RESUMO
Osteosarcoma (OS) is the most common primary malignant tumour of the bone with high mortality. Here, we comprehensively analysed the hypoxia signalling in OS and further constructed novel hypoxia-related gene signatures for OS prediction and prognosis. This study employed Gene Set Enrichment Analysis (GSEA), Weighted correlation network analysis (WGCNA) and Least absolute shrinkage and selection operator (LASSO) analyses to identify Stanniocalcin 2 (STC2) and Transmembrane Protein 45A (TMEM45A) as the diagnostic biomarkers, which further assessed by Receiver Operating Characteristic (ROC), decision curve analysis (DCA), and calibration curves in training and test dataset. Univariate and multivariate Cox regression analyses were used to construct the prognostic model. STC2 and metastasis were devised to forge the OS risk model. The nomogram, risk score, Kaplan Meier plot, ROC, DCA, and calibration curves results certified the excellent performance of the prognostic model. The expression level of STC2 and TMEM45A was validated in external datasets and cell lines. In immune cell infiltration analysis, cancer-associated fibroblasts (CAFs) were significantly higher in the low-risk group. And the immune infiltration of CAFs was negatively associated with the expression of STC2 (P < 0.05). Pan-cancer analysis revealed that the expression level of STC2 was significantly higher in Esophageal carcinoma (ESCA), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Lung squamous cell carcinoma (LUSC), and Stomach adenocarcinoma (STAD). Additionally, the higher expression of STC2 was associated with the poor outcome in those cancers. In summary, this study identified STC2 and TMEM45A as novel markers for the diagnosis and prognosis of osteosarcoma, and STC2 was shown to correlate with immune infiltration of CAFs negatively.
Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas , Peptídeos e Proteínas de Sinalização Intercelular , Aprendizado de Máquina , Osteossarcoma , Osteossarcoma/genética , Osteossarcoma/diagnóstico , Osteossarcoma/patologia , Humanos , Prognóstico , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Perfilação da Expressão Gênica , Nomogramas , Transcriptoma , Curva ROC , Feminino , Hipóxia/genética , MasculinoAssuntos
Neoplasias da Mama , Movimento Celular , Proliferação de Células , Proteínas de Membrana , MicroRNAs , Invasividade Neoplásica , Via de Sinalização Wnt , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Feminino , Movimento Celular/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Animais , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos , beta Catenina/metabolismo , beta Catenina/genéticaRESUMO
Adropin is a secreted peptide encoded by the energy homeostasisassociated gene, which also functions as a membranebound protein facilitating intercellular communication. This peptide has been detected in various tissues and body fluids, including the brain, liver, kidney, heart, pancreas, small intestine, endothelial cells and colostrum. Notably, the amino acid sequences of adropin are identical in humans, mice and rats. Previous studies have demonstrated that adropin levels fluctuate under different physiological and pathological conditions. Adropin plays a role in regulating carbohydrate metabolism, lipid metabolism and intercellular molecular signaling pathways, implicating its involvement in the progression of numerous diseases, such as acute myocardial infarction, lung injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, kidney disease, polycystic ovary syndrome, obesity, and diabetes, atherosclerosis, systemic sclerosis and cancer. Despite its significance, the precise role and mechanism of this protein remain inadequately understood and studied. To elucidate the function of adropin and its clinical research status, a systematic review of recent studies on adropin across various diseases was conducted. Additionally, several challenges and limitations associated with adropin research in both animal and clinical contexts were identified, aiming to offer valuable insights for future investigation.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Humanos , Animais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Metabolismo dos Lipídeos/genética , Transdução de Sinais , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologiaRESUMO
The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 had axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis showed that loss of Ntn1 did not affect bifurcation but rather altered turning angles. To distinguish their guidance functions, we examined mice with triple deletion of Ntn1, Slit1, and Slit2 and found a completely disorganized dorsal funiculus. Comparing mice with different genotypes using immunolabeling and single axon tracing revealed additive guidance errors, demonstrating the independent roles of Ntn1 and Slit. Moreover, the same defects were observed in embryos lacking their cognate receptors. These in vivo studies thus demonstrate the presence of multi-factorial guidance mechanisms that ensure proper formation of a common branched axonal structure during spinal cord development.
