IGFBP7 regulates cell proliferation and migration through JAK/STAT pathway in gastric cancer and is regulated by DNA and RNA methylation.

New biomarkers for early diagnosis of gastric cancer (GC), the second leading cause of cancer-related death, are urgently needed. IGFBP7, known to play various roles in multiple tumours, is complexly regulated across diverse cancer types, as evidenced by our pancancer analysis. Bioinformatics analysis revealed that IGFBP7 expression was related to patient prognosis, tumour clinicopathological characteristics, tumour stemness, microsatellite instability and immune cell infiltration, as well as the expression of oncogenes and immune checkpoints. GSEA links IGFBP7 to several cancer-related pathways. IGFBP7 deficiency inhibited GC cell proliferation and migration in vitro. Furthermore, an in vivo nude mouse model revealed that IGFBP7 downregulation suppressed the tumorigenesis of GC cells. Western blotting analysis showed that the JAK1/2-specific inhibitor ruxolitinib could rescue alterations induced by IGFBP7 overexpression in GC cells. Additionally, our bioinformatics analysis and in vitro assays suggested that IGFBP7 is regulated by DNA methylation at the genetic level and that the RNA m6A demethylase FTO modulates it at the posttranscriptional level. This study emphasizes the clinical relevance of IGFBP7 in GC and its influence on cell proliferation and migration via the JAK/STAT signalling pathway. This study also highlights the regulation of IGFBP7 in GC by DNA and m6A RNA methylation.

Up-regulated Lnc BTU promotes the production of duck plague virus DNA polymerase and inhibits the activation of JAK-STAT pathway to facilitate duck plague virus replication.

Duck plague virus (DPV) is the only herpes virus known to be transmissible among aquatic animals, leading to immunosuppression in ducks, geese and swans. Long noncoding RNAs (LncRNA) are known to participate in viral infections, acting as either immune defenders or viral targets to evade the host response, but their precise roles in waterfowl virus infections are yet to be fully understood. This study aimed to investigate the role of LncRNA in DPV-induced innate immune responses. Results showed that DPV infection greatly upregulated Lnc BTU expression in duck embryo fibroblasts (DEF) and Lnc BTU promoted DPV replication. Mechanically, 4 DPV proteins, namely UL46, UL42, VP22 and US10, interacted with Lnc BTU, leading to its upregulation. Specifically, Lnc BTU facilitated the production of DNA polymerase by enhancing UL42 expression, thereby promoting DPV replication. Additionally, Lnc BTU suppressed STAT1 expression by targeting the DNA binding domain (DBD) and promoting STAT1 degradation through the proteasome pathway. Furthermore, Lnc BTU inhibited the production of key antiviral factors such as IFN-α, IFN-ß, MX and OASL during DPV infection. Treatment with 2 JAK-STAT pathway activators in DEFs resulted in the inhibition of Lnc BTU expression and DPV replication. Interestingly, DPV infection led to a decrease in STAT1 levels, which was reversed by Si-Lnc BTU. These findings suggest that DPV relies on Lnc BTU to inhibit the activation of the JAK-STAT pathway and limit the production of type 1 interferons (IFN) to complete immune evasion. Our study highlights the novel role of DPV proteins UL46, UL42, VP22, US10 as RNA-binding proteins in modulating the innate antiviral immune response, and discover the role of a new host factor, Lnc BTU, in DPV immune evasion, Lnc BTU and STAT1 can be used as a potential therapeutic target for DPV infection and immune evasion.

Time-course analysis of antibody and cytokine response after the third SARS-CoV-2 vaccine dose.

