal wounds. In this study, we investigate MED1's functional effects on oral mucosal wound healing and its underlying mechanism. The epithelial-specific MED1 null (Med1epi-/-) mice were established using the Cre-loxP system with C57/BL6 background. A 3 mm diameter wound was made in the cheek mucosa of the 8-week-old mice. In vivo experiments were conducted using HE staining and immunostaining with Ki67 and uPAR antibodies. The in vitro study used lentiviral transduction, scratch assays, qRT-PCR, and Western blotting to reveal the underlying mechanisms. The results showed that ablation of MED1 accelerated oral mucosal wound healing in 8-week-old mice. As a result of ablation of MED1, Activin A/Follistatin expression was altered, resulting in an activation of the JNK/c-Jun pathway. Similarly, knockdown of MED1 enhanced the proliferation and migration of keratinocytes in vitro, promoting re-epithelialization, which accelerates the healing of oral mucosal wounds. Our study reveals a novel role for MED1 in oral keratinocytes, providing a new molecular therapeutic target for accelerated wound healing.
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Sistema de Sinalização das MAP Quinases , Cicatrização , Camundongos , Animais , Cicatrização/genética , Queratinócitos/metabolismo , Reepitelização , Epiderme/metabolismo , Movimento Celular , Subunidade 1 do Complexo Mediador/metabolismoRESUMO
There are many factors that influence the academic achievements of medical students, but how personality and brain modulate the academic achievements of medical students remains unclear. The study collected the personality, brain imaging, and academic data from 448 medical students at Tianjin Medical University with admission time between 2008 and 2017. Four types of academic achievements, including behavioral and social sciences, clinical sciences and skills, basic biomedical sciences, and scientific methods, were assessed by the academic records of 58 courses. Personality was evaluated by Tridimensional Personality Questionnaire and Neuroticism Extraversion Openness Personality Inventory. Brain structural and functional properties, including gray matter volume, spontaneous brain activity and functional connectivity, were computed based on magnetic resonance imaging (MRI). Linear regression was used to evaluate the associations between personality and academic achievements. A voxel-wise correlation was used to identify areas of the brain where structural and functional properties were associated with academic achievements. Mediation analysis was used to test whether brain properties and personality independently contribute to academic achievements. Our results showed that novelty seeking (NS) was negatively correlated, and conscientiousness was positively correlated with all types of academic achievements. Brain functional properties showed negatively correlated with academic achievement in basic biomedical sciences. However, we did not find any mediation effect of the brain functional properties on the association between personality (NS and conscientiousness) and academic achievement in basic biomedical sciences, nor mediation effect of the personality (NS and conscientiousness) on the association between brain functional properties and academic achievement in basic biomedical sciences. These findings suggest that specific personality (NS and conscientiousness) and brain functional properties independently contribute to academic achievements in basic biomedical sciences, and that modulation of these properties may benefit academic achievements among medical students.
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Tissue engineering to develop alternatives for the maintenance, restoration, or enhancement of injured tissues and organs is gaining more and more attention. In tissue engineering, the scaffold used is one of the most critical elements. Its characteristics are expected to mimic the native extracellular matrix and its unique topographical structures. Recently, the topographies of scaffolds have received increasing attention, not least because different topographies, such as aligned and random, have different repair effects on various tissues. In this review, we have focused on various technologies (electrospinning, directional freeze-drying, magnetic freeze-casting, etching, and 3-D printing) to fabricate scaffolds with different topographic orientations, as well as discussed the physicochemical (mechanical properties, porosity, hydrophilicity, and degradation) and biological properties (morphology, distribution, adhesion, proliferation, and migration) of different topographies. Subsequently, we have compiled the effect of scaffold orientation on the regeneration of vessels, skin, neural tissue, bone, articular cartilage, ligaments, tendons, cardiac tissue, corneas, skeletal muscle, and smooth muscle. The compiled information in this review will facilitate the future development of optimal topographical scaffolds for the regeneration of certain tissues. In the majority of tissues, aligned scaffolds are more suitable than random scaffolds for tissue repair and regeneration. The underlying mechanism explaining the various effects of aligned and random orientation might be the differences in "contact guidance", which stimulate certain biological responses in cells.
