Janus Kinase/signal Transducer And Activator Of Transcription Research Articles

Methamphetamine-induced cardiotoxicity: in search of protective transcriptional mechanisms.

Crystalline methamphetamine hydrochloride is an illegal drug with ahigh addictive potential, better known by its colloquial name "ice" or "crystal meth". The abuse of this drug has led to significant health problems worldwide. Like other amphetamine-type stimulants, chronic consumption of methamphetamine leads to direct toxic effects on the central nervous system, causing cognitive impairment, depressive behavior, and other severe neurological or psychiatric symptoms. Besides its neurotoxicity, the drug exhibits numerous deleterious effects on the cardiovascular system, including hypertension, accelerated atherosclerosis, vasospasm-induced acute coronary syndromes, sudden cardiac death, and dilated cardiomyopathy with congestive heart failure and left ventricular dysfunction. The excessive release of catecholamines upon methamphetamine exposure causes vasoconstriction and vasospasm, which ultimately lead to hypertension, tachycardia, endothelial dysfunction, and cardiotoxicity. While numerous studies have focused on transcription factors expressed in the brain that cause the neurotoxic effects of the drug, much less is known about transcription factors involved in the development of methamphetamine-induced heart failure. In this article, we provide an overview of the Janus kinase-signal transducer and activator of transcription3 (JAK-STAT3) pathway involved in ischemia/reperfusion injury in the myocardium, which may be activated by the vasospasm-inducing action of the drug. However, much more work is needed to decipher the precise role of STAT protein family members, including the potentially cardioprotective STAT3, in the pathogenesis of methamphetamine-induced cardiotoxicity.

Downregulation of BmSTAT transcription factor promoted nucleopolyhedrovirus replication in Bombyx mori

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a crucial role in the viral immune processes of organisms, with STAT being a key transcription factor downstream in this pathway. The STAT gene of Bombyx mori has two splicing forms, named BmSTAT-S and BmSTAT-L. This study compared the effects of the two splicing forms on Bombyx mori nucleopolyhedrovirus (BmNPV) infection through cell-level interference and further explored whether BmSTAT participates in the immune response to BmNPV infection via transgenic intervention at the individual level. Our research results indicated that BmNPV upregulates the expression of BmSTAT-S and BmSTAT-L in Bombyx mori BmE cells and larvae. Furthermore, BmE cells with interference of BmSTAT-S or BmSTAT-L displayed significantly higher expression levels of the viral gene GP41 and increased viral fluorescence compared to the control group after 48 h of infection with BmNPV. Then, we constructed transgenic silkworms with genetic interference, and the results showed that both the transgenic silkworms with systemic interference and midgut-specific interference of the two splice forms of BmSTAT exhibited significantly reduced survival rates and increased viral replication numbers after infection with BmNPV. The above results indicated that the BmSTAT gene is involved in the immune response of Bombyx mori to BmNPV and these findings lay the foundation for further research on the mechanism of JAK/STAT signaling pathway involvement in BmNPV infection.

Oral administration of ruxolitinib in psoriasis vulgaris: A case report of plaque psoriasis accompanied by myelofibrosis secondary to polisitemia vera successfully treated with oral ruxolitinib.

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune cell infiltration. Various therapies have been discovered for psoriasis, including topical treatments, phototherapy, conventional systemic agents such as methotrexate, retinoids and ciclosporine, as well as biologics. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway inhibitors targeting Tumor Necrosis Factor alpha (TNF-α), interleukin (IL)-23 and IL-17 can be effective in psoriasis. Ruxolitinib is a US Food and Drug Administration-approved first-generation Janus kinase inhibitor for polycythemia vera, myelofibrosis, and acute graft-versus-host disease. Ruxolitinib cream has been investigated in various dermatologic diseases, including atopic dermatitis, vitiligo, psoriasis, and alopecia areata. However, there is limited data on the efficacy of oral ruxolitinib in patients with psoriasis vulgaris. Here, we report a patient diagnosed with myelofibrosis coexisting with psoriasis vulgaris, successfully treated with oral ruxolitinib.