The widespread administration of an additional dose of the SARS-CoV-2 vaccine has been promoted across adult populations, demonstrating a robust immune response against COVID-19. Longitudinal studies provide crucial data on the durability of immune response after the third vaccination. This study aims to explore the antibody response, neutralizing activity, and cytokine response against the SARS-CoV-2 ancestral strain (wild-type) and its variants during the timeline before and after the administration of the third vaccine dose. Anti-spike antibody titers and neutralizing antibodies blocking ACE2 binding to spike antigens were measured in 62 study participants at baseline, and on days 7, 21, and 180 post-vaccination. Cytokine levels were assessed at the same points except for day 180, with an additional measurement on day 3 post-vaccination. The analysis revealed no substantial variation in anti-spike antibody titer against the SARS-CoV-2 ancestral strain between the pre-vaccination phase and three days following the third dose. However, a significant nine-fold increase in these titers was observed by day 7, maintained until day 21. Although a decrease was observed by day 180, all participants still had detectable antibody levels. A similar trend was noted for neutralizing antibodies, with a four-fold rise by day 7 post-vaccination. At day 180, a diminution of neutralizing antibody titers was evident for both wild-type and all variants, including Omicron subvariant. A transient increase in cytokine activity, notably involving components of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, such as CXCL10 and IL-10, was observed within three days after the third dose. This study underscores a distinct amplification of humoral immune response seven days following the third SARS-CoV-2 vaccine dose and observes a decline in neutralizing antibody titers 180 days following the third dose, thus indicating the temporal humoral effectiveness of booster vaccination. A short-term cytokine surge, notably involving the JAK/STAT pathway, highlights the dynamic immune modulation post-vaccination.

Targeting signaling pathways with andrographolide in cancer therapy (Review).

Terpenoids are a large group of naturally occurring organic compounds with a wide range of components. A phytoconstituent in this group, andrographolide, which is derived from a plant called Andrographis paniculate, offers a number of advantages, including anti-inflammatory, anticancer, anti-angiogenesis and antioxidant effects. The present review elucidates the capacity of andrographolide to inhibit signaling pathways, namely the nuclear factor-κB (NF-κB), hypoxia-inducible factor 1 (HIF-1), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Wnt/ß-catenin and mitogen-activated protein kinase (MAPK) pathways, which are involved in cellular processes and responses such as the inflammatory response, apoptosis and angiogenesis. Inhibiting pathways enables andrographolide to exhibit its anticancer effects against breast, colorectal and lung cancer. The present review focuses on the anticancer effects of andrographolide, specifically in breast, colorectal and lung cancer through the NF-κB, HIF-1 and JAK/STAT signaling pathways. Therefore, the Google Scholar, PubMed and ScienceDirect databases were used to search for references to these prevalent types of cancer and the anticancer mechanisms of andrographolide associated with them. The following key words were used: Andrographolide, anticancer, JAK/STAT, HIF-1, NF-κB, PI3K/AKT/mTOR, Wnt/ß-catenin and MAPK pathways, and the literature was limited to studies published between 2010 to 2023. The present review article provides details about the different involvements of signaling pathways in the anticancer mechanisms of andrographolide.

Tofacitinib prevents depressive-like behaviors through decreased hippocampal microgliosis and increased BDNF levels in both LPS-induced and CSDS-induced mice.

Depressive disorders are a global mental health challenge that is closely linked to inflammation, especially in the post-COVID-19 era. The JAK-STAT pathway, which is primarily associated with inflammatory responses, is not fully characterized in the context of depressive disorders. Recently, a phase 3 retrospective cohort analysis heightened that the marketed JAK inhibitor tofacitinib is beyond immune diseases and has potential for preventing mood disorders. Inspired by these clinical facts, we investigated the role of the JAK-STAT signaling pathway in depression and comprehensively assessed the antidepressant effect of tofacitinib. We found that aberrant activation of the JAK-STAT pathway is highly conserved in the hippocampus of classical depressive mouse models: LPS-induced and chronic social defeat stress (CSDS)-induced depressive mice. Mechanistically, the JAK-STAT pathway mediates proinflammatory cytokine production and microgliosis, leading to synaptic defects in the hippocampus of both depressive models. Remarkably, the JAK inhibitor tofacitinib effectively reverses these phenomena, contributing to its antidepressant effect. These findings indicate that the JAK/STAT pathway could be implicated in depressive disorders, and suggest that the JAK inhibitor tofacitinib has a potential translational implication for preventing mood disorders far beyond its current indications.