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Background: Familial hypercholesterolemia (FH) can elevate serum low-density lipoprotein cholesterol (LDL-C) levels, which can promote the progression of acute coronary syndrome (ACS). However, the effect of FH on the prognosis of ACS remains unclear. Methods: In this prospective cohort study, 223 patients with ACS having LDL-C ≥ 135.3 mg/dL (3.5 mmol/L) were enrolled and screened for FH using a multiple-gene FH panel. The diagnosis of FH was defined according to the ACMG/AMP criteria as carrying pathogenic or likely pathogenic variants. The clinical features of FH and the relationship of FH to the average 16.6-month risk of cardiovascular events (CVEs) were assessed. Results: The prevalence of molecularly defined FH in enrolled patients was 26.9%, and coronary artery lesions were more severe in patients with FH than in those without (Gensini score 66.0 vs. 28.0, respectively; P < 0.001). After lipid lowering, patients with FH still had significantly higher LDL-C levels at their last visit (73.5 ± 25.9 mg/dL vs. 84.7 ± 37.1 mg/dL; P = 0.013) compared with those without. FH increased the incidence of CVEs in patients with ACS [hazard ratio (HR): 3.058; 95% confidence interval (CI): 1.585-5.900; log-rank P < 0.001]. Conclusion: FH is associated with an increased risk of CVEs in ACS and is an independent risk factor for ACS. This study highlights the importance of genetic testing of FH-related gene mutations in patients with ACS.
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As the development of wireless communication devices tends to be highly integrated, the miniaturization of very low frequency (VLF) antenna units has always been an unresolved issue. Here, a novel VLF mechanical communication antenna using magnetoelectric (ME) laminates with bending-mode structure is realized. ME laminates combines magnetostrictive Metglas amorphous ribbons and piezoelectric 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3single crystal plates. From the simulation, we confirmed that the ME laminates can reduce the resonance peak from 18 kHz to 7.5 kHz by bending-mode structure. Experiment results show the resonance frequency can be farther reduced to 6.3 kHz by clamping one end of the ME antenna. The ME laminate exhibits a giant converse ME coefficient of 6 Oe cm V-1at 6.3 kHz. The magnetic flux density generated by the ME antenna has been tested along with distance ranging from 0 to 60 cm and it is estimated that a 1 fT flux could be detected around 100 m with an excitation power of 10 mW.
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OBJECTIVES: The aim of this study was to investigate the dose-response relationship of admission fasting glucose (FBG) with corona virus disease 2019 (COVID-19) mortality and to further evaluate potential interactions of hyperglycemia with inflammation and hypercoagulation on COVID-19 outcomes. METHODS: This retrospective study included 2555 consecutively hospitalized patients with COVID-19, until death or discharge, in Wuhan Union hospital between January 1 and April 9, 2020. The poor early outcomes included admission to intensive care unit, intubation, and deaths occurring within 28 days. We used splines nested in Cox regression to visualize dose-response associations and generalized additive models to fit three-dimensional (3D) trend plots for joint effects of FBG with markers of inflammation and coagulation. RESULTS: J-shaped associations existed between hospitalized mortality or poor early outcomes and FBG with a nadir at 5 mmol/L, which were more evident in women. 3D plots demonstrated significant joint effect trends, and patients with hyperglycemia and high neutrophil-lymphocyte ratio, C-reactive protein, lactate dehydrogenase, procalcitonin, d-dimer, and interleukin-6 had 7.4-25.3-fold risks; the proportions of joint associations attributed to additive interactions reached 30% to 54%. CONCLUSIONS: FBG was associated with hospitalized mortality and poor early outcomes in a J-shaped manner, and a combination of hyperglycemia, inflammation, hypercoagulation, and cytokines conferred a dramatically higher risk.