Assuntos
Orientação de Axônios , Axônios , Gânglios Espinais , Proteínas do Tecido Nervoso , Netrina-1 , Medula Espinal , Animais , Netrina-1/metabolismo , Netrina-1/genética , Camundongos , Medula Espinal/metabolismo , Medula Espinal/embriologia , Axônios/metabolismo , Axônios/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Orientação de Axônios/fisiologia , Gânglios Espinais/metabolismo , Gânglios Espinais/embriologia , Camundongos Knockout , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genéticaRESUMO
Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homoeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
Assuntos
Glicoproteínas , Peptídeos e Proteínas de Sinalização Intercelular , Estresse Oxidativo , Humanos , Glicoproteínas/metabolismo , Animais , Camundongos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Proliferação de Células , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Apoptose/efeitos dos fármacos , Nutrientes/metabolismo , Camundongos Nus , Adaptação Fisiológica , Regulação Neoplásica da Expressão GênicaRESUMO
This study aims to investigate the effect of Mineral Trioxide Aggregate (MTA), a bioactive endodontic cement, and Concentrated Growth Factor (CGF), a second-generation autologous growth factor, on pulpotomy-induced pulp inflammation. The study utilized the maxillary anterior central teeth of thirty-six young male Sprague Dawley rats. Forty-eight teeth were randomly assigned to two groups (12 rats/group; 24 teeth/group) based on the capping material (MTA or CGF). Subsequently, two subgroups (MTAG and CGFG) were formed per group (12 teeth/group) based on the time following pulpotomy (2-weeks and 4-weeks). The central teeth of the 12 animals assigned to the control group (CG) were not manipulated in any way, both in the 2-week group and in the 4-week group. Tissue samples extracted from rats at the end of the experiment were stained with H&E for histopathological analysis. For immunohistochemical analysis, primary antibodies for TNF-α and NF-kß/65 were incubated. Data obtained from semi-quantitative analysis were assessed for normal distribution using Skewness-Kurtosis values, Q-Q plot, Levene's test, and the Shapiro-Wilk test on statistical software. A P value < 0.05 was considered significant. When compared with the control group, both MTAG and CGFG showed increased edematous and inflammatory areas. In MTAG, edematous and inflammatory areas decreased significantly from the 2nd week (2(2-2), 2(1-2)) to the 4th week (1(1-1), 1(0-1)), while in CGFG, edematous areas decreased (2(2-3), 1.5(1-2)), and inflammatory areas increased significantly (2(2-3), 3(2-2.5)). When compared with the control group, TNF-α and NF-kß/p65 positivity were higher in both MTAG and CGFG. In MTAG, TNF-α [2(1.5-2)] and NF-kß/p65 [1.5(1-2)] positivity decreased significantly from the 2nd week to the 4th week [TNF-α: 1(1-1), NF-kß/p65: 1(1-2)], while no significant change was observed in CGFG. In conclusion, this study revealed a reduction in cells showing TNF-α and NF-kß/p65 positivity in the MTA treatment group compared to the CGF group. Although MTA demonstrated more favorable results than CGF in mitigating pulpal inflammation within the scope of this study, further experimental and clinical investigations are warranted to obtain comprehensive data regarding CGF.
