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Annals of Neurology Aug 2023Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested... (Meta-Analysis)
Meta-Analysis
Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin-17 and Janus Kinase-Signal Transducers and Activators of Transcription Signaling.
OBJECTIVE
Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS.
METHODS
We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization.
RESULTS
Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10 ), type 2 diabetes (OR 1.08, p = 2.3 × 10 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10 ), and vitamin D level (OR 0.75, p = 9.4 × 10 ).
INTERPRETATION
By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397.
Topics: Humans; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Interleukin-17; Mendelian Randomization Analysis; Multiple Sclerosis; Polymorphism, Single Nucleotide; Psoriasis; Risk Factors; Janus Kinases; STAT Transcription Factors
PubMed: 37127916
DOI: 10.1002/ana.26672 -
Journal of Ethnopharmacology Dec 2023Allium cepa L. (A. cepa) is one of the oldest cultivated plants in the world. A. cepa has been used in traditional folk medicine to treat inflammatory disease in several...
ETHNOPHARMACOLOGICAL RELEVANCE
Allium cepa L. (A. cepa) is one of the oldest cultivated plants in the world. A. cepa has been used in traditional folk medicine to treat inflammatory disease in several regions, such as Palestine and Serbia. A. cepa peel has a higher content of flavonoids, such as quercetin, than the edible parts. These flavonoids alleviate inflammatory diseases. However, the anti-inflammatory effects of A. cepa peel extract-obtained using various extraction methods-and their underlying mechanisms require further investigation.
AIM OF THE STUDY
Although research to find safe anti-inflammatory substances in various natural products has been actively conducted for many years, it is important to continue identifying potential anti-inflammatory effects in natural materials. The purpose of this study was to investigate the ethnopharmacological properties of the A. cepa peel extract, whose efficacy when obtained through different extraction methods and underlying action mechanisms is not well known. The present study specifically aimed to observe the anti-inflammatory effects of the A. cepa peel extracts obtained using various extraction methods and the related detailed mechanisms of A. cepa peel extracts in lipopolysaccharide (LPS)-induced RAW264.7 cells.
MATERIALS AND METHODS
The total flavonoid content of the A. cepa peel extracts was determined the diethylene glycol colorimetric method and measured using a calibration curve prepared using quercetin as a standard solution. The antioxidant activity was evaluated using the ABTS assay, and cytotoxicity was measured using the MTT assay. NO production was measured using Griess reagent. Protein levels were measured by western blotting, and mRNA expression was measured by RT-qPCR. Secreted cytokines were analyzed using ELISA or cytokine arrays. In the GSE160086 dataset, we calculated Z-scores for individual genes of interest and displayed using a heat map.
RESULTS
Of the three A. cepa peel extracts obtained using different extraction methods, the A. cepa peel 50% EtOH extract (AP50E) was the most effective at inhibiting LPS-induced nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Furthermore, AP50E significantly reduced the levels of pro-inflammation cytokines interleukin (IL)-1α, IL-1β, IL-6, and IL-27. Additionally, AP50E directly inhibited the Janus kinase-signaling transducer and activator of transcription (JAK-STAT) pathway.
CONCLUSIONS
These results showed that AP50E exhibited an anti-inflammatory effect in LPS-induced RAW264.7 mouse macrophages by directly inhibiting JAK-STAT signaling. Based on these findings, we propose AP50E as a potential candidate for the development of preventive or therapeutic agents against inflammatory diseases.
Topics: Animals; Mice; Janus Kinases; Signal Transduction; Lipopolysaccharides; Onions; Macrophages; Quercetin; STAT Transcription Factors; RAW 264.7 Cells; Anti-Inflammatory Agents; Cytokines; Plant Extracts; Nitric Oxide
PubMed: 37385574
DOI: 10.1016/j.jep.2023.116851 -
Pharmacological Research Jun 2024The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines,... (Review)
Review
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.