RSAD2 suppresses viral replication by interacting with the Senecavirus A 2 C protein.

Senecavirus A (SVA), an emerging virus that causes blisters on the nose and hooves, reduces the production performance of pigs. RSAD2 is a radical S-adenosylmethionine (SAM) enzyme, and its expression can suppress various viruses due to its broad antiviral activity. However, the regulatory relationship between SVA and RSAD2 and the mechanism of action remain unclear. Here, we demonstrated that SVA infection increased RSAD2 mRNA levels, whereas RSAD2 expression negatively regulated viral replication, as evidenced by decreased viral VP1 protein expression, viral titres, and infected cell numbers. Viral proteins that interact with RSAD2 were screened, and the interaction between the 2 C protein and RSAD2 was found to be stronger than that between other proteins. Additionally, amino acids (aa) 43-70 of RSAD2 were crucial for interacting with the 2 C protein and played an important role in its anti-SVA activity. RSAD2 was induced by type I interferon (IFN-I) via Janus kinase signal transducer and activator of transcription (JAK-STAT), and had antiviral activity. Ruxolitinib, a JAK-STAT pathway inhibitor, and the knockdown of JAK1 expression substantially reduced RSAD2 expression levels and antiviral activity. Taken together, these results revealed that RSAD2 blocked SVA infection by interacting with the viral 2 C protein and provide a strategy for preventing and controlling SVA infection.

Translocator protein (TSPO) inhibits Nosema bombycis proliferation in silkworm, Bombyx mori.

Pebrine disease, caused by Nosema bombycis (Nb) infection in silkworms, is a severe and long-standing disease that threatens sericulture. As parasitic pathogens, a complex relationship exists between microsporidia and their hosts at the mitochondrial level. Previous studies have found that the translocator protein (TSPO) is involved in various biological functions, such as membrane potential regulation, mitochondrial autophagy, immune responses, calcium ion channel regulation, and cell apoptosis. In the present study, we found that TSPO expression in silkworms (BmTSPO) was upregulated following Nb infection, leading to an increase in cytoplasmic calcium, adenosine triphosphate, and reactive oxygen species levels. Knockdown and overexpression of BmTSPO resulted in the promotion and inhibition of Nb proliferation, respectively. We also demonstrated that the overexpression of BmTSPO promotes host cell apoptosis and significantly increases the expression of genes involved in the immune deficiency and Janus kinase-signal transducer and the activator of the transcription pathways. These findings suggest that BmTSPO activates the innate immune signalling pathway in silkworms to regulate Nb proliferation. Targeting TSPO represents a promising approach for the development of new treatments for microsporidian infections.

Immune-Molecular Link between Thyroid and Skin Autoimmune Diseases: A Narrative Review.

Autoimmune skin disorders, including Psoriasis, Lichen Planus, Vitiligo, Atopic Dermatitis, and Alopecia Areata, arise from a combination of genetic predisposition, external factors, and immunological dysfunction. It is well-documented that there is a strong correlation between autoimmune thyroid diseases and a range of dermatological disorders, especially urticaria. This review investigates possible links between autoimmune thyroiditis and a broader spectrum of autoimmune skin conditions, analyzing shared genetic markers, immunological mechanisms, and clinical correlations. Common pathogenic mechanisms include disrupted immune tolerance and oxidative stress, leading to chronic inflammation. Genetic factors, such as IL-23 receptor gene variants, increase the risk for Psoriasis, Alopecia Areata, and Hashimoto's thyroiditis. Additionally, CTLA-4 mutations enhance susceptibility to autoimmune thyroid and skin disorders. Shared genetic susceptibility was also reported in Lichen Planus and Vitilgo, even if different genetic loci might be involved. The breakdown of the immune system can determine a pro-inflammatory state, facilitating the development of autoimmunity and auto-antibody cross-reactions. The presence of similar antigens in skin cells and thyrocytes might explain why both tissues are affected. The significant overlap between these conditions emphasizes the necessity for a comprehensive diagnosis workup and treatment. Future research should focus on clarifying specific immunological pathways and identifying novel biomarkers.

