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Introduction: Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. Method: In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. Results: A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Discussion: Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) significantly impacts the quality of life due to its prolonged duration and lack of effective treatment. Recent findings suggest that targeting neuroinflammation is a promising approach for treating NP. G protein‐coupled receptor 55 (GPR55), a member of the GPCR family, plays an important role in neuroinflammatory regulation. CID16020046, a GPR55 agonist, possesses promising anti‐neuroinflammatory effects. Herein, the therapeutic effect of CID16020046 on NP was investigated in an NP rat model. The NP model was established using the unilateral sciatic nerve chronic constriction injury (CCI) assay. Both sham and CCI rats were intraperitoneally administered with 20 mg/kg CID16020046. NP was assessed using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). First, we showed that GPR55 was downregulated in the spinal dorsal horn of CCI rats. After CCI rats were treated with CID16020046, the values of PWT and PWL were increased, indicating their effect on pain relief. The treated rats had attenuated release of inflammatory cytokines in the spinal cord, decreased spinal malondialdehyde (MDA) levels, and increased spinal glutathione peroxidase (GSH‐PX) activity. Additionally, the increased levels of phosphorylated nuclear factor (NF)‐κB p65 in CCI rats were significantly alleviated by CID16020046 treatment. Mechanistically, we showed that CID16020046 significantly suppressed the activation of the Janus kinase (JAK2)/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the spinal cord of CCI‐treated rats. However, Colivelin TFA (a STAT3 agonist) abolished the effect of CID16020046 on JAK2/STAT3 activation. In conclusion, our data demonstrate that the activation of GPR55 by CID16020046 alleviates NP and neuroinflammation in CCI rats by mediating the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

To investigate the effects of resveratrol (Res) on human fetal scleral fibroblasts (HFSFs) and its potential mechanism. HFSFs were randomly divided into the Res-treated group and the control group. Following, HFSFs were treated with or without a concentration of 10 μM Res for 48 h. To detect the expression of related genes, reverse transcription quantitative PCR (RT-qPCR) and western blotting were used. The apoptosis rate of different groups was determined using flow cytometry. The mRNA expression of matrix metalloproteinase 2 (MMP-2), Collagen, Type I, Alpha 1 (COL1A1), Janus Kinase 2 (JAK2), and Signal Transducer and Activator of Transcription 3 (STAT3)" was downregulated in the Res-treatment group compared to the control group, according to RT-qPCR. Western blotting revealed that Res therapy reduced the expression of MMP-2, JAK2, P-JAK2, STAT3, P-STAT3, and Bcl-2 associated protein X (Bax) while increasing the expression of COL1A1 and B-cell lymphoma-2 (Bcl-2). Flow cytometry showed that the cell apoptosis rate was significantly lower in HFSFs treated with Res. In conclusion, these findings suggest that Res increases COL1A1 expression while inhibiting MMP-2 and cell apoptosis in HFSFs, possibly through modulation of the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant tumor of the skin. B7 homolog 4 (B7-H4) and B7-H5 (B7 homolog 5) are associated with a variety of tumors. Investigate the potential role of B7-H4 and B7-H5 in regulating the tumorigenesis and progression of CSCC. B7-H4 and B7-H5 transcriptome data were collected from GEO and TCGA databases and subjected to bioinformatical analysis by protein–protein interaction (PPI) network, functional enrichment analysis, immune analysis, and drug–gene interaction prediction analysis. We characterized the expression of B7-H4 and B7-H5 in carcinoma tissues of CSCC patients by immunohistochemistry. Meanwhile, the clinical correlation of B7-H4 and B7-H5 in CSCC was explored by statistical analysis. B7-H4 and B7-H5 genes were under-expressed in CSCC and correlated with tumor staging. According to GO and KEGG Pathway enrichment analysis, B7-H4, and B7-H5 can regulate the proliferation and activation of T cells, lymphocytes, and monocytes, and the expression of cytokines, such as IL-6 and IL-10, in CSCC. B7-H4 and B7-H5 are also jointly involved in the occurrence and development of CSCC via the JAK-STAT and Notch signaling pathways. We found that B7-H4 and B7-H5 proteins were abnormally highly expressed in CSCC tissue and correlated with tumor size and stage. Our findings offer new insights into the pathogenesis of CSCC and suggest that B7-H4 and B7-H5 are novel tissue biomarkers and promising therapeutic targets for CSCC. [ABSTRACT FROM AUTHOR]

BACKGROUND In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of the testis-specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain high blood pressure during hypertension. METHODS Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral microinjection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1β, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the BP in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1β and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high BP in hypertensive rats, making it a potential therapeutic target for hypertension. [ABSTRACT FROM AUTHOR]

Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro, and reduced tumor growth in vivo. Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas. [ABSTRACT FROM AUTHOR]

