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Pebrine disease, caused by Nosema bombycis (Nb) infection in silkworms, is a severe and long-standing disease that threatens sericulture. As parasitic pathogens, a complex relationship exists between microsporidia and their hosts at the mitochondrial level. Previous studies have found that the translocator protein (TSPO) is involved in various biological functions, such as membrane potential regulation, mitochondrial autophagy, immune responses, calcium ion channel regulation, and cell apoptosis. In the present study, we found that TSPO expression in silkworms (BmTSPO) was upregulated following Nb infection, leading to an increase in cytoplasmic calcium, adenosine triphosphate, and reactive oxygen species levels. Knockdown and overexpression of BmTSPO resulted in the promotion and inhibition of Nb proliferation, respectively. We also demonstrated that the overexpression of BmTSPO promotes host cell apoptosis and significantly increases the expression of genes involved in the immune deficiency and Janus kinase-signal transducer and the activator of the transcription pathways. These findings suggest that BmTSPO activates the innate immune signalling pathway in silkworms to regulate Nb proliferation. Targeting TSPO represents a promising approach for the development of new treatments for microsporidian infections.
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Parkinson's disease (PD) is characterized by neuroinflammation, progressive loss of dopaminergic neurons, and accumulation of α-synuclein (α-Syn) into insoluble aggregates called Lewy pathology. The Line 61 α-Syn mouse is an established preclinical model of PD; Thy-1 is used to promote human α-Syn expression, and features of sporadic PD develop at 9-18 months of age. To accelerate the PD phenotypes, we injected sonicated human α-Syn preformed fibrils (PFFs) into the striatum, which produced phospho-Syn (p-α-Syn) inclusions in the substantia nigra pars compacta and significantly increased MHC Class II-positive immune cells. Additionally, there was enhanced infiltration and activation of innate and adaptive immune cells in the midbrain. We then used this new model, Line 61-PFF, to investigate the effect of inhibiting the JAK/STAT signaling pathway, which is critical for regulation of innate and adaptive immune responses. After administration of the JAK1/2 inhibitor AZD1480, immunofluorescence staining showed a significant decrease in p-α-Syn inclusions and MHC Class II expression. Flow cytometry showed reduced infiltration of CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, dendritic cells, macrophages, and endogenous microglia into the midbrain. Importantly, single-cell RNA-Sequencing analysis of CD45+ cells from the midbrain identified 9 microglia clusters, 5 monocyte/macrophage (MM) clusters, and 5 T-cell (T) clusters, in which potentially pathogenic MM4 and T3 clusters were associated with neuroinflammatory responses in Line 61-PFF mice. AZD1480 treatment reduced cell numbers and cluster-specific expression of the antigen-presentation genes H2-Eb1, H2-Aa, H2-Ab1, and Cd74 in the MM4 cluster and proinflammatory genes such as Tnf, Il1b, C1qa, and C1qc in the T3 cluster. Together, these results indicate that inhibiting the JAK/STAT pathway suppresses the activation and infiltration of innate and adaptive cells, reducing neuroinflammation in the Line 61-PFF mouse model.
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Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias , Enfermedad de Parkinson , Factores de Transcripción STAT , Transducción de Señal , alfa-Sinucleína , Animales , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/antagonistas & inhibidores , Factores de Transcripción STAT/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/inmunología , Humanos , Ratones Transgénicos , Ratones Endogámicos C57BL , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/inmunología , Pirimidinas/farmacologíaRESUMEN
BACKGROUND: It has been described in mice models that myeloproliferative neoplasm (MPN) with JAK2-V617F mutation has an increased expression of programmed death-ligand 1 (PD-L1) in megakaryocytes leading to cancer immune evasion by inhibiting the T-lymphocytes. AIMS: To quantify and compare the PD-L1 expression on bone marrow (BM) of patients with MPN JAK2 positive, negative, and normal controls. METHODS: We collected BM of patients with MPN JAK2 positive, negative and normal controls from 1990 to 2019. We also created a scoring system to quantify PD-L1 expression in megakaryocytes. RESULTS: We obtained 14 BM with JAK2 positive PMF, 5 JAK2 negative PMF, and 10 patients with normal BM biopsies. PD-L1 expression was higher in the JAK2 positive group compared with the control group with a score of 212.6 versus 121.1 (t-value 2.05, p-value 0.025). In addition, the score was higher in the PMF group regardless of JAK2 mutational status when compared with the control group with score of 205.9 versus 121.1 (t-value 2.12, p-value 0.021). There was no difference in the PD-L1 score between the JAK2 negative versus the control group 187.2 versus 121.1 (t-value 1.02, p-value 0.162). CONCLUSION: These findings suggest that PMF patients with a JAK2 mutation have a higher PD-L1 expression in megakaryocytes compared with the control group. We postulate that the combination of checkpoint and JAK2 inhibitors may be an active treatment option in JAK2 mutated PMF given the higher PD-L1 expression.
