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1.
Eur Rev Med Pharmacol Sci ; 28(9): 3290, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38766781

RESUMEN

Correction to: Eur Rev Med Pharmacol Sci 2015; 19 (17): 3208-3217. PMID: 26400524-published online on September 14, 2015. After publication, a reader brought to our attention a mistake in Figure 4. The journal found that Figure 3 was mistakenly inserted twice in the galley proof, resulting in the publication of the same figure for Figures 3 and 4. The publisher is, therefore, substituting Figure 4 with the correct figure provided at the time of submission as follows: There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/9429.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Proteínas Supresoras de la Señalización de Citocinas , MicroARNs/metabolismo , MicroARNs/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Invasividad Neoplásica
2.
Redox Biol ; 71: 103100, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38484644

RESUMEN

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.


Asunto(s)
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/patología
3.
Front Immunol ; 15: 1320077, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38533493

RESUMEN

Background: The family of Suppressor of Cytokine Signaling (SOCS) acts as a controller of the duration and intensity of cytokine function by negatively regulating the JAK-STAT signaling pathway. SOCS' role in inflammatory diseases in animal models is well demonstrated. However, its role in the development of human disease is still under investigation. SOCS3 plays an important role in tumor development where its downregulation has been implicated in the pathogenesis of various solid tumors such as triple-negative breast cancer. Aim: The aim of this work was to study (1) the expression of SOCS3 in smokers' lungs and its relation to the degree of inflammation and (2) SOCS3 regulation by microRNA (miRNA) in alveolar-macrophage (AM)-derived extracellular vesicles (EVs) in bronchoalveolar lavage (BAL). Methods: Group A: 35 smokers' [19 with COPD (SC) and 16 without COPD (S)] and 9 nonsmokers (NS); SOCS3, TNFα in AM, and CD8+ T cells were quantified by immunohistochemistry, in lung tissue. Group B: additional 9 SC, 11 S, and 5 NS; AM-EVs expressing SOCS3 (CD14+SOCS3+) and SOCS3 suppressors miRNA-19a-3p and 221-3p in EVs were quantified by flow cytometry and PCR, in BAL. Results: The percentage of SOCS3+ AM was higher in SC [68 (6.6-99)%] and S [48 (8-100)%] than in NS [9.6 (1.9-61)%; p = 0.002; p = 0.03] and correlated with % of TNFα+AM (r = 0.48; p = 0.0009) and CD8+ T cells (r = 0.44; p = 0.0029). In BAL, the CD14+SOCS3+ EVs/µL were increased in SC [33 (21-74)] compared to S [16 (8-37); p = 0.03] and NS [9 (7-21); p = 0.003]. Conversely, miRNA-19a-3p and miRNA-221-3p expression were increased in S when compared to SC [19 (2-53) vs. 3 (0.6-8); p = 0.03 and 3 (0.005-9.6) vs. 0.2 (0.08-0.7); p = 0.05]. Conclusions: The suppressor function of SOCS3 in COPD seems to be overridden by other factors and does not follow the animal-model paradigm. Expression of SOCS3 in BAL macrophage-derived EVs might be useful to assess the degree of inflammation and possible progression of COPD. Downregulation of SOCS3, by miRNA, in smokers without COPD might contribute to the risk of developing cancer in these patients.


Asunto(s)
MicroARNs , Enfermedad Pulmonar Obstructiva Crónica , Animales , Humanos , Líquido del Lavado Bronquioalveolar , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Inflamación , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Cells ; 13(6)2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38534350

RESUMEN

Inflammatory skin diseases include a series of disorders characterized by a strong activation of the innate and adaptive immune system in which proinflammatory cytokines play a fundamental role in supporting inflammation. Skin inflammation is a complex process influenced by various factors, including genetic and environmental factors, characterized by the dysfunction of both immune and non-immune cells. Psoriasis (PS) and atopic dermatitis (AD) are the most common chronic inflammatory conditions of the skin whose pathogeneses are very complex and multifactorial. Both diseases are characterized by an immunological dysfunction involving a predominance of Th1 and Th17 cells in PS and of Th2 cells in AD. Suppressor of cytokine signaling (SOCS) proteins are intracellular proteins that control inflammatory responses by regulating various signaling pathways activated by proinflammatory cytokines. SOCS signaling is involved in the regulation and progression of inflammatory responses in skin-resident and non-resident immune cells, and recent data suggest that these negative modulators are dysregulated in inflammatory skin diseases such as PS and AD. This review focuses on the current understanding about the role of SOCS proteins in modulating the activity of inflammatory mediators implicated in the pathogenesis of inflammatory skin diseases such as PS and AD.