Topics: Humans; Janus Kinases; STAT Transcription Factors; Drug Discovery; Animals; Signal Transduction; Janus Kinase Inhibitors; Molecular Targeted Therapy
PubMed: 38777110
DOI: 10.1016/j.phrs.2024.107217 -
Autoimmunity Reviews Nov 2023Pain is a significant issue in rheumatoid arthritis (RA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease,... (Review)
Review
Pain is a significant issue in rheumatoid arthritis (RA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease, residual chronic pain remains a major unmet medical need in RA. Pain in RA can be secondary to inflammation but can also generate neuroendocrine responses that initiate neurogenic inflammation and enhance cytokine release, leading to persistent hyperalgesia. In addition to well-known cytokines such as TNFα and IL-6, other cytokines and the JAK-STAT pathway play a role in pain modulation and inflammation. The development of chronic pain in RA involves processes beyond inflammation or structural damage. Residual pain is often observed in patients even after achieving remission or low disease activity, suggesting the involvement of non-inflammatory and central sensitization mechanisms. Moreover, fibromyalgia syndrome (FMS) is prevalent in RA patients and may contribute to persistent pain. Factors such as depression, sleep disturbance, and pro-inflammatory cytokines may contribute to the development of fibromyalgia in RA. It is essential to identify and diagnose concomitant FMS in RA patients to better manage their symptoms. Further research is needed to unravel the complexities of pain in RA. Finally, recent studies have shown that JAK inhibitors effectively reduce residual pain in RA patients, suggesting pain-reducing effects independent of their anti-inflammatory properties.
Topics: Humans; Fibromyalgia; Chronic Pain; Janus Kinases; Quality of Life; Signal Transduction; STAT Transcription Factors; Arthritis, Rheumatoid; Inflammation; Cytokines
PubMed: 37634676
DOI: 10.1016/j.autrev.2023.103423 -
PLoS Pathogens Nov 2023Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs) that target cellular IRFs and/or other innate-immune and stress signaling regulators...
Human herpesvirus 8 (HHV-8) encodes four viral interferon regulatory factors (vIRFs) that target cellular IRFs and/or other innate-immune and stress signaling regulators and suppress the cellular response to viral infection and replication. For vIRF-1, cellular protein targets include IRFs, p53, p53-activating ATM kinase, BH3-only proteins, and antiviral signaling effectors MAVS and STING; vIRF-1 inhibits each, with demonstrated or likely promotion of HHV-8 de novo infection and productive replication. Here, we identify direct interactions of vIRF-1 with STAT3 and STAT-activating Janus kinase TYK2 (the latter reported previously by us to be inhibited by vIRF-1) and suppression by vIRF-1 of cytokine-induced STAT3 activation. Suppression of active, phosphorylated STAT3 (pSTAT3) by vIRF-1 was evident in transfected cells and vIRF-1 ablation in lytically-reactivated recombinant-HHV-8-infected cells led to increased levels of pSTAT3. Using a panel of vIRF-1 deletion variants, regions of vIRF-1 required for interactions with STAT3 and TYK2 were identified, which enabled correlation of STAT3 signaling inhibition by vIRF-1 with TYK2 binding, independently of STAT3 interaction. A viral mutant expressing vIRF-1 deletion-variant Δ198-222 refractory for TYK2 interaction and pSTAT3 suppression was severely compromised for productive replication. Conversely, expression of phosphatase-resistant, protractedly-active STAT3 led to impaired HHV-8 replication. Cells infected with HHV-8 mutants expressing STAT3-refractory vIRF-1 deletion variants or depleted of STAT3 displayed reduced vIRF-1 expression, while custom-peptide-promoted STAT3 interaction could effect increased vIRF-1 expression and enhanced virus replication. Taken together, our data identify vIRF-1 targeting and inhibition of TYK2 as a mechanism of STAT3-signaling suppression and critical for HHV-8 productive replication, the importance of specific pSTAT3 levels for replication, positive roles of STAT3 and vIRF-1-STAT3 interaction in vIRF-1 expression, and significant contributions to lytic replication of STAT3 targeting by vIRF-1.
Topics: Humans; Herpesvirus 8, Human; Interferon Regulatory Factor-1; Janus Kinases; STAT3 Transcription Factor; Tumor Suppressor Protein p53; TYK2 Kinase; Host-Pathogen Interactions
PubMed: 37983265
DOI: 10.1371/journal.ppat.1011806 -
The Aging Male : the Official Journal... Dec 2023Janus kinase-2 (JAK2) inhibitors are now being tried in basic research and clinical practice in prostate cancer (PCa). However, the causal relationship between JAK2 and...
BACKGROUND
Janus kinase-2 (JAK2) inhibitors are now being tried in basic research and clinical practice in prostate cancer (PCa). However, the causal relationship between JAK2 and PCa has not been uniformly described. Here, we examined the cause-effect relation between JAK2 and PCa.