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Antígeno B7-H1 , Janus Quinasa 2 , Mielofibrosis Primaria , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Mutación , Médula Ósea/patología , Megacariocitos/patología , Megacariocitos/metabolismo , Anciano de 80 o más Años , Estudios de Casos y ControlesRESUMEN
OBJECTIVE: The E3 ubiquitin ligase is well recognized as a significant contributor to glioblastoma (GBM) progression and has promise as a prospective therapeutic target. This study explores the contribution of E3 ubiquitin ligase RNF122 in the GBM progression and the related molecular mechanisms. METHODS: RNF122 expression levels were evaluated using qRT-PCR, WB, and IHC, while functional assays besides animal experiments were used to assess RNF122's effect on GBM progression. We also tested the RNF122 impact on JAK2/STAT3/c-Myc signaling using WB. RESULTS: RNF122 was upregulated in GBM and correlated to the advanced stage and poor clinical outcomes, representing an independent prognostic factor. Based on functional assays, RNF122 promotes GBM growth and cell cycle, which was validated further in subsequent analyses by JAK2/STAT3/c-Myc pathway activation. Moreover, JAK2/STAT3 signaling pathway inhibitor WP1066 can weaken the effect of overexpression RNF122 on promoting GBM progression. CONCLUSION: Our results revealed that RNF122 caused an aggressive phenotype to GBM and was a poor prognosticator; thus, targeting RNF122 may be effectual in GBM treatment.
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Neoplasias Encefálicas , Glioblastoma , Janus Quinasa 2 , Proteínas Proto-Oncogénicas c-myc , Factor de Transcripción STAT3 , Transducción de Señal , Ubiquitina-Proteína Ligasas , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Masculino , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Femenino , Animales , Línea Celular Tumoral , Ratones Desnudos , Persona de Mediana Edad , Ratones , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Ratones Endogámicos BALB C , Péptidos y Proteínas de Señalización IntracelularRESUMEN
This study investigated the structure of Pleurocinus ostreatus polysaccharide (POP-1) and its effect on immunocompromised mice induced by cyclophosphamide (CY). Novel POP-1 was α- and ß-glucopyranose, its molecular weight was 4.78 × 104 Da, it was mainly composed of glucose (88.9%), and it also contained galactose (2.97%), mannose (5.02%), fucose (0.3%), arabinose (0.21%), ribose (0.04%), galactose acid (0.17%), and glucose acid (1.45%). After POP-1 was administered to immunosuppressed mice, results showed that POP-1 increased the body weight, spleen, and thymus index and enhanced T lymphocyte proliferation in mice. POP-1 up-regulated the expression of CD3+, CD4+, and CD8+ lymphocytes and the ratio of CD4+/CD8+ in the mouse spleen to increase immunoglobulin (IgM, IgG, and IgA) and secrete cytokines (IL-2, IL-6, TNF-α, and IFN-γ) through activation of the JAK/STAT1 signaling pathway. Moreover, POP-1 remarkably reversed the gut-microbiota dysbiosis in immunosuppressed mice by increasing the abundance of Muribaculaceae, Lactobacillaceae, Blautia, and Ligilactobacillus and altered the fecal metabolites by increasing hexahomomethionine, DG(8:0/20:4(5Z, 8Z, 11Z, 14Z)-OH(20)/0:0, 2-((3-aminopyridin-2-yl)methylene)hydrazinecarbothioamide, Ginkgoic acid, and carboxy-ethyl-hydroxychroman, which is closely related to the immunity function. This study indicates that P. ostreatus polysaccharide effectively restores immunosuppressive activity and can be a functional ingredient in food and pharmaceutical products.
