Janus Kinase-signal Transducer Research Articles

Biomimetic polydopamine loaded with janus kinase inhibitor for synergistic vitiligo therapy via hydrogel microneedles

BackgroundBoth oxidative stress and autoimmune responses play crucial roles in the development of vitiligo. Under oxidative stress, the apoptotic melanocytes expose self-antigens and release high mobility group box 1 (HMGB1), triggering autoimmune activation and recruiting CD8+ T cells. This process further leads to the destruction of melanocytes, resulting in the lack of melanin granules. Additionally, the accumulated CD8+ T cells release interferon-γ (IFN-γ) to activate janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in keratinocytes. Both oxidative stress and IFN-γ-JAK-STAT activation induce keratinocytes to express and release T cell chemotactic factors, exacerbating the process of vitiligo. Reducing the accumulation of CD8+ T cells by safeguarding melanocytes and keratinocytes from oxidative stress may be contemplated as a promising approach for vitiligo therapy.ResultsIn this study, we introduce a novel therapeutic agent called PDA-JAKi, which is capable of both eliminating oxidative stress and inhibiting T cell activation. Specifically, we have incorporated the janus kinase inhibitor (JAKi) tofacitinib into antioxidant polydopamine (PDA) nanoparticles, resulting in the formation of uniform PDA-JAKi nanodrug. PDA-JAKi effectively mitigates oxidative stress-induced apoptosis in melanocytes, reducing the antigen presentation and release of HMGB1. In addition, PDA-JAKi simultaneously attenuates oxidative stress and blocks the IFN-γ-JAK-STAT pathway to reduce the expression of C-X-C motif chemokine ligand 9/10/16 (CXCL9/10/16) in keratinocytes. We precisely deliver this therapeutic agent to the dermis using microneedle (MN) patches, aiming to enhance therapeutic efficacy compared to traditional drug administration methods. After PDA-JAKi MN treatment, the symptoms of vitiligo in mice are alleviated, and the affected areas regain pigmentation. Enhancements have been observed in the dermal thickness, the numbers of melanocytes and the content of melanin within the treated skin area. Moreover, there is a notable reduction in reactive oxygen species (ROS) level. Concurrently, substantial decreases were noted in CD8+ T cell infiltration, as well as the levels of IFN-γ and chemotactic factors CXCL9/10/16.ConclusionsIn summary, PDA-JAKi MN patches emerge as a promising therapeutic agent for vitiligo treatment.

Distinct single cell transcriptional profile in CD4+ T-lymphocytes among obese children with asthma.

Introduction: Obesity is a risk factor for asthma morbidity, associated with less responsiveness to inhaled corticosteroids. CD4+ T-cells are central to the immunology of asthma and may contribute to the unique obese asthma phenotype. We sought to characterize the single cell CD4+ Transcriptional profile differences in obese children with asthma compared to normal weight children with asthma. Methods: Eight normal weight and obese participants with asthma were clinically phenotyped and matched based on asthma control. Peripheral blood (PB) CD4+ T-cells were sorted, and single cell RNA sequencing was conducted. Cell clusters were identified by canonical gene expression, differential gene expression and reactome pathway analysis was applied. The obese PB bulk transcriptomic signature from the U-BIOPRED pediatric cohort was assessed in our cohort as well. Results: Obese children with asthma have a distinct CD4+ transcriptional profile with differential gene expression. There were more activated protein tyrosine phosphate receptor type C (PTPRC)high cells and less PTPRClow in the obese children. Obese children had higher enrichment of the neutrophil degranulation, interleukin-7 (IL-7) receptor and IL-7-related janus kinase-signal transducer and activator of transcription signaling pathways. Genes previously associated with more severe asthma, IL-32, FKBP5 gene expression, IL-6 and Rho transcriptional signaling, were also enriched in obese children with asthma. Discussion: Our findings shed insight into the molecular mechanisms underpinning more severe and steroid-resistant asthma among obese children. Further investigation is needed to identify potential new therapeutic targets for this group.

Predictive factors for treatment responses to baricitinib in severe alopecia areata: A retrospective, multivariate analysis of 70 cases from a single center.

