Ameliorative Effect and Mechanism of Qingwen Baiduyin on Lipopolysaccharide-induced Acute Lung Injury / 中国实验方剂学杂志

To investigate the therapeutic effect and mechanism of Qingwen Baiduyin on acute lung injury （ALI） in mice induced by lipopolysaccharide （LPS）. MethodA total of 144 C57BL/6 mice were randomly divided into the following groups： a normal group， a model group （LPS， 5 mg·kg-1）， a dexamethasone group （5 mg·kg-1）， and low-， medium-， and high-dose Qingwen Baiduyin groups （14.105， 28.21， 56.42 g·kg-1）. The mice were treated once daily for 5 days. One hour after the final administration， the ALI model was established by intratracheal instillation of LPS， and samples were collected at 6 h and 24 h after modeling. The arterial blood gas index of mice was analyzed. The total protein content， total cell count， Evans blue dye （EBD） content， and lung tissue wet-to-dry weight ratio （W/D） of bronchoalveolar lavage fluid （BALF） were measured. Hematoxylin-eosin （HE） staining was performed to assess the pathological changes in mouse lung tissue. Western blot was used to detect the expression levels of key proteins in the Janus kinase 1/signal transducer and activator of transcription 1/interferon regulatory factor 1 （JAK1/STAT1/IRF1） signaling pathway in lung tissue. ResultCompared with the normal group， the model group showed reduced arterial oxygen pressure （pO2）， oxygen saturation （SO2）， and lung tissue W/D （P<0.05， P<0.01）， increased carbon dioxide pressure （pCO2）， total protein content， total cell count， EBD content， interferon-γ （IFN-γ）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， chemokine CXC ligand 1 （CXCL1）， chemokine CXC ligand 2 （CXCL2）， chemokine CXC ligand 9 （CXCL9）， and chemokine CXC ligand 10 （CXCL10） content （P<0.05， P<0.01）， thickening of the alveolar walls， fusion of alveolar cavities， and infiltration of inflammatory cells in lung tissue， increased proportion of M1 macrophage polarization and lung cell apoptosis （P<0.05）， and increased protein expression levels of JAK1， phosphorylated JAK1 （p-JAK1）， inducible nitric oxide synthase （iNOS）， STAT1， phosphorylated STAT1 （p-STAT1）， IRF1， gasdermin D （GSDMD）， and mixed lineage kinase domain-like protein （MLKL） （P<0.05， P<0.01）. Compared with the model group， Qingwen Baiduyin significantly increased pO2， SO2， and lung tissue W/D （P<0.05， P<0.01）， improved the pathological changes in lung tissue， and reduced pCO2， total protein content， total cell count， EBD content， IFN-γ， TNF-α， IL-1β， CXCL1， CXCL2， CXCL9， and CXCL10 content， proportion of M1 macrophage polarization， and protein expression levels of JAK1， p-JAK1， iNOS， STAT1， p-STAT1， IRF1， GSDMD， and MLKL （P<0.05， P<0.01）. ConclusionQingwen Baiduyin can improve the lung inflammatory response and reduce lung cell apoptosis in mice with ALI by inhibiting the JAK1/STAT1/IRF1 signaling pathway， thereby exerting a lung-protective effect.

Butyrate facilitates immune clearance of colorectal cancer cells by suppressing STAT1-mediated PD-L1 expression

Abstract Objective Immunotherapy has been proven to improve the prognosis of patients with advanced malignancy but has shown limited efficacy in patients with Colorectal Cancer (CRC). Increasing evidence suggests that butyrate, a bacterial metabolite, enhances the efficacy of cancer therapies by modulating immune responses. Here, the effect and the mechanism of butyrate on anti-PD-L1 therapy were investigated in CRC. Methods The expression of PD-L1 and STAT1, and the lysine acetylation of STAT1 in CRC cells were observed after treatment with butyrate (2, 5, and 10 mM) for 24h or butyrate (5 mM) for 8, 16, and 24h. Site-directed mutations of STAT1 (K410R or K413R) were introduced to determine the role of STAT1 acetylation in modulating PD-L1 expression. The effect of butyrate on the cytotoxicity of CD8+ T-cells against CRC cells with or without PD-L1 overexpression was explored in vitro and in vivo. Results Butyrate could suppress IFN-γ-induced PD-L1 up-regulation in CRC cells in a dose- and time-dependent way. Butyrate promoted the lysine acetylation of STAT1 to reduce STAT1 expression. Non-acetylated mutant STAT1 not only ameliorated butyrate-induced suppression of lysine acetylation and nuclear translocation of STAT1 but also blocked the effect of butyrate on PD-L1. Butyrate attenuated the IFN-γ-induced impairment of CD8+ T-cell cytotoxicity against CRC cells. Meanwhile, butyrate suppressed CRC tumor growth by enhancing CD8+ T-cell infiltration. However, directly overexpressing PD-L1 in CRC cells could abolish the effect of butyrate. Conclusion Butyrate strengthens the immune response to CRC cells by suppressing PD-L1 expression via acetylation of STAT1.

