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Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma.
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Estrés Oxidativo , Proteína 1 Supresora de la Señalización de Citocinas , Proteína 3 Supresora de la Señalización de Citocinas , Animales , Estrés Oxidativo/efectos de los fármacos , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Ratones , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Humanos , Inflamación/inmunología , Inflamación/tratamiento farmacológico , Córnea/metabolismo , Córnea/inmunología , Epitelio Pigmentado de la Retina/metabolismo , Oftalmopatías/tratamiento farmacológico , Oftalmopatías/inmunología , Oftalmopatías/metabolismo , Péptidos/farmacología , Péptidos/uso terapéutico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: To locate the candidate therapeutic target genes involved in ferroptosis in steroid-induced osteonecrosis of the femoral head (SONFH). STUDY DESIGN: Bioinformatics analysis study. Place and Duration of the Study: Department of Orthopaedic Surgery, Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Guangdong, China, from March to July 2023. METHODOLOGY: After processing the gene expression omnibus (GEO) data with the R programming language, differentially expressed ferroptosis-related genes in SONFH were identified. To pinpoint the genes most strongly linked to SONFH in association with ferroptosis, least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) were employed. Subsequently, the screened essential genes were analysed to investigate immune cell infiltration, and competing endogenous RNA (ceRNA) networks involving these marker genes were constructed. RESULTS: The machine learning algorithms identified three genes i.e., SOCS1 (suppressor of cytokine signalling1), MYCN (N-myc proto-oncogene protein), and KLF2 (Kruppel-like factor 2) as diagnostic feature biomarkers associated with ferroptosis. Additionally, CIBERSORT analysis revealed that alterations in the immune microenvironment, such as Macrophages M1, Monocytes, and T cells CD4 naive, could be linked to SOCS1, MYCN, and KLF2. Moreover, the competing endogenous RNA (ceRNA) network exposed a complex regulatory relationship based on marker genes. CONCLUSION: SOCS1, MYCN, and KLF2 are potential biomarkers associated with ferroptosis in SONFH, pending confirmation in future studies. KEY WORDS: Steroid-induced osteonecrosis of the femoral head, Ferroptosis, Machine learning, Genetic analysis.
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Necrosis de la Cabeza Femoral , Ferroptosis , Aprendizaje Automático , Humanos , Ferroptosis/genética , Necrosis de la Cabeza Femoral/genética , Necrosis de la Cabeza Femoral/inducido químicamente , Biomarcadores/metabolismo , Biología Computacional , Esteroides , Proto-Oncogenes Mas , Proteína 1 Supresora de la Señalización de Citocinas/genéticaRESUMEN
Background: Chronic rhinosinusitis (CRS) is an inflammatory condition classified into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP). Th cells manage inflammatory cells in CRS. Suppressor of Cytokine Signaling (SOCS) proteins regulate Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in Th cells by polarizing toward Th1, Th2, and Th17 cells. This study evaluated the levels of SOCS1,3,5 in CRS patients to find associations with Th cells. Methods: In this cross-sectional study, 20 CRSwNP patients, 12 CRSsNP patients, and 12 controls participated. The infiltration of CD4+ T cells was determined using immunohistochemistry. The expression of specific transcription factors and SOCS proteins was assessed using real-time PCR. Cytokine levels were evaluated using ELISA. SOCS protein levels were investigated using western blot analysis. Results: The expression of SOCS3 increased in the CRSwNP group compared to CRSsNP and control groups (p <0.001). SOCS3 protein levels increased in the CRSwNP group compared to CRSsNP (p <0.05) and control (p <0.001) groups. Although there was a significant difference in SOCS5 expression between CRSsNP and control groups, SOCS5 protein levels were significantly different between CRSsNP and control (p <0.001) and CRSwNP (p <0.05) groups. Conclusions: Targeted therapies may be suggested for CRS by modulating SOCS3 and SOCS5 proteins that are responsible for polarization of Th cells toward Th2 or Th1 cells, respectively. JAK-STAT pathway targeting, which encompasses numerous cells, can be limited to SOCS proteins to more effectively orchestrate Th cell differentiation.