Alopecia areata (AA) is a chronic, autoimmune skin disease characterized by non-scarring hair loss. Baricitinib, a Janus kinase inhibitor (JAKi), prevents hair loss and promotes hair regrowth by inhibiting the inflammatory Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway involved in cytotoxic T cell responses targeting hair follicles. The introduction of JAKi has transformed treatment against severe AA. However, treatment responses to JAKi are highly variable among patients, and the predictors of responsiveness remain insufficiently elucidated. This study aimed to identify independent predictive factors for the efficacy of baricitinib in patients with severe AA using multivariate analyses. A retrospective study was conducted on 70 severe AA patients who started baricitinib treatment at Tohoku University Hospital between July 2022 and August 2023. The primary outcome was the percentage of patients achieving a Severity of Alopecia Tool (SALT) score of ≤20 after 9 months of baricitinib treatment. Multivariate analysis assessed potential predictors of baricitinib treatment responses, including AA type, sex, age, disease duration, history of atopic dermatitis, intravenous methylprednisolone pulse (IVMP) therapy, and Clinician-Reported Outcome (ClinRO) measures for eyebrows and eyelashes. Achievement of a SALT score of ≤20 and SALT score improvement rates were used as objective variables in the multivariate analyses. Among the 70 patients completing 9 months of baricitinib treatment, 41% achieved a SALT score of ≤20. Multivariate analyses identified several independent predictors for positive outcomes, including shorter disease duration (≤4 years), history of IVMP, therapy SALT score of ≤95 at baricitinib initiation, and female sex. Further, we found differential response patterns based on AA type and sex. Specifically, AA type significantly influenced treatment responses, with ophiasis alopecia (OA) associated with the poorest improvement rate. In summary, the response to baricitinib in AA is significantly influenced by sex, AA type, disease duration, history of IVMP, and pre-treatment SALT score.

Inula japonica Thunb. and its active compounds ameliorate airway inflammation by suppressing JAK-STAT signaling.

Asthma, a chronic inflammatory disease, remains a global health challenge due to its complex pathophysiology and the limited treatment efficacy. This study explored the effect of Inula japonica Thunb. water extract (IJW) on asthma and its protective mechanisms. To assess the effects of IJW, we established an experimental asthma model in BALB/c mice using ovalbumin (OVA). Airway hyper-responsiveness (AHR) in response to methacholine was measured. We quantified inflammatory cell infiltration and cytokine and chemokine levels in bronchoalveolar lavage fluid (BALF), as well as total IgE levels in serum. Staining with hematoxylin and eosin and periodic acid-Schiff was used to examine the impact of IJW on lung pathology. We performed RNA sequencing to identify differentially expressed genes, which were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. We used interleukin (IL)-4/IL-13-treated human bronchial epithelial (HBE) cells to explore the associated mechanisms. IJW showed therapeutic effects against OVA-induced asthma by alleviating AHR, peribronchial inflammation, mucus hypersecretion, and collagen fiber deposition. It reduced total IgE levels in the serum and IL-4, IL-5, IL-13, eotaxin, macrophage-derived chemokines, and periostin levels in BALF. In IL-4/IL-13-treated HBE cells, IJW and its components suppressed the Janus kinase-signal transducer and activator of the transcription (JAK-STAT) signaling. These findings support IJW's potential as a pharmacological agent for allergic airway inflammation and asthma.

Translating tissue expression of STAT 1, 3 and 6 in prurigo nodularis to clinical efficacy of oral tofacitinib – A prospective single-arm investigational study

Background Interleukin (IL)-4, IL-13, IL-17, IL-22 and IL-3 are overexpressed in prurigo nodularis (PN). They mediate their action via the Janus Kinase (JAK) Signal transducer and activator of transcription (STAT) pathway. Objectives Our aim was to study the expression of tissue STAT1, STAT3, and STAT6, as well as the efficacy of the JAK-STAT inhibitor, tofacitinib, in PN. Methods A prospective study was conducted in a tertiary care hospital. Patients with PN were recruited after excluding secondary causes. Pruritus was graded using Pruritus Grading System Score (PGSS). All cases underwent histological assessment using immunohistochemical markers for STAT1, STAT3, and STAT6 in both lesional and perilesional skin. Tofacitinib was initiated at a dose of 5 mg twice daily or 11 mg once daily and then tapered to a maintenance dose. The final PGSS at the time of data evaluation, as well as the occurrence of remissions and relapses, was assessed. Results The majority of the 17 patients included in the study had moderate to severe disease. Immunohistochemical analysis revealed marked tissue expression of STAT6 in 13 and STAT3 in 10 patients, while STAT1 expression was seen in only 4 patients [p < 0.05], suggesting a Th2/Th17 tissue response. The mean onset of action of tofacitinib was 11.2 ± 6.44 days and the mean duration of treatment was 5.6 ± 2.2 months. A significant reduction in PGSS was noted after treatment (66.1%, P value 0.0004). Fourteen of the patients maintained remission on low-dose therapy (5 mg OD or A/D) while one patient experienced a relapse. No serious adverse effects were noted. Limitation We could not study the tissue cytokines and the expression of STATs after achieving clinical response on oral tofacitinib. Conclusion The efficacy of tofacitinib in PN is based on its inhibitory effect on Th2 and Th17 cytokines, which is dependent on STAT6 and STAT3.

