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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 -
Cellular Signalling Aug 2020The most common form of polycystic kidney disease (PKD) in humans is caused by mutations in the PKD1 gene coding for polycystin1 (PC1). Among the many identified or... (Review)
Review
The most common form of polycystic kidney disease (PKD) in humans is caused by mutations in the PKD1 gene coding for polycystin1 (PC1). Among the many identified or proposed functions of PC1 is its ability to regulate the activity of transcription factors of the STAT family. Most STAT proteins that have been investigated were found to be aberrantly activated in kidneys in PKD, and some have been shown to be drivers of disease progression. In this review, we focus on the role of signal transducer and activator of transcription (STAT) signaling pathways in various renal cell types in healthy kidneys as compared to polycystic kidneys, on the mechanisms of STAT regulation by PC1 and other factors, and on the possibility to target STAT signaling for PKD therapy.
Topics: Animals; Humans; Janus Kinases; Kidney; Models, Biological; Polycystic Kidney Diseases; STAT Transcription Factors; Signal Transduction
PubMed: 32325185
DOI: 10.1016/j.cellsig.2020.109639 -
International Journal of Molecular... Oct 2021For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant... (Review)
Review
For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.
Topics: Adamantane; Colitis; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Piperidines; Pyridines; Pyrimidines; Pyrroles; Triazoles
PubMed: 34768752
DOI: 10.3390/ijms222111322 -
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 -
Frontiers in Immunology 2022The Janus kinase (JAK) family enzymes are non-receptor tyrosine kinases that phosphorylate cytokine receptors and signal transducer and activator of transcription (STAT)... (Review)
Review
The Janus kinase (JAK) family enzymes are non-receptor tyrosine kinases that phosphorylate cytokine receptors and signal transducer and activator of transcription (STAT) proteins in the JAK-STAT signaling pathway. Considering that JAK-STAT signal transduction is initiated by the binding of ligands, such as cytokines to their receptors, dysfunctional JAKs in the JAK-STAT pathway can lead to severe immune system-related diseases, including autoimmune disorders. Therefore, JAKs are attractive drug targets to develop therapies that block abnormal JAK-STAT signaling. To date, various JAK inhibitors have been developed to block cytokine-triggered signaling pathways. However, kinase inhibitors have intrinsic limitations to drug selectivity. Moreover, resistance to the developed JAK inhibitors constitutes a recently emerging issue owing to the occurrence of drug-resistant mutations. In this review, we discuss the role of JAKs in the JAK-STAT signaling pathway and analyze the structures of JAKs, along with their conformational changes for catalysis. In addition, the entire structure of the murine JAK1 elucidated recently provides information on an interaction mode for dimerization. Based on updated structural information on JAKs, we also discuss strategies for disrupting the dimerization of JAKs to develop novel JAK inhibitors.
Topics: Animals; Mice; Janus Kinases; Signal Transduction; Janus Kinase Inhibitors; STAT Transcription Factors; Cytokines; Immune System Diseases
PubMed: 36569926
DOI: 10.3389/fimmu.2022.1075192 -
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 -
International Journal of Molecular... Apr 2022Inflammatory arthritis has been reported to be associated with the development of osteoporosis. Recent research has investigated the mechanisms of bone metabolism in... (Review)
Review
Inflammatory arthritis has been reported to be associated with the development of osteoporosis. Recent research has investigated the mechanisms of bone metabolism in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Progress in both animal and clinical studies has provided a better understanding of the osteoclastogenesis-related pathways regarding the receptor activator of nuclear factor-κB ligand (RANKL), anti-citrullinated protein antibodies (ACPAs), and Wnt signaling and Dickkopf-related protein 1 (Dkk-1). The complex interplay between inflammatory cytokines and bone destruction has been elucidated, especially that in the interleukin-17/23 (IL-17/23) axis and Janus kinase and signal transducer and activator of transcription (JAK-STAT) signaling. Moreover, advances in biological and targeted therapies have achieved essential modifications to the bone metabolism of these inflammatory arthritis types. In this narrative review, we discuss recent findings on the pathogenic effects on bone in RA and SpA. Proinflammatory cytokines, autoantibodies, and multiple signaling pathways play an essential role in bone destruction in RA and SpA patients. We also reviewed the underlying pathomechanisms of bone structure in biological and targeted therapies of RA and SpA. The clinical implications of tumor necrosis factor inhibitors, abatacept, rituximab, tocilizumab, Janus kinase inhibitors, and inhibitors of the IL-17/23 axis are discussed. Since these novel therapeutics provide new options for disease improvement and symptom control in patients with RA and SpA, further rigorous evidence is warranted to provide a clinical reference for physicians and patients.
Topics: Animals; Arthritis, Rheumatoid; Bone Density; Cytokines; Humans; Interleukin-17; Janus Kinases; Spondylarthritis
PubMed: 35456929
DOI: 10.3390/ijms23084111 -
Frontiers in Immunology 2022Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer.... (Review)
Review
Signal transducer and activator of transcription 3 (STAT3) is a member of the Janus kinase (JAK)-STAT pathway, which is one of the key pathways contributing to cancer. STAT3 regulates transcription downstream of many cytokines including interleukin (IL)-6 and IL-10. In cancer, STAT3 is mainly described as a tumor promoter driving tumor cell proliferation, resistance to apoptosis, angiogenesis and metastasis and aberrant activation of STAT3 is associated with poor prognosis. STAT3 is also an important driver of immune evasion. Among many other immunosuppressive mechanisms, STAT3 aids tumor cells to escape natural killer (NK) cell-mediated immune surveillance. NK cells are innate lymphocytes, which can directly kill malignant cells but also regulate adaptive immune responses and contribute to the composition of the tumor microenvironment. The inborn ability to lyse transformed cells renders NK cells an attractive tool for cancer immunotherapy. Here, we provide an overview of the role of STAT3 in the dynamic interplay between NK cells and tumor cells. On the one hand, we summarize the current knowledge on how tumor cell-intrinsic STAT3 drives the evasion from NK cells. On the other hand, we describe the multiple functions of STAT3 in regulating NK-cell cytotoxicity, cytokine production and their anti-tumor responses . In light of the ongoing research on STAT3 inhibitors, we also discuss how targeting STAT3 would affect the two arms of STAT3-dependent regulation of NK cell-mediated anti-tumor immunity. Understanding the complexity of this interplay in the tumor microenvironment is crucial for future implementation of NK cell-based immunotherapies.
Topics: Cytokines; Humans; Interleukin-6; Janus Kinases; Killer Cells, Natural; Neoplasms; STAT3 Transcription Factor; Tumor Microenvironment
PubMed: 35865518
DOI: 10.3389/fimmu.2022.947568 -
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 -
Genes May 2023The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the... (Review)
Review
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.
Topics: Female; Humans; Janus Kinases; Signal Transduction; Uterine Cervical Neoplasms; Papillomavirus Infections; STAT Transcription Factors
PubMed: 37372319
DOI: 10.3390/genes14061141