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Expert Opinion on Pharmacotherapy 2023Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or... (Review)
Review
INTRODUCTION
Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or macrovascular events. Characteristic aquagenic pruritus and fatigue can have a substantial impact on quality of life. Over time, a minority will transform into more aggressive conditions such as post-PV myelofibrosis or acute myeloid leukemia. The JAK1 and 2 inhibitor Ruxolitinib has been approved for the treatment of PV after the failure of first-line therapies. Other JAK inhibitors have not been extensively tested in PV.
AREAS COVERED
In this article, we describe how PV is diagnosed and conventional treatments before moving to cover the status of JAK inhibitors as a therapeutic option for this disease and other novel therapies following a literature review.
EXPERT OPINION
Ruxolitinib when used for PV delivers control of blood counts and reduces disease-related symptoms. Recent data have also suggested that treatment with Ruxolitinib can improve event-free survival and may be associated with disease modification. Adverse effects of Ruxolitinib such as the increased risk of infection and squamous cell skin cancers, most likely to be linked to immunosuppression and prior lines of therapies, require careful consideration.
Topics: Humans; Polycythemia Vera; Janus Kinase Inhibitors; Quality of Life; Pyrazoles; Nitriles; Janus Kinase 2
PubMed: 37343285
DOI: 10.1080/14656566.2023.2228688 -
Aging and Disease Feb 2024Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and... (Review)
Review
Chronic pain is a notable health concern because of its prevalence, persistence, and associated mental stress. Drugs targeting chronic pain with potent abirritation, and minimal side effects remain unidentified. Substantial evidence indicates that the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a distinct and critical role in different stages of chronic pain. Aberrant activation of the JAK2/STAT3 signaling pathway is evident in multiple chronic pain models. Moreover, an increasing number of studies have demonstrated that the downregulation of JAK2/STAT3 can attenuate chronic pain in different animal models. In this review, we investigated the mechanism and role of the JAK2/STAT3 signaling pathway in modulating chronic pain. The aberrant activation of JAK2/STAT3 can trigger chronic pain by interacting with microglia and astrocytes, releasing proinflammatory cytokines, inhibiting anti-inflammatory cytokines, and regulating synaptic plasticity. We also retrospectively reviewed current reports on JAK2/STAT3 pharmacological inhibitors that demonstrated their significant therapeutic potential in different types of chronic pain. In summary, our results provide strong evidence that the JAK2/STAT3 signaling pathway is a promising therapeutic target for chronic pain.
Topics: Animals; Janus Kinase 2; Chronic Pain; STAT3 Transcription Factor; Retrospective Studies; Signal Transduction; Cytokines
PubMed: 37307838
DOI: 10.14336/AD.2023.0515 -
Nature Reviews. Rheumatology Apr 2024Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I... (Review)
Review
Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family of intracellular signalling molecules. By participating in signalling pathways downstream of type I interferons, IL-12, IL-23 and IL-10, TYK2 elicits a distinct set of immune events to JAK1, JAK2 and JAK3. TYK2 polymorphisms have been associated with susceptibility to various rheumatic diseases including systemic lupus erythematosus and dermatomyositis. In vitro and animal studies substantiate these findings, highlighting a role for TYK2 in diseases currently managed by antagonists of cytokines that signal through TYK2. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib, has now been approved for the treatment of psoriasis. Phase II trials of deucravacitinib have also reported positive results in the treatment of psoriatic arthritis and systemic lupus erythematosus, with a preliminary safety profile that seems to differ from that of the JAK1, JAK2 and JAK3 inhibitors. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials. Overall, TYK2 inhibitors hold promise for the treatment of a distinct spectrum of autoimmune diseases and could potentially have a safety profile that differs from other JAK inhibitors.