Assuntos
Compostos de Alumínio , Compostos de Cálcio , Óxidos , Pulpotomia , Silicatos , Animais , Masculino , Ratos , Compostos de Alumínio/farmacologia , Compostos de Cálcio/farmacologia , Compostos de Cálcio/uso terapêutico , Combinação de Medicamentos , Peptídeos e Proteínas de Sinalização Intercelular , NF-kappa B/metabolismo , Óxidos/farmacologia , Pulpite/patologia , Pulpite/metabolismo , Pulpotomia/métodos , Distribuição Aleatória , Ratos Sprague-Dawley , Silicatos/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The protein-induced fluorescence change technique was employed to investigate the interactions between proteins and their DNA substrates modified with the Cy3 fluorophore. It has been reported that the human hepatoma-derived growth factor (HDGF), containing the chromatin-associated N-terminal proline-tryptophan-tryptophan-proline (PWWP) domain (the N-terminal 100 amino acids of HDGF) capable of binding the SMYD1 promoter, participates in various cellular processes and is involved in human cancer. This project investigated the specific binding behavior of HDGF, the PWWP domain, and the C140 domain (the C-terminal 140 amino acids of HDGF) sequentially using protein-induced fluorescence change. We found that the binding of HDGF and its related proteins on Cy3-labeled 15 bp SMYD1 dsDNA will cause a significant decrease in the recorded Cy3 fluorophore intensity, indicating the occurrence of protein-induced fluorescence quenching. The dissociation equilibrium constant was determined by fitting the bound fraction curve to a binding model. An approximate 10-time weaker SMYD1 binding affinity of the PWWP domain was found in comparison to HDGF. Moreover, the PWWP domain is required for DNA binding, and the C140 domain can enhance the DNA binding affinity. Furthermore, we found that the C140 domain can regulate the sequence-specific binding capability of HDGF on SMYD1.
Assuntos
Proteínas de Ligação a DNA , DNA , Peptídeos e Proteínas de Sinalização Intercelular , Ligação Proteica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , DNA/química , DNA/metabolismo , Domínios Proteicos , Sítios de Ligação , Carbocianinas/química , Proteínas Musculares , Fatores de TranscriçãoRESUMO
This narrative review was planned to explore the efficacy of plasma-rich protein in musculoskeletal injuries, emphasising its impact on inflammatory markers, growth factors and the healing process. Musculoskeletal disorders pose a significant global health concern, with the plasmarich protein therapy emerging as a promising rehabilitative technique due to its potential to enhance healing. The therapy utilises the patients' cells to stimulate growth, repair tissues, and modulate inflammation, offering a shift towards patient-friendly, non-hospitalised treatment. Through the modulation of inflammatory phases, stimulation of proliferative phases, and enhancement of remodelling phases, the plasma-rich protein therapy contributes to the expedited healing of musculoskeletal injuries. Clinical evidence supports its efficacy in reducing recovery time and managing pain, underscoring its therapeutic potential in musculoskeletal rehabilitation.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular , Cicatrização , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Cicatrização/fisiologia , Inflamação , Biomarcadores/sangue , Doenças Musculoesqueléticas/terapia , Proteínas SanguíneasRESUMO
OBJECTIVE: Atopic dermatitis (AD) is characterized by compositional and structural changes to the skin at lesional sites. Alteration to the levels and organization of both protein and lipid components are associated with disease status and lead to impaired barrier and hydration. Corneodesmosin (CDSN) and the arrangement and length of the intercellular lipid lamellae (ICLL) are altered in disrupted skin states. The aim of this research was to profile the distribution of CDSN and the ICLL in the stratum corneum (SC) at lesional and non-lesional sites in AD-prone skin and to investigate the impact of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. METHODS: An IRB-approved study was conducted with participants with active AD. From a small subset of participants, tape strips were collected from lesional and non-lesional sites on the arm, prior to and after twice daily application, over 4 weeks of an eczema calming lotion containing petroleum jelly, fatty acids, and colloidal oatmeal. Fluorescent antibody staining was used to investigate the distribution of CDSN. Transmission electron microscopy (TEM) was used to characterize the ICLL. RESULTS: The distribution/coverage of CDSN was similar between lesional and non-lesional sites at baseline; application of the lotion resulted in a more defined honeycomb/peripheral distribution. Normalized ICLL (nICLL) was lower in baseline samples from lesional sites relative to non-lesional sites. Application of the lotion increased this parameter by the end of the study at all sites. CONCLUSION: The eczema calming lotion containing petroleum jelly, fatty acids and colloidal oatmeal provided changes in corneodesmosomal proteins distribution and ICLL, consistent with improvements in corneocyte maturation and improved barrier function in the skin of individuals with atopic dermatitis.