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Rinitis , Sinusitis , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas , Humanos , Sinusitis/metabolismo , Sinusitis/inmunología , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Enfermedad Crónica , Masculino , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Rinitis/metabolismo , Rinitis/inmunología , Femenino , Adulto , Persona de Mediana Edad , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Estudios Transversales , Pólipos Nasales/metabolismo , Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Transducción de Señal , RinosinusitisRESUMEN
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
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Homeostasis , Inflamación , Neoplasias , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Neoplasias/inmunología , Neoplasias/terapia , Homeostasis/inmunología , Inflamación/inmunología , Animales , Transducción de Señal , Autoinmunidad , Citocinas/metabolismo , Citocinas/inmunologíaRESUMEN
Type I diabetes is an autoimmune disease mediated by T-cell destruction of ß cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include CLEC16A and SOCS1. While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.
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Linfocitos T CD4-Positivos , Diabetes Mellitus Tipo 1 , Elementos de Facilitación Genéticos , Predisposición Genética a la Enfermedad , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Humanos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Elementos de Facilitación Genéticos/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Estudio de Asociación del Genoma Completo , Lectinas Tipo C/genética , Variación Genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter CuantitativoRESUMEN
At present, the function of SOCS1 in Kashin-Beck disease (KBD) has not been reported. This study aims to explore the expression and mechanism of SOCS1 in KBD, and provide theoretical basis for the prevention and treatment of KBD. The expression of SOCS1 were measured by qRT-PCR and Western blot. ELISA was used to detect the content of SOCS1 in serum and synovial fluid. CCK-8 kits were selected to measure the cell viability. Methylation Specific PCR (MSP) assay is used to detect the methylation level of SOCS1 in chondrocytes. Flow cytometry was used to analyze the apoptosis rate of chondrocytes in different groups. The expression of apoptosis related proteins (caspase-3 and caspase-9) and Cytochrome c were detected using Western blot. The mitochondrial ROS, ATP and the activity of mitochondrial respiratory chain complexes were detected using commercial kits. The results showed that the expression of SOCS1 significantly increases in KBD patients and T-2 induced chondrocytes. Further research has found that the methylation levels of SOCS1 were significantly reduced in KBD patients and T-2 induced chondrocytes. Functional studies have found that SOCS1 silencing inhibited chondrocyte apoptosis and mitochondrial dysfunction. More importantly, SOCS1 regulated mitochondrial mediated chondrocyte apoptosis through the IGF-1/IGF-1R/FAK/Drp1 pathway. In conclusion, SOCS1 expression is increased and methylation levels are decreased in KBD, and is involved in regulating mitochondrial mediated apoptosis in T-2 induced chondrocytes through IGF-1/IGF-1R/FAK/Drp1 signaling. This study provides new theoretical basis for the treatment and prevention of KBD in clinical practice.
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Apoptosis , Condrocitos , Metilación de ADN , Mitocondrias , Regiones Promotoras Genéticas , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Apoptosis/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Condrocitos/metabolismo , Mitocondrias/metabolismo , Mitocondrias/genética , Regiones Promotoras Genéticas/genética , Enfermedad de Kashin-Beck/metabolismo , Enfermedad de Kashin-Beck/genética , Enfermedad de Kashin-Beck/patología , Masculino , Persona de Mediana Edad , Femenino , Células Cultivadas , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genéticaRESUMEN
An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.
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Anemia Hemolítica Autoinmune , Autoinmunidad , Haploinsuficiencia , Lupus Eritematoso Sistémico , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Humanos , Haploinsuficiencia/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Femenino , Masculino , Niño , Autoinmunidad/genética , Adolescente , Mutación , Trombocitosis/genética , Trombocitosis/inmunología , Proteína 1 Supresora de la Señalización de Citocinas/genética , Autoanticuerpos/inmunología , Citocinas/metabolismo , Preescolar , Linfocitos T/inmunología , TrombocitopeniaRESUMEN
SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.