Puerarin alleviates osteoporosis in rats by targeting the JAK2/STAT3 signaling pathway.

Osteoporosis (OP) is a common chronic progressive bone disease that increases fracture risk in postmenopausal women. Research suggests that puerarin (Pue) may be an effective treatment for OP. This study examined the effects and underlying mechanisms of Pue in treating postmenopausal osteoporosis (PMOP) in rats. Sprague-Dawley (SD) rats underwent bilateral ovariectomy to simulate PMOP and were then treated with subcutaneous injections of Pue. Bone mineral density (BMD) was measured using a bone densitometer. Micro-CT scans assessed femur bone structure and various parameters were calculated: bone volume fraction (BV/TV), bone surface density (BS/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and bone surface area-to-bone volume ratio (BS/BV). Hematoxylin-eosin (HE) staining was employed to observe femoral tissue pathology. Serum levels of bone formation metabolism-related markers-osteocalcin (OC), bone alkaline phosphatase (BALP), and procollagen type I N-terminal propeptide (PINP)-were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in bone tissue were evaluated using Western blotting assay. The results showed improved bone density and reduced bone loss in rats treated with Pue. There were also significant increases in serum levels of OC and BALP, indicating enhanced osteogenesis. Furthermore, there was a decrease in activation of the JAK2/STAT3 pathway in femoral tissue, suggesting a pathway inhibition. These findings indicate that Pue may combat osteoporosis by promoting osteogenesis and inhibiting activation of the JAK2/STAT3 pathway activation.

JAK/STAT signaling pathway is involved in antibacterial immunity in the green peach aphid Myzus persicae (Sulzer)

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway within the innate immune system plays a crucial role in defending insects against bacterial, fungal, and viral pathogens. In this study, we identified and cloned five key genes of this signaling pathway in Myzus persicae: MpDome-1, MpDome-2, MpJak, MpStat92E-1, and MpStat92E-2. Our results illustrated that these genes were highly expressed in first, second and third-instar nymphs. Tissue-specific expression analysis revealed that the five genes were predominantly expressed in the gut. Upon bacterial challenge, particularly with Staphylococcus aureus, the expression levels of all five genes were significantly upregulated. Additionally, Escherichia coli infection significantly upregulated the expression levels of MpDome-1 and MpDome-2, while MpJak, MpStat92E-1 and MpStat92E-2 were weakly upregulated. Functional analysis through RNA interference-mediated knockdown of these target genes revealed a significant increase in mortality following infection with E. coli and S. aureus compared with the control group. These findings suggest that the JAK/STAT signaling pathway is crucial for immune defense against bacterial infections in M. persicae.

MiRNA-153 attenuates progression of non-small cell lung cancer through targeting positive regulatory/SET domain 2

Background: To explore whether micro ribonucleic acid (miR)-153 regulates positive regulatory/SET domain 2 (PRDM2) in a targeted manner and affects the proliferation and apoptosis of non-small cell lung cancer (NSCLC) A549 cells. Methodology: The expressions of miR-153 and PRDM2 in NSCLC tissues and A549 cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). TargetScan was utilized to predict miR-153 target genes. Methyl thiazolyl tetrazolium (MTT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were carried out to study the cell proliferation and apoptosis. Western blotting was performed to examine the changes in the proteins in the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway following the miR-153 overexpression. Results: The expression of miR-153 was decreased and that of PRDM2 was increased in NSCLC tissues and cells. Target genes regulated by miR-153 participated in self-vascular development, miRNA metabolic process and the Wnt signaling pathway. The overexpression of miR-153 led to an obvious reduction in the proliferation ability of A549 cells, a notable increase in apoptotic cells, and significant decreases in phosphorylated (p)-JAK2 and p-STAT3 proteins. Dual-luciferase reporter gene assay revealed that miR-153 could directly modulate the expression level of PRDM2. Conclusion: MiR-153 directly targets PRDM2 and affects A549 cell proliferation and apoptosis through the JAK/STAT pathway. Keywords: Non-small cell lung cancer; miR-153; positive regulatory/SET domain 2; Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway.