Topics: Animals; Humans; Janus Kinase Inhibitors; Lupus Erythematosus, Systemic; Protein Kinase Inhibitors; Psoriasis; Rheumatic Diseases; TYK2 Kinase
PubMed: 38467779
DOI: 10.1038/s41584-024-01093-w -
Frontiers in Immunology 2024Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with... (Review)
Review
Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.
Topics: Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Psoriasis; Biological Products; Janus Kinases
PubMed: 38444845
DOI: 10.3389/fimmu.2024.1341632 -
Journal of Cellular and Molecular... Oct 2023Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic...
Although combination chemotherapy is widely used for bladder cancer (BC) treatment, the recurrence and progression rates remain high. Therefore, novel therapeutic targets are required. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) contributes to tumourigenesis and immune evasion in several cancers; however, its biological function in BC remains unknown. This study aimed to investigate the expression, prognostic value and protumoural function of MTHFD2 in BC and elucidate the mechanism of programmed death-ligand 1 (PD-L1) upregulation by MTHFD2. An analysis using publicly available databases revealed that a high MTHFD2 expression was correlated with clinical features and a poor prognosis in BC. Furthermore, MTHFD2 promoted the growth, migration, invasion and tumourigenicity and decreased the apoptosis of BC cells in vivo and in vitro. The results obtained from databases showed that MTHFD2 expression was correlated with immune infiltration levels, PD-L1 expression, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The expression of MTHFD2, PD-L1 and JAK/STAT signalling pathway-related proteins increased after interferon gamma treatment and decreased after MTHFD2 knockdown. Moreover, addition of a JAK/STAT pathway activator partially reduced the effect of MTHFD2 knockdown on BC cells. Collectively, our findings suggest that MTHFD2 promotes the expression of PD-L1 through the JAK/STAT signalling pathway in BC.
Topics: Humans; B7-H1 Antigen; Signal Transduction; Janus Kinases; STAT Transcription Factors; Urinary Bladder Neoplasms
PubMed: 37480214
DOI: 10.1111/jcmm.17863 -
Expert Opinion on Pharmacotherapy 2023The approach to myelofibrosis (MF) has been revolutionized in recent years, overcoming the traditional therapies, often not very effective. Janus kinase inhibitors (JAKi... (Review)
Review
INTRODUCTION
The approach to myelofibrosis (MF) has been revolutionized in recent years, overcoming the traditional therapies, often not very effective. Janus kinase inhibitors (JAKi - from ruxolitinib up to momelotinib) were the first class of drugs with considerable results.
AREAS COVERED
Ongoing, new molecules are being tested that promise to give hope even to those patients not eligible for bone marrow transplants who become intolerant or are refractory to JAKi, for which therapeutic hopes are currently limited. Telomerase, murine double minute 2 (MDM2), phosphatidylinositol 3-kinase δ (PI3Kδ), BCL-2/xL, and bromodomain and extra-terminal motif (BET) inhibitors are the drugs with promising results in clinical trials and close to closure with consequent placing on the market, finally allowing JAK to look beyond. The novelty of the MF field was searched in the PubMed database, and the recently completed/ongoing trials are extrapolated from the ClinicalTrial website.
EXPERT OPINION
From this point of view, the use of new molecules widely described in this review, probably in association with JAKi, will represent the future treatment of choice in MF, leaving, in any case, the potential new approaches actually in an early stage of development, such as the use of immunotherapy in targeting CALR, which is coming soon.
Topics: Humans; Animals; Mice; Janus Kinase Inhibitors; Primary Myelofibrosis; Antineoplastic Agents; Nitriles; Protein Kinase Inhibitors; Janus Kinase 2
PubMed: 37341682
DOI: 10.1080/14656566.2023.2228695 -
International Journal of Nanomedicine 2023In chronic periodontitis, exosomes transport various informative substances between osteoclasts and osteoblasts in alveolar bone. Herein, we aimed to investigate the...