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Transformación Celular Neoplásica , Proteína 1 Supresora de la Señalización de Citocinas , Proteína 3 Supresora de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Animales , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Transducción de Señal , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Dermatitis/inmunología , Dermatitis/metabolismo , Quinasas Janus/metabolismo , Piel/inmunología , Piel/patología , Piel/metabolismoRESUMEN
Objective To explore the relationship between the expression levels of microRNA-155 (miR-155) and suppressor of cytokine signaling 1 (SOCS1) in the colonic mucosal tissue of patients with ulcerative colitis (UC) and the severity of the disease.Methods A total of 130 UC patients admitted to the Second Affiliated Hospital of Hebei North University from September 2021 to June 2023 were selected.According to the modified Mayo score system,the patients were assigned into an active stage group (n=85) and a remission stage group (n=45).According to the modified Truelove and Witts classification criteria,the UC patients at the active stage were assigned into a mild group (n=35),a moderate group (n=30),and a severe group (n=20).A total of 90 healthy individuals who underwent colonoscopy for physical examination or those who had normal colonoscopy results after single polypectomy and excluded other diseases were selected as the control group.The colonic mucosal tissues of UC patients with obvious lesions and the colonic mucosal tissue 20 cm away from the anus of the control group were collected.The levels of miR-155 and SOCS1 mRNA in tissues were determined by fluorescence quantitative PCR,and the expression of SOCS1 protein in tissues was determined by immunohistochemistry.The correlations of the levels of miR-155 and SOCS1 mRNA in the colonic mucosal tissue with the modified Mayo score of UC patients were analyzed.The values of the levels of miR-155 and SOCS1 mRNA in predicting the occurrence of severe illness in the UC patients at the active stage were evaluated.Results Compared with the control group and the remission stage group,the active stage group showed up-regulated expression level of miR-155,down-regulated level of SOCS1 mRNA,and decreased positive rate of SOCS1 protein in the colonic mucosal tissue (all P<0.001).The expression level of miR-155 and modified Mayo score in colonic mucosal tissues of UC patients at the active stage increased,while the mRNA level of SOCS1 was down-regulated as the disease evolved from being mild to severe (all P<0.001).The modified Mayo score was positively correlated with the miR-155 level and negative correlated with the mRNA level of SOCS1 in colonic mucosal tissues of UC patients (all P<0.001).The high miR-155 level (OR=2.762,95%CI=1.284-5.944,P=0.009),low mRNA level of SOCS1 (OR=2.617,95%CI=1.302-5.258,P=0.007),and modified Mayo score≥12 points (OR=3.232,95%CI=1.450-7.204,P=0.004) were all risk factors for severe disease in the UC patients at the active stage.The area under curve of miR-155 combined with SOCS1 mRNA in predicting severe illness in the UC patients at the active stage was 0.920.Conclusions The expression levels of miR-155 and SOCS1 mRNA were correlated with the disease severity in the UC patients at the active stage.The combination of the two indicators demonstrates good performance in predicting the occurrence of severe illness in UC patients at the active stage.
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Colitis Ulcerosa , Mucosa Intestinal , MicroARNs , Proteína 1 Supresora de la Señalización de Citocinas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Colitis Ulcerosa/genética , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Colitis Ulcerosa/fisiopatología , Colon/metabolismo , Colon/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , MicroARNs/genética , MicroARNs/metabolismo , Índice de Severidad de la Enfermedad , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
BACKGROUND AND AIM: Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15-20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease. METHOD: This study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs). Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP. RESULT: This study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples. CONCLUSION: This suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients.