Autosomal recessive complete signal transducer and activator of transcription 1 deficiency in a newborn: a case report / 中华围产医学杂志

We reported the clinical data of a neonate admitted to the Second Affiliated Hospital (Yuying Children's Hospital) of Wenzhou Medical University in November 2021 with autosomal recessive complete signal transducer and activator of transcription 1 ( STAT1) deficiency identified by whole exome sequencing. The baby boy received bacillus of calmette-guerin (BCG) vaccine 2 d after birth and presented with persistent high fever, increased white blood cell count and increased level of C-reactive protein (CRP) on 21 d after birth. Human cytomegalovirus (HCMV) was detected in both blood and bone marrow specimens. The patient improved after comprehensive treatment with antiviral agents, antibiotics and intravenous gammaglobulin. Oral anti-viral drugs were prescribed on discharge. However, the baby was rehospitalized due to a fever at 55 days. HCMV and Mycobacterium tuberculosis complex were detected in blood samples. The infant was transferred to the Children's Hospital of Fudan University due to persistent high fever even after active management and died after treatment withdrawal at 69 d after birth because of worsening infections and multiple organ failure. A homozygous mutation in the STAT1 gene was detected [c.1011_1012del, NM_007315: exon11: c.1011_1012del (p.V339Pfs*18)] and the child was diagnosed as autosomal recessive complete STAT1 deficiency. We concluded that the clinical manifestations of autosomal recessive complete STAT1 deficiency are bacterial infections caused by lethal low-pathogenic mycobacteria and life-threatening virus infections. Whole exome sequencing is of great value for early diagnosis and timely treatment. The prognosis of this disease is very poor, but the condition of the patients might be improved in a short period with early anti-tuberculosis and anti-viral treatment.

Dermatofitosis por Microsporum gypseum en un niño con inmunodeficiencia primaria / Microsporum gypseum dermatophytosis in a child with primary immunodeficiency

El Microsporum gypseum es un hongo geofílico que puede producir lesiones cutáneas inflamatorias en personas sanas. Se han descripto lesiones más extensas en pacientes inmunocomprometidos. Se presenta el caso de un paciente con dermatofitosis, con exámenes micológicos positivos para Candida sp, Epidermophytom floccosum y Trichophyton tonsurans, al que, ante la mala respuesta al tratamiento con griseofulvina e itraconazol a dosis habituales, se le realizó biopsia cutánea para cultivo que evidenció la presencia de M. gypseum. Debido a la extensión y a la mala respuesta al tratamiento, se realizó evaluación inmunológica y se diagnosticó un defecto en STAT1 con ganancia de función (STAT1-GOF). Los pacientes que tienen esta inmunodeficiencia primaria son susceptibles a las infecciones micóticas, especialmente por Candida, pero también, aunque en menor medida, a virus y bacterias. El paciente aquí presentado recibió tratamiento prolongado con antimicóticos imidazólicos sistémicos, con resolución de las lesiones.

Microsporum gypseum is a geophilic fungus that can cause inflammatory skin lesions in heathy people. More extensive lesions have been described in immunocompromised patients. We present a patient with extensive dermatophytosis, which mycological examination led the identification of Candida sp, Epidermophyton Floccosum and Trichophyton tonsurans and showed poor response to treatment with griseofulvina and itraconazol at usual doses. When skin biopsy was performed, it had positive culture for M. gypseum. Due to the extension and poor response to treatment, immunological assessment was performed and it showed a defect of STAT1 with gain of function (STAT 1-GOF). Patients with primary immunodeficiency are susceptible to fungal infections, especially Candida but also virus and bacteria, although to a lesser extent. The patient received long-term treatment with systemic imidazole antifungal recovering for the lesions.

