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Blood Nov 2023
Topics: Humans; Receptors, Thrombopoietin; Janus Kinase 2
PubMed: 37995103
DOI: 10.1182/blood.2023022061 -
Expert Opinion on Investigational Drugs 2023JAK inhibitors (JAKis), used in the treatment of myelofibrosis, have entered standard treatment, providing significant improvements in spleen size and symptom burden.... (Review)
Review
INTRODUCTION
JAK inhibitors (JAKis), used in the treatment of myelofibrosis, have entered standard treatment, providing significant improvements in spleen size and symptom burden. Although splenomegaly provides a reduction and some improvement in cytopenia, there is still a way to go. Novel JAKis are being investigated to overcome barriers to treatment access, such as therapeutic challenges, intolerance, and unresponsiveness.
AREAS COVERED
This review includes the current status of JAKi treatment for myelofibrosis, mainly focusing on investigational JAKis; jaktinib, lestaurtinib, itacitinib, gandotinib, BMS-911543, ilginatinib, TQ05105, and flonoltinib maleate. MEDLINE and clinicaltrials.gov were screened to identify all completed or active studies on this topic. The outcomes of the preclinical studies and clinical trials are presented and discussed for each drug.
EXPERT OPINION
In patients with myelofibrosis, momelotinib was effective in treating anemia, whereas jaktinib was effective in both anemia and Total Symptom Score (TSS). More phase 3 studies are needed to provide more precise evidence. The increasing variety of JAKis will allow for more personalized treatment options for myelofibrosis in the future. The potential impact on disease progression, molecular responses, and the duration of this response will become important parameters for future evaluations of these drugs.
Topics: Humans; Primary Myelofibrosis; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Anemia; Janus Kinase 2
PubMed: 37811861
DOI: 10.1080/13543784.2023.2269078 -
Molecular Cancer Jan 2024Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT)... (Review)
Review
Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.
Topics: Humans; Janus Kinases; STAT Transcription Factors; Myeloproliferative Disorders; Leukemia; Signal Transduction
PubMed: 38273387
DOI: 10.1186/s12943-023-01929-1 -
Journal of Dermatological Science Mar 2024Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as... (Review)
Review
Vitiligo is an autoimmune disease involving melanocyte-targeting T cells initiated by environmental and genetic factors. Steroids and tacrolimus have been used as topical treatments. Recently, novel topical agents targeting Janus kinase (JAK), a family of tyrosine kinases that regulates cytokine signaling, have emerged. Ruxolitinib is the first approved in vitiligo therapy. Furthermore, ritlecitinib is currently under clinical trials for oral treatment of active vitiligo. In this review, we discuss the possibility of topical JAK inhibitors as promising options for the treatment of vitiligo with regard to their mechanism of action, efficacy and safety.
Topics: Humans; Janus Kinase Inhibitors; Vitiligo; Protein Kinase Inhibitors; Janus Kinases; Administration, Topical
PubMed: 38326166
DOI: 10.1016/j.jdermsci.2023.12.008 -
Journal of Virology Oct 2023African swine fever virus (ASFV) completes the replication process by resisting host antiviral response inhibiting interferon (IFN) secretion and interferon-stimulated...
African swine fever virus (ASFV) completes the replication process by resisting host antiviral response inhibiting interferon (IFN) secretion and interferon-stimulated genes (ISGs) function. 2', 5'-Oligoadenylate synthetase gene 1 (OAS1) has been reported to inhibit the replication of various RNA and some DNA viruses. However, the regulatory mechanisms involved in the ASFV-induced IFN-related pathway still need to be fully elucidated. Here, we found that OAS1, as a critical host factor, inhibits ASFV replication in an RNaseL-dependent manner. Furthermore, overexpression of OAS1 can promote the activation of the JAK-STAT pathway promoting innate immune responses. In addition, OAS1 plays a new function, which could interact with ASFV P72 protein to suppress ASFV infection. Mechanistically, OAS1 enhances the proteasomal degradation of P72 by promoting TRIM21-mediated ubiquitination. Meanwhile, P72 inhibits the production of avSG and affects the interaction between OAS1 and DDX6. Our findings demonstrated OAS1 as an important target against ASFV replication and revealed the mechanisms and intrinsic regulatory relationships during ASFV infection.
Topics: Animals; African Swine Fever; African Swine Fever Virus; Capsid Proteins; Interferons; Janus Kinases; Signal Transduction; STAT Transcription Factors; Swine; Virus Replication; Tripartite Motif Proteins; 2',5'-Oligoadenylate Synthetase
PubMed: 37815352
DOI: 10.1128/jvi.01217-23 -
Science (New York, N.Y.) Jun 2024Janus kinase (JAK) inhibitors improve antitumor responses.
Janus kinase (JAK) inhibitors improve antitumor responses.
Topics: Humans; Neoplasms; Janus Kinases; Janus Kinase Inhibitors; Animals; Mice
PubMed: 38900897
DOI: 10.1126/science.adq1717 -
Frontiers in Immunology 2023Fufang Honghua Buji (FHB) granules, have proven efficacy against vitiligo in long-term clinical practice. However, its major active chemical components and molecular...
Combining network pharmacology, molecular docking, molecular dynamics simulation, and experimental verification to examine the efficacy and immunoregulation mechanism of FHB granules on vitiligo.