[Display omitted] • 18 β -GA protects against CIRI in vivo and in vitro. • Insufficient autophagy at the later stages of reperfusion leads to apoptosis. • 18 β -GA inhibits apoptosis and activates autophagy by suppressing the JAK2/STAT3 pathway. Cerebral ischemia/reperfusion injury (CIRI) is a common feature of ischemic stroke leading to a poor prognosis. Effective treatments targeting I/R injury are still insufficient. The study aimed to investigate the mechanisms, by which glycyrrhizic acid (18 β -GA) in ameliorates CIRI. Our results showed that 18 β -GA significantly decreased the infarct volume, neurological deficit scores, and pathological changes in the brain tissue of rats after middle cerebral artery occlusion. Western blotting showed that 18 β -GA inhibited the expression levels of phosphorylated JAK2 and phosphorylated STAT3. Meanwhile, 18 β -GA increased LC3-II protein levels in a reperfusion duration-dependent manner, which was accompanied by an increase in the Bcl-2/Bax ratio. Inhibition of 18 β -GA-induced autophagy by 3-methyladenine (3-MA) enhanced apoptotic cell death. In addition, 18 β -GA inhibited the JAK2/STAT3 pathway, which was largely activated in response to oxygen-glucose deprivation/reoxygenation. However, the JAK2/STAT3 activator colivelin TFA abolished the inhibitory effect of 18 β -GA, suppressed autophagy, and significantly decreased the Bcl-2/Bax ratio. Taken together, these findings suggested that 18 β -GA pretreatment ameliorated CIRI partly by triggering a protective autophagy via the JAK2/STAT3 pathway. Therefore might be a potential drug candidate for treating ischemic stroke. [ABSTRACT FROM AUTHOR]

To explore the effects and mechanisms of the Xianhecao-Huanglian drug pair on autophagy-mediated intervention in acute inflammatory bowel disease (IBD) via the JAK2/STAT3 pathway. The study examined the underlying mechanisms of action of Xianhecao (APL) and Huanglian (CR) using a mouse model of dextran sodium sulfate (DSS)-induced acute inflammatory bowel disease (IBD) and in an in vitro model of IBD induced by lipopolysaccharide (LPS). The assessment of the therapeutic efficacy of the Xianhecao-Huanglian drug combination in a mouse model of IBD caused by DSS included the following parameters: Assessment of weight loss or gain. Measurement of the disease activity index (DAI). Assessment of histological damage. Determination of organ index. Measurement of colon length. Ascertain the levels of inflammatory cytokines in the intestinal tissues and serum of mice. Immunohistochemistry (IHC) for the measurement of tight junction protein concentrations in the colon mucosa, including ZO-1, claudin-1, and occludin. Measurement of mucin levels, specifically Mucin 2 (Muc2). Hematoxylin and eosin (HE) staining for the observation of histopathological alterations in colonic tissues. Examining the effect on goblet cells using periodic acid-Schiff (PAS) labeling. Application of Western blot and immunofluorescence techniques for the detection of autophagy-related markers in colonic tissues and proteins associated with the JAK2/STAT3 pathway. A cell inflammation model of IBD was induced through LPS stimulation, and a serum containing the Xianhecao-Huanglian drug pair (referred to as ACHP-DS) was formulated. Cell viability, anti-proinflammatory cytokines, tight junction proteins, mucins, autophagy-related markers, and the JAK2/STAT3 signaling pathway were assessed. The Xianhecao-Huanglian drug pair significantly ameliorated the symptoms and survival quality of acute IBD mice, reducing the disease activity index score, raising MUC2 secretion and tight junction protein expression to improve the integrity of the intestinal barrier, and preserving goblet cell function; thus, protecting the intestines. It effectively restrained triggering the signaling pathway that involves JAK2 and STAT3, leading to the suppression of inflammation and amelioration of colonic inflammation damage. Additionally, it induced autophagy in mouse colonic tissues.The in vitro experiments demonstrated that the Xianhecao-Huanglian drug combination enhanced the viability of LOVO and NCM460 cells when exposed to LPS stimulation. Furthermore, it suppressed the production of inflammatory cytokines such as IL-6, IL-1β, as well as TNF-α, whilst increasing the production of IL-10, ZO-1, along with MUC2. These effects collectively led to the alleviation of inflammation and the restoration of mucosal integrity. The results were consistent with what was shown in the in vivo trial. Moreover, the medication demonstrated effectiveness in reducing JAK2 along with STAT3 phosphorylation levels in the LPS-induced inflammatory model of IBD cells. The intervention with either the Xianhecao-Huanglian drug combination-containing serum or the JAK2/STAT3 pathway inhibitor AG490 reversed the pro-inflammatory effects and increased autophagy levels in the LPS-stimulated cells. The Xianhecao-Huanglian drug combination modulates the JAK2/STAT3 pathway, leading to the induction of autophagy, which serves as an intervention for IBD. [ABSTRACT FROM AUTHOR]