Gain-of-function STAT1 mutation and visceral leishmaniasis

ABSTRACT Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

Molecular Mechanism of "Transmission Between Lung and Brain" of Influenza and Intervention Effect of Maxing Shigantang Based on JAK1/STAT1 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore the molecular mechanism of "transmission between the lung and brain" of influenza based on Janus kinase 1/signal transducer and activator of transcription 1（JAK1/STAT1） signaling pathway and further investigate the intervention effect of Maxing Shigantang （MXSGT）. MethodA total of 100 SPF BALB/c mice were randomly divided into a normal group，a model group，an oseltamivir group （21.63 mg·kg-1·d-1），an antiviral granules group（3.9 g·kg-1·d-1）， and an MXSGT group（6.05 g·kg-1·d-1）， with 20 mice in each group. The pneumonia model was induced in mice except for those in the normal group by intranasal infection of influenza A virus（IAV）. Twenty-four hours after modeling，mice were treated with corresponding drugs， while those in the normal group and the model group received the same amount of normal saline by gavage， once a day for 3 and 7 days. The pathological changes in the lung and brain were observed by hematoxylin-eosin（HE）staining. The mRNA expression of IAV nucleoprotein（NP），JAK1， and STAT1 in the lung and brain was detected by real-time quantitative polymerase chain reaction（Real-time PCR）， and the protein expression of JAK1 and STAT1 in the lung and brain was detected by Western blot. Immunohistochemical method was used to detect the expression of phosphorylated（p）-STAT1 in the lung and brain tissues， and enzyme-linked immunosorbent assay（ELISA） was used to detect the serum levels of interleukin-1β（IL-1β） and interleukin-10（IL-10）. ResultCompared with the normal group， the model group showed obvious pathological changes in the lung tissues and cerebral cortex， increased relative mRNA expression of IAV NP in the lung （P<0.01）， elevated mRNA and protein expression of JAK1 and STAT1 in the lung and brain tissues （P<0.05，P<0.01），up-regulated expression level of p-STAT1 in lung tissues and cerebral cortex （P<0.05，P<0.01）， and increased serum level of IL-1β （P<0.05）. Compared with the model group， the MXSGT group showed alleviated pathological damage to lung tissues and cerebral cortex， decreased relative mRNA expression of IAV NP in lung tissues（P<0.01），reduced mRNA and protein expression levels of JAK1 and STAT1 in lung tissues and brain tissues（P<0.05，P<0.01）， and increased serum level of IL-10（P<0.01）. ConclusionThe abnormal activation of the JAK1-STAT1 signaling pathway may be one of the molecular mechanisms of "transmission between the lung and brain" of influenza. As an effective compound prescription against the influenza virus，MXSGT can alleviate the pathological damage of brain tissues in mice infected with IAV by regulating the level of cytokines mediated by this pathway.

Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF-κB and STAT1/STAT3 signaling / 中国天然药物

Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1β, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.

Baicalein reduces Aβ25-35-induced PC12 cell damage by inhibiting the JAK2/STAT1 pathway / 药学学报

This study investigated the mechanism by which baicalein protected PC12 cells from Aβ25-35-induced injury. PC12 cells were treated with Aβ25-35 (20 μmol·L-1) and the ability of baicalein to prevent apoptosis was investigated by monitoring changes in cell morphology, Hoechst 33342 staining, and measurement of inflammatory factors. Western blotting was used to detect the expression of the apoptosis-related proteins cysteinyl aspartate specific proteinase-3 (caspase-3), cleaved cysteinyl aspartate specific proteinase-3 (cleaved caspase-3), proteins involved in the Janus kinase 2/signal transducer and activator of transcription 1 (JAK2/STAT1) pathway, and downstream inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The results show that baicalein (80 μmol·L-1) can significantly inhibit apoptosis and the release of inflammatory factor IL-8 and TNF-α in Aβ25-35-treated PC12 cells. Western blotting results showed that baicalein can inhibit the phosphorylation of JAK2 and STAT1 and decrease the expression of downstream iNOS and COX-2, thereby inhibiting the JAK2/STAT1 signaling pathway and preventing Aβ25-35-induced PC12 cell damage.