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BACKGROUND: Bacterial keratitis is a common cause of blindness. Antibiotic treatment leads to the rapid release of lipopolysaccharide (LPS), which can activate corneal fibroblasts and cause persistent and excessive inflammatory responses. The anti-inflammatory drugs currently used to treat keratitis have serious side effects. Therefore, the ability of sodium butyrate (NaB), which can suppress the production of proinflammatory cytokines and promote the production of anti-inflammatory cytokines, to ameliorate keratitis was assessed in the present study. METHODS: The effect of NaB on the viability of primary human corneal fibroblasts was assayed with a CCK-8 kit. Cell migration was assessed by an in vitro scratch assay. Cell phenotypes were assessed by Western blotting and immunofluorescence staining. An antibody array was used to measure the production of proinflammatory cytokines and chemokines. RESULTS: At 0-1 mM, NaB had no significant effect on cell viability, promoted the expression of the keratocyte marker keratocan and inhibited the fibroblast marker vimentin. Inhibition of cell migration was observed in the wound healing assay. By targeting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, NaB decreased the levels of inflammation-related cytokines and chemokines whose expression was induced by LPS. CONCLUSIONS: NaB maintained the keratocyte phenotype, inhibited cell migration, and relieved LPS-induced inflammatory responses through the JAK/STAT signalling pathway.
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Overactivation of the JAK/STAT pathway is one of the drivers for the pathophysiology of hepatocellular carcinoma (HCC). We propose a Phase Ib study to evaluate the safety and efficacy of itacitinib, a selective JAK1 inhibitor, as a second-line treatment for patients with advanced or metastatic HCC.Twenty-five patients will receive 400 mg itacitinib orally daily, 28-day cycle. Safety will be reviewed prior to each cycle. Tumor response assessed every 2 months until disease progression, death or withdrawal. Tumor biopsies and blood samples will be taken for presence of JAK1 mutations.Activation of JAK/STAT pathway drives HCC development and is associated with immunotherapy resistance. Itacitinib is hypothesized to be safe and effective in HCC patients that have progressed after first-line therapies.Clinical Trial Registration: EudraCT: 2017-004437-81 NCT04358185 (ClinicalTrials.gov).
[Box: see text].
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The c-MPL-TPO axis regulates hematopoiesis by activating various signalling cascades, including JAK/STAT, MAPK/ERK, and PIK3/AKT. Here, we have summarized how TPO is regulated by c-MPL and, how mutations in the c-MPL regulate hematopoiesis. We also focus on its non-hematological regulatory role in diseases like Unstable Angina and pathways like DNA damage repair, skeletal homeostasis, & apoptotic regulation of neurons/HSCs at the embryonic state. We discuss the therapeutic efficiency of c-MPL and, its potential to be developed as a bio-marker for detecting metastasis and development of chemo-resistance in various cancers, justifying the multifaceted nature of c-MPL. We have also highlighted the importance of c-MPL isoforms and their stoichiometry in controlling the HSC quiescent and proliferative state. The regulation of the ratio of different isoforms through gene-therapy can open future therapeutic avenues. A systematic understanding of c-MPL-isoforms would undoubtedly take one step closer to facilitating c-MPL from basic-research towards translational medicine.
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Sarcoidosis is an inflammatory, non-caseating granulomatous multisystem disease associated with JAK-STAT (Janus kinases-signal transducer and activator of transcription proteins) pathway activation. We present a patient with severe multi-systemic sarcoidosis who showed marked improvement with tofacitinib with regards to pulmonary, cutaneous, nasal and laryngeal disease. Tofacitinib prevented critical laryngeal stenosis from progressing to tracheostomy, induced regression of cutaneous lesions and improved pulmonary function in this steroid-resistant and immunosuppressive intolerant case. This case report supports further the role of JAK-inhibitors in the treatment of systemic sarcoidosis. Laryngoscope, 2024.