Asunto(s)
Dermatitis Atópica , Psoriasis , Humanos , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Transducción de Señal/genética , Citocinas/metabolismo , Inflamación
5.
Int Immunopharmacol ; 129: 111576, 2024 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-38350353

RESUMEN

Cyanogramide (AC14), a novel alkaloid, isolated from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus. However, the exact role of AC14 in inflammatory bowel disease (IBD) is poorly understood. Our results demonstrated that AC14 exhibited significant inhibition of IL-6 release in THP-1 cells and a "Caco-2/THP-1" coculture system after stimulation with LPS for 24 h. However, no significant effect on TNF-α production was observed. Furthermore, in 2.5 % DSS-induced colitis mice, AC14 treatment led to improvement in body weight, colon length, and intestine mucosal barrier integrity. AC14 also suppressed serum IL-6 production and modulated dysregulated microbiota in the mice. Mechanistically, AC14 was found to inhibit the phosphorylation of Janus kinase (JAK) 2 and signal transducers and activators of transcription (STAT) 3, while simultaneously elevating the expression of suppressor of cytokine signaling (SOCS) 3, both in vivo and in vitro. These findings suggest that AC14 exerts its suppressive effects on IL-6 production in DSS-induced IBD mice through the JAK2-STAT3-SOCS3 signaling pathway. Our study highlights the potential of AC14 as a therapeutic agent for the treatment of IBD.


Asunto(s)
Alcaloides , Antineoplásicos , Enfermedades Inflamatorias del Intestino , Poríferos , Humanos , Ratones , Animales , Interleucina-6/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Células CACO-2 , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Janus Quinasa 2/metabolismo , Poríferos/metabolismo , Alcaloides/uso terapéutico , Factor de Transcripción STAT3/metabolismo
6.
Int J Mol Sci ; 25(4)2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38396957

RESUMEN

This study aimed to identify and evaluate drug candidates targeting the kinase inhibitory region of suppressor of cytokine signaling (SOCS) 3 for the treatment of allergic rhinitis (AR). Utilizing an artificial intelligence (AI)-based new drug development platform, virtual screening was conducted to identify compounds inhibiting the SH2 domain binding of SOCS3. Luminescence assays assessed the ability of these compounds to restore JAK-2 activity diminished by SOCS3. Jurkat T and BEAS-2B cells were utilized to investigate changes in SOCS3 and STAT3 expression, along with STAT3 phosphorylation in response to the identified compounds. In an OVA-induced allergic rhinitis mouse model, we measured serum levels of total IgE and OVA-specific IgE, performed real-time PCR on nasal mucosa samples to quantify Th2 cytokines and IFN-γ expression, and conducted immunohistochemistry to analyze eosinophil levels. Screening identified 20 hit compounds with robust binding affinities. As the concentration of SOCS3 increased, a corresponding decrease in JAK2 activity was observed. Compounds 5 and 8 exhibited significant efficacy in restoring JAK2 activity without toxicity. Treatment with these compounds resulted in reduced SOCS3 expression and the reinstatement of STAT3 phosphorylation in Jurkat T and BEAS-2B cells. In the OVA-induced allergic rhinitis mouse model, compounds 5 and 8 effectively alleviated nasal symptoms and demonstrated lower levels of immune markers compared to the allergy group. This study underscores the promising nonclinical efficacy of compounds identified through the AI-based drug development platform. These findings introduce innovative strategies for the treatment of AR and highlight the potential therapeutic value of targeting SOCS3 in managing AR.