MicroRNA-146a inhibition promotes total neurite outgrowth and suppresses cell apoptosis, inflammation, and STAT1/MYC pathway in PC12 and cortical neuron cellular Alzheimer's disease models

This study aimed to explore the effect of microRNA (miR)-146a inhibition on regulating cell apoptosis, total neurite outgrowth, inflammation, and STAT1/MYC pathway in Alzheimer's disease (AD). PC12 and cortical neuron cellular AD models were constructed by Aβ1-42 insult. For the former model, nerve growth factor (NGF) stimulation was previously conducted. miR-146a inhibitor and negative-control (NC) inhibitor were transfected into the two cellular AD models, and then cells were named miR-inhibitor group and NC-inhibitor group, respectively. After transfection, cell apoptosis, total neurite outgrowth, supernatant inflammation cytokines, and STAT1/MYC pathway were detected. miR-146a expression was similar between PC12 cellular AD model and control cells (NGF-stimulated PC12 cells), while miR-146a expression was increased in cortical neuron cellular AD model compared with control cells (rat embryo primary cortical neurons). In both PC12 and cortical neuron cellular AD models, miR-146a expression was reduced in miR-inhibitor group compared with NC-inhibitor group after transfection. Furthermore, cell apoptosis was attenuated, while total neurite outgrowth was elevated in miR-inhibitor group compared with NC-inhibitor group. As for supernatant inflammatory cytokines, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-17 levels were lower in miR-inhibitor group than in NC-inhibitor group. Additionally, STAT1 and c-Myc mRNA and protein expressions were attenuated in miR-inhibitor group compared with NC-inhibitor group. In conclusion, miR-146a potentially represented a viable therapeutic target for AD.

Nova mutação no gene STAT1 associada com candidíase mucocutânea crônica / New STAT1 gene mutation associated with chronic mucocutaneous candidiasis

Mutações no gene STAT1 (signal transducer and activator of transcription 1) têm sido identificadas como responsáveis pela maioria dos casos sindrômicos da candidíase mucocutânea crônica com herança autossômica dominante (AD). Nesse artigo, descrevemos uma menina de 7 anos que apresentou candidíase da mucosa oral e unhas, além de infecção disseminada da pele e couro cabeludo por Microspora gipseum. Recentemente, a paciente foi diagnosticada e tratada de meningite por Cryptococcus neoformans. Na família não existem outros casos de candidíase. A avaliação imunológica incluiu a detecção de subpopulações de linfócitos (CD3, CD4, CD8, CD20 e células NK), assim como a dosagem de IgG, IgA, IgM e IgE, subclasses de IgG e autoanticorpos. Excluindo-se discreta diminuição de CD3, CD4, CD8, NK e leve aumento de IgG1, os demais exames estiveram dentro da normalidade. O sequenciamento do exoma detectou uma rara mutação em heterozigose no exon 14 do domínio de ligação do DNA (DNA-binding domain) do gene STAT1, ocasionando um provável ganho de função (GOF) responsável pela doença (Gly384Asp). Essa variação foi também identificada pelo sequenciamento de Sanger, não estando reportada nos bancos de dados públicos e apresentando elevado potencial de dano (índice CADD=32). Será interessante contarmos com informações clínicas e estudos com outros pacientes para conhecermos mais essa mutação patológica. Além da apresentação do caso, discutiremos as formas de tratamento existentes.

STAT1 (signal transducer and activator of transcription 1) gene mutations have been identified as responsible for most syndromic cases of chronic mucocutaneous candidiasis with autosomal dominant (AD) inheritance. In this article, we described a 7-year-old girl who presented with candidiasis of the oral mucosa and nails, as well as disseminated infection of the skin and scalp caused by Microsporum gypseum. Recently, the patient was diagnosed and treated for Cryptococcus neoformans meningitis. There are no other cases of candidiasis in the family. The immunological evaluation consisted of detection of subpopulations of lymphocytes (CD3, CD4, CD8, CD20, and NK cells), as well as measurement of IgG, IgA, IgM, and IgE, IgG subclasses, and autoantibodies. Excluding a slight decrease in CD3, CD4, CD8, NK and a minimal increase in IgG1, the others were within normal limits. Exome sequencing detected a rare heterozygous variation in exon 14 of the DNA-binding domain of the STAT1 gene, causing a probable gain of function (GOF) responsible for the disease (Gly384Asp). This variation was also identified by Sanger sequencing, but it was not reported in public databases and had a high potential for damage (Combined Annotation-Dependent Depletion [CADD] score = 32). Having clinical information and conducting studies of other patients will be helpful to learn more about this pathological mutation. In addition to the presentation of the case, we will discuss the existing forms of treatment.

