Molecular dissection of Janus kinases as drug targets for inflammatory diseases

Kwon, Sunghoon

doi:10.3389/fimmu.2022.1075192

Cited by 6 publications

(4 citation statements)

References 59 publications

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“…Most cytokines and growth factors that bind to their receptors result in phosphorylation of receptor-associated JAKs [13]. JAKi selectively interfere with the adenosine triphosphate-binding site of JAKs, resulting in suppression of downstream signalling pathways [14].…”

Section: Discussionmentioning

confidence: 99%

Drug Retention Rates of Janus Kinase Inhibitors in Rheumatoid Arthritis Patients with Therapy-Induced Lymphopenia

Temmoku

Miyata²,

Suzuki

et al. 2023

JCM

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Objectives: To determine whether drug-induced lymphocytopenia is associated with drug retention rates of JAKi (tofacitinib or baricitinib) in rheumatoid arthritis (RA) patients. Methods: Patients with RA who were initiated with tofacitinib (n = 38) or baricitinib (n = 74) between July 2015 and July 2022 and continued for at least 4 months were enrolled in this study. Absolute lymphocyte count (ALC) value was obtained pre-treatment and monthly after initiation of JAKi (up to 4 months). Associations between ALC nadir at an early phase (up to 4 months) from JAKi initiation and drug retention rates were analysed. Results: 112 patients (87 females; age, 71.2 ± 14.0 years; disease duration, 9.2 ± 10.5 months; DAS28-CRP, 3.60 ± 1.12; DAS28-ESR, 4.43 ± 1.29; CDAI, 17.9 ± 12.9; C-reactive protein, 3.07 ± 3.43 mg/dL; and lymphocyte count, 1361.9 ± 538.7 per μL) treated with tofacitinib or baricitinib were retrospectively analysed. Lymphocytopenia (>10% decline in lymphocyte count to pre-treatment basal levels) was observed in a quarter of RA patients treated with JAKi (tofacitinib; 16 baricitinib; 14). RA patients with lymphopenia were associated with the lower drug retention rates of tofacitinib compared to those without lymphocytopenia. The reduced drug retention rates in patients with lymphocytopenia were attributed to the discontinuation of tofacitinib due to AEs. Whereas lymphocytopenia was not associated with lower drug retention rates of baricitinib. Pre-treatment absolute lymphocyte counts did not affect the drug retention rates of JAKi in patients with RA. Conclusions: These findings suggest that lymphopenia during the first 4 months from the initiation of JAKi is associated with reduced drug retention rates in patients with RA due to AEs, which is exclusively associated with the use of tofacitinib.

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Section: Discussionmentioning

confidence: 99%

Drug Retention Rates of Janus Kinase Inhibitors in Rheumatoid Arthritis Patients with Therapy-Induced Lymphopenia

Temmoku

Miyata²,

Suzuki

et al. 2023

JCM

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“…These proteins relay extracellular signals from the cell surface to the nucleus to express the target genes [33,34]. Since their discovery, the STAT protein family of transcription factors has been thoroughly researched in relation to cancer [35]. The seven members of the STAT family are STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 [36,37].…”

Section: Stat3 Signaling Cascade and Tumorigenesismentioning

confidence: 99%

Terpenoid-Mediated Targeting of STAT3 Signaling in Cancer: An Overview of Preclinical Studies

Khan,

Pandey,

Verma

et al. 2024

Biomolecules

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Cancer has become one of the most multifaceted and widespread illnesses affecting human health, causing substantial mortality at an alarming rate. After cardiovascular problems, the condition has a high occurrence rate and ranks second in terms of mortality. The development of new drugs has been facilitated by increased research and a deeper understanding of the mechanisms behind the emergence and advancement of the disease. Numerous preclinical and clinical studies have repeatedly demonstrated the protective effects of natural terpenoids against a range of malignancies. Numerous potential bioactive terpenoids have been investigated in natural sources for their chemopreventive and chemoprotective properties. In practically all body cells, the signaling molecule referred to as signal transducer and activator of transcription 3 (STAT3) is widely expressed. Numerous studies have demonstrated that STAT3 regulates its downstream target genes, including Bcl-2, Bcl-xL, cyclin D1, c-Myc, and survivin, to promote the growth of cells, differentiation, cell cycle progression, angiogenesis, and immune suppression in addition to chemotherapy resistance. Researchers viewed STAT3 as a primary target for cancer therapy because of its crucial involvement in cancer formation. This therapy primarily focuses on directly and indirectly preventing the expression of STAT3 in tumor cells. By explicitly targeting STAT3 in both in vitro and in vivo settings, it has been possible to explain the protective effect of terpenoids against malignant cells. In this study, we provide a complete overview of STAT3 signal transduction processes, the involvement of STAT3 in carcinogenesis, and mechanisms related to STAT3 persistent activation. The article also thoroughly summarizes the inhibition of STAT3 signaling by certain terpenoid phytochemicals, which have demonstrated strong efficacy in several preclinical cancer models.

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“…Figure 4 shows the specific genes induced at 1 h post lens wounding that were linked to leukocyte, T cell, cytokine, or immune response pathways, and those induced genes that function in two or more of these pathways. For example, induction of the messenger RNA for Janus kinase 1 (JAK1) is uniquely associated with cytokine signaling [41]. The Venn diagram illustrates the number of upregulated genes that are unique and shared between each group, with a total of 338 genes identified.…”

Section: Rna-seq Analysis Reveals That Lens Wounding Rapidly Induces ...mentioning

confidence: 99%

Immune Responses Induced at One Hour Post Cataract Surgery Wounding of the Chick Lens

DeDreu,

Basta,

Walker

et al. 2023

Biomolecules

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While the lens is an avascular tissue with an immune-privileged status, studies have now revealed that there are immune responses specifically linked to the lens. The response to lens injury, such as following cataract surgery, has been shown to involve the activation of the resident immune cell population of the lens and the induction of immunomodulatory factors by the wounded epithelium. However, there has been limited investigation into the immediate response of the lens to wounding, particularly those induced factors that are intrinsic to the lens and its associated resident immune cells. Using an established chick embryo ex vivo cataract surgery model has made it possible to determine the early immune responses of this tissue to injury, including its resident immune cells, through a transcriptome analysis. RNA-seq studies were performed to determine the gene expression profile at 1 h post wounding compared to time 0. The results provided evidence that, as occurs in other tissues, the resident immune cells of the lens rapidly acquired a molecular signature consistent with their activation. These studies also identified the expression of many inflammatory factors by the injured lens that are associated with both the induction and regulation of the immune response.

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Molecular dissection of Janus kinases as drug targets for inflammatory diseases

Cited by 6 publications

References 59 publications

Drug Retention Rates of Janus Kinase Inhibitors in Rheumatoid Arthritis Patients with Therapy-Induced Lymphopenia

Drug Retention Rates of Janus Kinase Inhibitors in Rheumatoid Arthritis Patients with Therapy-Induced Lymphopenia

Terpenoid-Mediated Targeting of STAT3 Signaling in Cancer: An Overview of Preclinical Studies

Immune Responses Induced at One Hour Post Cataract Surgery Wounding of the Chick Lens

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