METHODS
Two-sample Mendelian randomization (MR) analysis of genetic variation data of JAK2, PCa from IEU OpenGWAS Project was performed by inverse variance weighted, MR-Egger, and weighted median. Cochran's heterogeneity test and MR-Egger multiplicity analysis were performed to normalize the MR analysis results to reduce the effect of bias on the results.
RESULTS
Five instrumental variables were identified for further MR analysis. Specifically, combining the inverse variance-weighted (OR: 1.0009, 95% CI: 1.0001-1.0015, = 0.02) and weighted median (OR: 1.0009, 95% CI: 1.0000-1.0017, = 0.03). Sensitivity analysis showed that there was no heterogeneity ( = 0.448) and horizontal multiplicity ( = 0.770) among the instrumental variables.
CONCLUSIONS
We found JAK2 was associated with the development of PCa and was a risk factor for PCa, which might be instructive for the use of JAK2 inhibitors in PCa patients.
Topics: Humans; Male; Janus Kinase 2; Mendelian Randomization Analysis; Prostatic Neoplasms; Risk Factors
PubMed: 37706641
DOI: 10.1080/13685538.2023.2257300 -
Frontiers in Bioscience (Landmark... Aug 2023Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes progressive joint damage. The Janus kinase (JAK) inhibitors (JAK-I) represent a new therapeutic...
BACKGROUND
Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes progressive joint damage. The Janus kinase (JAK) inhibitors (JAK-I) represent a new therapeutic option for RA patients, blocking the intracellular JAK-STAT pathway. Today, no studies have been conducted to determine whether new biomarkers could better reflect disease activity in patients treated with JAK-I than traditional disease activity indicators. Thus, the aim of our study was to determine additional disease activity biomarkers in RA patients receiving selective JAK-1 inhibitors.
METHODS
we enrolled 57 patients with RA: 34 patients were treated with Upadacitinib (UPA) and 23 patients with Filgotinib (FIL). All patients were evaluated for clinimetry with DAS28 and Crohn's Disease Activity Index (CDAI), number of tender and swollen joints, Visual Analogic Scale (VAS), Physician Global Assessment (PhGA), and Health Assessment Questionnaire (HAQ), at baseline and at the 12th week of treatment. Lymphocyte subpopulations, complete blood count, erythrocyte sedimentation rate (ESR), C-Reactive Protein (CRP), anti-cyclic citrullinated peptide antibodies (APCA), rheumatoid factor (RF) IgM, interleukin 6 (IL-6), circulating calprotectin (cCLP), tumor necrosis factor α (TNFα), soluble urokinase Plasminogen Activator Receptor (suPAR), complement functional activity were measured at baseline and after the 12th week of treatment.
RESULTS
in both groups of patients, we documented a significant reduction in the clinimetric parameters DAS28, CDAI, number of tender joints, number of swollen joints, VAS, PhGA, and HAQ. Moreover, significant differences were reported for laboratory parameters of ESR, CRP, IL-6, suPAR, cCLP, and PLT/L ratio in both groups. However, no difference was demonstrated between the two groups for changes in renal, hepatic, and lipid parameters.
CONCLUSIONS
the suPAR and cCLP levels may lead towards a different therapeutic choice between UPA and FIL, with the expression of two different RA pathophenotypes directing FIL towards a lymphocyte-poor form and UPA towards a myeloid form of RA.
Topics: Humans; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Interleukin-6; Janus Kinases; Receptors, Urokinase Plasminogen Activator; Signal Transduction; STAT Transcription Factors
PubMed: 37664943
DOI: 10.31083/j.fbl2808176 -
Skinmed 2023LITFULO (ritlecitinib) capsules were recently approved for the treatment of severe alopecia areata in adolescents and adults, aged ≥12 years. Ritlecitinib is the...