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.

Interference without interferon: interferon-independent induction of interferon-stimulated genes and its role in cellular innate immunity

ABSTRACT Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, which leads to the transcription of a battery of genes, collectively known as IFN-stimulated genes (ISGs). While the well-established role of IFNs in coordinating the innate immune response against viral infections is widely acknowledged, recent years have provided a more distinct comprehension of the functional significance attributed to non-canonical, IFN-independent induction of ISGs. In this review, we summarize the non-conventional signaling pathways of ISG induction. These alternative pathways offer new avenues for developing antiviral strategies or immunomodulation in various diseases.

Anti-inflammation Mechanisms of Flavones Are Highly Sensitive to the Position Isomers of Flavonoids: Acacetin vs Biochanin A.

Acacetin (ACA) and biochanin A (BCA) are isomeric monomethoxyflavones with different structural positions of the 4'-methoxy-phenyl group. Both of them are present in many commonly consumed foods, such as citrus fruits and vegetables, and have been discovered with anti-inflammatory activities, but their mechanisms of action are not clearly elucidated at the molecular level. Herein, we reported the structure-activity relationship of ACA and BCA regarding their potency in inhibiting nitric oxide (NO) production, proinflammatory enzyme expression, and mRNA expression of proinflammatory cytokines in the lipopolysaccharide (LPS)-induced RAW 264.7 cells. Furthermore, transcriptome analysis was conducted to map out the overall pathways impacted by these two isomers. Our results showed that ACA possessed higher suppressive activity in nitric oxide (NO) production (IC50 = 23.93 ± 1.74 μM for ACA and IC50 = 71.41 ± 8.07 μM for BCA), inducible nitric oxide synthase (iNOS) expression, and proinflammatory interleukin (IL)-1β mRNA expression, but lower inhibitory activity in IL-6 mRNA expression as compared with BCA. Although two compounds were revealed to bind to c-Src protein according to drug affinity responsive target stability (DARTS) and western blotting results, molecular docking and molecular dynamics (MD) simulation showed that they had different binding sites, which subsequently resulted in different signaling transduction. ACA primarily exerted anti-inflammatory activity through the mitogen-activated protein kinase (MAPK) signaling pathway, the tumor necrosis factor (TNF) signaling pathway, and the hypoxia-inducible factor (HIF)-1 signaling pathway, while BCA was particularly involved in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway, the nuclear factor kappa B (NF-κB) signaling pathway, the TNF signaling pathway, and the toll-like receptor (TLR) signaling pathway. Moreover, two isomers remained stable in the cell culture medium and did not encounter the biotransformation process in RAW 264.7 cells. However, BCA exhibited insufficient cellular uptake ability and transport efficiency in macrophages compared to ACA. Taken together, ACA is more promising for controlling inflammation and worthy of further study for human use.

Signaling pathways and targeted therapy for rosacea.