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Neoplasias Colorrectales , Islas de CpG , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Factor II del Crecimiento Similar a la Insulina , Homólogo 1 de la Proteína MutL , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Metilación de ADN/genética , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Islas de CpG/genética , Femenino , Pólipos del Colon/genética , Pólipos del Colon/metabolismo , Pólipos del Colon/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Masculino , Regulación hacia Abajo/genética , Simulación por Computador , Persona de Mediana Edad , Adenoma/genética , Adenoma/metabolismo , Adenoma/patología , Regiones Promotoras Genéticas/genética , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Perfilación de la Expresión Génica/métodos , Anciano , PronósticoRESUMEN
Ulcerative colitis (UC) is characterized by a chronic and protracted course and often leads to a poor prognosis. Patients with this condition often experience postoperative complications, further complicating the management of their condition. Tetrastigma hemsleyanum polysaccharide (THP) has demonstrated considerable potential as a treatment for inflammatory bowel disease. However, its underlying mechanism in the treatment of UC remains unclear. This study systematically and comprehensively investigated the effects of THP on dextran sulfate-induced UC mice and illustrated its specific mechanism of action. The colon and spleen in UC mice were restored after THP treatment. The levels of key markers, such as secretory immunoglobulin A, ß-defensin, and mucin-2 were increased, collagen deposition and epithelial cell apoptosis were decreased. Notably, THP administration led to increased levels of Ki67 and tight junction proteins in colon tissue and reduced colon tissue permeability. THP contributed to the restored balance of intestinal flora. Furthermore, THP downregulated the expressions of the proinflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17 and promoted those of the regulatory factors forkhead box protein P3. It also exerted anti-inflammatory effects by promoting suppressor of cytokine signaling (SOCS1) expression and inhibiting the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our results demonstrated that THP had an efficacy comparable to that of JAK inhibitor in treating UC. In addition, THP might play a role in UC therapy through modulation of the SOCS1/JAK2/STAT3 signaling pathway and remodeling of the intestinal mucosal barrier.
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Colitis Ulcerosa , Funcion de la Barrera Intestinal , Mucosa Intestinal , Polisacáridos , Transducción de Señal , Vitaceae , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Funcion de la Barrera Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Janus Quinasa 2/metabolismo , Ratones Endogámicos C57BL , Polisacáridos/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Vitaceae/químicaRESUMEN
Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.
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Progresión de la Enfermedad , Quinasas Janus , Metástasis Linfática , Neoplasias del Pene , Factor de Transcripción STAT4 , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Masculino , Neoplasias del Pene/patología , Neoplasias del Pene/genética , Neoplasias del Pene/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Metástasis Linfática/patología , Metástasis Linfática/genética , Quinasas Janus/metabolismo , Factor de Transcripción STAT4/metabolismo , Factor de Transcripción STAT4/genética , Regulación Neoplásica de la Expresión Génica , Carcinogénesis/genética , Carcinogénesis/patología , Transducción de Señal , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.
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Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Animales , Quinasas Janus/metabolismo , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia , Haploinsuficiencia , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/genética , Terapia GenéticaRESUMEN