LITFULO (ritlecitinib) capsules were recently approved for the treatment of severe alopecia areata in adolescents and adults, aged ≥12 years. Ritlecitinib is the active ingredient and a dual inhibitor of Janus kinase 3 and the tyrosine kinase expressed in hepatocellular carcinoma kinase family. It prevents immune attack on the hair follicles that leads to hair loss. In a phase 2b-3 dose-dependant study, five doses of oral ritlecitinib and placebo administered once daily (QD) were investigated. Ritlecitinib demonstrated efficacy in achieving the primary outcome, Severity of Alopecia Tool (SALT) score of ≤20, at week 24 (31% [38/124] 200-mg ritlecitinib QD for 4 weeks, then 50 mg QD for 20 weeks; 22% [27/121] 200-mg ritlecitinib QD for 4 weeks, then 30 mg QD for 20 weeks; 23% [29/124] 50-mg ritlecitinib QD; 14% [17/119] 30-mg ritlecitinib QD; 2% [1/59] 10-mg ritlecitinib QD; and 2% [2/130] placebo). Mild to moderate common adverse effects were observed, which included headache, nasopharyngitis, and upper respiratory tract infection. The recommended regimen of ritlecitinib capsules is 50 mg QD with without food and swallowed whole.
Topics: Adult; Adolescent; Humans; Alopecia Areata; Janus Kinase Inhibitors; Janus Kinase 3; Pyrimidines; Alopecia; Protein Kinase Inhibitors
PubMed: 38051245
DOI: No ID Found -
International Immunopharmacology Sep 2023JAK kinase includes four family members: JAK1, JAK2, JAK3, and TYK2. It forms the JAK-STAT pathway with signal transmitters and activators of subscription (STAT). This... (Review)
Review
JAK kinase includes four family members: JAK1, JAK2, JAK3, and TYK2. It forms the JAK-STAT pathway with signal transmitters and activators of subscription (STAT). This pathway is one of the main mechanisms by which many cytokine receptors transduce intracellular signals, it is associated with the occurrence of various immune, inflammatory, and tumor diseases. JAK inhibitors block the signal transduction of the JAK-STAT pathway by targeting JAK kinase. Based on whether they target multiple subtypes of JAK kinase, JAK inhibitors are categorized into pan-JAK inhibitors and selective JAK inhibitors. Compared with pan JAK inhibitors, selective JAK inhibitors are associated with a specific member, thus more targeted in therapy, with improved efficacy and reduced side effects. Currently, a number of JAK inhibitors have been approval for disease treatment. This review summarized the current application status of JAK inhibitors that have been marketed, advances of JAK inhibitors currently in phase Ш clinical trials, and the structure-activity relationship of them, with an intention to provide references for the development of novel JAK inhibitors.
Topics: Janus Kinase Inhibitors; Janus Kinases; Signal Transduction; STAT Transcription Factors; Structure-Activity Relationship; Protein Kinase Inhibitors
PubMed: 37478665
DOI: 10.1016/j.intimp.2023.110660 -
International Journal of Molecular... Dec 2023Abnormal activation of receptor tyrosine kinases (RTKs) contributes to tumorigenesis, while protein tyrosine phosphatases (PTPs) contribute to tumor control. One of the... (Review)
Review
Abnormal activation of receptor tyrosine kinases (RTKs) contributes to tumorigenesis, while protein tyrosine phosphatases (PTPs) contribute to tumor control. One of the most representative PTPs is Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1), which is associated with either an increased or decreased survival rate depending on the cancer type. Hypermethylation in the promoter region of , the gene for the SHP-1 protein, is a representative epigenetic regulation mechanism that suppresses the expression of SHP-1 in tumor cells. SHP-1 comprises two SH2 domains (N-SH2 and C-SH2) and a catalytic PTP domain. Intramolecular interactions between the N-SH2 and PTP domains inhibit SHP-1 activity. Opening of the PTP domain by a conformational change in SHP-1 increases enzymatic activity and contributes to a tumor control phenotype by inhibiting the activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway. Although various compounds that increase SHP-1 activation or expression have been proposed as tumor therapeutics, except sorafenib and its derivatives, few candidates have demonstrated clinical significance. In some cancers, SHP-1 expression and activation contribute to a tumorigenic phenotype by inducing a tumor-friendly microenvironment. Therefore, developing anticancer drugs targeting SHP-1 must consider the effect of SHP-1 on both cell biological mechanisms of SHP-1 in tumor cells and the tumor microenvironment according to the target cancer type. Furthermore, the use of combination therapies should be considered.
Topics: Humans; Epigenesis, Genetic; Combined Modality Therapy; Carcinogenesis; Catalytic Domain; Janus Kinases; Tumor Microenvironment
PubMed: 38203502
DOI: 10.3390/ijms25010331