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COVID-19 , Hiperglicemia , Glicemia/metabolismo , COVID-19/complicações , Citocinas , Jejum , Feminino , Glucose , Humanos , Hiperglicemia/complicações , Inflamação/complicações , Prognóstico , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2RESUMO
Doxorubicin (DOX), a commonly used antitumor agent, is often accompanied by its dosage-dependent cardiotoxicity, which incorporates ferroptosis in its pathogenesis. Protein arginine methyltransferase 4 (PRMT4) is a transcription regulator involved in the modulation of oxidative stress and autophagy, but its role in DOX-induced cardiomyopathy (DIC) and ferroptosis remains elusive. Herein, we aimed to investigate the involvement and the underlying mechanisms of PRMT4 in the pathogenesis of DIC. Our present study revealed that the expression level of PRMT4 was markedly decreased in DOX-treated cardiomyocytes. Interestingly, it is noted that PRMT4 overexpression accelerated ferroptosis to aggravate DIC, while its gene disruption or pharmaceutical inhibition exhibited the opposite effect. Mechanistically, our observation demonstrated that PRMT4 interacted with the nuclear factor erythroid 2-related factor 2 (Nrf2) to promote its enzymatic methylation, which restricted the nuclear translocation of Nrf2 and subsequently suppressed the transcription of glutathione peroxidase 4 (GPX4). Importantly, the detrimental role of PRMT4 in DOX-induced cardiomyocyte ferroptosis was abolished by Nrf2 activation or Fer-1 administration. Collectively, our data reveal that PRMT4 inhibits Nrf2/GPX4 signaling to accelerate ferroptosis in DIC, suggesting that targeting PRMT4 may present as a potential preventive strategy against the development of DIC.
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Antineoplásicos , Cardiomiopatias , Ferroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Proteína-Arginina N-Metiltransferases , Humanos , Antineoplásicos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Doxorrubicina/toxicidade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Proteína-Arginina N-Metiltransferases/metabolismoRESUMO
Myocardial fibrosis is a concomitant bioprocess associated with many cardiovascular diseases (CVDs). Daidzein is an isoflavone that has been used for the treatment of CVDs. This study aimed to reveal its role in myocardial fibrosis. Our results indicate that daidzein had a nontoxic effect on cardiac fibroblasts and that TGF-ß1 and TGFßRI levels were gradually decreased by daidzein in a dose-dependent manner. In the current study, we show that daidzein significantly inhibited TGF-ß1-induced mRNA and protein expression of α-SMA, collagen I, and collagen III. Accordingly, immunofluorescence staining of α-SMA was performed. Daidzein also inhibited TGF-ß1-induced cardiac fibroblast proliferation and migration. Mechanistically, daidzein inhibited the TGF-ß/SMAD signaling pathway induced by TGF-ß1 in cardiac fibroblasts. Additionally, daidzein ameliorated MI-induced cardiac dysfunction and cardiac fibrosis in vivo. Based on these findings, we conclude that daidzein reduces TGF-ß1-induced cardiac fibroblast activation by partially regulating the TGF-ß1/SMAD2/3 signaling pathway.
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Doenças Cardiovasculares/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Isoflavonas/farmacologia , Miocárdio/patologia , Animais , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/uso terapêutico , Humanos , Isoflavonas/administração & dosagem , Isoflavonas/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
NF-erythroid 2-related factor 2 (Nrf2) is a major transcription factor to protect cells against reactive oxygen species (ROS) and reactive toxicants. Meanwhile, Nrf2 can inhibit contact dermatitis through redox-dependent and -independent pathways. However, the underlying mechanisms of how Nrf2 mediates irritant contact dermatitis (ICD) are still unclear. In this article, we elucidated the role of Nrf2 in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute ICD. Our study demonstrated that the ear thickness, redness, swelling, and neutrophil infiltration were significantly increased, accompanied by increased expression of inflammatory cytokines (IL-1α, IL-1ß, IL-6, etc.) and decreased expression of antioxidant genes (HO-1 and NQO1) in Nrf2 knockout mice. Moreover, ERK phosphorylation was elevated in mouse embryonic fibroblasts (MEFs) from Nrf2 knockout mouse. Inhibition of ERK significantly alleviated TPA-induced cutaneous inflammation and ROS accumulation in MEFs derived from mouse. Conversely, ROS scavenging inhibited the ERK activation and TPA-induced inflammation in MEFs. Taken together, the findings illustrate the key role of the Nrf2/ROS/ERK signaling pathway in TPA-induced acute ICD.