What a tangled web we weave: crosstalk between JAK-STAT and other signalling pathways during development in Drosophila.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway is a key player in animal development and physiology. Although it functions in a variety of processes, the net output of JAK-STAT signalling depends on its spatiotemporal activation, as well as extensive crosstalk with other signalling pathways. Drosophila, with its relatively simple signal transduction pathways and plethora of genetic analysis tools, is an ideal system for dissecting JAK-STAT signalling interactions. In this review, we explore studies in Drosophila revealing that JAK-STAT signalling lies at the nexus of a complex network of interlinked pathways, including epidermal growth factor receptor (EGFR), c-Jun N-terminal kinase (JNK), Notch, Insulin, Hippo, bone morphogenetic protein (BMP), Hedgehog (Hh) and Wingless (Wg). These pathways can synergise with or antagonise one another to produce a variety of outcomes. Given the conserved nature of signal transduction pathways, we conclude with our perspective on the implication of JAK-STAT signalling dysregulation in human diseases, and how studies in Drosophila have the potential to inform and influence clinical research.

The Ability of SOCS1 to Cross-Regulate GM-CSF Signaling is Dose Dependent.

Suppressor of cytokine signaling (SOCS) 1 is a key negative regulator of interferon (IFN), interleukin (IL)12, and IL-2 family cytokine signaling through inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. To investigate the temporal induction of SOCS1 in response to cytokine in live cells and its selective regulation of signaling pathways, we generated a mouse expressing a Halo-tag-SOCS1 fusion protein (Halo-SOCS1) under control of the endogenous Socs1 promoter. Homozygous Halo-SOCS1 mice (Halo-Socs1KI/KI) were viable with minor T cell abnormalities, most likely due to enhanced Halo-SOCS1 expression in thymocytes compared with the untagged protein. IFNγ and IL-4 induced Halo-SOCS1 expression in macrophages derived from Halo-Socs1KI/KI mice, and a critical level of SOCS1 expression was required for inhibition of both IFNγ and granulocyte macrophage-colony stimulating factor (GM-CSF)-driven JAK-STAT signaling. In contrast, IFNγ priming to induce SOCS1 did not cross-regulate IL-4 signaling. This study indicates that while SOCS1 expression needs to exceed a critical threshold to inhibit IFNγ signaling, its selective regulation of cytokine signaling results from an as yet undetermined, level of regulatory control.

Research progress on the pathogenesis of psoriasis and its small molecule inhibitors.

Psoriasis is a prevalent chronic systemic immune disease characterized by T-cellmediated hyperproliferation of keratinized cells. Among its various manifestations, plaque-type psoriasis is the most common. Treatment options for psoriasis encompass topical medications, biological therapies, phototherapy techniques, and others. However, traditional treatments are associated with numerous side effects. In contrast, targeted therapy has garnered increasing attention due to its high selectivity, strong safety profile, and favorable therapeutic outcomes. Patients with psoriasis lesions exhibit elevated levels of proinflammatory cytokines compared with the general population. These proinflammatory cytokines have been implicated in mediating psoriasis pathogenesis by inducing keratinocyte proliferation through multiple signaling pathways within the body. This study will delve into the Janus kinase-signal transducers and activators of transcription, phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB, also known as AKT), and nuclear factor Kappa-light-chain-enhancer of activated B cells signaling pathways to elucidate their roles in mediating psoriasis pathogenesis. In addition, we will summarize potential targets relevant to the treatment of psoriasis and discuss the design and activity assessment of their inhibitors. It also provides new insights for further in-depth study of psoriasis and development of novel molecularly targeted inhibitors.