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VEXAS syndrome, an uncommon yet severe autoimmune disorder stemming from a mutation in the UBA1 gene, is the focus of this paper. The overview encompasses its discovery, epidemiological traits, genetic underpinnings, and clinical presentations. Delving into whether distinct genotypes yield varied clinical phenotypes in VEXAS patients, and the consequent adjustment of treatment strategies based on genotypic and clinical profiles necessitates thorough exploration within the clinical realm. Additionally, the current therapeutic landscape and future outlook are examined, with particular attention to the potential therapeutic roles of IL-6 inhibitors and JAK inhibitors, alongside an elucidation of prevailing limitations and avenues for further research. This study contributes essential theoretical groundwork and clinical insights for both diagnosing and managing VEXAS syndrome.
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Interleucina-6 , Inhibidores de las Cinasas Janus , Enzimas Activadoras de Ubiquitina , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Inhibidores de las Cinasas Janus/uso terapéutico , Enzimas Activadoras de Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Mutación , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/diagnósticoRESUMEN
INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by persistent itching. Conventional treatments for AD include topical corticosteroids and calcineurin inhibitors, but there are emerging therapies targeting the JAK-TYK2 pathway that are promising for the treatment of AD. AREAS COVERED: This review comprehensively explores the pathogenesis, triggers, clinical manifestations, and conventional treatment options for AD. In addition, we discuss novel therapeutic agents targeting alternative signaling pathways, with a focus on clinical trials evaluating tyrosine kinase 2 (TYK2) inhibitors, including systemic and topical agents. We also provide a detailed assessment of ICP-332 efficacy, safety, and potential adverse effects in moderate-to-severe AD. EXPERT OPINION: Janus kinase inhibitors that have been recently approved have shown promise for the treatment of AD, especially for patients with severe phenotypes. Preliminary findings from randomized controlled trials suggest that TYK2 inhibitors exhibit rapid efficacy and acceptable safety in the management of AD; however, additional investigations, including long-term trials, are warranted to fully understand their efficacy and safety profile.
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Background Granuloma annulare (GA) is a necrobiotic granulomatous disorder that may sometimes be resistant to treatment, especially the generalised form. Tofacitinib has recently shown promise in the treatment of non-infective granulomatous dermatosis. Objectives In this study, we aimed to evaluate the response of generalised GA to oral tofacitinib. Methods This was a retrospective case series in patients of generalised GA who were treated with oral tofacitinib 5 mg twice a day in a tertiary care centre in north India. Baseline clinical details and histopathological findings were reviewed. Treatment response was noted in the form of clearance of lesions (complete or partial) along with the time taken to achieve the maximum response. Results A total of 15 patients of generalised GA were included in this study, amongst whom nine patients were resistant to conventional therapies whilst the remaining were treatment naïve. Complete clearance of lesions was noted in 11 patients at a mean treatment duration of 4.4 ± 2.1 months whereas clearance was partial in four, with a mean follow-up duration post- treatment in patients who had partial clearance, which is 7.3 ± 2.8 month, with a reduction in erythema and infiltration in those lesions. Adverse effects in the form of hyperlipidemia were observed in two patients. Conclusion Tofacitinib, a JAK-STAT inhibitor is beneficial in treating GA, especially in those with generalised and recalcitrant disease.
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IBD (inflammatory bowel disease) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been implicated in the cause of IBD, although the cause of the disease remains unknown. IL-12 and IL-23 and their downstream signaling pathways participate in the pathogenesis of inflammatory bowel disease. Early and aggressive treatment with biologic therapies or novel small molecules is needed to decrease complications and the need for hospitalization and surgery. The landscape of inflammatory bowel disease (IBD) treatment has tremendously improved with the development of biologics and small molecule drugs. Several novel biologics and small molecule drugs targeting IL-12 and IL-23 and their downstream targets have shown positive efficacy and safety data in clinical trials, and several drugs have been approved for the treatment of IBD. In the future, numerous potential emerging therapeutic options for IBD treatment are believed to come to the fore, achieving disease cure.