Interferon-gamma signaling is downregulated in peripheral blood mononuclear cells from asthma patients / A sinalização de interferon-gama é diminuída em células mononucleares do sangue periférico de pacientes asmáticos

Introduction: Interferon-gamma (IFN-g) signaling is mediated by crosstalk of receptors, such as IFN-g receptor 1 (IFN-g R1), transcription factors, such as signal transducer and activator of transcription 1 (STAT1) and suppressors of cytokine signaling 1 (SOCS1). Here, we evaluated the role of IFN-g signaling in peripheral blood mononuclear cells (PBMCs) from asthma patients and control individuals. Methods: PBMCs from adult healthy nonasthmatic controls (n = 12; male and female, 18-60 years old) and patients diagnosed with asthma (n = 18; male and female, 18-60 years old) were stimulated with IFN-g (0.25, 0.5 and/or 1.0 ng/mL) and, after 24h, the production of CXC motif chemokine 10 (CXCL10) was evaluated (by enzyme linked immunosorbent assay) as well as the expression of IFN-g R1, STAT1 (both by flow cytometry assay) and SOCS1 (by real-time qPCR assay). Results: CXCL10 production was reduced in a dose-dependent manner in PBMCs from asthma patients stimulated with IFN-g when compared to control individuals. While IFN-g induced an increase in IFN-g R1 expression and phosphorylated STAT1 (pSTAT1) activation in PBMCs from the control group, a reduction in both IFN-g R1 and pSTAT1 was observed in PBMCs from asthma patients. IFN-g increased SOCS1 mRNA expression in PBMCs from asthma patients when compared to IFN-g-stimulated cells from control individuals. Conclusion: Taken together, our results demonstrated that IFN-g signaling is downregulated in asthma patients.

Introdução: A sinalização de interferon-gama (IFN-g) é mediada por receptores, como o receptor 1 de IFN-gama (IFN-gR1), fatores de transcrição, como o transdutor de sinal e o ativador de transcrição 1 (STAT1) e supressores de sinalização de citocina 1 (SOCS1). Neste trabalho, avaliamos o papel da sinalização de IFN-g em células mononucleares do sangue periférico (PBMCs) de indivíduos com asma e controle. Métodos: Células mononucleares do sangue periférico (PBMCs) de adultos saudáveis e não asmáticos (n = 12, homens e mulheres, 18-60 anos) e pacientes diagnosticados com asma (n = 18, homens e mulheres, 18-60 anos) foram estimuladas com IFN-g (0,25, 0,5 e/ou 1,0 ng/mL) e após 24 horas a produção de CXCL10 foi avaliada por ensaio de imunoabsorção enzimática (ELISA), bem como o receptor 1 de IFN-g (IFN-g R1). Também foram avaliadas as expressões do transdutor de sinal e ativador da transcrição 1 (STAT1) (por citometria de fluxo) e supressor de expressão de sinalização de citocinas 1 (SOCS1) (por ensaio qPCR em tempo real). Resultados: A produção de CXCL10, uma quimiocina induzida por IFNg, foi reduzida de maneira dependente da dose em PBMCs de pacientes com asma estimulados com IFN-g (0,25-1,0 ng/mL) quando comparado ao grupo controle. Enquanto IFN-g induziu um aumento da expressão de IFN-g R1 e ativação da fosforilação de STAT1 (pSTAT1) em PBMCs do grupo controle, uma redução de ambas (IFN-g R1 e pSTAT1) foi observada em PBMCs de pacientes com asma. O IFN-g aumentou as PBMCs de expressão do mRNA de SOCS1 de pacientes com asma quando comparado às células estimuladas por IFN-g do controle. Conclusão: Em conjunto, nossos resultados demonstraram que a sinalização de IFN-g é sub-regulada em pacientes com asma.