HSV-2 Manipulates Autophagy through Interferon Pathway: A Strategy for Viral Survival.

Autophagy, an evolutionarily conserved cellular process, influences the regulation of viral infections. While the existing understanding indicates that Herpes Simplex Virus type 2 (HSV-2) maintains a basal level of autophagy to support its viral yield, the precise pathways governing the induction of autophagy during HSV-2 infection remain unknown. Therefore, this study aims to explore the role of type I interferons (IFN-I) in modulating autophagy during HSV-2 infection and to decode the associated signaling pathways. Our findings revealed an interplay wherein IFN-I regulates the autophagic response during HSV-2 infection. Additionally, we investigated the cellular pathways modulated during this complex process. Exploring the intricate network of signaling events involved in autophagy induction during HSV-2 infection holds promising therapeutic implications. Identifying these pathways advances our understanding of host-virus interactions and holds the foundation for developing targeted therapeutic strategies against HSV-2. The insight gained from this study provides a platform for exploring potential therapeutic targets to restrict HSV-2 infections, addressing a crucial need in antiviral research.

Geniposide attenuates influenza virus-induced pneumonia by regulating inflammatory cytokines production. Evidences to elucidate the followed pathway.

BACKGROUND: Influenza virus-induced pneumonia (IVP) is an infectious pulmonary disease characterized by exacerbated pulmonary inflammation caused by invasion of the influenza virus. IVP continues to threaten public health due to its high morbidity and mortality rates. Geniposide is one of the major bioactive constituents of G. jasminoides, which exerts antiviral and anti-inflammatory effects on influenza A virus (IAV) infection. PURPOSE: To investigate therapeutic effects and comprehensive mechanisms of geniposide on IAV infection and subsequent pneumonia. METHODS: ICR mice were infected intranasally with H1N1 (A/FM/1/47) to detect the anti-IAV activity of geniposide. Proteomics combined with function-integrated analysis were conducted to gain insight into the comprehensive mechanisms of geniposide. Subsequently, western blot was used to detect the phosphorylation of signal transducer and activator of transcription 1 (STAT1), signal transducer and activator of transcription 2 (STAT2), Interferon regulatory factor 9 (IRF9) and Janus kinase 1 (JAK1) in Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in lung tissue. Finally, RT-qPCR was used to detect the levels of interleukin 6 (IL-6), interleukin 17 (IL-17), interferon-γ (IFN-γ) and the STAT1 inhibitor (fludarabine) was used to verify the targeting between STAT1 and geniposide in RAW cells. RESULTS: Geniposide could significantly reduce the lung index, diminish lung pathology, decrease the virus loads and the inflammatory cytokines expression induced by IAV infection. A total of 411 differentially expressed proteins were identified among control, model, and geniposide-treated group in proteomic analysis. According to function-integrated analysis, 15 KEGG pathways were enriched and divided into 9 groups (modules), including influenza A, NOD-like receptor signaling, RIG-I-like receptor signaling, and so on. Among these modules, the most intensely interacting module pair was the NOD-like receptor signaling and influenza A, in which STAT1 and STAT2 acted as hubs with critical bridgeness role in the target network of geniposide. This indicated that geniposide may mitigate inflammation and alleviate IVP by JAK/STAT signaling pathways. Moreover, validation experiments confirmed that geniposide can significantly inhibit STAT1 and STAT2 phosphorylation as well as down-regulated expression of IL-6, IFN-γ and IL-17 in lung. Furthermore, when RAW cells were treated with the STAT1 inhibitor (fludarabine), the inhibitory effect of geniposide on IFN-γ and IL-6 was attenuated significantly. CONCLUSIONS: Geniposide can attenuate IAV-induced pneumonia by regulating inflammatory cytokines production through the JAK/STAT pathway.

IL-17A activates JAK/STAT signaling to affect drug metabolizing enzymes and transporters in HepaRG cells.