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Enfermedades Inflamatorias del Intestino , Interleucina-12 , Interleucina-23 , Inhibidores de las Cinasas Janus , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Inhibidores de las Cinasas Janus/uso terapéutico , Interleucina-23/antagonistas & inhibidores , Interleucina-23/metabolismo , Interleucina-23/inmunología , Interleucina-12/antagonistas & inhibidores , Interleucina-12/metabolismo , Interleucina-12/inmunología , Animales , Transducción de Señal/efectos de los fármacosRESUMEN
Chlamydia trachomatis has adapted to subvert signaling in epithelial cells to ensure successful intracellular development. Interferon-γ (IFNγ) produced by recruited lymphocytes signals through the JAK/STAT pathway to restrict chlamydial growth in the genital tract. However, during Chlamydia infection in vitro, addition of IFNγ does not fully induce nuclear localization of its transcription factor STAT1 and expression of its target gene, IDO1. We hypothesize that this altered interferon response is a result of Chlamydia targeting components of the IFNγ-JAK/STAT pathway. To assess the ability of replicating Chlamydia to dampen interferon signaling, HEp2 human epithelial cells were infected with C. trachomatis serovar L2 for 24 hours prior to exposure to physiologically relevant levels of IFNγ (500 pg/mL). This novel approach enabled us to observe reduced phospho-activation of both STAT1 and its kinase Janus Kinase 2 (JAK2) in infected cells compared with mock-infected cells. Importantly, basal JAK2 and STAT1 transcript and protein levels were dampened by infection even in the absence of interferon, which could have implications for cytokine signaling beyond IFNγ. Additionally, target genes IRF1, GBP1, APOL3, IDO1, and SOCS1 were not fully induced in response to IFNγ exposure. Infection-dependent decreases in transcript, protein, and phosphoprotein were rescued when de novo bacterial protein synthesis was inhibited with chloramphenicol, restoring expression of IFNγ-target genes. Similar Chlamydia-dependent dampening of STAT1 and JAK2 transcript levels was observed in infected HeLa and END1 endocervical cells and in HEp2s infected with C. trachomatis serovar D, suggesting a conserved mechanism of dampening the interferon response by reducing the availability of key signaling components. IMPORTANCE: As an obligate intracellular pathogen that has evolved to infect the genital epithelium, Chlamydia has developed strategies to prevent detection and antimicrobial signaling in its host to ensure its survival and spread. A major player in clearing Chlamydia infections is the inflammatory cytokine interferon-γ (IFNγ), which is produced by immune cells that are recruited to the site of infection. Reports of IFNγ levels in endocervical specimens from Chlamydia-infected patients range from 1 to 350 pg/mL, while most in vitro studies of the effects of IFNγ on chlamydial growth have used 15-85-fold higher concentrations. By using physiologically relevant concentrations of IFNγ, we were able to assess Chlamydia's ability to modulate its signaling. We found that Chlamydia decreases the expression of multiple components that are required for inducing gene expression by IFNγ, providing a possible mechanism by which Chlamydia trachomatis can attenuate the immune response in the female genital tract to cause long-term infections.
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Cutaneous hypersensitivity reactions (CHRs) are complex inflammatory skin disorders that affect humans and dogs. This study examined the inflammatory and immune responses leading to skin damage, inflammation, and irritation by investigating gene expression through quantitative PCR (qPCR) and protein localization through the immunohistochemistry (IHC) of specific receptors and molecules involved in CHRs. Formalin-fixed paraffin-embedded (FFPE) samples from canine CHR skin (n = 20) and healthy dog skin (n = 3) were analyzed for expression levels of eight genes, including members of the pattern recognition receptor (PRR) family, CD209 and CLEC4G, the Regakine-1-like chemokine, and acute phase proteins (APPs), LBP-like and Hp-like genes. Additionally, we examined the local involvement of IL-6, Janus Kinase 1 (JAK1), and the signal transducer activator of transcription 3 (STAT3) in the CHR cases. The study demonstrated statistically significant increases in the expression levels of CD209, Hp-like (p < 0.01), LBP-like, Regakine-1-like, and CLEC4G (p < 0.05) genes in CHRs compared to healthy controls. Conversely, IL-6, JAK1, and STAT3 showed no significant difference between the two groups (p > 0.05). Protein analysis revealed JAK1 and STAT3 expression in CHR hyperplastic epithelial cells, dermal fibroblasts, and endothelial cells of small capillaries, indicating a possible involvement in the JAK/STAT pathway in local inflammatory response regulation. Our findings suggest that the skin plays a role in the development of CHRs.