Rosacea is a chronic skin inflammatory disease with a global prevalence ranging from 1% to 20%. It is characterized by facial erythema, telangiectasia, papules, pustules, and ocular manifestations. Its pathogenesis involves a complex interplay of genetic, environmental, immune, microbial, and neurovascular factors. Recent studies have advanced our understanding of its molecular basis, focusing on toll-like receptor (TLR) 2 pathways, LL37 expression, mammalian target of rapamycin (mTOR) activation, interleukin (IL)-17 signaling, transient receptor potential vanilloid (TRPV) functions, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. LL37-associated signaling pathways, particularly involving TLR2 and mTORC1, are critical in the pathogenesis of rosacea. LL37 interacts with signaling molecules such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), nuclear factor kappa B (NF-κB), inflammasomes, C-X-C motif chemokine ligand 8 (CXCL8), mas-related G-protein-coupled receptor X2 (MRGPRX2)-TRPV4, and vascular endothelial growth factor (VEGF). This interaction activates macrophages, neutrophils, mast cells, and vascular endothelial cells, leading to cytokine release including tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β, C motif chemokine ligand (CCL) 5, CXCL9, and CXCL10. These processes contribute to immune response modulation, inflammation, and angiogenesis in rosacea pathophysiology. The IL-17 signaling pathway also plays a crucial role in rosacea, affecting angiogenesis and the production of inflammatory cytokines. In addition, recent insights into the JAK/STAT pathways have revealed their integral role in inflammatory and angiogenic mechanisms associated with rosacea. Rosacea treatment currently focuses on symptom management, with emerging insights into these molecular pathways providing more targeted and effective therapies. Biological agents targeting specific cytokines, IL-17 inhibitors, JAK inhibitors, and VEGF antagonists are promising for future rosacea therapy, aiming for enhanced efficacy and fewer side effects. This review provides a comprehensive overview of the current knowledge regarding signaling pathways in rosacea and potential targeted therapeutic strategies.

403 Impact of lysine, methionine, and histidine deficiencies on gene expression and upstream transcriptional regulators in bovine mammary epithelial cells: An RNA-sequencing analysis

Abstract Essential (E) amino acids (AA) may alter bovine mammary epithelial cell functions by impacting mRNA expression of genes through their upstream transcription factors. The objective of this research was to study the impact of EAA deficiencies on gene expression and to identify upstream transcriptional factors mediating their effects in bovine mammary epithelial cells. Epithelial cells were collected from the mammary glands of lactating dairy cows and cultured in combined media of DMEM/F12 and Medium 170, differentiated for 5 d, and subsequently treated in triplicate for 60 h with a control medium containing all EAA at normal plasma concentrations for cows (CTL), or a medium with 20 μM Lys (LY), 5 μM Met (LM), or 10 μM His (LH), which are each 25% of normal concentration. RNA was isolated from the cells and sequenced on an Illumina NovaSeq 6000 producing 150 base pair paired-end reads with a minimum sequencing depth of 150 million reads. Reads were cleaned with ‘fastp’ (Chen et al., 2018), aligned to the bovine reference genome (ARS-UCD1.2) using ‘STAR’ aligner (Dobin et al., 2013), and genes counted using ‘featureCounts’ (Liao et al., 2014). Differential expression of genes between treatment pairs was determined using the ‘DESeq2’ package (Love et al., 2014) in R. Genes with an absolute log2 fold change ≥ 1 and a false discovery rate of < 0.05 were considered differentially expressed. The number of differentially expressed genes relative to CTL was 780 for LY, 383 for LH, and 536 for LM. QIAGEN Ingenuity Pathway Analysis (IPA) identified four pathways consistently affected across LY, LM, and LH: kinetochore metaphase signaling, mitotic roles of polo-like kinase, cell cycle: G2/M DNA damage checkpoint regulation, and interferon signaling (Figure 1-3). Notably, the kinetochore metaphase signaling pathway was identified as the most significant across all treatments, suggesting a strong link to cell proliferation and apoptosis during EAA deficiency. The interferon signaling might be related to the Janus kinase 2/signal transducer and activator of transcription 5 (Jak2/STAT5) pathway which can promote the expression of genes encoding milk proteins such as β-casein and β-lactoglobulin. Furthermore, the IPA identified upstream transcription factors related to cell proliferation, apoptosis, autophagy, protein translation, endoplasmic reticulum biogenesis, and amino acid metabolism including NUPR1, FOXM1, MYC, CCND1, TP53, DDIT3, and ATF4 across all treatments. The findings suggest that AA deprivation regulates bovine mammary epithelial cell function by instigating amino acid response pathways and altering secretory cell number.