Asunto(s)
Inteligencia Artificial , Rinitis Alérgica , Ratones , Animales , Ovalbúmina , Mucosa Nasal/metabolismo , Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Inmunoglobulina E/metabolismo , Ratones Endogámicos BALB C , Modelos Animales de Enfermedad
7.
Front Immunol ; 15: 1362224, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38415248

RESUMEN

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.


Asunto(s)
Neoplasias , Proteínas Supresoras de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Linfocitos T/metabolismo
8.
mBio ; 15(3): e0321323, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38376239

RESUMEN

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.


Asunto(s)
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 , ARN
9.
Int J Biol Macromol ; 262(Pt 1): 129876, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38310055

RESUMEN

Impaired polarization of M1 to M2 macrophages has been reported in diabetic wounds. We aimed to improve this polarization by down-regulation of expression of the "Suppressor of Cytokine Signaling 3" (SOCS3) gene in macrophages. Two oligodeoxynucleotide (ASO) sequences were designed against SOC3 mRNA and were loaded to mannosylated-polyethyleneimine (Man-PEI). The optimum N/P ratio for Man-PEI-ASO was determined to be 8 based on loading efficiency, particle size, zeta potential, cellular uptake and cytotoxicity assay. pH stability of ASO in Man-PEI-ASO and its protection from DNase I was confirmed. After in vitro treatment of macrophages with Man-PEI-ASO, SOCS3 was downregulated, SOCS1 upregulated, and SOCS1/SOCS3 ratio increased. Also, expressions of macrophage markers of M2 (IL-10, Arg1, CD206) increased and those of M1 (IL-1ß, NOS2, CD68) decreased, and secretion of pro-inflammatory cytokines (TNF-α and IL-1ß) decreased while that of anti-inflammatory cytokine IL-4 increased. All suggested a polarization into M2 phenotype. Finally, the Man-PEI-ASO was loaded in hydrogel and applied to a diabetic wound model in mice. It improved the healing to the level observed in non-diabetic wounds. We show that using antisense sequences against SOC3 mRNA, macrophage polarization could be directed into the M2 phenotype and healing of diabetic wound could be highly improved.


Asunto(s)
Diabetes Mellitus , Proteínas Supresoras de la Señalización de Citocinas , Humanos , Ratones , Animales , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Cicatrización de Heridas , Diabetes Mellitus/metabolismo , Macrófagos/metabolismo , ARN Mensajero/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo
10.
Int Immunopharmacol ; 130: 111638, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38373387

RESUMEN

L-arginine, as an essential substance of the immune system, plays a vital role in innate immunity. MiR155, a multi-functional microRNA, has gained importance as a regulator of homeostasis in immune cells. However, the immunoregulatory mechanism between L-arginine and miR155 in bacterial infections is unknown. Here, we investigated the potential role of miR155 in inflammation and the molecular regulatory mechanisms of L-arginine in Streptococcus uberis (S. uberis) infections. And we observed that miR155 was up-regulated after infection, accompanying the depletion of L-arginine, leading to metabolic disorders of amino acids and severe tissue damage. Mechanically, the upregulated miR155 mediated by the p65 protein played a pro-inflammatory role by suppressing the suppressor of cytokine signaling 6 (SOCS6)-mediated p65 ubiquitination and degradation. This culminated in a violently inflammatory response and tissue damage. Interestingly, a significant anti-inflammatory effect was revealed in L-arginine supplementation by reducing miR155 production via inhibiting p65. This work firstly uncovers the pro-inflammatory role of miR155 and an anti-inflammatory mechanism of L-arginine in S.uberis infection with a mouse mastitis model. Collectively, we provide new insights and strategies for the prevention and control of this important pathogen, which is of great significance for ensuring human food health and safety.