OBJECTIF: La dermatite atopique (DA) est caractérisée par des modifications de la composition et de la structure de la peau au niveau des sites lésionnels. L'altération des taux et de l'organisation des composants protéiques et lipidiques est associée au statut de la maladie, et entraîne une altération de la barrière et de l'hydratation. La cornéodesmosine (CDSN), et la disposition et la longueur des lamelles lipidiques intercellulaires (LLIC) sont altérées dans les états cutanés perturbés. L'objectif de cette étude était d'établir le profil de la distribution de la CDSN et des LLIC dans la couche cornée (CC) au niveau des sites lésionnels et non lésionnels dans la peau sujette à la DA, et d'étudier l'impact d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. MÉTHODES: Une étude approuvée par un CPP a été menée auprès de participants atteints de DA active. Dans un petit sousensemble de participants, des bandes adhésives ont été prélevées sur des sites lésionnels et non lésionnels du bras, avant et après l'application deux fois par jour pendant 4 semaines d'une lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale. Une coloration par anticorps fluorescents a été utilisée pour étudier la distribution de la CDSN. La microscopie électronique en transmission (MET) a été utilisée pour caractériser les LLIC. RÉSULTATS: La distribution/couverture de la CDSN était similaire entre les sites lésionnels et non lésionnels à l'entrée dans l'étude; l'application de la lotion a entraîné une distribution en nid d'abeille/périphérique plus définie. Le taux normalisé de LLIC (LLICn) était plus faible dans les échantillons prélevés à l'entrée dans l'étude au niveau des sites lésionnels par rapport aux sites non lésionnels. L'application de la lotion a augmenté ce paramètre à la fin de l'étude pour tous les sites. CONCLUSIONS: La lotion apaisante contre l'eczéma contenant de la vaseline, des acides gras et de l'avoine colloïdale a entraîné des changements dans la distribution des protéines cornéodesmosomales et des LLIC, ce qui correspond à des améliorations de la maturation des cornéocytes et de la fonction de barrière de la peau des personnes atteintes de dermatite atopique.
Assuntos
Dermatite Atópica , Humanos , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Adulto , Masculino , Feminino , Glicoproteínas/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipídeos/química , Eczema/tratamento farmacológico , Eczema/patologia , Eczema/metabolismo , Creme para a Pele , Adulto Jovem , Epiderme/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Pessoa de Meia-IdadeRESUMO
The immune system is integral to the surveillance and eradication of tumor cells. Interactions between the natural killer group 2 member D (NKG2D) receptor and its ligands (NKG2DLs) are vital for activating NKG2D receptorpositive immune cells, such as natural killer cells. This activation enables these cells to identify and destroy tumor cells presenting with NKG2DLs, which is an essential aspect of tumor immunity. However, tumor immune escape is facilitated by soluble NKG2DL (sNKG2DL) shed from the surface of tumor cells. The production of sNKG2DL is predominantly regulated by metalloproteinases [a disintegrin and metalloproteinases (ADAM) and matrix metalloproteinase (MMP) families] and exosomes. sNKG2DL not only diminish immune recognition on the tumor cell surface but also suppress the function of immune cells, such as NK cells, and reduce the expression of the NKG2D receptor. This process promotes immune evasion, progression, and metastasis of tumors. In this review, an indepth summary of the mechanisms and factors that influence sNKG2DL production and their contribution to immune suppression within the tumor microenvironment are provided. Furthermore, due to the significant link between sNKG2DLs and tumor progression and metastasis, they have great potential as novel biomarkers. Detectable via liquid biopsies, sNKG2DLs could assess tumor malignancy and prognosis, and act as pivotal targets for immunotherapy. This could lead to the discovery of new drugs or the enhancement of existing treatments. Thus, the application of sNKG2DLs in clinical oncology was explored, offering substantial theoretical support for the development of innovative immunotherapeutic strategies for sNKG2DLs.