Sodium butyrate alleviates lipopolysaccharide-induced inflammation through JAK/STAT signalling in primary human corneal fibroblasts

BackgroundBacterial keratitis is a common cause of blindness. Antibiotic treatment leads to the rapid release of lipopolysaccharide (LPS), which can activate corneal fibroblasts and cause persistent and excessive inflammatory responses. The anti-inflammatory drugs currently used to treat keratitis have serious side effects. Therefore, the ability of sodium butyrate (NaB), which can suppress the production of proinflammatory cytokines and promote the production of anti-inflammatory cytokines, to ameliorate keratitis was assessed in the present study. MethodsThe effect of NaB on the viability of primary human corneal fibroblasts was assayed with a CCK-8 kit. Cell migration was assessed by an in vitro scratch assay. Cell phenotypes were assessed by Western blotting and immunofluorescence staining. An antibody array was used to measure the production of proinflammatory cytokines and chemokines. ResultsAt 0–1 mM, NaB had no significant effect on cell viability, promoted the expression of the keratocyte marker keratocan and inhibited the fibroblast marker vimentin. Inhibition of cell migration was observed in the wound healing assay. By targeting the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, NaB decreased the levels of inflammation-related cytokines and chemokines whose expression was induced by LPS. ConclusionsNaB maintained the keratocyte phenotype, inhibited cell migration, and relieved LPS-induced inflammatory responses through the JAK/STAT signalling pathway.

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

BackgroundInfluenza 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. PurposeTo investigate therapeutic effects and comprehensive mechanisms of geniposide on IAV infection and subsequent pneumonia. MethodsICR 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. ResultsGeniposide 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. ConclusionsGeniposide can attenuate IAV-induced pneumonia by regulating inflammatory cytokines production through the JAK/STAT pathway.

Ruxolitinib Has a Protective Effect on Ovarian and Endometrial Tissues in Diabetic Rats via STAT3 Pathway

Background: Hyperglycemia is associated with ovarian dysfunction. Advanced glycation end products (AGE) may affect ovarian function by binding to particular AGE receptors (RAGE). Hematopoiesis and immunological conditioning are both controlled by the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Many JAK-STAT signaling inhibitors, including ruxolitinib, have been approved to treat inflammatory disorders. We aimed to examine the potential protective effect of ruxolitinib, on ovarian dysfunction by comparing biochemical, pro-inflammatory, and histological abnormalities in a diabetic rat model. Methods: 24 female Wistar albino rats were included in the study. Diabetes was induced by streptozotocin (STZ) in 16 rats. Group 1: control (no diabetes mellitus, n = 8), Group 2 (diabetic = 8, 1 mL/kg/day saline, 4 weeks), and Group 3 (diabetic, n = 8, 2 mg/kg/day ruxolitinib, 4 weeks). The animals were euthanized, and bilateral hysterectomy and ovariectomy were performed for histopathological examination. The levels of signal transducer and activator of transcription 3 (STAT3) in tissue supernatants were measured. Results: Endometrial gland, ovarian stromal, and ovarian follicle degeneration scores were higher in group 2 compared with group 3 at p < 0.001, whereas ovarian STAT3 level was significantly higher in group 2 compared with group 3 at p < 0.001. Conclusions: Ruxolitinib can be a promising candidate for providing endometrial and ovarian structure continuity by JAK-STAT inhibition in diabetes.

Sedative-Hypnotic Effect and Mechanism of Carbon Nanofiber Loaded with Essential Oils of Ligusticum chuanxiong (Ligusticum chuanxiong Hort.) and Finger Citron (Citrus medica L. var. sarcodactylis) on Mice Models of Insomnia.