BACKGROUND AND PURPOSE: Atherosclerosis is the primary pathological basis of cardiovascular disease. Ferroptosis is a regulated form of cell death, a process of lipid peroxidation driven by iron, which can initiate and promote atherosclerosis. STAT6 is a signal transducer that shows a potential role in regulating ferroptosis, but, the exact role in ferroptosis during atherogenesis remains unclear. The Traditional Chinese Medicine Maijitong granule (MJT) is used for treating cardiovascular disease and shows a potential inhibitory effect on ferroptosis. However, the antiatherogenic effect and the underlying mechanism remain unclear. In this study, we determined the role of STAT6 in ferroptosis during atherogenesis, investigated the antiatherogenic effect of MJT, and determined whether its antiatherogenic effect was dependent on the inhibition of ferroptosis. METHODS: 8-week-old male LDLR-/- mice were fed a high-fat diet (HFD) at 1st and 10th week, respectively, to assess the preventive and therapeutic effects of MJT on atherosclerosis and ferroptosis. Simultaneously, the anti-ferroptotic effects and mechanism of MJT were determined by evaluating the expression of genes responsible for lipid peroxidation and iron metabolism. Subsequently, we reanalyzed microarray data in the GSE28117 obtained from cells after STAT6 knockdown or overexpression and analyzed the correlation between STAT6 and ferroptosis. Finally, the STAT6-/- mice were fed HFD and injected with AAV-PCSK9 to validate the role of STAT6 in ferroptosis during atherogenesis and revealed the antiatherogenic and anti-ferroptotic effect of MJT. RESULTS: MJT attenuated atherosclerosis by reducing plaque lesion area and enhancing plaque stability in both preventive and therapeutic groups. MJT reduced inflammation via suppressing inflammatory cytokines and inhibited foam cell formation by lowering the LDL level and promoting ABCA1/G1-mediated lipid efflux. MJT ameliorated the ferroptosis by reducing lipid peroxidation and iron dysregulation during atherogenesis. Mechanistically, STAT6 negatively regulated ferroptosis by transcriptionally suppressing SOCS1/p53 and DMT1 pathways. MJT suppressed the DMT1 and SOCS1/p53 via stimulating STAT6 phosphorylation. In addition, STAT6 knockout exacerbated atherosclerosis and ferroptosis, which abolished the antiatherogenic and anti-ferroptotic effects of MJT. CONCLUSION: STAT6 acts as a negative regulator of ferroptosis and atherosclerosis via transcriptionally suppressing DMT1 and SOCS1 expression and MJT attenuates atherosclerosis and ferroptosis by activating the STAT6-mediated inhibition of DMT1 and SOCS1/p53 pathways, which indicated that STAT6 acts a novel promising therapeutic target to ameliorate atherosclerosis by inhibiting ferroptosis and MJT can serve as a new therapy for atherosclerosis treatment.
Asunto(s)
Aterosclerosis , Proteínas de Transporte de Catión , Medicamentos Herbarios Chinos , Ferroptosis , Factor de Transcripción STAT6 , Proteína 1 Supresora de la Señalización de Citocinas , Animales , Ferroptosis/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Factor de Transcripción STAT6/metabolismo , Masculino , Medicamentos Herbarios Chinos/farmacología , Ratones , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Transducción de Señal/efectos de los fármacos , Receptores de LDL/metabolismo , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Toxoplasmosis is a prevalent parasitic infection caused by Toxoplasma gondii known to induce complex immune responses, to control the infection. MicroRNAs (miRNAs) are a cluster of small noncoding RNAs that are reported to have regulatory functions in the immune response. The objective of this study is to assess the expression of miR-155 and its targets, Src homology-2 domain-containing inositol 5- phosphatase 1 (SHIP-1) and suppressor of cytokine signaling-1 (SOCS1), in non-pregnant Iraqi women seropositive for toxoplasmosis. The study included 55 non-pregnant women positive for toxoplasmosis (20 in the acute phase and 35 in the chronic phase) and 35 non-pregnant women negative for toxoplasmosis (control group). Serum samples were collected from all participants to investigate the expression of miR-155 by RTâPCR, in addition to the levels of SOCS1 and SHIP-1 measured by ELISA. The results showed a significant increase in the expression of miR-155 in both groups of acute and chronic toxoplasmosis compared to the control group. Lower levels of SOCS1 and SHIP-1 were found in acutely infected women compared to those with chronic infection and non-infected women. These findings showed the possible critical impact of miR-155 on host immune response during T.gondii infection, proposing that miR-155 can be explored as a prospective target to support host immune response against infectious diseases, with special help in early detection and management of toxoplasmosis in high-risk immunocompromised patients. Further studies are needed to evaluate the molecular pathways by which miRNAs improve immunity against toxoplasmosis.