Asunto(s)
Arginina , Mastitis , MicroARNs , Infecciones Estreptocócicas , Animales , Femenino , Humanos , Ratones , Arginina/metabolismo , Inflamación/metabolismo , MicroARNs/genética , Infecciones Estreptocócicas/metabolismo , Streptococcus/fisiología , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Mastitis/inmunología , Mastitis/metabolismo
11.
Nat Commun ; 15(1): 603, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38242867

RESUMEN

CD8+ T cells play an important role in anti-tumor immunity. Better understanding of their regulation could advance cancer immunotherapies. Here we identify, via stepwise CRISPR-based screening, that CUL5 is a negative regulator of the core signaling pathways of CD8+ T cells. Knocking out CUL5 in mouse CD8+ T cells significantly improves their tumor growth inhibiting ability, with significant proteomic alterations that broadly enhance TCR and cytokine signaling and their effector functions. Chemical inhibition of neddylation required by CUL5 activation, also enhances CD8 effector activities with CUL5 validated as a major target. Mechanistically, CUL5, which is upregulated by TCR stimulation, interacts with the SOCS-box-containing protein PCMTD2 and inhibits TCR and IL2 signaling. Additionally, CTLA4 is markedly upregulated by CUL5 knockout, and its inactivation further enhances the anti-tumor effect of CUL5 KO. These results together reveal a negative regulatory mechanism for CD8+ T cells and have strong translational implications in cancer immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Proteínas Cullin , Ubiquitina-Proteína Ligasas , Animales , Ratones , Linfocitos T CD8-positivos/metabolismo , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteómica , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
12.
Cytokine ; 174: 156461, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38065046

RESUMEN

Establishing a balance between Th1 and Th2 subsets and M1- and M2-type macrophages is essential for the control of Leishmania infection. The suppressors of cytokine secretion (SOCS) proteins, particularly SOCS1 and SOCS3, play a significant role in regulating cytokine-triggered signaling pathways, thereby impacting the macrophage-and effector T-cell mediated antileishmanial immune response. In addition to the pro-inflammatory cytokines, Leishmania-derived lipophosphoglycan (LPG) and CpG-DNA interact with TLR2 and TLR9 to trigger SOCS expression. The aberrant levels of SOCS1 and SOCS3 expression in Leishmania-infected macrophages impair macrophage-T-cell interaction perturbing the balance in macrophage subsets polarization. This hinders macrophage apoptosis and macrophage-mediated leishmanicidal activity, both support the establishment of infection and parasite replication. Furthermore, aberrant SOCS3 levels in T-cells disrupt Th1 differentiation and aid in parasite replication, lesion development, and pathological immune responses. Strategically, selective modulation of SOCS expression and function in immune effector cells may reduce parasite survival and prevent disease progression.


Asunto(s)
Leishmania , Proteínas Supresoras de la Señalización de Citocinas , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Citocinas/metabolismo , Inmunidad
13.
Microbes Infect ; 26(3): 105282, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38135025

RESUMEN

Mycobacterium tuberculosis (Mtb) infection leads to upregulation of Suppressors of Cytokine signaling (SOCS) expression in host macrophages (Mϕ). SOCS proteins inhibit cytokine signaling by negatively regulating JAK/STAT. We investigated this host-pathogen dialectic at the level of transcription. We used phorbol-differentiated THP-1 Mϕ infected with Mtb to investigate preferential upregulation of some SOCS isoforms that are known to inhibit signaling by IFN-γ, IL-12, and IL-6. We examined time kinetics of likely transcription factors and signaling molecules upstream of SOCS transcription, and survival of intracellular Mtb following SOCS upregulation. Our results suggest a plausible mechanism that involves PGE2 secretion during infection to induce the PKA/CREB axis, culminating in nuclear translocation of C/EBPß to induce expression of SOCS1. Mtb-infected Mϕ secreted IL-10, suggesting a mechanism of induction of STAT3, which may subsequently induce SOCS3. We provide evidence of temporal variation in SOCS isoform exspression and decay. Small-interfering RNA-mediated knockdown of SOCS1 and SOCS3 restored the pro-inflammatory milieu and reduced Mtb viability. In mice infected with Mtb, SOCS isoforms persisted across Days 28-85 post infection. Our results suggest that differential temporal regulation of SOCS isoforms by Mtb drives the host immune response towards a phenotype that facilitates the pathogen's survival.