Assuntos
Células Matadoras Naturais , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Neoplasias , Evasão Tumoral , Microambiente Tumoral , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células Matadoras Naturais/imunologia , Microambiente Tumoral/imunologia , Ligantes , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
Goosecoid (GSC), translated from a homeobox gene, is a protein that participates in metastasis of various cancers. Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies associated with a poor diagnosis and prognosis. To develop new treatment target or biomarker for PAAD, this study intended to assess the effects and the molecular mechanism of GSC on PAAD metastasis. The expressive discrepancy of GSC in PAAD and normal tissues/cells was compared by both the quantitative PCR and western blot. The effects of GSC silencing and GSC over-expression on PAAD cells and TGF-ß signaling were proved by wound-healing assay, cell counting kit-8, Transwell assay and western blot. From the results, GSC mRNA and protein levels were enriched in PAAD cancer tissues and cells. GSC silencing prohibited metastasis of PAAD cells including the ability to invade, migrate and epithelial-mesenchymal transition (EMT), whereas GSC upregulation stimulated these cells behaviors above. GSC silencing reversed the effects on cellular processes induced by activation of the TGF-ß pathway. Furthermore, silencing of GSC postponed tumor growth in xenograft model. In summary, GSC was abundantly expressed in PAAD, which activated the TGF-ß pathway to enhance cell metastasis and tumor development.
Assuntos
Adenocarcinoma , Transição Epitelial-Mesenquimal , Metástase Neoplásica , Neoplasias Pancreáticas , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , Humanos , Camundongos , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
A relevant role of osteopontin (OPN) and gremlin 1 (Grem1) in regulating cardiac tissue remodeling and formation of heart failure (HF) are documented, with the changes of OPN and Grem1 levels in blood plasma due to acute ischemia, ischemic heart disease-induced advanced HF or dilatative cardiomyopathy being the primary focus in most of these studies. However, knowledge on the early OPN and Grem1 proteins expression changes within cardiomyocytes during remodeling due to chronic ischemia remains insufficient. The aim of this study was to determine the OPN and Grem1 proteins expression changes in human cardiomyocytes at different stages of ischemic HF. A semi-quantitative immunohistochemical analysis was performed in 105 myocardial tissue samples obtained from the left cardiac ventricles. Increased OPN immunostaining intensity was already detected in the stage A HF group, compared to the control group (p < 0.001), and continued to increase in the stage B HF (p < 0.001), achieving the peak of immunostaining in the stages C/D HF group (p < 0.001). Similar data of Grem1 immunostaining intensity changes in cardiomyocytes were documented. Significantly positive correlations were detected between OPN, Grem1 expression in cardiomyocytes and their diameter as well as the length, in addition to positive correlation between OPN and Grem1 expression changes within cardiomyocytes. These novel findings suggest that OPN and Grem1 contribute significantly to reorganization of cellular geometry from the earliest stage of cardiomyocyte remodeling, providing new insights into the ischemic HF pathogenesis.