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MicroARNs , Proteína 1 Supresora de la Señalización de Citocinas , Toxoplasma , Toxoplasmosis , Adulto , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven , Enfermedad Aguda , Enfermedad Crónica , Irak/epidemiología , MicroARNs/genética , MicroARNs/sangre , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Toxoplasma/genética , Toxoplasma/inmunología , Toxoplasmosis/parasitología , Toxoplasmosis/genética , AdolescenteRESUMEN
Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.
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Asma , Interleucina-13 , Animales , Humanos , Ratones , Sistema de Transporte de Aminoácidos y+ , Asma/genética , Asma/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Pulmón/metabolismo , Ratones Endogámicos BALB C , Ovalbúmina/metabolismo , Ovalbúmina/uso terapéutico , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/uso terapéutico , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Células Th2/metabolismo , Células Th2/patologíaRESUMEN
Long non-coding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in various diseases has been verified. However, the underlying mechanism of CDKN2B-AS1 contributes to the development of allergic rhinitis (AR) remains unknown. To evaluate the impact of CDKN2B-AS1 on AR, BALB/c mice were sensitized by intraperitoneal injection of normal saline containing ovalbumin (OVA) and calmogastrin to establish an AR model. Nasal rubbing and sneezing were documented after the final OVA treatment. The concentrations of IgE, IgG1, and inflammatory elements were quantified using ELISA. Hematoxylin and eosin (H&E) staining and immunofluorescence were used to assess histopathological variations and tryptase expression, respectively. StarBase, TargetScan and luciferase reporter assays were applied to predict and confirm the interactions among CDKN2B-AS1, miR-98-5p, and SOCS1. CDKN2B-AS1, miR-98-5p, and SOCS1 levels were assessed by quantitative real-time PCR (qRT-PCR) or western blotting. Our results revealed that CDKN2B-AS1 was obviously over-expressed in the nasal mucosa of AR patients and AR mice. Down-regulation of CDKN2B-AS1 significantly decreased nasal rubbing and sneezing frequencies, IgE and IgG1 concentrations, and cytokine levels. Furthermore, down-regulation of CDKN2B-AS1 also relieved the pathological changes in the nasal mucosa, and the infiltration of eosinophils and mast cells. Importantly, these results were reversed by the miR-98-5p inhibitor, whereas miR-98-5p directly targeted CDKN2B-AS1, and miR-98-5p negatively regulated SOCS1 level. Our findings demonstrate that down-regulation of CDKN2B-AS1 improves allergic inflammation and symptoms in a murine model of AR through the miR-98-5p/SOCS1 axis, which provides new insights into the latent functions of CDKN2B-AS1 in AR treatment.
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MicroARNs , ARN Largo no Codificante , Rinitis Alérgica , Animales , Humanos , Ratones , Regulación hacia Abajo , Inmunoglobulina E , Inmunoglobulina G , Ratones Endogámicos BALB C , MicroARNs/genética , Rinitis Alérgica/inducido químicamente , Rinitis Alérgica/genética , ARN Largo no Codificante/genética , Estornudo , Proteína 1 Supresora de la Señalización de Citocinas/genéticaRESUMEN
INTRODUCTION: The aim of this study was to investigate the effect and mechanism of kaempferol on alcoholic steatohepatitis. METHODS: C57BL/6 N mice were utilized to establish Binge-on-Chronic alcohol exposure mice model. Kaempferol was given as the interventional drug to chronic alcohol-fed mice for 6 weeks to assess its effects. In vitro, intestinal epithelial Caco-2 cells were stimulated by alcohol, and miRNA-155 mimics were used to further study the effect of kaempferol to miRNA-155 signaling in intestinal epithelial cells. HE staining and oil red O staining were used to observe the liver and intestinal tissue damage in each group of mice, and ALT, AST, IL-1ß, and TNF-α were detected by kits; lipopolysaccharide (LPS) expression was detected by ELISA kit, and the expression of IL-1ß and TNF-α was assessed by qRT-PCR; Western blot was utilized to assess the excessive inflammatory response of liver and colon tissue and the related signaling pathway activation. RESULTS: Kaempferol treatment significantly improved pathological changes such as steatosis and vacuolated lesions