Asunto(s)
Mycobacterium tuberculosis , Humanos , Animales , Ratones , Proteína 1 Supresora de la Señalización de Citocinas/genética , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Macrófagos/microbiología , Interleucina-12 , Isoformas de Proteínas/metabolismo
14.
Sci Rep ; 13(1): 21814, 2023 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-38071211

RESUMEN

Metastasis of hepatoblastoma (HB) is a key factor that impairs the prognosis and treatment of children. The suppressor of cytokine signaling 2 (SOCS2) is a classical negative feedback protein that regulates cytokine signal transduction and has been known to be downregulated in several tumor, but the molecular mechanisms of its involvement in HB metastasis are unknown. We found that SOCS2 was a gene down-regulated in hepatoblastoma and associated with HB metastasis through bioinformatics. The qRT-PCR, Western blot and IHC showed that SOCS2 was significantly lower in HB tissues. Clinicopathological correlation analysis revealed that low expression of SOCS2 was significantly correlated with tumor metastasis (P = 0.046) and vascular invasion (P = 0.028), associated with poor prognosis. Overexpression of SOCS2 inhibited the migration and invasion of hepatoblastoma cells, while knockdown of SOCS2 expression promoted these malignant phenotypes. In vivo studies revealed overexpression of SOCS2 inhibited the formation of lung metastasis. Up-regulation of SOCS2 in HB cell inhibited EMT and JAK2/STAT5. Conversely, down-regulation of SOCS2 promoted EMT and JAK2/STAT5. The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB.


Asunto(s)
Hepatoblastoma , Neoplasias Hepáticas , Niño , Humanos , Hepatoblastoma/genética , Regulación hacia Abajo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Neoplasias Hepáticas/patología , Citocinas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo
15.
Cancer Lett ; 579: 216465, 2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-38084702

RESUMEN

Lung cancer is a highly heterogeneous malignancy, and despite the rapid development of chemotherapy and radiotherapy, acquired drug resistance and tumor progression still occur. Thus, it is urgent to identify novel therapeutic targets. Our research aims to screen novel biomarkers associated with the prognosis of lung carcinoma patients and explore the potential regulatory mechanisms. We obtained RNA sequencing (RNA-seq) data of lung cancer patients from public databases. Clinical signature analysis, weighted gene coexpression network analysis (WGCNA) and the random forest algorithm showed that C1q/tumor necrosis factor-related protein-6 (CTRP6) is a core gene related to lung cancer prognosis, and it was determined to promote tumor proliferation and metastasis both in vivo and in vitro. Mechanistically, silencing CTRP6 was determined to promote xCT/GPX4-involved ferroptosis through functional assays related to lipid peroxidation, Fe2+ concentration and mitochondrial ultrastructure. By performing interactive proteomics analyses in lung tumor cells, we identified the interaction between CTRP6 and suppressor of cytokine signaling 2 (SOCS2) leading to SOCS2 ubiquitination degradation, subsequently enhancing the downstream xCT/GPX4 signaling pathway. Moreover, significant correlations between CTRP6-mediated SOCS2 and ferroptosis were revealed in mouse models and clinical specimens of lung cancer. As inducing ferroptosis has been gradually regarded as an alternative strategy to treat tumors, targeting CTRP6-mediated ferroptosis could be a potential strategy for lung cancer therapy.


Asunto(s)
Ferroptosis , Neoplasias Pulmonares , Animales , Humanos , Ratones , Adipoquinas/metabolismo , Ferroptosis/genética , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Pronóstico , Transducción de Señal , Proteínas Supresoras de la Señalización de Citocinas/metabolismo
16.
J Clin Immunol ; 44(1): 36, 2023 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-38157076