Assuntos
Insuficiência Cardíaca , Peptídeos e Proteínas de Sinalização Intercelular , Isquemia Miocárdica , Miócitos Cardíacos , Osteopontina , Osteopontina/metabolismo , Osteopontina/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Humanos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Masculino , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patologia , Pessoa de Meia-Idade , Feminino , IdosoRESUMO
BACKGROUND: Osteosarcoma is a soft tissue neoplasm with elevated recurrence risk and highly metastatic potential. Metal response element binding transcriptional factor 2 (MTF2) has been revealed to exert multiple activities in human tissues. The present research was conducted to explore the functions and related response mechanism of MTF2 in osteosarcoma which have not been introduced yet. METHODS: Bioinformatics tools identified the differential MTF2 expression in osteosarcoma tissues. MTF2 expression in osteosarcoma cells was examined with Western blot. Cell Counting Kit-8 (CCK-8) assay, 5-Ethynyl-2'-deoxyuridine (EDU) staining, wound healing as well as transwell assays measured cell proliferation, migration and invasion, respectively. Flow cytometry assay detected the cellular apoptotic level. Western blot also measured the expressions of proteins associated with epithelial mesenchymal transition (EMT), apoptosis and enhancer of zeste homolog 2 (EZH2)/secreted frizzled-related protein 1 (SFRP1)/Wnt signaling. Co-immunoprecipitation (Co-IP) assay confirmed MTF2-EZH2 interaction. RESULTS: MTF2 expression was increased in osteosarcoma tissues and cells. MTF2 interference effectively inhibited the proliferation, migration and invasion of osteosarcoma cells and promoted the cellular apoptotic rate. MTF2 directly bound to EZH2 and MTF2 silence reduced EZH2 expression, activated SFRP1 expression and blocked Wnt signaling in osteosarcoma cells. EZH2 upregulation or SFRP1 antagonist WAY-316606 partly counteracted the impacts of MTF2 down-regulation on the SFRP1/Wnt signaling and the biological phenotypes of osteosarcoma cells. CONCLUSIONS: MTF2 might down-regulate SFRP1 to activate Wnt signaling and drive the progression of osteosarcoma via interaction with EZH2 protein.
Assuntos
Neoplasias Ósseas , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste , Osteossarcoma , Via de Sinalização Wnt , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Via de Sinalização Wnt/fisiologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Proliferação de Células/fisiologia , Linhagem Celular Tumoral , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Apoptose/fisiologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Movimento Celular/fisiologia , Progressão da Doença , Regulação Neoplásica da Expressão GênicaRESUMO
Objective: To investigate the clinicopathological features of renal leukocyte chemokine type 2 amyloidosis (ALECT2). Methods: The prevalence, clinical characteristics, renal histopathological features, and renal outcome of 15 patients with ALECT2 by kidney biopsy were collected in the Department of Kidney Pathology, Shanxi Medical University Second Hospital, Taiyuan, China from January 1993 to December 2023. Immunohistochemistry and mass spectrometry for amyloid proteins were carried out. Results: Fifteen patients with ALECT2 were included in the study, representing 12.93% (15/116) of the renal biopsy-proven amyloidosis cases. There were 5 males and 10 females. The median age at diagnosis was 61 years. All patients had various degrees of proteinuria; 7 patients had nephrotic syndrome; 3 patients had renal insufficiency; 7 patients had microscopic hematuria. Renal biopsy showed that strongly orangophilic amyloid proteins distributed mainly in the renal cortical interstitium, vascular walls, the glomerular mesangium and/or glomerular basement membrane. Eight cases were diagnosed with ALECT2 alone and 7 cases combined with other renal diseases, including 4 cases with membranous nephropathy, 2 cases with IgA nephropathy, and 1 case with subacute tubular interstitial nephropathy. ALECT2 patients with concurrent renal disease showed a higher proteinuria level than those without (3.48 g/24 h versus 4.58 g/24 h). All patients were corroborated by immunohistochemistry to exhibit the specific location of LECT2 in the amyloid fibrils. Mass spectrometry analysis revealed LECT2 polypeptide in 9 patients. Except two patients with worsening renal function, the others showed stable renal function during the mean follow-up period of 12.5 months. Conclusions: ALECT2 is the second common type of renal amyloidosis in our center. The majority of ALECT2 patients show concurrent renal diseases, with a high rate of membranous nephropathy. Amyloid deposits distribute mainly in the cortical interstitium of the kidney, the glomerular mesangium and vascular walls. Mass spectrometry is the most sensitive and specific method for detecting LECT2 amyloidosis.