(1) Background: Insomnia is a neurological illness that poses a significant threat to both physical and mental health. It results in the activation of neuroglial cells, heightened neuroinflammation, oxidative stress, and disruptions in the Hypothalamic-Pituitary-Adrenal (HPA) axis. Ligusticum Chuanxiong (CX) and Finger citron (FC) are frequently utilized botanicals for addressing sleeplessness. Both herbs possess notable anti-inflammatory properties in their volatile oils. However, their effectiveness is hindered by the nasal mucosal irritation and instability they exhibit. (2) Methods: This study involved the preparation of a nanofiber composite system using carbon nanofiber (CNF) suspensions containing essential oils of Ligusticum chuanxiong-Finger citron (CXEO-FCEO-CNF). The effects and mechanisms of these essential oils in improving insomnia were investigated using an insomnia mouse model after encapsulation. (3) Results: The CXEO-FCEO-CNF had an average particle size of 103.19 ± 1.64 nm. The encapsulation rates of essential oils of Ligusticum chuanxiong (CXEO) and essential oils of Finger citron (FCEO) were 44.50% and 46.15%, respectively. This resulted in a considerable improvement in the stability of the essential oils over a period of 30 days. The essential oils effectively decreased the irritation of the nasal mucosa following encapsulation. Furthermore, CXEO-FCEO-CNF enhanced voluntary activity and sleep in mice with insomnia, notably boosted the activity of superoxide dismutase (SOD), reduced the concentration of lipoxidized malondialdehyde (MDA), decreased the levels of hormones associated with the HPA axis, and regulated the levels of neurotransmitters, resulting in a beneficial therapeutic outcome. CXEO-FCEO-CNF contains a total of 23 active ingredients, such as alpha-Asarone, (E)-methyl isoeugenol, and Senkyunolide. These ingredients primarily work by modulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling system to decrease oxidative stress and inflammatory reactions. (4) Conclusions: This study presented initial evidence that the combination of CXEO and FCEO in nanofiber formulations effectively reduces the nasal mucosal irritation and instability of essential oils. Furthermore, it demonstrated the potential anti-neuroinflammatory and therapeutic effects of these formulations in treating insomnia. Overall, this study provides a theoretical foundation for developing new essential oil formulations derived from herbs.

Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade

Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-β triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.

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 β3-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.

Inhibition of STRA6 suppresses NSCLC growth via blocking STAT3/SREBP-1c axis-mediated lipogenesis.

Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Stimulated by retinoic acid 6 (STRA6), a vitamin A transporter has shown to be involved in the pathogenesis of cancers. Nevertheless, the function of STRA6 in non-small cell lung cancer (NSCLC) progression remains undefined. We obtained cancer and adjacent tissues from NSCLC patients and conducted functional experiments on STRA6 on NSCLC cell lines and mice. High STRA6 expression is correlated with poor prognosis in patients with NSCLC. Results from in vitro and in vivo animal studies showed that STRA6 knockdown suppressed the proliferation, migration, and invasion of NSCLC cells in vitro and tumor growth in vivo through regulation of lipid synthesis. Mechanistically, STRA6 activated a Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling cascade which inducing the expression of STAT3 target gene. By inducing the expression of the target gene of STAT3, sterol regulatory element binding protein 1 (SREBP-1), STRA6 promotes SREBP-1-mediated adipogenesis and provides energy for NSCLC cell growth. Our study uncovers a novel STRA6/STAT3/SREBP-1 regulatory axis that enhances NSCLC metastasis by reprogramming of lipid metabolism. These results demonstrate the potential use of STRA6 as a biomarker for diagnosing NSCLC, which may therefore potentially serve as a therapeutic target for NSCLC.

Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome.

Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD.

Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo nicotinamide adenine dinucleotide (NAD + ) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail, we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a decrease of NAD + . We further demonstrate that Trp degradation along the KP occurs locally in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT in-vitro induces NAD + depletion and a pro-inflammatory state, which can largely be rescued by bypassing QPRT via other NAD + precursors. We hence propose a model of impaired de-novo NAD + synthesis from Trp in IBD. These findings point towards the replenishment of NAD + precursors as a novel therapeutic pathway in IBD.