Search

Background Janus kinase (JAK) inhibitors have shown encouraging results in the treatment of alopecia areata (AA), an autoimmune form of hair loss, in small, uncontrolled studies and case reports. Objective To conduct a biopsy sub-study during the randomized, double-blind, placebo-controlled first 24 weeks of a phase 2a clinical trial that evaluated the efficacy and safety of ritlecitinib, an inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and brepocitinib, an inhibitor of tyrosine kinase 2 (TYK2)/JAK1 in the treatment of AA. Methods Change in biomarkers in lesional scalp biopsies between baseline and weeks 12 and 24 was an exploratory endpoint, and 46 patients participated from the ritlecitinib (n = 18), brepocitinib (n = 16), and placebo (n = 12) groups. Correlations of biomarkers with hair regrowth, measured using the Severity of Alopecia Tool (SALT) score, were also evaluated. Results At week 24, both ritlecitinib and brepocitinib demonstrated improvement exceeding 100% in the lesional scalp transcriptome toward a nonlesional profile. At week 12, the improvements in scalp tissue were greater with brepocitinib than ritlecitinib; however, at week 24, the improvements were greater with ritlecitinib. Conclusions For both ritlecitinib and brepocitinib, improvement in the SALT scores was positively associated with expression of Th1 markers and negatively associated with expression of hair keratins. Larger, long-term clinical trials are warranted.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) intracellular signaling pathway is implicated in the pathogenesis of a number of inflammatory dermatoses. Clinical trials and other studies have demonstrated the efficacy of JAK inhibitors in the treatment of a variety of dermatologic conditions. Here we review JAK inhibitors currently under investigation for the treatment of alopecia areata, vitiligo, sarcoidosis, necrobiosis lipoidica, granuloma annulare, and systemic lupus erythematosus with a special emphasis on safety and the implications of JAK inhibitors during the novel coronavirus 2019 pandemic.

Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocyte-mediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice.

Tyrosine kinase 2 (Tyk2) is a member of the Janus family of protein tyrosine kinases (Jaks). Tyk2 associates with interferon (IFN)-α, IFN-β, interleukin (IL)-6, IL-10, IL-12, and IL-23 receptors and mediates their downstream signaling pathways. Based on our data using Tyk2-deficient mice and cells, Tyk2 plays crucial roles in the differentiation, maintenance, and function of T helper 1 (Th1) and Th17 cells, and its dysregulation may promote autoimmune and/or inflammatory diseases. IFN-α-induced growth inhibition of B lymphocyte progenitors is dependent on Tyk2-mediated signals to regulate death-associated protein (Daxx) nuclear localization and Daxx-promyelocytic leukemia protein interactions. Tyk2-deficient mice show impaired constitutive production of type I IFNs by macrophages under steady-state conditions. When heat-killed Cutibacterium acnes is injected intraperitoneally, Tyk2-deficient mice show less granuloma formation through enhanced prostaglandin E2 and protein kinase A activities, leading to high IL-10 production by macrophages. Thus, Tyk2 is widely involved in the immune and inflammatory response at multiple events; therefore, Tyk2 is likely to be a suitable target for treating patients with autoimmune and/or chronic inflammatory diseases. Clinical trials of Tyk2 inhibitors have shown higher response rates and improved tolerability in the treatment of patients with psoriasis and inflammatory bowel diseases. Taken together, Tyk2 inhibition has great potential for clinical application in the management of a variety of diseases.

Clustered protocadherins (Pcdhs) are a large family of cadherin-like cell adhesion proteins that are central for neurite self-avoidance and neuronal connectivity in the brain. Their downstream nonreceptor tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2, also known as Ptk2b, Cakb, Raftk, Fak2, and Cadtk) is predominantly expressed in the hippocampus. We constructed Pyk2-null mouse lines and found that these mutant mice showed enhancement in contextual fear memory, without significant change in auditory-cued and spatial-referenced learning and memory. In addition, by preparing Y402F mutant mice, we observed that Pyk2 suppressed contextual fear memory in an autophosphorylation-independent manner. Moreover, using high-throughput RNA sequencing, we found that immediate early genes, such as Npas4, cFos, Zif268/Egr1, Arc, and Nr4a1, were enhanced in Pyk2-null mice. We further showed that Pyk2 disruption affected pyramidal neuronal complexity and spine dynamics. Thus, we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2-null mice provide a model for understanding fear-related disorders. These findings have interesting implications regarding dysregulation of the Pcdh‒Pyk2 axis in neuropsychiatric disorders.

Juvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy. Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1–3, TYK2, and STAT1–6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM. Supplementary Information The online version contains supplementary material available at 10.1186/s12969-021-00637-8.

Activating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical efficacy, JAKi resistance often occurs resulting in relapse. In this study, we modeled potential mechanisms of JAKi resistance in TYK2-rearranged ALL cells in vitro in order to recapitulate possible clinical scenarios and provide a rationale for alternative therapies. Cerdulatinib resistant B-cells, driven by the MYB-TYK2 fusion oncogene, were generated by long-term exposure to the drug. Sustained treatment of MYB-TYK2-rearranged ALL cells with cerdulatinib led to enhanced and persistent JAK/STAT signaling, co-occurring with JAK1 overexpression. Hyperactivation of JAK/STAT signaling and JAK1 overexpression was reversible as cerdulatinib withdrawal resulted in re-sensitization to the drug. Importantly, histone deacetylase inhibitor (HDACi) therapies were efficacious against cerdulatinib-resistant cells demonstrating a potential alternative therapy for use in TYK2-rearranged B-ALL patients who have lost response to JAKi treatment regimens.

Elena Campione,1 Terenzio Cosio,1 Monia Di Prete,2 Caterina Lanna,1 Annunziata Dattola,1 Luca Bianchi1 1Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, 00133, Italy; 2Anatomic Pathology, University of Rome Tor Vergata, Rome, 00133, ItalyCorrespondence: Elena CampioneDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier,1, Rome, 00133, ItalyTel +39.06.20900252Email elena.campione@uniroma2.itAbstract: Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words “psoriasis” and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies - especially systemic ones and those using small molecules – and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.Keywords: psoriasis, janus kinase inhibitors, tyrosine kinase 2 inhibitors, phosphodiesterase 4 inhibitors, IL-36 receptors inhibitors

Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disease without a clear mechanism or drugs for treatment. Therefore, it is crucial to reveal the underlying molecular mechanism and identify potential drugs for PAH. In this study, we first integrated three human lung tissue datasets (GSE113439, GSE53408, GSE117261) from GEO. A total of 151 differentially expressed genes (DEGs) were screened, followed by KEGG and GO enrichment analyses and PPI network construction. Five hub genes (CSF3R, NT5E, ANGPT2, FGF7, and CXCL9) were identified by Cytoscape (Cytohubba). GSEA and GSVA were performed for each hub gene to uncover the potential mechanism. Moreover, to repurpose known and therapeutic drugs, the CMap database was retrieved, and nine candidate compounds (lypressin, ruxolitinib, triclabendazole, L-BSO, tiaprofenic acid, AT-9283, QL-X-138, huperzine-a, and L-741742) with a high level of confidence were obtained. Then ruxolitinib was selected to perform molecular docking simulations with ANGPT2, FGF7, NT5E, CSF3R, JAK1, JAK2, JAK3, TYK2. A certain concentration of ruxolitinib could inhibit the proliferation and migration of rat pulmonary artery smooth muscle cells (rPASMCs) in vitro. Together, these analyses principally identified CSF3R, NT5E, ANGPT2, FGF7 and CXCL9 as candidate biomarkers of PAH, and ruxolitinib might exert promising therapeutic action for PAH.

Several studies have previously reported that exposure to stress provokes behavioral changes, including antinociception, in rodents. In the present study, we studied the effect of acute cold-water (4°C) swimming stress (CWSS) on nociception and the possible changes in several signal molecules in male ICR mice. Here, we show that 3 min of CWSS was sufficient to produce antinociception in tail-flick, hot-plate, von-Frey, writhing, and formalin-induced pain models. Significantly, CWSS strongly reduced nociceptive behavior in the first phase, but not in the second phase, of the formalin-induced pain model. We further examined some signal molecules' expressions in the dorsal root ganglia (DRG) and spinal cord to delineate the possible molecular mechanism involved in the antinociceptive effect under CWSS. CWSS reduced p-ERK, p-AMPKα1, p-AMPKα2, p-Tyk2, and p-STAT3 expression both in the spinal cord and DRG. However, the phosphorylation of mTOR was activated after CWSS in the spinal cord and DRG. Moreover, p-JNK and p-CREB activation were significantly increased by CWSS in the spinal cord, whereas CWSS alleviated JNK and CREB phosphorylation levels in DRG. Our results suggest that the antinociception induced by CWSS may be mediated by several molecules, such as ERK, JNK, CREB, AMPKα1, AMPKα2, mTOR, Tyk2, and STAT3 located in the spinal cord and DRG.