Assuntos
Amiloidose , Nefropatias , Rim , Síndrome Nefrótica , Humanos , Masculino , Amiloidose/metabolismo , Amiloidose/patologia , Amiloidose/diagnóstico , Feminino , Pessoa de Meia-Idade , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/patologia , Rim/patologia , Nefropatias/patologia , Nefropatias/metabolismo , Proteinúria , Biópsia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Glomerulonefrite Membranosa/patologia , Glomerulonefrite Membranosa/metabolismo , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/metabolismo , Idoso , Hematúria/etiologia , Insuficiência Renal/metabolismoRESUMO
OBJECTIVE: To evaluate the efficacy of Cortexin in the treatment of patients with post-Covid impairment. MATERIAL AND METHODS: Treatment results of 109 patients with post-Covid cognitive impairment aged from 42 to 65 years were analyzed. The main group (MG, n=52), 29 (55.8%) men and 23 (44.2%) women, average age 58.1±4.9 years, who received Cortexin continuously for 20 days at a dose of 10 mg i.m., after 3, 6 months. The comparison group included 57 people, 31 (54.4%) men and 26 (45.6%) women (average age 59.3±3.8 years). The effectiveness of therapy was assessed using neuropsychological testing with international scales. RESULTS: During treatment, statistically significant differences were obtained in MG patients in the form of improved concentration (p<0.05), increased control of exutative functions (p<0.05), and auditory-verbal memory (p=0.002). There were no adverse events in the MG. CONCLUSION: Cortexin is highly effective and safe, and can be recommended as part of a combined staged therapy for post-Covid cognitive impairment. Thus, the study confirms the feasibility of using Cortexin, which has a neurocytoprotective effect.
Assuntos
COVID-19 , Disfunção Cognitiva , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/tratamento farmacológico , COVID-19/complicações , Idoso , Adulto , SARS-CoV-2 , Resultado do Tratamento , Testes Neuropsicológicos , Tratamento Farmacológico da COVID-19 , Síndrome de COVID-19 Pós-Aguda , Fármacos Neuroprotetores/uso terapêutico , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.
Assuntos
Proliferação de Células , Progressão da Doença , Peptídeos e Proteínas de Sinalização Intercelular , Neoplasias Pancreáticas , Fator de Transcrição AP-1 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Animais , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , Camundongos , Regulação Neoplásica da Expressão Gênica , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular/genética , Microambiente Tumoral , Masculino , Camundongos Nus , Elementos Facilitadores Genéticos/genética , FemininoRESUMO
The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.
Assuntos
Tecido Adiposo Branco , Osso e Ossos , Dieta Hiperlipídica , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos Knockout , Obesidade , Osteoblastos , Animais , Obesidade/metabolismo , Obesidade/genética , Obesidade/etiologia , Tecido Adiposo Branco/metabolismo , Osteoblastos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Dieta Hiperlipídica/efeitos adversos , Osso e Ossos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Masculino , Tecido Adiposo Marrom/metabolismo , Camundongos Endogâmicos C57BL , Adipócitos/metabolismo , Transdução de SinaisRESUMO
The Dlk1-Dio3 domain is important for normal embryonic growth and development. The heart is the earliest developing and functioning organ of the embryo. In this study, we constructed a transcriptional termination model by inserting termination sequences and clarified that the lack of long non-coding RNA (lncRNA) expression in the Dlk1-Dio3 domain caused the death of maternal insertion mutant (MKI) and homozygous mutant (HOMO) mice starting from E13.5. Parental insertion mutants (PKI) can be born and grow normally. Macroscopically, dying MKI and HOMO embryos showed phenomena such as embryonic edema and reduced heart rate. Hematoxylin and eosin (H.E.) staining showed thinning of the myocardium in MKI and HOMO embryos. In situ hybridization (IHC) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) showed downregulation of lncGtl2, Rian, and Mirg expression in MKI and HOMO hearts. The results of single-cell RNA sequencing (scRNA-Seq) analysis indicated that the lack of lncRNA expression in the Dlk1-Dio3 domain led to reduced proliferation of epicardial cells and may be an important cause of cardiac dysplasia. In conclusion, this study demonstrates that Dlk1-Dio3 domain lncRNAs play an integral role in ventricular development.