RESUMEN

By inhibition of JAK-STAT signaling, SOCS1 acts as a master regulator of the cytokine response across numerous tissue types and cytokine pathways. Haploinsufficiency of SOCS1 has recently emerged as a monogenic immunodysregulatory disease with marked clinical variability. Here, we describe a patient with severe dermatitis, recurrent skin infections, and psoriatic arthritis that harbors a novel heterozygous mutation in SOCS1. The variant, c.202_203delAC, generates a frameshift in SOCS1, p.Thr68fsAla*49, which leads to complete loss of protein expression. Unlike WT SOCS1, Thr68fs SOCS1 fails to inhibit JAK-STAT signaling when expressed in vitro. The peripheral immune signature from this patient was marked by a redistribution of monocyte sub-populations and hyper-responsiveness to multiple cytokines. Despite this broad hyper-response across multiple cytokine pathways in SOCS1 haploinsufficiency, the patient's clinical disease was markedly responsive to targeted IL4Rα- and IL17-blocking therapy. In accordance, the mutant allele was unable to regulate IL4Rα signaling. Further, patient cells were unresponsive to IL4/IL13 while on monoclonal antibody therapy. Together, this study reports a novel SOCS1 mutation and suggests that IL4Rα blockade may serve as an unexpected, but fruitful therapeutic target for some patients with SOCS1 haploinsufficiency.


Asunto(s)
Haploinsuficiencia , Proteínas Supresoras de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , 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 , Transducción de Señal , Citocinas/metabolismo , Interleucina-17/genética
17.
Angew Chem Int Ed Engl ; 62(49): e202312603, 2023 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-37847126

RESUMEN

Immunotherapies have shed light on the treatment of many cancers, but have not improved the outcomes of glioma (GBM). Here, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) was associated with the GBM-associated immunosuppression and developed a multifunctional nanomedicine, which silenced SOCS1 in the tumor microenvironment (TME) of GBM and triggered strong antitumor immunity against GBM. Synthetic high-density lipoprotein (sHDL) was selected as the nanocarrier and a peptide was used to facilitate the blood-brain-barrier (BBB) penetration. The nanocarrier was loaded with a small interfering RNA (siRNA), a peptide, and an adjuvant to trigger antitumor immunity. The nanomedicine concentrated on the TME in vivo, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. Our work provides an alternative strategy to simultaneously target and modulate the TME in GBM patients and points to an avenue for enhancing the efficacy of immunotherapeutics.


Asunto(s)
Glioma , Microambiente Tumoral , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/genética , Lipoproteínas HDL , Nanomedicina , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Glioma/terapia , ARN Interferente Pequeño/genética , Línea Celular Tumoral
18.
Biomolecules ; 13(10)2023 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-37892192

RESUMEN

The cytokine-inducible SH2 domain-containing (CISH) protein was the first member of the suppressor of cytokine signaling (SOCS) family of negative feedback regulators discovered, being identified in vitro as an inducible inhibitor of erythropoietin (EPO) signaling. However, understanding of the physiological role played by CISH in erythropoiesis has remained limited. To directly assess the function of CISH in this context, mice deficient in CISH were characterized with respect to developmental, steady-state, and EPO-induced erythropoiesis. CISH was strongly expressed in the fetal liver, but CISH knockout (KO) mice showed only minor disruption of primitive erythropoiesis. However, adults exhibited mild macrocytic anemia coincident with subtle perturbation particularly of bone marrow erythropoiesis, with EPO-induced erythropoiesis blunted in the bone marrow of KO mice but enhanced in the spleen. Cish was expressed basally in the bone marrow with induction following EPO stimulation in bone marrow and spleen. Overall, this study indicates that CISH participates in the control of both basal and EPO-induced erythropoiesis in vivo.


Asunto(s)
Eritropoyesis , Proteínas Supresoras de la Señalización de Citocinas , Animales , Ratones , Anemia/genética , Citocinas , Eritropoyesis/fisiología , Transducción de Señal/fisiología , Dominios Homologos src , Proteínas Supresoras de la Señalización de Citocinas/metabolismo
19.
BMC Pulm Med ; 23(1): 385, 2023 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-37828534