Several cytokines involved in inflammatory pathologies signal via the Janus kinase-signal transducer and activator of transcription pathway. Four JAKs are known: JAK1, JAK2, JAK3 and TYK2. The specific activation of JAKs and STATs determines the biological effects of each cytokine. JAK1 is involved in the signalling of ‘γc’ receptor cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21), pro-inflammatory cytokines including IL-6, as well as IFN. The critical position of JAK1 downstream of these cytokines suggests that JAK1-selective inhibitors are comparable to non-selective ones, without the unwanted consequences of JAK2- or JAK3-blockade. JAK inhibition has led to a better understanding of the biology of synovial inflammation and bone homeostasis. Moreover, the efficacy of non-selective JAK inhibitors and novel JAK1-selective drugs in RA supports a role for JAK1 in its pathogenesis. JAK1-selective drugs are also showing promise in axial spondyloarthritis, suggesting that they may target additional regulatory pathways that impact cytokines such as TNF and IL-17A, which do not use JAKs. Additionally, evidence now supports a JAK1 predominance in the signalling of IL-6 and oncostatin M, and indirectly, of TNF in synovial fibroblasts, macrophages and endothelial cells. Notably, bone homeostasis is also dependent on cytokines relying on JAK1 signalling to promote receptor activator of NF-κB ligand expression in osteoblasts and T cells, contributing to osteoclastogenesis. Here, the contribution of JAK1 over other kinases is unclear. While beneficial effects of JAK inhibitors on bone erosion are supported by preclinical and clinical data, effects on new bone formation in axial spondyloarthritis requires additional study. CME: This supplement is CME Accredited. To receive a CME certificate of participation, you should: Read all the papers in the supplement Register or log in at www.paradigmmc.com/962 to complete and submit the post activity assessment. You must answer 70% of the questions correctly to earn credit. You will have unlimited opportunities to successfully complete the assessment. You will receive a maximum of 7.0 AMA PRA Category 1 Credits(TM) upon successful completion of the assessment.

The type I interferon (IFN-I) system is important for antiviral and anticancer immunity. Prolonged activation of IFN/JAK/STAT signaling is closely associated with autoimmune diseases. TRIM10 dysfunction may be associated closely with certain autoimmune disorders. Here, we observed that the serum TRIM10 protein level is lower in patients with systemic lupus erythematosus than in healthy control subjects. We speculated the possible involvement of TRIM10-induced modulation of the IFN/JAK/STAT signaling pathway in systemic lupus erythematosus. In line with our hypothesis, TRIM10 inhibited the activation of JAK/STAT signaling pathway triggered by various stimuli. TRIM10 restricted the IFN-I/JAK/STAT signaling pathway, which was independent of its E3 ligase activity. Mechanistically, TRIM10 interacted with the intracellular domain of IFNAR1 and blocked the association of IFNAR1 with TYK2. These data suggest the possible TRIM10 suppresses IFN/JAK/STAT signaling pathway through blocking the interaction between IFNAR1 and TYK2. Targeting TRIM10 is a potential strategy for treating autoimmune diseases.

Rb1-inducible coiled-coil 1 (RB1CC1) has been demonstrated to function as an inhibitor of proline-rich/Ca-activated tyrosine kinase 2 (PYK2) by binding to the kinase domain of PYK2, which promotes the proliferation, invasion, and migration of renal cell carcinoma (RCC) cells. Additionally, in breast cancer, PYK2 positively regulates the expression of transcriptional co-activator with PDZ-binding motif (TAZ) which in turn can enhance PDL1 levels in breast and lung cancer cells. The current study was performed to decipher the impact of RB1CC1 in the progression of RCC via regulation of the PYK2/TAZ/PDL1 signaling axis. Expression of RB1CC1 and PYK2 was quantified in clinical tissue samples from RCC patients. The relationship between TAZ and PYK2, TAZ and PDL1 was then validated. The cellular processes of doxorubicin (DOX)-induced human RCC cell lines including the abilities of proliferation, colony formation, sphere formation and apoptosis, as well as the tumorigenicity of transfected cells, were evaluated after the alteration of RB1CC1 expression. RB1CC1 exhibited decreased expression in RCC tissues and was positively correlated with patient survival. RB1CC1 could inhibit the activity of PYK2, which in turn stimulated the stability of TAZ protein by phosphorylating TAZ. Meanwhile, TAZ protein activated PDL1 transcription by binding to the promoter region of PDL1. RB1CC1 overexpression or PYK2 knockdown could help everolimus (EVE) to inhibit tumor proliferation and activate immune response. Taken together, RB1CC1 can potentially augment the response of RCC cells to immunotherapy by suppressing the PYK2/TAZ/PDL1 signaling axis.