Assuntos
Proteínas de Ligação ao Cálcio , Regulação da Expressão Gênica no Desenvolvimento , Coração , Iodeto Peroxidase , RNA Longo não Codificante , Animais , RNA Longo não Codificante/genética , Camundongos , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Coração/embriologia , Coração/crescimento & desenvolvimento , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Feminino , Desenvolvimento Embrionário/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proliferação de Células/genética , Embrião de Mamíferos/metabolismo , Proteínas NuclearesRESUMO
This study aimed to perform clinical and radiographic investigations of the effect of regenerative endodontic procedures (REPs) with and without concentrated growth factor (CGF). Fifty-six non-vital and immature teeth from 56 patients were randomly categorized into two groups. Following chemical and mechanical preparation, REPs with and without CGF as a scaffold was induced in the blood clot (BLC) group and the CGF group. All patients were clinically and radiographically evaluated at 6-month and 12-month intervals to monitor their progress and treatment outcomes. When considering the total number of patients, the follow-up rate was 96.4% (54 out of 56 patients) over a 12-month period. Favorable clinical and radiographic outcomes were observed in 92.6% of patients (25 out of 27) in both the CGF and BLC groups; there were no significant differences between the two groups in these respects (p > 0.05). Notable differences were, however, observed in radiographic measurements relating to the development of root length and radiographic root area when compared between the CGF and BLC groups at both the 6-month and 12-month follow-up intervals (p < 0.05). REPs have been proven to represent a conservative and effective approach for promoting maturogenesis in non-vital and immature teeth. Furthermore, the incorporation of CGF as scaffolds holds promising potential for enhancing the desired biological outcomes of this regenerative technique. These findings highlight the clinical significance and potential benefits of CGF supplementation in REPs, further supporting its application in the field of endodontics.
Assuntos
Dente Pré-Molar , Peptídeos e Proteínas de Sinalização Intercelular , Endodontia Regenerativa , Alicerces Teciduais , Dente não Vital , Humanos , Endodontia Regenerativa/métodos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Masculino , Criança , Feminino , Dente Pré-Molar/diagnóstico por imagem , Dente não Vital/terapia , Dente não Vital/diagnóstico por imagem , Mandíbula/diagnóstico por imagem , Adolescente , Resultado do Tratamento , Raiz Dentária/diagnóstico por imagemRESUMO
Xenopus embryos provide a favorable material to dissect the sequential steps that lead to dorsal-ventral (D-V) and anterior-posterior (A-P) cell differentiation. Here, we analyze the signaling pathways involved in this process using loss-of-function and gain-of-function approaches. The initial step was provided by Hwa, a transmembrane protein that robustly activates early ß-catenin signaling when microinjected into the ventral side of the embryo leading to complete twinned axes. The following step was the activation of Xenopus Nodal-related growth factors, which could rescue the depletion of ß-catenin and were themselves blocked by the extracellular Nodal antagonists Cerberus-Short and Lefty. During gastrulation, the Spemann-Mangold organizer secretes a cocktail of growth factor antagonists, of which the BMP antagonists Chordin and Noggin could rescue simultaneously D-V and A-P tissues in ß-catenin-depleted embryos. Surprisingly, this rescue occurred in the absence of any ß-catenin transcriptional activity as measured by ß-catenin activated Luciferase reporters. The Wnt antagonist Dickkopf (Dkk1) strongly synergized with the early Hwa signal by inhibiting late Wnt signals. Depletion of Sizzled (Szl), an antagonist of the Tolloid chordinase, was epistatic over the Hwa and Dkk1 synergy. BMP4 mRNA injection blocked Hwa-induced ectopic axes, and Dkk1 inhibited BMP signaling late, but not early, during gastrulation. Several unexpected findings were made, e.g., well-patterned complete embryonic axes are induced by Chordin or Nodal in ß-catenin knockdown embryos, dorsalization by Lithium chloride (LiCl) is mediated by Nodals, Dkk1 exerts its anteriorizing and dorsalizing effects by regulating late BMP signaling, and the Dkk1 phenotype requires Szl.