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Cardiac fibrosis is characterized by the over-proliferation, over-transdifferentiation and over-deposition of extracellular matrix (ECM) of cardiac fibroblasts (CFs). Cardiac sympathetic activation is one of the leading causes of myocardial fibrosis. Meanwhile, cardiac fibrosis is often together with cardiac inflammation, which accelerates fibrosis by mediating inflammatory cytokines secretion. Recently, the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) signaling pathway has been confirmed by its vital role during the progression of cardiac fibrosis. Thus, JAK/STAT3 signaling pathway is thought to be a potential therapeutic target for cardiac fibrosis. Baricitinib (BR), a novel JAK1/2 inhibitor, has been reported excellent effects of anti-fibrosis in multiple fibrotic diseases. However, little is known about whether and how BR ameliorates cardiac fibrosis caused by chronic sympathetic activation. Isoproterenol (ISO), a ß-Adrenergic receptor (ß-AR) nonselective agonist, was used to modulate chronic sympathetic activation in mice. As expected, our results proved that BR ameliorated ISO-induced cardiac dysfunction. Meanwhile, BR attenuated ISO-induced cardiac fibrosis and cardiac inflammation in mice. Moreover, BR also inhibited ISO-induced cardiac fibroblasts activation and macrophages pro-inflammatory secretion. As for mechanism studies, BR reduced ISO-induced cardiac fibroblasts by JAK2/STAT3 and PI3K/Akt signaling, while reduced ISO-induced macrophages pro-inflammatory secretion by JAK1/STAT3 and NF-κB signaling. In summary, BR alleviates cardiac fibrosis and inflammation caused by chronic sympathetic activation. The underlying mechanism involves BR-mediated suppression of JAK1/2/STAT3, PI3K/Akt and NF-κB signaling.
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Azetidinas , Fibroblastos , Fibrosis , Ratones Endogámicos C57BL , Purinas , Pirazoles , Sulfonamidas , Animales , Fibrosis/tratamiento farmacológico , Azetidinas/farmacología , Azetidinas/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Masculino , Fibroblastos/efectos de los fármacos , Purinas/farmacología , Purinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Miocardio/patología , Isoproterenol , Células Cultivadas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , FN-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Citocinas/metabolismo , Humanos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
The Dengue virus (DENV), primarily spread by Aedes aegypti and also by Aedes albopictus in some regions, poses significant global health risks. Alternative techniques are urgently needed because the current control mechanisms are insufficient to reduce the transmission of DENV. Introducing Wolbachia pipientis into Ae. aegypti inhibits DENV transmission, however, the underlying mechanisms are still poorly understood. Innate immune effector upregulation, the regulation of autophagy, and intracellular competition between Wolbachia and DENV for lipids are among the theories for the mechanism of inhibition. Furthermore, mainly three immune pathways Toll, IMD, and JAK/STAT are involved in the host for the suppression of the virus. These pathways are activated by Wolbachia and DENV in the host and are responsible for the upregulation and downregulation of many genes in mosquitoes, which ultimately reduces the titer of the DENV in the host. The functioning of these immune pathways depends upon the Wolbachia, host, and virus interaction. Here, we summarize the current understanding of DENV recognition by the Ae. aegypti's immune system, aiming to create a comprehensive picture of our knowledge. Additionally, we investigated how Wolbachia regulates the activation of multiple genes associated with immune priming for the reduction of DENV.