SBL-JP-0004: A promising dual inhibitor of JAK2 and PI3KCD against gastric cancer.

Gastric cancer (GC) remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional therapies. The phosphoinositide 3-kinase and PI3K and Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathways play pivotal roles in GC progression, making them attractive targets for therapeutic interventions. This study applied a computational and molecular dynamics simulation approach to identify and characterize SBL-JP-0004 as a potential dual inhibitor of JAK2 and PI3KCD kinases. KATOIII and SNU-5 GC cells were used for in vitro evaluation. SBL-JP-0004 exhibited a robust binding affinity for JAK2 and PI3KCD kinases, as evidenced by molecular docking scores and molecular dynamics simulations. Binding interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target proteins. SBL-JP-0004 displayed an half-maximal inhibitory concentration (IC50) value of 118.9 nM against JAK2 kinase and 200.9 nM against PI3KCD enzymes. SBL-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells, with half-maximal growth inhibitory concentration (GI50) values of 250.8 and 516.3 nM, respectively. A significant elevation in the early phase apoptosis (28.53% in KATOIII cells and 26.85% in SNU-5 cells) and late phase apoptosis (17.37% in KATOIII cells and 10.05% in SNU-5 cells) were observed with SBL-JP-0004 treatment compared to 2.1% and 2.83% in their respective controls. The results highlight SBL-JP-0004 as a promising dual inhibitor targeting JAK2 and PI3KCD kinases for treating GC and warrant further preclinical and clinical investigations to validate its utility in clinical settings.

Butyrate-producing Faecalibacterium prausnitzii suppresses natural killer/T-cell lymphoma by dampening the JAK-STAT pathway

BackgroundNatural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes.ObjectiveTo characterise the gut microbiota feature and identify...

The multiple-action allosteric inhibition of TYK2 by deucravacitinib: insights from computational simulations

Participating in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, TYK2 emerges as a promising therapy target in controlling various autoimmune diseases, including psoriasis and multiple sclerosis. Deucravacitinib (DEU) is a novel oral TYK2-specific inhibitor approved in 2022 that is clinically effective in moderate to severe psoriasis trials. Upon the AlphaFold2 predicted TYK2 pseudokinase domain (JH2) and kinase domain (JH1), we explored the details of the underlined allosteric inhibition mechanism on TYK2 JH2-JH1 with the aid of molecular dynamics simulation. Our results suggest that the allosteric inhibition of DEU on TYK2 is accomplished by affecting the JH2-JH1 interface and hampering the state transition and ATP binding in JH1. Particularly, DEU binding stabilized the autoinhibitory interface between JH2 and JH1 while disrupting the formation of the activation interface. As a result, the negative regulation of JH2 on JH1 was greatly enhanced. These findings offer additional details on the pseudokinase-dependent autoinhibition of the JAK kinase domain and provide theoretical support for the JH2-targeted drug discovery in JAK members.

The Role of Delta-Opioid Receptor in Mediating the Cardioprotective Effects of Morphine Preconditioning via the JAK2/STAT3 Pathway in a Failing Heart