The founding family member, Interleukin (IL)-17A, is commonly known as IL-17 and has garnered increasingly attention for proinflammatory functions in autoimmune disorders. Although the effects of IL-17A on hepatic important drug-metabolizing enzymes and transporters (DMETs) expression still remain unclear, it is critical to ascertain owing to the well-established alterations of the drug disposition capacity of the liver occurring during immune imbalance. The present study was designed to explore the effects and mechanisms of IL-17A on DMETs mRNA and protein expression in HepaRG cells by real-time quantitative reverse transcription polymerase chain reaction and Western blot, respectively. It is discovered that IL-17A can inhibit most DMETs mRNA expression (drug-metabolizing enzymes of CYP1A2, CYP3A4, CYP2C9, CYP2C19, GSTA1 and UGT1A1 and transporters of NTCP, OCT1, OATP1B1, BCRP and MDR1) as well as the protein expression of CYP3A4 and CYP2C19, via the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. Thus, abnormal regulation of DMETs in IL-17A-mediated immune disorders such as psoriasis may cause alterations in pharmacokinetic processes and may occasionally result in unexpected drug-drug interactions (DDIs) in clinical practice.

circ_SMA4 promotes gastrointestinal stromal tumors malignant progression by sponging miR-494-3p/KIT axis and activating JAK/STAT pathway.

Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are implicated in the development and progression of various tumors. The aim of this study was to investigate the effects of circ_SMA4 in Gastrointestinal Stromal Tumors (GISTs) malignant progression. Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in GISTs. The effect of circ_SMA4 on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo settings. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_SMA4/miR-494-3p/ KIT axis. The results revealed that circ_SMA4 was significantly upregulated in GISTs, and exhibited high diagnostic efficiency with an AUC of 0.9824 (P < 0.01). circ_SMA4 promoted cell proliferation, invasion, migration, while inhibiting apoptosis in GISTs cells, both in vitro and in vivo. Silencing circ_SMA4 partially inhibited GISTs malignant progression. Additionally, circ_SMA4 acted as a competing endogenous RNA (ceRNA) by targeting miR-494-3p, and KIT was identified as a functional gene for miR-494-3p in GISTs. Furthermore, the results confirmed that circ_SMA4/miR-494-3p/ KIT axis plays a role in activating the JAK/STAT signaling pathway in GISTs. Therefore, for the first time, we have identified and emphasized that circ_SMA4 is significantly upregulated and plays an oncogenic role in GISTs by sponging miR-494-3p to activate the KIT/JAK/STAT pathway. These findings underscore circ_SMA4 may serve as a novel diagnostic biomarker and therapeutic target for GISTs.

Cannabidiol Alleviates Imiquimod-Induced Psoriasis by Inhibiting JAK2-STAT3 in a Mouse Model.

Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown efficacy in treating psoriasis, a chronic inflammatory skin disease affecting 1-3% of the global population; however, the mechanisms remain unclear. This study investigated CBD's effects on imiquimod (IMQ)-induced psoriasis in mice, which were divided into five groups: Control, IMQ, Clobetasol, 0.01% CBD, and 0.1% CBD. After inducing psoriasis with IMQ, clobetasol or CBD was applied. Psoriasis severity was assessed using the Psoriasis Area and Severity Index (PASI), with histopathological changes examined via hematoxylin and eosin staining. Gene expression of inflammatory markers (Il1b, Il6, Il12b, Il17a, Il22, and Tnf) was analyzed by RT-PCR, while protein levels of signal transducer and activator of transcription (STAT)3, P-STAT3, Janus kinase (JAK)2, and JAK3 were evaluated through western blot and immunohistochemistry. The results demonstrated that CBD significantly reduced PASI scores, epidermal thickness, keratosis, hyperproliferation, and inflammation. Moreover, CBD inhibited the IL-23 receptor-mediated JAK2-STAT3 signaling pathway, leading to the downregulation of Il1b, Il6, Il12b, Il17a, Il22, and Tnf expression. These findings suggest that CBD effectively alleviates psoriasis-like symptoms in mice and may serve as a promising therapeutic agent for psoriasis by targeting the JAK2-STAT3 pathway.