BACKGROUND
Fufang Honghua Buji (FHB) granules, have proven efficacy against vitiligo in long-term clinical practice. However, its major active chemical components and molecular mechanisms of action remain unknown. The purpose of this study was to confirm the molecular mechanism of FHB's therapeutic effect on vitiligo utilizing network pharmacology, molecular docking, and molecular dynamics simulation prediction, as well as experimental verification.
METHODS
Traditional Chinese Medicine Systems Pharmacology (TCMSP) and HERB databases were used to obtain the chemical composition and action targets of FHB. Online Mendelian Inheritance in Man (OMIM), DrugBank, DisGeNET, GeneCards, and Therapeutic Target Database (TTD) databases were applied to screen for vitiligo-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed through the Matascape database. Molecular docking and dynamics simulation methods were for the analysis of the binding sites and binding energies between the FHB's active components and the targets. Finally, a vitiligo mouse model was created, and the therapeutic effect and molecular mechanism of action of FHB were validated using enzyme linked immunosorbent assay (ELISA), western blot (WB), and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, hematoxylin-eosin staining (HE) and blood biochemical assays were conducted to assess the biosafety of FHB.
RESULT
The screening of chemical composition and targets suggested that 94 genetic targets of FHB were associated with vitiligo. The bioinformatics analysis suggested that luteolin, quercetin, and wogonin may be major active components, and nuclear factor-kappa B p65 subunit (RELA), signal transducer, and activator of transcription (STAT) 3 and RAC-alpha serine/threonine-protein kinase (AKT) 1 may be potential targets of FHB-vitiligo therapy. Molecular docking and dynamics simulation further demonstrated that luteolin, quercetin, and wogonin all bound best to STAT3. Through experimental verification, FHB has been demonstrated to alleviate the pathogenic characteristics of vitiligo mice, suppress the JAK-STAT signaling pathway, reduce inflammation, and increase melanogenesis. The safety evaluation experiments also demonstrated the non-toxicity of FHB.
CONCLUSIONS
FHB exerts anti-inflammatory and melanogenesis-promoting effects via the effect of multi-component on multi-target, among which the JAK-STAT pathway is a validated FHB-vitiligo target, providing new ideas and clues for the development of vitiligo therapy.
Topics: Animals; Mice; Vitiligo; Molecular Docking Simulation; Network Pharmacology; Janus Kinases; Luteolin; Molecular Dynamics Simulation; Quercetin; STAT Transcription Factors; Signal Transduction; Databases, Genetic
PubMed: 37575231
DOI: 10.3389/fimmu.2023.1194823 -
Developmental Cell Jan 2024Microglia are highly heterogeneous as resident immune cells in the central nervous system. Although the proinflammatory phenotype of microglia is driven by the metabolic...
Microglia are highly heterogeneous as resident immune cells in the central nervous system. Although the proinflammatory phenotype of microglia is driven by the metabolic transformation in the disease state, the mechanism of metabolic reprogramming in microglia and whether it affects surrounding astrocyte progenitors have not been well elucidated. Here, we illustrate the communication between microglial metabolism and astrogenesis during embryonic development. The transcription factor BTB and CNC homology 1 (Bach1) reduces lactate production by inhibiting two key enzymes, HK2 and GAPDH, during glycolysis. Metabolic perturbation of microglia reduces lactate-dependent histone modification enrichment at the Lrrc15 promoter. The microglia-derived LRRC15 interacts with CD248 to participate in the JAK/STAT pathway and influence astrogenesis. In addition, Bach1 mice exhibit abnormal neuronal differentiation and anxiety-like behaviors. Altogether, this work suggests that the maintenance of microglia metabolic homeostasis during early brain development is closely related to astrogenesis, providing insights into astrogenesis and related diseases.
Topics: Animals; Female; Mice; Pregnancy; Brain; Janus Kinases; Lactates; Microglia; Signal Transduction; STAT Transcription Factors
PubMed: 38101413
DOI: 10.1016/j.devcel.2023.11.018 -
Translational Neurodegeneration Oct 2023Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.
Topics: Humans; Amyotrophic Lateral Sclerosis; Janus Kinase Inhibitors; Neurodegenerative Diseases; Central Nervous System; Janus Kinases
PubMed: 37828541
DOI: 10.1186/s40035-023-00380-y -
Indian Journal of Dermatology,... 2023The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has been identified as a key player in the pathophysiology of alopecia areata... (Review)
Review
The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has been identified as a key player in the pathophysiology of alopecia areata and a potential target for therapy. Here, we give a narrative review of what is known about Janus kinase inhibitors in alopecia areata. Several clinical trials as well as smaller studies have demonstrated hair regrowth and remission with oral Janus kinase inhibitors therapy, even in patients who failed conventional treatment. Baricitinib is the only US FDA-approved treatment for alopecia areata but data for other oral Janus kinase inhibitors such as tofacitinib, ruxolitinib and ritlecitinib are also promising. Fewer clinical trials have investigated topical Janus kinase inhibitors for alopecia areata, with many of them terminated early due to unfavourable results. Overall, Janus kinase inhibitors are an efficacious addition to the therapeutic arsenal for treatment-refractory alopecia areata. Further work is needed to examine the effects of long-term usage of Janus kinase inhibitors, the efficacy of topical Janus kinase inhibitors, as well as to identify biomarkers that could predict differential therapeutic responses to the various Janus kinase inhibitors.
Topics: Humans; Alopecia Areata; Janus Kinase Inhibitors; Alopecia; Hair; Janus Kinases
PubMed: 37436019
DOI: 10.25259/IJDVL_1093_2022