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Aedes , Virus del Dengue , Dengue , Inmunidad Innata , Mosquitos Vectores , Wolbachia , Aedes/inmunología , Aedes/virología , Aedes/microbiología , Wolbachia/fisiología , Wolbachia/inmunología , Animales , Virus del Dengue/inmunología , Virus del Dengue/fisiología , Dengue/inmunología , Dengue/transmisión , Dengue/virología , Mosquitos Vectores/inmunología , Mosquitos Vectores/virología , Mosquitos Vectores/microbiología , Interacciones Huésped-Patógeno/inmunología , Humanos , Transducción de Señal/inmunologíaRESUMEN
Thyroid hormones (THs) are essential in neuronal and glial cell development and differentiation, synaptogenesis, and myelin sheath formation. In addition to nuclear receptors, TH acts through αvß3-integrin on the plasma membrane, influencing transcriptional regulation of signaling proteins that, in turn, affect adhesion and survival of nerve cells in various neurologic disorders. TH exhibits protective properties during brain hypoxia; however, precise intracellular mechanisms responsible for the preventive effects of TH remain unclear. In this study, we investigated the impact of TH on integrin αvß3-dependent downstream systems in normoxic and hypoxic conditions of pheochromocytoma PC12 cells. Our findings reveal that triiodothyronine (T3), acting through αvß3-integrin, induces activation of the JAK2/STAT5 pathway and suppression of the SHP2 in hypoxic PC12 cells. This activation correlates with the downregulation of the expression palmitoyltransferase-ZDHHC2 and ZDHHC9 genes, leading to a subsequent decrease in palmitoylation and phosphorylation of Fyn tyrosine kinase. We propose that these changes may occur due to STAT5-dependent epigenetic silencing of the palmitoyltransferase gene, which in turn reduces palmitoylation/phosphorylation of Fyn with a subsequent increase in the survival of cells. In summary, our study provides the first evidence demonstrating the involvement of integrin-dependent JAK/STAT pathway, SHP2 suppression, and altered post-translational modification of Fyn in protective effects of T3 during hypoxia.
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Rheumatoid arthritis (RA) is a highly prevalent autoimmune disorder. The pathogenesis of the disease is complex and involves various cellular populations, including fibroblast-like synoviocytes, macrophages, and T cells, among others. Identification of signalling pathways and molecules that actively contribute to the development of the disease is crucial to understanding the mechanisms involved in the chronic inflammatory environment present in affected joints. Recent studies have demonstrated that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway regulates the behaviour of immune cells and contributes to the progression of RA. Several JAK inhibitors, such as tofacitinib, baricitinib, upadacitinib, and filgocitinib, have been developed, and their efficacy and safety in patients with RA have been comprehensively investigated in a number of clinical trials. Consequently, JAK inhibitors have been approved and registered as a treatment for patients with RA. In this review, we discuss the involvement of JAK/STAT signalling in the pathogenesis of RA and summarise the potential beneficial effects of JAK inhibitors in cells implicated in the pathogenesis of the disease. Moreover, we present the most important phase 3 clinical trials that evaluated the use of these agents in patients.
Asunto(s)
Artritis Reumatoide , Inhibidores de las Cinasas Janus , Quinasas Janus , Humanos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Animales , Antirreumáticos/uso terapéutico , Antirreumáticos/farmacologíaRESUMEN
Lung cancer (LC) is a major inducer of cancer-related death. We aim to reveal the effect of Calsequestrin2 (CASQ2) on macrophage polarization and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in LC. Hub genes were determined from protein-protein interaction networks based on GSE21933 and GSE1987 data sets using bioinformatic analysis. Expression of hub genes was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, wound-healing, colony formation, and transwell assays were performed to assess the impact of CASQ2 on LC cells. A xenograft mouse model was evaluated using hematoxylin-eosin, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining to investigate the effect of CASQ2 on LC. The role of CASQ2 in regulating macrophage polarization and JAK/STAT pathway was evaluated by western blot andRT-qPCR. We screened out 155 common differentially expressed genes in GSE21933 and GSE1987 data sets. Myomesin-2, tyrosine kinase, sex determining region Y-box 2, platelet and endothelial cell adhesion molecule 1, matrix metallopeptidase 9, claudin-5, caveolin-1, CASQ2, recombinant ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2), and ankyrin repeat domain 1 were identified as the hub genes with high prediction value. CASQ2 was selected as a pivotal regulator of LC. In vitro experiments and xenograft models revealed that CASQ2 overexpression suppressed proliferation, colony formation, migration, invasion of LC cells, and tumor growth in vivo. Additionally, overexpression of CASQ2 promoted the expression of M1 macrophage markers (cluster of differentiation 80 [CD80], interleukin [IL]-12, inducible nitric oxide synthase [iNOS]), while decreasing the expression of M2 macrophage markers (CD163, IL-10, Arg1) in tumor-associated macrophages and xenograft tissues. Finally, we found that overexpression of CASQ2 inhibited JAK/STAT pathway. CASQ2 is a novel biomarker, which can alleviate LC via inhibiting M2 tumor-associated macrophage polarization and JAK/STAT pathway.