BACKGROUND
In chronic periodontitis, exosomes transport various informative substances between osteoclasts and osteoblasts in alveolar bone. Herein, we aimed to investigate the effect of exosomal micro-ribonucleic acid (miRNA/miR)-5134-5p derived from osteoclasts on osteoblastic proliferation and differentiation and the development of periodontitis in vivo and in vitro.
METHODS
The effects of OC-Exos on the proliferation and differentiation of osteoblasts were identified by Real-time quantitative reverse polymerase chain reaction (qRT-PCR), Western blot(WB), alkaline phosphatase(ALP) staining, etc. Exosomal miRNA expression was analyzed by sequencing. The sites of miRNA action were predicted through TargetScan and tested by double luciferase assay. After transfecting miR-5134-5p mimic/inhibitor into osteoblasts, we measured the proliferation and differentiation of osteoblasts by ALP staining and WB, etc. Furthermore, OC-Exos were injected into the gingival sulcus at the ligation site. Inflammation was observed by Hematoxylin-eosin (H&E) staining, the expression of inflammatory factors were detected by qRT-PCR, the resorption of alveolar bone was observed by Micro CT.
RESULTS
Osteoblastic proliferation and differentiation were negatively regulated by OC-Exos in vitro. miRNA sequencing analysis revealed that miR-5134-5p expression was significantly elevated in OC-Exos, which also increased in osteoblasts following OC-Exo intervention. The dual-luciferase assay revealed that miR-5134-5p and Janus kinase 2 (JAK2) had binding sites. miR-5134-5p-mimics could upregulate miR-5134-5p expression in osteoblasts while downregulating Runt-related transcription factor 2(Runx2), phosphorylated-JAK2 (p-JAK2), and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) expression and inhibited osteogenic differentiation. However, miR-5134-5p-inhibitor had the opposite effect. In vivo, the OC-Exo group demonstrated morphological disruption of periodontal tissue, massive inflammatory cell infiltration, upregulation of inflammatory factors mRNA expression, a significant decrease in BV/TV, and an increase in the cementoenamel junction and alveolar bone crest distance.
CONCLUSION
Osteoclast-derived exosomal miR-5134-5p inhibits osteoblastic proliferation and differentiation via the JAK2/STAT3 pathway. OC-Exos exacerbate periodontal tissue inflammation and accelerate alveolar bone resorption in mice with experimental periodontitis.
Topics: Mice; Animals; Osteogenesis; Osteoclasts; Janus Kinase 2; STAT3 Transcription Factor; MicroRNAs; Cell Differentiation; Osteoblasts; Periodontitis; Inflammation; Homeostasis; Luciferases
PubMed: 37441084
DOI: 10.2147/IJN.S413692 -
Immunity, Inflammation and Disease Dec 2023High-mobility group box 1 (HMGB1) is a highly conserved nonhistone nuclear protein found in the calf thymus and participates in a variety of intracellular processes such... (Review)
Review
High-mobility group box 1 (HMGB1) is a highly conserved nonhistone nuclear protein found in the calf thymus and participates in a variety of intracellular processes such as DNA transcription, replication and repair. In the cytoplasm, HMGB1 promotes mitochondrial autophagy and is involved in in cellular stress response. Once released into the extracellular, HMGB1 becomes an inflammatory factor that triggers inflammatory responses and a variety of immune responses. In addition, HMGB1 binding with the corresponding receptor can activate the downstream substrate to carry out several biological effects. Meanwhile, HMGB1 is involved in various signaling pathways, such as the HMGB1/RAGE pathway, HMGB1/NF-κB pathway, and HMGB1/JAK/STAT pathway, which ultimately promote inflammation. Moreover, HMGB1 may be involved in the pathogenesis of asthma by regulating downstream signaling pathways through corresponding receptors and mediates a number of signaling pathways in asthma, such as HMGB1/TLR4/NF-κB, HMGB1/RAGE, HMGB1/TGF-β, and so forth. Accordingly, HMGB1 emerges as a therapeutic target for asthma.