Pseudouridine is the most abundant yet unexplored RNA modification in glioblastoma. Cui and coworkers find that PUS7, a pseudouridine depositing enzyme, promotes tumor growth and can be targeted by small molecule inhibitors. Mechanistically, PUS7 modifies tRNAs, reduces TYK2 translation, and downregulates a proliferation-restricting interferon-STAT1 pathway in glioblastoma.

Psoriasis is a common immune-mediated inflammatory disease affecting approximately 2% of individuals living in Western countries. Patients with psoriasis suffer from a multitude of comorbidities su...

This study analyzed the effects of the plant extracts (Citrus limon, Solanum lycopersicum, Zingiber officinale, Vitis vinifera and Allium sativum) on the growth of mammalian cells (Vero and MDA-MB-231) and evaluated the most effective plant extract for the expression of specific genes of the JAK/STAT pathway in human breast cancer cells. An antiproliferative bioassay involving neutral red-dye uptake was used to determine the anticancerous potential of plant extracts. In Vero cells, the ginger methanolic extract was least effective; whereas the lemon methanolic extract was more effective with 64 dilutions with IC50 51.42%. In MDA-MB-231 cells, the tomato and ginger methanolic, and grape water extracts were least effective, whereas lemon water extract was most effective with 32 dilutions with IC50 48.67%, by upregulating JAK1, JAK2, TYK2, IRF7 and IRF3 gene expressions of the JAK/STAT pathway. C. limon inhibited the growth of both Vero and MDA-MB 231 cells. It suggested that C. limon has anti-cancer potential by inducing the JAK/STAT pathway.

Janus kinases (Jaks) are a family of nonreceptor tyrosine kinase that include four different members, viz., Jak1, Jak2, Jak3, and Tyk2. Jaks play critical roles in immune cells functions; however, recent studies suggest they also play essential roles in nonimmune cell physiology. This review highlights the significance of epithelial Jaks in understanding the molecular basis of some of the diseases through regulation of epithelial-mesenchymal transition, cell survival, cell growth, development, and differentiation. Growth factors and cytokines produced by the cells of hematopoietic origin use Jak kinases for signal transduction in both immune and nonimmune cells. Among Jaks, Jak3 is widely expressed in both immune cells and in intestinal epithelial cells (IECs) of both humans and mice. Mutations that abrogate Jak3 functions cause an autosomal severe combined immunodeficiency disease (SCID) while activating Jak3 mutations lead to the development of hematologic and epithelial cancers. A selective Jak3 inhibitor CP-690550 (Xeljanz) approved by the FDA for certain chronic inflammatory conditions demonstrates immunosuppressive activity in rheumatoid arthritis, psoriasis, and organ transplant rejection. Here, we also focus on the consequences of Jak3-directed drugs on adverse effects in light of recent discoveries in mucosal epithelial functions of Jak3 with some information on other Jaks. Lastly, we brief on structural implications of Jak3 domains beyond the immune cells. As information about the roles of Jak3 in gastrointestinal functions and associated diseases are only just emerging, in the review, we summarize its implications in gastrointestinal wound repair, inflammatory bowel disease, obesity-associated metabolic syndrome, and epithelial cancers. Lastly, we shed lights on identifying potential novel targets in developing therapeutic interventions of diseases associated with dysfunctional IEC.

ObjectiveJanus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety.MethodsIn vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers.ResultsJAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib.ConclusionFilgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.