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Dermatite de Contato , Fator 2 Relacionado a NF-E2 , Animais , Camundongos , Fibroblastos/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação , Irritantes , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Acetato de TetradecanoilforbolRESUMO
Metastasis is the main reason for the high mortality of patients and indeed a difficult task in the treatment of cutaneous melanoma. Therefore, it is of great clinical value to explore the molecular mechanism of cutaneous metastatic melanoma and develop novel therapies. MED1, acting as a factor required for activator-dependent transcription, is reported to be involved in carcinogenesis and progression. In this study, we found that MED1 was highly expressed in patients with cutaneous melanoma. MED1 downregulation could induce cellular epithelial-to-mesenchymal transition and promote migration, invasion, and metastasis of cutaneous melanoma in vivo and in vitro. Further analysis showed that in Med1 knockdown cells, the TGFß/SMAD2 signaling pathway mediated an increase in epithelial-to-mesenchymal transition phenotype and migration. The opposite results were observed after treatment with TGFß inhibitors. To further explore the mechanism, we found that MED1 interacted with SMAD2, and MED1 downregulation could protect SMAD2 from degradation by inhibiting SMAD2 ubiquitination. Together, these results suggest that MED1 inhibited TGFß signaling pathway to reduce cell epithelial-to-mesenchymal transition phenotype and migration through SMAD2 ubiquitination in the metastasis of cutaneous melanoma. Our findings elucidated the role of MED1 in the metastasis of cutaneous melanoma and provided a target for the therapeutic strategies of cutaneous melanoma.
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Subunidade 1 do Complexo Mediador , Melanoma , Neoplasias Cutâneas , Proteína Smad2 , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo , Transição Epitelial-Mesenquimal , Humanos , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Melanoma/patologia , Transdução de Sinais/genética , Neoplasias Cutâneas/patologia , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ubiquitinação , Melanoma Maligno CutâneoRESUMO
Scleroderma, characterized by extensive fibrosis and vascular alterations, involves excessive fibroblast activation, uncontrolled inflammation, and abnormal collagen deposition. Previous studies showed that administrations of either 1,25(OH)2D3 or vitamin D analog effectively decreased or reversed skin fibrosis by regulating the extracellular matrix homeostasis. The actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR), a transcription regulator crucial for skin homeostasis. Although evidence suggests that keratinocyte-fibroblast interaction influences the development of scleroderma, the role of keratinocytes in scleroderma remains unknown. Here, we demonstrated that the ablation of VDR in keratinocytes greatly exacerbated dermal fibrosis in HOCl-induced scleroderma in mice. The deficiency of VDR in the epidermis marked increased dermal thickness, inflammatory cell infiltration, and severe collagen deposition in comparison to the control group in HOCl-treated skin. Moreover, significant elevations in expression levels of mRNA for collagen overproduction (Col1A1, Col1A2, Col3A1, α-SMA, MMP9, TGF-ß1) and proinflammatory cytokines (IL-1ß, IL-6, CXCL1, CXCL2) were observed in VDR conditional KO versus control mice following HOCl treatment. Collectively, these results suggest that VDR in keratinocytes plays a pivotal role in scleroderma progression, and the interplay between keratinocytes and fibroblasts deserves more attention regarding the exploration of the pathogenesis and treatment for scleroderma.