BACKGROUND: Failing heart is more likely to suffer from myocardial ischemia/reperfusion (I/R) injury. This poses a great challenge for anesthesiologists in managing patients with heart failure during major surgery. Evidence from animal studies suggests that the delta-opioid receptor (DOR) contributes to alleviating acute myocardial injuries. However, little is known regarding the cardioprotective effects of cardiac DOR in patients with chronic heart failure. This study aimed to examine DOR expression in failing hearts and explore how DOR regulates the Janus kinase signal transducer and activator of the transcription-3 (JAK/STAT3) pathway to mediate morphine-induced cardio protection in heart failure. METHODS: We measured the DOR protein levels in human and rat heart tissues with chronic heart failure. To investigate the cardioprotective role of DOR, we administered the DOR-specific antagonist, naltrindole (NTD), and JAK2 inhibitor, AG490, before morphine preconditioning (MPC) in an isolated perfusion model of myocardial I/R injury in postinfarcted failing rat heart. We examined the infarct size, cardiac enzymes, cardiac function, cardiomyocyte apoptosis, apoptosis-related proteins, and STAT3 phosphorylation in the heart. RESULTS: The protein levels of DOR were significantly elevated in the myocardial tissues of humans and rats with chronic heart failure, by 1.4-fold (mean difference 0.41; 95% confidence interval [CI], 0.04–0.78; P = .032) and 2.3-fold (mean difference 1.26; 95% CI, 0.25–2.28; P = .009), respectively, compared to control tissues. Disease severity positively correlated with DOR expression (human: R2 = 0.316, P = .004; rat: R2 = 0.871, P = .021). Blocking DOR substantially reversed the cardioprotective effects of MPC in postinfarcted rat hearts, increasing the mean (standard deviation) percentage of infarct size from 15.0 (3.9)% to 30.8 (7.7)% (P < .001). Similarly, AG490 inhibited MPC restoration of cardiomyocyte apoptosis (33.3 [4.2]% vs 16.6 [3.4]%; P < .001). Both NTD and AG490 markedly suppressed STAT3 phosphorylation by 60.1% (mean difference 0.60; 95% CI, 0.27–0.93; P = .002) and 44.1% (mean difference 0.44; 95% CI, 0.06–0.83; P = .027), respectively, and also lowered the Bcl-2/Bax ratio by 85.5% (mean difference 0.86; 95% CI, 0.28–1.43; P = .006) and 68.2% (mean difference 0.68; 95% CI, 0.51–0.85; P < .001) respectively in heart tissues at the end of reperfusion. CONCLUSIONS: DOR protein levels increased in failing hearts of both humans and rats. Blocking cardiac DOR selectively reduced morphine-induced cardio protection by inhibiting the JAK2/STAT3 pathway. These findings indicate that cardiac DOR is a potential therapeutic target for protecting against heart failure due to I/R injury.

Traditional Chinese Herbal Medicine: Therapeutic Potential in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow obstruction and manifested by symptoms such as chronic cough, sputum, and dyspnea. Traditional Chinese medicine (TCM) has long been used to treat COPD. This article summarizes potential Chinese herbal medicines (CHM) for COPD treatment through a literature review and collation. The findings highlight 14 kinds of effective CHM for COPD, including Scutellaria radix, Salvia miltiorrhiza radix et rhizoma, Hippophae fructus, Ginseng radix et rhizoma, and Astragali radix. Flavonoids, terpenoids, alkaloids, and volatile oil constituents are the main bioactive components for the treatment of COPD. They mainly inhibit the tumor necrosis factor alpha/nuclear factor kappa B (TNF-α/NF-κB) signaling pathway by reducing the production and release of inflammatory factors such as interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), TNF-α, and NF-κB, thereby reducing inflammation in lungs of rats with COPD and protect the lung tissues. Some active ingredients can inhibit toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), Janus kinase-signal transducer and activator of transcription (JAK-STAT), and transforming growth factor beta (TGF-β) signaling pathways to express anti-inflammatory activity. This work establishes a foundation for using CHM in COPD treatment and offers new insights and approaches for developing novel anti-COPD drugs.

Cyclooxygenase-2/prostaglandin E2 pathway orchestrates the replication of infectious bronchitis virus in chicken tracheal explants.

Understanding the localized pathogenesis of infectious bronchitis virus (IBV) within the trachea of chickens is crucial for developing effective control strategies against this prevalent poultry pathogen. This study sheds light on the role of inducible cyclooxygenase (COX-2) and prostaglandin (PGE)2 in IBV pathogenesis using chicken tracheal organ culture (TOC) models. The findings reveal distinct patterns of COX-2 expression, PGE2 production, and immune responses associated with different IBV strains, highlighting the complexity of host-virus interactions. Furthermore, the identification of specific inhibitors targeting the COX-2/PGE2 pathway and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway provides potential therapeutic avenues for mitigating IBV infection in poultry. Overall, this study contributes to our understanding of the innate immune regulation of IBV infection within the trachea, laying the groundwork for the development of targeted interventions to control IBV outbreaks in poultry populations.

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.

Antiviral Effects of Avian Interferon-Stimulated Genes.