Many severe forms of COVID-19 have genetic causes, with variants providing information and thus supporting the hypothesis that moderate-intensity exercise would have a prophylactic role. In the case of genetic abnormalities related to the induction and amplification of type I interferons, in addition to curative administration of interferon, moderate intensity exercise could be used prophylactically. The same exercises inhibit the p38 MAPK pathway, being evaluated by clinical trials the drug inhibition of that pathway. In high physically active subjects, intermediate CCR2 monocyte decreased in response to moderate intensity exercise, and Cenicriviroc, an antagonist of the chemokine CCR5/CCR2b receptor, has been proposed for therapy. Exercise prevents the increased expression of Tyk2, and for COVID-19 therapy, corresponding to the defect of this gene, kinase inhibitors or Baricitinib have been proposed. The critical analysis of the data presented in the paper shows that for the prophylaxis of severe forms of COVID-19, moderate intensity exercises could be used.

Acrylamide is a chemical monomer; its polymer compounds are used in the manufacture of plastic, papers, adhesive tapes, dyes, and food packaging. Lately, scientists found that cooking (mainly roasting, baking, and frying) yields acrylamide. In addition to fried/baked potatoes, coffee and bakery products still contain substantial amounts of acrylamide. Acrylamide has toxic effects on different body systems include genitourinary, reproductive, nervous system, along with being a carcinogenic substance. The neurotoxicity of acrylamide includes central and peripheral neuropathy. In humans, the clinical manifestations include sensory or motor peripheral neuropathy, drowsiness, or cerebellar ataxia. Likewise, it presents with skeletal muscle weakness, hindlimb dysfunction, ataxia, and weight loss in animals. The suggested mechanisms for acrylamide neurotoxicity include direct inhibition of neurotransmission, cellular changes, inhibition of key cellular enzymes, and bonding of kinesin-based fast axonal transport. Moreover, it is suggested that acrylamide's molecular effect on SNARE core kinetics is carried out through the adduction of NSF and/or SNARE proteins. Lately, scientists showed disruption of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) cell signaling pathways in human differentiating neuroblastoma SH-SY5Y cells, exposed to acrylamide. Different treatment modalities have been revealed to shield against or hasten recovery from acrylamide-induced neuropathy in preclinical studies, including phytochemical, biological, and vitamin-based compounds. Still, additional studies are needed to elucidate the pathogenesis and to identify the best treatment modality.

Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-β-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-β-induced migration of HSCs at 0.25 μM in wound-healing assays.

Tyrosine kinase 2 (Tyk2), which associates with the receptors for type I interferon (IFN) and interleukins (IL)-6, IL-10, IL-12, and IL-23, is critical to mediate cytokine-induced signals. Tyk2 plays an essential role in the constitutive production of small amount of type I IFNs and in the promotion of differentiation from naive T cells into Th1 or Th17 effector cells via IL-12- and IL-23-induced signals. Additionally, Tyk2-mediated signaling suppresses the in vivo production of IL-10, which is a strong anti-inflammatory cytokine. The elevated IL-10 production in the peritoneal cells of Tyk2-deficient mice are alleviated by treatment with either diclofenac, a cyclooxygenase inhibitor, or H-89, a protein kinase A inhibitor. Notably, significantly higher basal prostaglandin E2 (PGE2) production is observed in peritoneal cavity of Tyk2-deficient mice than that of wild-type mice. Phosphorylation of cAMP response element-binding protein, induced by P. acnes and PGE2 addition, is upregulated in Tyk2-deficient macrophages. This indicates that higher IL-10 production in Tyk2-deficient mice is likely a result of the enhanced PGE2-protein kinase A pathway. Thus, Tyk2-mediated signaling regulates multiple events during immune and/or inflammatory responses.