RESUMEN

BACKGROUND: Pulmonary rehabilitation training is of great significance for the prognosis of chronic obstructive pulmonary disease (COPD) patients. The purpose of this study was to investigate the therapeutic effect and pathway of a new sequential noninvasive positive pressure ventilation (NIPPV) + inspiratory muscle training (IMT) therapy. METHODS: A total of 100 COPD patients were enrolled and randomly divided into oxygen therapy (OT), NIPPV, IMT and sequential (NIPPV + IMT) group. Lung function, exercise endurance, quality of life, and dyspnea symptoms were examined and recorded. Then, reactive oxygen species (ROS), malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) levels were detected by enzyme-linked immunoassay, and suppressor of cytokine signaling 5 (SOCS5)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway expression changes were detected by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. A mouse model of COPD was then established to further verify the effects of SOCS5/JAK2/STAT3 pathways on lung function and oxidative stress. RESULTS: After 8 weeks of treatment, NIPPV, IMT or sequential (NIPPV + IMT) significantly improved exercise endurance, quality of life and dyspnea, reduced oxidative stress, promoted SOCS5 expression and inhibited the activation of JAK2/STAT3 pathway, and no significant effect was observed on lung function of COPD patients. Notably, sequential (NIPPV + IMT) showed better therapeutic outcomes than either IMT or NIPPV alone. Moreover, results at the animal level showed that overexpression of SOCS5 significantly reduced pulmonary inflammatory infiltration, pathological changes and oxidative stress levels in COPD mice, enhanced lung function, and inhibited the activation of JAK2/STAT3 pathway. CONCLUSION: Our results elucidated that sequential (NIPPV + IMT) significantly relieved COPD development by regulating SOCS5/JAK2/STAT3 signaling-mediated oxidative stress.


Asunto(s)
Enfermedad Pulmonar Obstructiva Crónica , Factor de Transcripción STAT3 , Humanos , Animales , Ratones , Factor de Transcripción STAT3/metabolismo , Janus Quinasa 2/metabolismo , Calidad de Vida , Disnea/terapia , Estrés Oxidativo , Músculos/metabolismo , Respiración con Presión Positiva , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/farmacología
20.
Cytokine ; 171: 156346, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37751673

RESUMEN

BACKGROUND: Liver injury plays a major role in the development of sepsis. Liver damage after sepsis is an independent risk factor for multiple organ failure and death. Cancer susceptibility candidate 9 (CASC9) exerts a protective effect on sepsis-induced acute lung injury (ALI). However, the role and underlying mechanism haven't been fully evaluated. METHODS: Animal and cell models of sepsis were established in vivo and in vitro experiments. The histological and apoptosis analyses of liver tissues were tested by hematoxylin-eosin (HE) staining and terminal dUTP nick end labeling (TUNEL) assay, respectively. Serum levels of inflammatory cytokines were detected via using an enzyme-linked immunosorbent assay (ELISA). The expressions of CASC9, suppressor of cytokine signaling (SOCS)-1, Bcl-2, Bax, Bad, and caspase3 were measured by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. Cell counting kit-8 (CCK-8) and flow cytometry were applied to examine cell viability and apoptosis, respectively. RNA immunoprecipitation (RIP) and RNA-pull down assay were used to verify the binding relationships among CASC9, SOCS-1 and FUS. RESULTS: CASC9 and SOCS-1 were lowly expressed in animal and cell models of sepsis liver injury. CASC9 or SOCS-1 overexpression could inhibit cell apoptosis upon lipopolysaccharide (LPS) induction. Meanwhile, the serum levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and IL-8 were reduced by CASC9 or SOCS-1 overexpression in LPS-induced LO2 cells. Mechanistically, CASC9 interacted with fused in sarcoma (FUS) to stabilize the mRNA of SOCS-1. SOCS-1 silencing antagonized the effects of CASC9 on improving sepsis liver injury. CONCLUSION: CASC9 overexpression ameliorated the sepsis-induced liver injury, and the probable underlying mechanism may be that CASC9 stabilized the SOCS-1 mRNA by interacting with FUS.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , MicroARNs , ARN Largo no Codificante , Sepsis , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Lipopolisacáridos/farmacología , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Sepsis/complicaciones , Sepsis/patología , ARN Mensajero , Apoptosis , MicroARNs/genética
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