Interferons (IFNs) stimulate the expression of numerous IFN-stimulating genes via the Janus kinase-signal transducers and activators of the transcription (JAK-STAT) signaling pathway, which plays an important role in the host defense against viral infections. In mammals, including humans and mice, a substantial number of IFN-stimulated genes (ISGs) have been identified, and their molecular mechanisms have been elucidated. It is important to note that avian species are phylogenetically distant from mammals, resulting in distinct IFN-induced ISGs that may have different functions. At present, only a limited number of avian ISGs have been identified. In this review, we summarized the identified avian ISGs and their antiviral activities. As gene-editing technology is widely used in avian breeding, the identification of avian ISGs and the elucidation of their molecular mechanism may provide important support for the breeding of avians for disease resistance.

Integrated Transcriptomic Analyses of Liver and Mammary Gland Tissues Reveals the Regulatory Mechanism Underlying Dairy Goats at Late Lactation When Feeding Rumen-Protected Lysine.

Although low-protein diets can improve the nitrogen utilization efficiency and alleviate economic pressures in ruminants, they may also negatively impact dairy performance. Rumen-protected lysine (RPL) supplementation can improve the health status and growth performance of ruminants without compromising nitrogen utilization efficiency and feed intake. In this study, a total of thirty-three multiparous dairy goats in the late-lactation period were randomly divided into three groups that were separately fed the control diet (namely the protein-adequacy group), the low-protein diet (namely the protein-deficient group), and the RPL-supplemented protein-deficient diet (namely RPL-supplementation group) for five weeks. Here, we investigated the molecular mechanisms regarding how low-protein diets with RPL supplementation compromise lactation phenotypes in dairy goats through cross-tissue transcriptomic analyses. Dietary protein deficiency caused an imbalance in amino acid (AA) intake, disrupted hepatic function, and impaired milk synthesis. Transcriptomic analyses further showed that RPL supplementation exhibited some beneficial effects, like mitigating abnormal lipid and energy metabolism in the liver, elevating hepatic resistance to oxidative stress, improving the mammary absorption of AAs, as well as activating mammary lipid and protein anabolism primarily through peroxisome proliferator-activated receptor (PPAR) and janus kinase-signal transducer (JAK)-signal transducer and activator of transcription (STAT) signaling, respectively. RPL supplementation of a low-protein diet contributes to maintaining late lactation in dairy goats primarily through mitigating hepatic energy disturbances and activating both lipid and protein metabolism in the mammary glands. Since RPL supplementation initiated a series of comprised events on mammary protein and lipid metabolism as well as the hepatic function and energy generation in dairy goats under protein deficiency during late lactation, these findings thus provide some insights into how RPL supplementation helps maintain milk production and health in dairy mammals especially at late lactation.

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.

Roles of Growth Hormone-Dependent JAK-STAT5 and Lyn Kinase Signaling in Determining Lifespan and Cancer Incidence.

In rodents, loss of growth hormone (GH) or its receptor is associated with extended lifespan. We aimed to determine the signaling process resulting in this longevity using GH receptor (GHR)-mutant mice with key signaling pathways deleted and correlate this with cancer incidence and expression of genes associated with longevity. GHR uses both canonical janus kinase (JAK)2-signal transducer and activator of transcription (STAT) signaling as well as signaling via the LYN-ERK1/2 pathway. We used C57BL/6 mice with loss of key receptor tyrosines and truncation resulting in 1) loss of most STAT5 response to GH; 2) total inability to generate STAT5 to GH; 3) loss of Box1 to prevent activation of JAK2 but not LYN kinase; or 4) total knockout of the receptor. For each mutant we analyzed lifespan, histopathology to determine likely cause of death, and hepatic gene and protein expression. The extended lifespan is evident in the Box1-mutant males (retains Lyn activation), which have a median lifespan of 1016 days compared to 890 days for the Ghr-/- males. In the females, GhrBox1-/- mice have a median lifespan of 970 days compared to 911 days for the knockout females. Sexually dimorphic GHR-STAT5 is repressive for longevity, since its removal results in a median lifespan of 1003 days in females compared to 734 days for wild-type females. Numerous transcripts related to insulin sensitivity, oxidative stress response, and mitochondrial function are regulated by GHR-STAT5; however, LYN-responsive genes involve DNA repair, cell cycle control, and anti-inflammatory response. There appears to be a yin-yang relationship between JAK2 and LYN that determines lifespan.