Fangteng Liu,1,2 Hengyu Wu1 1Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang 330009, Jiangxi, People’s Republic of China; 2Faculty of Medicine, University of Munich, Munich 80336, GermanyCorrespondence: Hengyu Wu Tel +86-15270280590Email why_wuhengyu0590@163.comBackground: Janus kinases (JAKs) are a family of non-receptor tyrosine kinases involved in multiple malignancies. However, clinical values of JAKs as prognostic markers and potential mechanism as molecular targets in breast invasive carcinoma (BC) are not completely clarified.Methodology: TIMER, UALCAN and GEPIA were used to assess the expression and methylation levels of JAKs in BC. Kaplan–Meier Plotter, bc-GenExMiner, SurvExpress, TRGAted, MethSurv, and SurvivalMeth were used to assess the multilevel prognostic significance of JAKs in breast cancer patients. And cBioPortal, TIMER, STRING, GeneMANIA, NetworkAnalysis, LinkedOmics, DAVID 6.8, and Metascape were applied for multilayer networks and functional enrichment analyses. Correlations between immune cell infiltrates/their gene markers and JAKs were evaluated by TIMER.Results: We first explored the expression and methylation level of JAKs in breast cancer and found significantly reduced JAK1 and JAK2 expression at mRNA and protein levels, significantly higher JAK3 protein expression, and significantly increased TYK2 expression at mRNA level but decreased at protein level. In addition, hypermethylation of JAK3 and TYK2 and hypomethylation of JAK1 were found in tumor samples. In terms of prognostic values of JAKs in BC patients, low transcriptional levels of JAK1, JAK2, JAK3, and TYK2 indicated worse OS/DMFS/PPS/RFS/DFS, inferior DFS, worse RFS, and shorter OS/DMFS/RFS, respectively. The mRNA signature analysis showed that high-risk group had unfavorable OS/RFS/MFS. Low JAK2 protein level indicated unfavorable DSS/PFS in BC patients. Five CpGs of JAK1, four CpGs of JAK2, 20 CpGs of JAK3, and 13 CpGs of TYK2 were significantly associated with prognosis in BC patients. The DNA methylation signature analysis also suggested worse prognosis in the high-risk group. For potential biological roles of JAKs, interaction analyses, functional enrichment analyses for biological process, cellular component, molecular function, and KEGG pathway analyses of JAKs and their neighbor genes in BC were conducted. Kinase targets, gene–miRNA interactions, and transcription factor–gene interactions of JAKs were also identified. Furthermore, JAKs were found to be significantly related to immune infiltrates as well as the expression levels of multiple immune markers in BC.Conclusion: JAKs showed multilevel prognostic value and important biological roles in BC. They might serve as promising prognostic markers and possible targets in breast cancer.Keywords: Janus kinase, breast cancer, prognosis, immunity, biomarker, target

Genome-wide association studies identified variants in the transcription factor STAT4 gene and several other genes in the STAT4 signaling pathway, such as IL12A, IL12B, JAK2, and TYK2, which are associated with an increased risk of developing systemic lupus erythematosus (SLE) and other autoimmune diseases. Consistent with the genome-wide association studies data, STAT4 was shown to play an important role in autoimmune responses and autoimmunity development in SLE mouse models. Despite such important role for STAT4 in SLE development in mice and humans, little is known whether and how STAT4 may regulate extrafollicular Ab-forming cell (AFC) and follicular germinal center (GC) responses, two major pathways of autoreactive B cell development and autoantibody production. To our surprise, we found STAT4 to be largely dispensable for promoting autoimmune AFC and GC responses in various autoimmune- and SLE-prone mouse models, which strongly correlated with autoantibody production, and immune complex deposition and immune cell infiltration in the kidney. We further observed that STAT4 deficiency had no effects on AFC, GC, and Ag-specific Ab responses during protein Ag immunization or influenza virus infection. Additionally, CD4+ effector and follicular Th cell responses in autoimmune- and SLE-prone mice and protein Ag–immunized and influenza virus–infected mice were intact in the absence of STAT4. Together, our data demonstrate a largely dispensable role for STAT4 in AFC, GC, and Ab responses in SLE mouse models and in certain foreign Ag–driven responses.

Individuals with genetic defects show an increased susceptibility to poorly pathogenic mycobacteria including nontuberculous mycobacteria and Bacillus Calmette-Guerin (BCG). In previous studies, defects in multiple genes were identified to be associated with mycobacterium infection including tyrosine kinase 2 (TYK2). The mutations lead to insufficient production of interferon (IFN)-γ or an insufficient response to IFN-α/β, interleukin (IL)-6, IL-10, IL-12 and IL-23. Herein, we describe a case of Mycobacterium intracellulare infection in a male with abdominal pain and diarrhea. Whole exome sequencing of the genomes revealed a compound heterozygous mutation (c.3083A>G/c.2590C>T, p.N1028S/p.R864C) in the TYK2 gene. The patient recovered after two years of anti-mycobacterial treatment and no relapse was observed so far. We also reviewed 24 cases of mycobacterial infection associated with TYK2 deficiency which provides evidence of how personalised genomics can improve outcomes.