JAK/STAT Signaling Pathway Mediates Anti-Tumor Immunity of CD8+ T Cells in Renal Cancer.

Background: CD8+ T cells play a crucial role in immune responses, and have significant potential in tumor immunotherapy. The JAK/STAT pathway is essential for cytokine signal transduction and is linked to immune escape. However, its role in mediating CD8+ T cell anti-tumor immunity in renal cancer is not fully understood. Objective: To study the mechanisms underlying CD8+ T cell-mediated anti-tumor immunity and propose new possibilities for immunotherapy in patients with renal cancer. Methods: CD8+ T cells from mouse spleens were sorted using immunomagnetic beads, and their purity was confirmed by flow cytometry. Proliferation was analyzed using CCK-8 and CFSE assays. Activation of CD8+ T cells was assessed through ELISA and Western blotting. The malignant properties of Renca cells were evaluated through flow cytometry, Calcein-AM/PI staining, wound healing, Transwell, Western blot, and immunofluorescence. A subcutaneous tumor model in nude mice was used to examine the role of JAK1/STAT1 pathway in vivo. Results: Inhibitors of JAK1 and STAT1 significantly reduced the proliferation and activation of CD8+ T cell. Co-culture with CD8+ T cells increased apoptosis and inhibited the proliferation, migration, and invasion of Renca cells. The effects were diminished by JAK1 and STAT1 inhibitors, confirming that CD8+ T cells exert antitumor effects through the JAK1/STAT1 pathway. In vivo, inhibition of this pathway reduced the anti-tumor effects of CD8+ T cells. Conclusion: Inhibitors of JAK1 and STAT1 weakened the antitumor effects of CD8+ T cells, suggesting that targeting this pathway could enhance CD8+ T cell-mediated immunity in renal cancer.

Programmed death-ligand 1 expression in patients with primary or secondary myelofibrosis.

BACKGROUND: It has been described in mice models that myeloproliferative neoplasm (MPN) with JAK2-V617F mutation has an increased expression of programmed death-ligand 1 (PD-L1) in megakaryocytes leading to cancer immune evasion by inhibiting the T-lymphocytes. AIMS: To quantify and compare the PD-L1 expression on bone marrow (BM) of patients with MPN JAK2 positive, negative, and normal controls. METHODS: We collected BM of patients with MPN JAK2 positive, negative and normal controls from 1990 to 2019. We also created a scoring system to quantify PD-L1 expression in megakaryocytes. RESULTS: We obtained 14 BM with JAK2 positive PMF, 5 JAK2 negative PMF, and 10 patients with normal BM biopsies. PD-L1 expression was higher in the JAK2 positive group compared with the control group with a score of 212.6 versus 121.1 (t-value 2.05, p-value 0.025). In addition, the score was higher in the PMF group regardless of JAK2 mutational status when compared with the control group with score of 205.9 versus 121.1 (t-value 2.12, p-value 0.021). There was no difference in the PD-L1 score between the JAK2 negative versus the control group 187.2 versus 121.1 (t-value 1.02, p-value 0.162). CONCLUSION: These findings suggest that PMF patients with a JAK2 mutation have a higher PD-L1 expression in megakaryocytes compared with the control group. We postulate that the combination of checkpoint and JAK2 inhibitors may be an active treatment option in JAK2 mutated PMF given the higher PD-L1 expression.

In-silico assessment of novel peptidomimetics inhibitor targeting STAT3 and STAT4 N-terminal domain dimerization: A comprehensive study using molecular docking, molecular dynamics simulation, and binding free energy analysis.