Paeonol inhibits macrophage M1 polarization by down-regulating miR-155/JAK1-STAT1 pathway / 中国中药杂志

The aim of this paper was to investigate the effect and mechanism of paeonol on peritoneal macrophage M1 polarization in mice, explore whether the intervention action is related to the down-regulation of miR-155 and the inhibition of downstream JAK1-STAT1 pathway, and provide a new idea for the molecular mechanism of paeonol against atherosclerosis(AS). Lipopolysaccharide(LPS) and interferon-γ(IFN-γ) were used to stimulate macrophages for 24 hours to establish the M1 polarization model, and paeonol was given 24 hours before co-stimulation to provide a pre-protective effect on cells. CCK-8 assay was used to detect the cells damage induced by LPS and IFN-γ co-stimulation; flow cytometry was used to detect the expression of M1 surface markers F4/80 and CD86. ELISA was used to detect the secretion of interleukin 6(IL-6) and tumor necrosis factor-α(TNF-α) in supernatant. RT-qPCR was used to detect the expression of miR-155, and Western blot was used to detect the protein expression at JAK1-STAT1-SOCS1 pathway. The results showed that LPS and IFN-γ had no obvious damage to the cells at the optimal concentration, but they induced macrophages polarized to M1, resulted in high expression of M1 type marker factors F4/80 and CD86 on the cell surface, and increased secretion of IL-6 and TNF-α on the cell surface(P<0.05 or P<0.01). Paeonol significantly reduced the LPS and IFN-γ-induced high expression of F4/80 and CD86, the secretion of inflammatory factors IL-6 and TNF-α(P<0.05 or P<0.01), decreased the expression level of miR-155, significantly down-regulated the protein phosphorylation level of JAK1-STAT1 and up-regulated the protein expression of SOCS1(P<0.01) in RAW264.7 cells. The results showed that paeonol could inhibit M1 polarization of macrophages by down-regulating cell surface marker factors and inflammatory factors secreted by cells, which may be related to the down-regulation of miR-155 expression and the inhibition JAK1-STAT1 pathway activation.

Di (2-ethylhexyl) phthalate Disorders Lipid Metabolism via TYK2/STAT1 and Autophagy in Rats / 生物医学与环境科学（英文）

OBJECTIVE@#Previous studies have indicated that the plasticizer di (2-ethylhexyl) phthalate (DEHP) affects lipid accumulation; however, its underlying mechanism remains unclear. We aim to clarify the effect of DEHP on lipid metabolism and the role of TYK2/STAT1 and autophagy.@*METHODS@#In total, 160 Wistar rats were exposed to DEHP [0, 5, 50, 500 mg/(kg•d)] for 8 weeks. Lipid levels, as well as mRNA and protein levels of TYK2, STAT1, PPARγ, AOX, FAS, LPL, and LC3 were detected.@*RESULTS@#The results indicate that DEHP exposure may lead to increased weight gain and altered serum lipids. We observed that DEHP exposure affected liver parenchyma and increased the volume or number of fat cells. In adipose tissue, decreased TYK2 and STAT1 promoted the expression of PPARγ and FAS. The mRNA and protein expression of LC3 in 50 and 500 mg/(kg•d) groups was increased significantly. In the liver, TYK2 and STAT1 increased compensatorily; however, the expression of FAS and AOX increased, while LPL expression decreased. Joint exposure to both a high-fat diet and DEHP led to complete disorder of lipid metabolism.@*CONCLUSION@#It is suggested that DEHP induces lipid metabolism disorder by regulating TYK2/STAT1. Autophagy may play a potential role in this process as well. High-fat diet, in combination with DEHP exposure, may jointly have an effect on lipid metabolism disorder.

Candidiasis mucocutánea crónica: una mirada al entendimiento genético / Chronic mucocutaneous candidiasis: a look at genetic understanding

RESUMEN La candidiasis mucocutánea crónica se caracteriza por infecciones recurrentes o persistentes en la piel, las uñas y las mucosas, producida por especies de Candida sp. Esta va a ser secundaria a cualquier alteración en la inmunidad antimicótica, en la cual no solo la producción de IL-17, sino cualquier defecto en la diferenciación de los linfocitos T hacia su perfil TH17, juegan un papel fundamental y van a desencadenar una susceptibilidad a esta infección, que dependiendo de la etiología genética, puede ser una manifestación sindrómica con otras características clínicas y endocrinológicas asociadas. Aquí revisamos de manera práctica, clara y concisa los defectos genéticos hasta ahora encontrados, implicados en la aparición de la candidiasis mucocutánea crónica.

SUMMARY Chronic mucocutaneous candidiasis is an infectious phenotype characterized by recurrent or persistent infections in the skin, nails and mucous membranes produced by Candida sp. This is secondary to any alteration in the antifungal immunity, in which not only the production of IL-17, but any defect in the differentiation of the T lymphocytes towards their TH17 profile, play a fundamental role and will unchain a susceptibility to this infection; that depending on the genetic etiology, can be a syndromic manifestation with other associated infectious and endocrinological clinical characteristics. Here, we review in a practical, clear and concise manner, the genetic defects so far found to be involved in the appearance of chronic mucocutaneous candidiasis.