in liver tissue of the alcohol diet model group, and reduced serum ALT and AST enzyme activities and liver tissue interleukin-1ß and tumor necrosis factor-α mRNA expression levels. Kaempferol significantly reduced the expression of miRNA-155 in the intestinal tissue of alcohol-fed mice, significantly increased their cytokine suppressor signaling 1 (SOCS1) protein expression, inhibited the activation of nuclear factor kappa-B and significantly increased the production of the intestinal tight junction proteins occludin and zonula occludens-1. More importantly, kaempferol significantly reduced serum LPS levels in alcoholic steatohepatitis mice. In vitro experiments showed that compared with the control group, kaempferol significantly inhibited the expression level of miRNA-155 in Caco-2 cells under ethanol exposure, decreased the activation of nuclear factor kappa-B, led to an increase in the expression of SOCS1 protein, and increased the production level of occludin protein in Caco-2 cells under the effect of alcohol. In contrast, overexpression of miRNA-155 significantly decreased occludin and SOCS1 protein production and increased nuclear factor kappa-B activation levels in Caco-2 cells, and the administration of kaempferol significantly inhibited this effect. CONCLUSION: Kaempferol improved the stability of gut barrier function to ameliorate hepatic injury induced by alcohol intake through enhancing occludin protein expression, by targeting miR-155 to inhibit the excessive inflammatory response in the intestine.
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Mucosa Intestinal , Quempferoles , Ratones Endogámicos C57BL , MicroARNs , Transducción de Señal , Animales , MicroARNs/metabolismo , Quempferoles/farmacología , Quempferoles/uso terapéutico , Humanos , Transducción de Señal/efectos de los fármacos , Ratones , Masculino , Células CACO-2 , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Hepatitis Alcohólica/tratamiento farmacológico , Hepatitis Alcohólica/metabolismo , Ocludina/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína de la Zonula Occludens-1/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Modelos Animales de Enfermedad , FN-kappa B/metabolismo , Lipopolisacáridos , Factor de Necrosis Tumoral alfa/metabolismo , Etanol , Interleucina-1beta/metabolismo , Funcion de la Barrera IntestinalRESUMEN
DEAD-box helicase (DDX) family members play differential roles in regulating innate antiviral immune response. However, the physiological roles played by DDX4 in antiviral innate immunity remain unclear. In this study, we unveiled that DDX4 acts as a positive regulatory molecule of Type-I interferon (IFN-I)-mediated antiviral activity. Our findings demonstrate that IFN-I upregulates DDX4 protein levels, and subsequently, overexpression of DDX4 enhances the IFN-I-mediated signaling pathway. This creates a positive feedback loop that amplifies the antiviral response. DDX4 was found to bind with deubiquitinase ubiquitin-specific protease 7 (USP7), leading to the disruption of the interaction between USP7 and suppressor of cytokine signaling 1 (SOCS1) and the subsequent degradation of SOCS1. This process enhances the antiviral function of IFN-I. Our findings provide new insights into the regulatory role of DDX4 in the IFN-I response.IMPORTANCEDDX4, identified as a putative RNA helicase that modulates RNA secondary structure through RNA binding, is primarily acknowledged for its role in regulating mRNA translation within the germline. Nevertheless, the extent of DDX4's involvement in the antiviral innate immune response remains largely unexplored. This study presents evidence of a previously unrecognized positive feedback loop between DDX4 and the antiviral response, suggesting that disruption of this loop may serve as a novel mechanism for viral evasion. Furthermore, our findings elucidate a positive regulatory mechanism by which the DDX4/USP7/SOCS1 axis mediates the antiviral activity of Type-I interferon, which provides new insight into strategies for improving the efficacy of IFN-based antiviral therapy.
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Interferón Tipo I , Peptidasa Específica de Ubiquitina 7/genética , Peptidasa Específica de Ubiquitina 7/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Inmunidad Innata , ARNRESUMEN
Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity.