Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.
Humans ; Carcinoma, Squamous Cell/pathology* ; DNA ; Down-Regulation ; Flap Endonucleases/metabolism* ; Head and Neck Neoplasms ; Interferon-gamma/metabolism* ; Mouth Neoplasms/pathology* ; Phenotype ; Squamous Cell Carcinoma of Head and Neck ; Tumor Microenvironment ; Janus Kinases/metabolism*

Objective To explore the therapeutic effect of ethambutol tablets (EMB) on pulmonary tuberculosis (PTB) in rats and whether the action mechanism of EMB is related to Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Methods Sixty SD rats were assigned into a control group,a PTB group,a PTB+EMB group (30 mg/kg),and a PTB+EMB+Colivelin (JAK/STAT pathway activator) group (30 mg/kg+1 mg/kg) via the random number table method,with 15 rats in each group.The rats in other groups except the control group were injected with 0.2 ml of 5 mg/ml Mycobacterium tuberculosis suspension to establish the PTB model.After the modeling,the rats were administrated with corresponding drugs for 4 consecutive weeks (once a day).On days 1,14,and 28 of administration,the body weights of rats were measured and the Mycobacterium tuberculosis colonies were counted.Hematoxylin-eosin staining was carried out to detect the pathological changes in the lung tissue.Enzyme-linked immunosorbent assay was employed to measure the levels of interleukin(IL)-6,tumor necrosis factor-α (TNF-α),IL-1β,and interferon-γ (IFN-γ) in the serum.Flow cytometry was used to determine the levels of T lymphocyte subsets CD3+,CD4+,CD8+,and CD4+/CD8+.The 16S rRNA sequencing was performed to detect the relative abundance of the intestinal microorganisms.Western blotting was employed to determine the expression of the proteins in the JAK/STAT pathway. Results Compared with the control group,the modeling of PTB reduced the rat body weight (on days 14 and 28),increased Mycobacterium tuberculosis colonies,caused severe pathological changes in the lung tissue,and elevated the levels of IL-6,TNF-α,and IL-1β in serum and CD8+.Moreover,the modeling increased the relative abundance of Bacteroides,Peptococcus,Clostridium,Actinomyces,Lactobacillus,Verrucomicrobium,and Veillonella in the intestine,up-regulated the protein levels of phosphorylated JAK2 and phosphorylated STAT3 in the lung tissue,and lowered the levels of CD3+,CD4+,CD4+/CD8+,and IFN-γ levels (all P<0.001).Compared with the PTB group,PTB+EMB increased the rat body weight (on days 14 and 28),reduced Mycobacterium tuberculosis colonies,alleviated the pathological damage in lung tissue,lowered the levels of IL-6,TNF-α,and IL-1β in serum and CD8+.Moreover,the treatment decreased the relative abundance of Bacteroides,Peptococcus,Clostridium,Actinomyces,Lactobacillus,Verrucomicrobium,Veillonella in the intestine,down-regulated the protein levels of phosphorylated JAK2 and phosphorylated STAT3 in the lung tissue,and elevated the levels of CD3+,CD4+,CD4+/CD8+,and IFN-γ (all P<0.001).Colivelin weakened the alleviation effect of EMB on PTB (all P<0.001). Conclusion EMB can inhibit the JAK/STAT signaling pathway to alleviate the PTB in rat.
Animals ; Body Weight ; Ethambutol/pharmacology* ; Interferon-gamma/pharmacology* ; Interleukin-6/metabolism* ; Janus Kinases/pharmacology* ; Mycobacterium tuberculosis/metabolism* ; RNA, Ribosomal, 16S ; Rats ; Rats, Sprague-Dawley ; STAT Transcription Factors/pharmacology* ; Signal Transduction ; Tablets/pharmacology* ; Tuberculosis, Pulmonary/metabolism* ; Tumor Necrosis Factor-alpha/metabolism*

Carthamus tinctorius is proved potent in treating ischemic stroke. Flavonoids, such as safflower yellow, hydroxysafflor yellow A(HSYA), nicotiflorin, safflower yellow B, and kaempferol-3-O-rutinoside, are the main substance basis of C. tinctorius in the treatment of ischemic stroke, and HSYA is the research hotspot. Current studies have shown that C. tinctorius can prevent and treat ischemic stroke by reducing inflammation, oxidative stress, and endoplasmic reticulum stress, inhibiting neuronal apoptosis and platelet aggregation, as well as increasing blood flow. C. tinctorius can regulate the pathways including nuclear factor(NF)-κB, mitogen-activated protein kinase(MAPK), signal transducer and activator of transcription protein 3(STAT3), and NF-κB/NLR family pyrin domain containing 3(NLRP3), and inhibit the activation of cyclooxygenase-2(COX-2)/prostaglandin D2/D prostanoid receptor pathway to alleviate the inflammatory development during ischemic stroke. Additionally, C. tinctorius can relieve oxidative stress injury by inhibiting oxidation and nitrification, regulating free radicals, and mediating nitric oxide(NO)/inducible nitric oxide synthase(iNOS) signals. Furthermore, mediating the activation of Janus kinase 2(JAK2)/STAT3/suppressor of cytokine signaling 3(SOCS3) signaling pathway and phosphoinositide 3-kinase(PI3 K)/protein kinase B(Akt)/glycogen synthase kinase-3β(GSK3β) signaling pathway and regulating the release of matrix metalloproteinase(MMP) inhibitor/MMP are main ways that C. tinctorius inhibits neuronal apoptosis. In addition, C. tinctorius exerts the therapeutic effect on ischemic stroke by regulating autophagy and endoplasmic reticulum stress. The present study reviewed the molecular mechanisms of C. tinctorius in the treatment of ischemic stroke to provide references for the clinical application of C. tinctorius.
Carthamus tinctorius/chemistry* ; Chalcone/therapeutic use* ; Cyclooxygenase 2/metabolism* ; Cytokines/metabolism* ; Flavonoids/therapeutic use* ; Glycogen Synthase Kinase 3 beta/metabolism* ; Humans ; Ischemic Stroke/drug therapy* ; Janus Kinase 2/metabolism* ; Mitogen-Activated Protein Kinases/metabolism* ; NF-kappa B/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Nitric Oxide/metabolism* ; Nitric Oxide Synthase Type II/metabolism* ; Phosphatidylinositol 3-Kinase/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Prostaglandin D2 ; Proto-Oncogene Proteins c-akt/metabolism* ; Quinones/pharmacology*

Tofacitinib is a Janus kinase inhibitor and can block the Janus kinase-signal transducer and activator of transcription signal transduction pathway and reduce the production and release of a variety of cytokines. It has great potential in the treatment of various rheumatic diseases with a rapid onset of action and can reduce corticosteroid dependence and related adverse events. The therapeutic effect of tofacitinib in adult patients has been confirmed, and it has been increasingly used in pediatric patients in recent years. This article reviews the clinical application of tofacitinib in the treatment of pediatric autoimmune diseases.
Adult ; Child ; Humans ; Janus Kinases/metabolism* ; Piperidines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use* ; Pyrimidines/therapeutic use* ; Rheumatic Diseases/drug therapy*

Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer.
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Animals ; Antineoplastic Agents ; therapeutic use ; Biomedical Research ; methods ; trends ; Humans ; Janus Kinases ; antagonists & inhibitors ; metabolism ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; Neoplasm Metastasis ; STAT Transcription Factors ; antagonists & inhibitors ; metabolism ; Signal Transduction

OBJECTIVESTo investigate the mechanism of Liuwei Dihuang Pill (, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency.

METHODSIn this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group (Group A), PMOP Shen-yang deficiency group (Group B), PMOP without Shen deficiency group (Group C), and control group (Group N). Real-time polymerase chain reaction (RT-PCR) and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 (CLCF1), ankyrin repeat and SOCS box containing 1 (ASB1), and prokineticin 2 (PROK2) genes and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway.

RESULTSThe mRNA (P<0.05) and protein (P<0.01) expression levels of the CLCF1 gene in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gene were obviously up-regulated (P<0.01). After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated (both P<0.01), and the average bone density of the top femur had significantly increased (P<0.05). In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3.

CONCLUSIONSThe CLCF1 gene is an important gene associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gene expression and activation of the JAK/STAT signaling pathway.

Cytokines ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Gene Expression Regulation ; Humans ; Janus Kinases ; metabolism ; Middle Aged ; Osteoporosis, Postmenopausal ; drug therapy ; genetics ; RNA, Messenger ; genetics ; metabolism ; STAT Transcription Factors ; metabolism ; Signal Transduction ; Up-Regulation ; Yin Deficiency ; drug therapy ; genetics

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaive, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.
Administration, Oral ; Antirheumatic Agents/*administration & dosage/adverse effects ; Arthritis, Rheumatoid/diagnosis/*drug therapy/metabolism/physiopathology ; Biological Products/administration & dosage ; Disability Evaluation ; Drug Administration Schedule ; Humans ; Janus Kinases/antagonists & inhibitors/metabolism ; Molecular Targeted Therapy ; Predictive Value of Tests ; Protein Kinase Inhibitors/administration & dosage ; Recovery of Function ; Remission Induction ; Signal Transduction/drug effects ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists & inhibitors/metabolism

The epithelial cytokine response, associated with reactive oxygen species (ROS), is important in Helicobacter pylori (H. pylori)-induced inflammation. H. pylori induces the production of ROS, which may be involved in the activation of mitogen-activated protein kinases (MAPK), janus kinase/signal transducers and activators of transcription (Jak/Stat), and oxidant-sensitive transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), and thus, expression of interleukin-8 (IL-8) in gastric epithelial cells. alpha-lipoic acid, a naturally occurring thiol compound, is a potential antioxidant. It shows beneficial effects in treatment of oxidant-associated diseases including diabetes. The present study is purposed to investigate whether alpha-lipoic acid inhibits expression of inflammatory cytokine IL-8 by suppressing activation of MAPK, Jak/Stat, and NF-kappaB in H. pylori-infected gastric epithelial cells. Gastric epithelial AGS cells were pretreated with or without alpha-lipoic acid for 2 h and infected with H. pylori in a Korean isolate (HP99) at a ratio of 300:1. IL-8 mRNA expression was analyzed by RT-PCR analysis. IL-8 levels in the medium were determined by enzyme-linked immunosorbent assay. NF-kappaB-DNA binding activity was determined by electrophoretic mobility shift assay. Phospho-specific and total forms of MAPK and Jak/Stat were assessed by Western blot analysis. ROS levels were determined using dichlorofluorescein fluorescence. As a result, H. pylori induced increases in ROS levels, mRNA, and protein levels of IL-8, as well as the activation of MAPK [extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38], Jak/Stat (Jak1/2, Stat3), and NF-kappaB in AGS cells, which was inhibited by alpha-lipoic acid. In conclusion, alpha-lipoic acid may be beneficial for prevention and/or treatment of H. pylori infection-associated gastric inflammation.
Enzyme-Linked Immunosorbent Assay ; Epithelial Cells/metabolism ; Gastric Mucosa/*drug effects/metabolism/microbiology ; Gene Expression Regulation, Bacterial ; Helicobacter Infections/immunology/*metabolism ; Helicobacter pylori/drug effects/*pathogenicity ; Humans ; Interleukin-8/genetics/*metabolism ; JNK Mitogen-Activated Protein Kinases ; Janus Kinase 1 ; Mitogen-Activated Protein Kinases/*biosynthesis ; NF-kappa B/*metabolism ; RNA, Messenger/isolation & purification/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor ; Stomach/metabolism/*microbiology ; Thioctic Acid/*pharmacology

Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of clonal expansion of cytotoxic T- or NK-cells in blood and bone marrow, and often associated with autoimmune disorders. According to the current WHO classification of the hematopoietic and lymphoid tissue tumors, the clonal LGL expansions are further classified as T-cell large granular lymphocytic leukemia (T-LGLL), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. Since there is a general lack of awareness of this disease, some patients may be misdiagnosed or some cases may be missed when diagnosis was done. At present, the pathogenesis of LGLL remains incomplete and unclear, and the therapeutic effects are unsatisfactory. For this reason, it is necessary to find prognostic marks and therapeutic targets of this disease. The constitutive activation of JAK/STAT pathway has been claimed to be involved in the development of LGLL. Recently, the somatic mutations in the SH2 domain of STAT3 in LGLL are frequently observed, which lead to the activation of JAK/STAT pathway. STAT3 is the first molecular markers that are highly specific for LGLL, and STAT3 mutations have been rarely detected in other tumor types studied, thus the STAT3 mutations can be used as molecular markers for LGLL diagnosis and can provide a novel therapeutic target for patients with LGLL.
Humans ; Janus Kinases ; genetics ; metabolism ; Leukemia, Large Granular Lymphocytic ; genetics ; metabolism ; Mutation ; STAT3 Transcription Factor ; genetics ; metabolism ; Signal Transduction

Inflammation is a part of the complex biological responses of a tissue to injury that protect the organ by removing injurious stimuli and initiating the healing process, and is considered as a mechanism of innate immunity. To identify biologically active compounds against pathogenic inflammatory and immune responses, we fractionated water, aqueous methanol and n-hexane layers from nine kinds of leguminosae and examined anti-inflammatory activity of the fractions in human keratinocytes and mouse skin. Among the fractions, rf3 and rf4, isolated from the aqueous methanol layer of Astragalus sinicus L., exhibited the strongest reactive oxygen species (ROS)-scavenging and anti-inflammatory activities as measured by inhibition of the intracellular ROS production, nuclear factor-kappaB (NF-kappaB), janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphatidylinositol 3-kinase/Akt signaling in cytokine-stimulated human keratinocytes, as well as by effects on T-cell differentiation in mouse CD4+ T cells. In addition, topical application of rf3 and rf4 suppressed the progression of psoriasis-like dermatitis and expression of pro-inflammatory mediators in interleukin (IL)-23-injected mouse ears. Our results suggest that Astragalus sinicus L. may ameliorate chronic inflammatory skin diseases due to its antioxidant and anti-inflammatory activities via regulation of the intracellular ROS production, NF-kappaB, JAK/STAT and PI3/Akt signaling cascades as well as immune responses, and these results are the first report that Astragalus sinicus L. exhibits pharmacological activity.
Animals ; Anti-Inflammatory Agents/isolation & purification/*pharmacology/therapeutic use ; Astragalus Plant/*chemistry ; Cell Line ; Dermatitis/drug therapy ; Humans ; Interleukin-23/pharmacology ; Janus Kinases/metabolism ; Keratinocytes/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Plant Extracts/isolation & purification/*pharmacology/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; STAT Transcription Factors/metabolism ; Skin/*drug effects/metabolism