Role of signal transduction and transcription factors STAT1 and STAT3 in the pathogenesis of hepatocellular carcinoma and liver failure / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) and liver failure are common liver diseases in China and have extremely high incidence and mortality rates. Although there are many related studies, the detailed pathogenesis of these two diseases is still unknown. This article reviews the role of STAT1 and STAT3 phosphorylation proteins in the pathogenesis of HCC and liver failure, such as antiviral defense, acute phase response, liver injury, repair, inflammation, and transformation. A deep understanding of their role in the pathogenesis of HCC and liver failure and the development of related drugs with them as molecular targets play an important role in reducing mortality rate in clinical practice.

Bronchiectasis and Recurrent Respiratory Infections with a De Novo STAT1 Gain-of-Function Variant: First Case in Korea

Bronchiectasis is a chronic disease characterized by airway infection and inflammation, leading to permanent dilation of the bronchi. Evaluation of underlying etiology is important in managing young bronchiectasis patients with recurrent infections caused by unusual pathogens. The signal transducer and activator of transcription 1 (STAT1) protein plays a key role in STAT signaling and immune system regulation. Heterozygotes for gain-of-function (GOF) alleles of the STAT1 gene usually display autosomal dominant chronic mucocutaneous candidiasis (CMC) and a wide range of clinical features, such as bronchiectasis. Here, we report on a patient with CMC and bronchiectasis with various types of infections who carried a pathogenic variant of the STAT1 gene. The 24-year-old female presented with recurrent respiratory bacterial and nontuberculous mycobacterial infections complicated by severe bronchiectasis and CMC. Whole-exome sequencing revealed a c.800C>T (p.Ala267Val) heterozygous mutation in the STAT1 gene. Further analysis by Sanger sequencing of STAT1 from the patient and her parents revealed the patient had a de novo occurrence of the variant. This is the first report of a Korean patient with a GOF pathogenic variant in STAT1. Physicians should be aware of the existence of this variant as a genetic factor associated with CMC and bronchiectasis complicated by recurrent infection.

Molecular mechanism of Shaofu Zhuyu decoction in treating endometriosis dysmenorrhea based on GPER2/MAPK/STAT1 axis / 中国中药杂志

The aim of this paper is to study the molecular mechanism of Shaofu Zhuyu decoction in treating dysmenorrhea of endometriosis based on GPER2/MAPK/STAT1 axis. In this study, HE staining was used to observe the pathological changes of the rats in each group. The levels of TNF-α and IL-6 were detected by ELISA assay. The mRNA expressions of neurotransmitter receptor (NK1) and GPER were detected by qPCR. The protein contents of MAPK and STAT1 were detected by Western blot. According to the results, compared with the model group, Shaofu Zhuyu decoction could significantly improve the inflammation of the ectopic uterine cavity tissue, decrease the contents of TNF-α and IL-6 in the uterine cavity, the mRNA expressions of NK1 and GPER, and the protein expressions of MAPK and STAT1. In conclusion, Shaofu Zhuyu decoction could effectively inhibit the expressions of GPER2, MAPK and STAT1, decrease the levels of TNF-α, IL-6 and NK1 mRNA and relieve the inflammatory pain in patients with endometriosis.

Role of STAT1 signaling pathway in osteoblast apoptosis and effect of blocking the path / 中国医师杂志

Objective To investigate the role of signal transducer and activator of transcription (STAT1) signaling pathway in osteoblast apoptosis,and to study the effect of STAT1 inhibitor (fludarabine) on osteoblast.Methods The viability of the osteoblasts in different concentration of fludarabine was detected by cell counting kit-8 (CCK-8) assay.Osteoblasts were divided into 4 groups:control group,dexamethasone (Dex) group,fludarabine (Flu) group,and Dex + Flu group.Enzyme linked immunosorbent (ELISA) was used for determining the protein expression of Bcl-2 Associated X Protein (BAX),STAT1 and phosphorylation-sigual transducers and activators of transcription 1 (p-STAT1),and cleaved caspase-3 to reflect the apoptosis in all groups.Results Treatment with Dex increased the protein expression of apoptosis-related proteins and p-STAT1 in time-dependent and dose-dependent manner.Exposure of the cells to Flu,which was a selective STAT1 inhibitor,resulted in a decreased the protein levels of apoptosis-related proteins.Conclusions Our results suggest that fludarabine could suppress Dex-induced apoptosis through the inhibition of STATl-mediated up-regulation cleaved caspase-3 expression in osteoblasts.