Dysregulation in Janus kinase-Signal Transducer and Activation of Transcription (JAK-STAT) pathway is closely linked to various cancer types. The N-terminal domain (NTD) of STAT proteins, upon dimerization, assumes a multifaceted role with remarkable adaptability in mediating interactions between proteins. Consequently, the strategic targeting of the N-terminal domain of STATs has emerged as a promising tactic for disrupting dimerization and impeding the translocation of STAT proteins. In this study, we have deployed an integrated in-silico methodology to rationally design Peptidomimetic foldamers as inhibitors of the N-terminal domains of STAT3 and STAT4, with the objective of disrupting protein dimerization. Consequently, we have judiciously designed a series of peptidomimetics that encompass ß3-amino acids, bearing side chains that mimic the residues within interface II of the dimeric structures of the NTDs. Employing molecular docking techniques; we have assessed the binding affinity of these designed peptidomimetics toward both the NTDs. Furthermore, we have conducted an evaluation of the stability and conformational alterations within the docked complexes over an extensive Molecular Dynamics, subsequently computing the binding free energy utilizing MM/PBSA calculations. Our findings unequivocally demonstrate that the peptidomimetic foldamers we have devised (Peptide-A, Peptide-B, and Peptide-C) exhibit a propensity to bind to and impede the dimerization process of the NTDs of both STAT3 and STAT4. These outcomes serve to underscore the potential of these meticulously designed peptidomimetics as potential candidates meriting further exploration in the realm of cancer prevention and management.

Protein-coding circular RNA enhances antiviral immunity via JAK/STAT pathway in Drosophila.

RNA interference (RNAi) drives powerful antiviral immunity in plants and animals so that many viruses must express viral suppressor of RNAi (VSR) to establish virulent infection. However, little is known about the immune responses conferring resistance against viruses that have evolved the counter-defensive strategy to suppress antiviral RNAi. In this study, we discover that Drosophila cells infected with Drosophila C virus (DCV), a natural viral pathogen of Drosophila known to harbor a potent VSR, exhibit heightened expression of circular RNA circZfh1. circZfh1 confers virus resistance in the presence of viral suppression of antiviral RNAi. Furthermore, we validate that circZfh1 encodes a 274-amino acid protein, CRAV, essential for its antiviral activity. Notably, CRAV differs from its parental Zfh1 gene in a different reading frame, with the C-terminal 69 amino acids unique to CRAV. Our analysis also reveals the presence of CRAV in species within the melanogaster subgroup, with the C-terminal unique fragment undergoing accelerated evolution. Expression of CRAV upregulates the expression of the cytokine Upd3, which binds to its receptor, stimulating the JAK-STAT pathway and enhancing the immune response to DCV infection. Notably, CRISPR/Cas9 knockout of circZfh1 significantly enhances DCV replication in vitro and in vivo, with circZfh1-knockout adult flies displaying heightened disease susceptibility to DCV. In summary, our findings unveil a Drosophila protein-coding circular RNA that activates an innate immune signaling pathway crucial for virus resistance following the suppression of antiviral RNAi by viruses, thereby elucidating a novel counter-defensive strategy.IMPORTANCEEukaryotic hosts possess a complex, multilayered immune system that guards against pathogen invasion. In fruit flies, RNA interference (RNAi) drives robust antiviral immunity, prompting many viruses to express viral suppressors of RNAi (VSRs) to establish virulent infections. However, little is known about immune responses that confer resistance against viruses with potent VSRs. In this study, we discovered that Drosophila cells infected with Drosophila C virus (DCV), a natural viral pathogen possessing a potent VSR, upregulated the expression of circular RNA circZfh1. circZfh1 exhibits DCV-specific antiviral activity, encoding a 274-amino acid protein, CRAV, crucial for its antiviral effects. As a different reading frame from its parental Zfh1 gene, the C-terminal 69 amino acids are unique to CRAV, undergoing faster evolution. CRAV activates the JAK-STAT pathway, enhancing the immune response to DCV infection. Therefore, our work uncovers a new strategy for suppressing viral counter-defense through protein-coding circular RNA in fruit flies.

[Janus kinase inhibitors for skin disorders]. / Januskinaseinhibitoren für dermatologische Erkrankungen.