Topics: Humans; NF-kappa B; Signal Transduction; HMGB1 Protein; Janus Kinases; STAT Transcription Factors; Asthma
PubMed: 38156383
DOI: 10.1002/iid3.1124 -
Inflammation Research : Official... Sep 2023The therapeutic efficacy of systemic Janus kinase (JAK) inhibitors in moderate-to-severe atopic dermatitis (AD) is well established. However, the associated risk of... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The therapeutic efficacy of systemic Janus kinase (JAK) inhibitors in moderate-to-severe atopic dermatitis (AD) is well established. However, the associated risk of incident acne, which is a prevalent adverse event in AD patients treated with systemic JAK inhibitors, has yet to be systematically analyzed.
METHODOLOGY
To evaluate the risk of incident acne in AD patients treated with systemic JAK inhibitors, an extensive database search (clinicaltrials.gov, PubMed) was performed to identify publications eligible for inclusion from January 2020 to October 2022. Five randomized clinical trials (RCTs) of abrocitinib, four RCTs of upadacitinib, and one RCT of baricitinib, encompassing a total of 7901 participants, were included in the analysis. The risk difference for incident acne between systemic JAK inhibitors and controls was assessed using Review Manager, version 5.3, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS
Meta-analysis elucidated a significant difference in the risk of incident acne between AD participants receiving 200 mg abrocitinib (Mantel-Haenszel risk difference, 3.69; 95% CI 1.60-8.48; P < 0.01), 15 mg upadacitinib (Mantel-Haenszel risk difference, 4.61; 95% CI 2.79-7.62; P < 0.00001), and 30 mg upadacitinib (Mantel-Haenszel risk difference, 6.82; 95% CI 4.59-10.13; P < 0.00001) compared with controls receiving placebo or dupilumab. In contrast, no significant difference was found in the risk of incident acne between participants receiving 100 mg abrocitinib, 2 mg baricitinib, and 4 mg baricitinib, as compared with controls.
CONCLUSIONS
Based on the current evidence, there is an increased risk of acne related to systemic JAK inhibitors, particularly with abrocitinib and upadacitinib. For patients predisposed to acne, the balance between the benefits of symptomatic relief from AD and the potential risk of acne may need to be carefully considered. This study contributes to a nuanced understanding of the risk profile of systemic JAK inhibitors and has the potential to guide personalized treatment decisions for AD patients.
Topics: Humans; Dermatitis, Atopic; Janus Kinase Inhibitors; Acne Vulgaris; Janus Kinase 1
PubMed: 37707560
DOI: 10.1007/s00011-023-01789-x -
Current Hematologic Malignancy Reports Oct 2023Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor.... (Review)
Review
PURPOSE OF REVIEW
Chronic myeloproliferative neoplasms (MPN) represent a group of diseases characterised by constitutive activation of the JAK/STAT pathway in a clonal myeloid precursor. The therapeutic approach aims to treat the symptom burden (headache, itching, debilitation), splenomegaly, slow down the fibrotic proliferation in the bone marrow and reduce the risk of thrombosis/bleeding whilst avoiding leukaemic transformation.
RECENT FINDINGS
In recent years, the advent of JAK inhibitors (JAKi) has significantly broadened treatment options for these patients. In myelofibrosis, symptom control and splenomegaly reduction can improve quality of life with improved overall survival, not impacting progression into acute leukaemia. Several JAKi are available and used worldwide, and combination approaches are now being explored. In this chapter, we review the approved JAKi, highlighting its strengths, exploring potential guidelines in choosing which one to use and reasoning towards future perspectives, where the combinations of therapies seem to promise the best results.
Topics: Humans; Janus Kinase Inhibitors; Polycythemia Vera; Janus Kinases; Splenomegaly; Quality of Life; Thrombocythemia, Essential; Signal Transduction; STAT Transcription Factors; Myeloproliferative Disorders
PubMed: 37395943
DOI: 10.1007/s11899-023-00702-x