Effects of tacrolimus on the secretion of chemokines CXCL9 and CXCL10 by γ-interferon-simulated HaCaT cells / 中华皮肤科杂志

Objective To analyze effects of tacrolimus on the secretion of chemokines CXCL9 and CXCL10 by γ-interferon (IFN-γ)-simulated HaCaT cells,as well as phosphorylated Janus kinase 1 (p-JAK1) and phosphorylated signal transducer and activator of transcription 1 (p-STAT1),and to explore the mechanism of tacrolimus in the treatment of vitiligo.Methods HaCaT cells were treated with l,10,20,40,60,80,100,120 mg/L tacrolimus solution separately for 4 hours,and methyl thiazolyl tetrazolium (MTT) assay was performed to evaluate the cellular proliferative activity.HaCaT cells were divided into 4 groups:blank control group receiving no treatment,IFN-γgroup treated with 500 U/ml IFN-γfor 12 or 48 hours,tacrolimus group treated with 20 mg/L tacrolimus for 4 hours,and tacrolimus + IFN-γgroup treated with 20 mg/L tacrolimus for 4 hours followed by the treatment with 500 U/ml IFN-γfor 12 or 48 hours.Real-time fluorescence-based quantitative PCR was conducted to measure the mRNA expression of CXCL9 and CXCL10,Western blot analysis to determine the protein expression of CXCL9,CXCL10,p-JAK1,and p-STAT1,and enzyme-linked immunosorbent assay (ELISA) to detect the levels of CXCL9 and CXCL10 in the culture supernatants of HaCaT cells.Results Tacrolimus at the maximum concentration of 20 mg/L had no effect on the proliferation of HaCaT cells (P ＞ 0.05).After the pretreatment with 20 mg/L tacrolimus,the mRNA expression of CXCL9 and CXCL10 significantly decreased from 10 369.08 ± 7.99 and 290.02 ± 2.16 to 5 914.33 ± 4.59 and 114.96 ± 0.73,respectively,after the treatment with IFN-γ(both P ＜ 0.01),and the protein expression of CXCL9,CXCL10,p-JAK1,and p-STAT1 also significantly decreased from 8.47 ± 0.29,7.87 ± 0.17,4.20 ± 0.18 and 4.29 ± 0.11 to 7.36 ± 0.13,7.36 ± 0.09,2.60 ± 0.16 and 3.62 ± 0.19,respectively,after the treatment with IFN-γ (all P ＜ 0.01).Moreover,the levels of CXCL9 and CXCL10 in the culture supernatants of HaCaT cells significantly decreased in the IFN-γgroup (1 213.36 ± 0.95,1 722.41 ± 2.57,respectively) compared with the tacrolimus + IFN-γ group (426.45 ± 0.31,554.12 ± 0.56,respectively,both P ＜ 0.01).Conclusion Tacrolimus can inhibit the secretion of CXCL9,CXCL10,p-JAK1 and p-STAT1 by HaCaT cells stimulated by IFN-γ.

Design, synthesis and evaluation of anti-inflammatory effect of novel berberine derivatives on IL-6/STAT signaling pathway / 药学学报

Interleukin-6 (IL-6)/signal transducers and activators of transcription (STAT) signaling pathway is closely related to the development and progression of atherosclerosis (AS). Taking Chinese natural product berberine (BBR) as the leading compound, a series of novel BBR analogues defined on different types of substituents on position 3 or/and 9 were designed, synthesized and evaluated for their inhibitory activities on phosphorylation of STAT-1 and STAT-3 induced by IL-6. The structure-activity relationship indicated that introduction of rigid fragment on position 3 or 9 was beneficial for enhancing their activities. Among them, compounds 2b and 9 exhibited the most satisfactory potency. The study revealed that the compounds 2b and 9 exhibit anti-inflammatory potencies via activating AMPK, and down-regulation of phosphorylation of STAT1 and STAT3 induced by IL-6 in HUVEC cells. These results suggest that BBR derivatives may inhibit the inflammatory response mediated by the IL-6/STAT signaling pathway through regulation of AMPK, which provides useful insight into the development of BBR derivatives for treatment of atherosclerosis.