Immune factors such as interferon­É£ and interleukin 4 belong to the group of cytokines that are dependent on type I/II receptors for their signal transmission. Upon activation, these receptors transmit their signal to the cell nucleus and, thus, modulate gene transcription via a signaling cascade consisting of Janus kinases (JAK). This family of four kinases (JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK2)) subsequently activate members of the signal transducer and activator of transcription (STAT). This finding turned the JAK/STAT signaling pathway into a pharmacological target for the treatment of inflammatory diseases in which cytokines using type I/II receptors play a pathogenic role. In 2018, the European Medicines Agency (EMA) approved tofacitinib for the treatment of psoriatic arthritis. This was the first approval of a JAK/STAT pathway inhibitor for patients treated by dermatologists and rheumatologists. Since then, several new JAK inhibitors have been approved for dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and plaque-type psoriasis. In addition, JAK inhibitors are being investigated for the treatment of many other skin diseases. Thus, systemic JAK inhibitors complete the spectrum of immunotherapeutics with a broader immunological approach compared to monoclonal antibodies. The low molecular weight of JAK inhibitors enables the preparation of these drugs for both systemic and topical administration. Their utilization could represent a valuable alternative to topical steroids. The safety profile of JAK inhibitors must be taken into account. Possible long-term effects may become apparent in the next few years. This article describes both approved JAK inhibitors and relevant new JAK inhibitors that are promising candidates for approval as therapeutics in dermatology.

The Molecular Signature Related to Local Inflammatory and Immune Response in Canine Cutaneous Hypersensitivity Reactions: A Preliminary Study.

Cutaneous hypersensitivity reactions (CHRs) are complex inflammatory skin disorders that affect humans and dogs. This study examined the inflammatory and immune responses leading to skin damage, inflammation, and irritation by investigating gene expression through quantitative PCR (qPCR) and protein localization through the immunohistochemistry (IHC) of specific receptors and molecules involved in CHRs. Formalin-fixed paraffin-embedded (FFPE) samples from canine CHR skin (n = 20) and healthy dog skin (n = 3) were analyzed for expression levels of eight genes, including members of the pattern recognition receptor (PRR) family, CD209 and CLEC4G, the Regakine-1-like chemokine, and acute phase proteins (APPs), LBP-like and Hp-like genes. Additionally, we examined the local involvement of IL-6, Janus Kinase 1 (JAK1), and the signal transducer activator of transcription 3 (STAT3) in the CHR cases. The study demonstrated statistically significant increases in the expression levels of CD209, Hp-like (p < 0.01), LBP-like, Regakine-1-like, and CLEC4G (p < 0.05) genes in CHRs compared to healthy controls. Conversely, IL-6, JAK1, and STAT3 showed no significant difference between the two groups (p > 0.05). Protein analysis revealed JAK1 and STAT3 expression in CHR hyperplastic epithelial cells, dermal fibroblasts, and endothelial cells of small capillaries, indicating a possible involvement in the JAK/STAT pathway in local inflammatory response regulation. Our findings suggest that the skin plays a role in the development of CHRs.

Recent progress in tyrosine kinase 2 inhibitors for atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by persistent itching. Conventional treatments for AD include topical corticosteroids and calcineurin inhibitors, but there are emerging therapies targeting the JAK-TYK2 pathway that are promising for the treatment of AD. AREAS COVERED: This review comprehensively explores the pathogenesis, triggers, clinical manifestations, and conventional treatment options for AD. In addition, we discuss novel therapeutic agents targeting alternative signaling pathways, with a focus on clinical trials evaluating tyrosine kinase 2 (TYK2) inhibitors, including systemic and topical agents. We also provide a detailed assessment of ICP-332 efficacy, safety, and potential adverse effects in moderate-to-severe AD. EXPERT OPINION: Janus kinase inhibitors that have been recently approved have shown promise for the treatment of AD, especially for patients with severe phenotypes. Preliminary findings from randomized controlled trials suggest that TYK2 inhibitors exhibit rapid efficacy and acceptable safety in the management of AD; however, additional investigations, including long-term trials, are warranted to fully understand their efficacy and safety profile.