Introduction: The Janus kinase (JAK) family includes four cytoplasmic tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) constitutively bound to several cytokine receptors. JAKs phosphorylate downstream signal transducers and activators of transcription (STAT). JAK-STAT5 pathways play a critical role in basophil and mast cell activation. Previous studies have demonstrated that inhibitors of JAK-STAT pathway blocked the activation of mast cells and basophils. Methods: In this study, we investigated the in vitro effects of ruxolitinib, a JAK1/2 inhibitor, on IgE- and IL-3-mediated release of mediators from human basophils, as well as substance P-induced mediator release from skin mast cells (HSMCs). Results: Ruxolitinib concentration-dependently inhibited IgE-mediated release of preformed (histamine) and de novo synthesized mediators (leukotriene C4) from human basophils. Ruxolitinib also inhibited anti-IgE- and IL-3-mediated cytokine (IL-4 and IL-13) release from basophils, as well as the secretion of preformed mediators (histamine, tryptase, and chymase) from substance Pactivated HSMCs. Discussion: These results indicate that ruxolitinib, inhibiting the release of several mediators from human basophils and mast cells, is a potential candidate for the treatment of inflammatory disorders. [ABSTRACT FROM AUTHOR]

Background and Objective: Chronic atrophic gastritis (CAG) is a complex chronic disease caused by multiple factors that frequently occurs disease in the clinic. The worldwide prevalence of CAG is high. Interestingly, clinical CAG patients often present with a variety of symptom phenotypes, which makes it more difficult for clinicians to treat. Therefore, there is an urgent need to improve our understanding of the complexity of the clinical CAG population, obtain more accurate disease subtypes, and explore the relationship between clinical symptoms and medication. Therefore, based on the integrated platform of complex networks and clinical research, we classified the collected patients with CAG according to their different clinical characteristics and conducted correlation analysis on the classification results to identify more accurate disease subtypes to aid in personalized clinical treatment. Method: Traditional Chinese medicine (TCM) offers an empirical understanding of the clinical subtypes of complicated disorders since TCM therapy is tailored to the patient's symptom profile. We gathered 6,253 TCM clinical electronic medical records (EMRs) from CAG patients and manually annotated, extracted, and preprocessed the data. A shared symptom-patient similarity network (PSN) was created. CAG patient subgroups were established, and their clinical features were determined through enrichment analysis employing community identification methods. Different clinical features of relevant subgroups were correlated based on effectiveness to identify symptom-botanical botanical drugs correspondence. Moreover, network pharmacology was employed to identify possible biological relationships between screened symptoms and medications and to identify various clinical and molecular aspects of the key subtypes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: 5,132 patients were included in the study: 2,699 males (52.60%) and 2,433 females (47.41%). The population was divided into 176 modules. We selected the first 3 modules (M29, M3, and M0) to illustrate the characteristic phenotypes and genotypes of CAG disease subtypes. The M29 subgroup was characterized by gastric fullness disease and internal syndrome of turbidity and poison. The M3 subgroup was characterized by epigastric pain and disharmony between the liver and stomach. The M0 subgroup was characterized by epigastric pain and dampness-heat syndrome. In symptom analysis, The top symptoms for symptom improvement in all three subgroups were stomach pain, bloating, insomnia, poor appetite, and heartburn. However, the three groups were different. The M29 subgroup was more likely to have stomach distention, anorexia, and palpitations. Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon were the most popular botanical drugs. The M3 subgroup has a higher incidence of yellow urine, a bitter tongue, and stomachaches. Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora were the botanical drugs used. Vomiting, nausea, stomach pain, and appetite loss are common in the M0 subgroup. The primary medications are Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia. Through GO and KEGG pathway analysis, We found that in the M29 subgroup, Citrus medica, Solanum nigrum, Jiangcan, Shan ci mushrooms, and Dillon may exert their therapeutic effects on the symptoms of gastric distension, anorexia, and palpitations by modulating apoptosis and NF-κB signaling pathways. In the M3 subgroup, Smilax glabra, Cyperus rotundus, Angelica sinensis, Conioselinum anthriscoides, and Paeonia lactiflora may be treated by NF-κB and JAK-STAT signaling pathway for the treatment of stomach pain, bitter mouth, and yellow urine. In the M0 subgroup, Scutellaria baicalensis, Smilax glabra, Picrorhiza kurroa, Lilium lancifolium, and Artemisia scoparia may exert their therapeutic effects on poor appetite, stomach pain, vomiting, and nausea through the PI3K-Akt signaling pathway. Conclusion: Based on PSN identification and community detection analysis, CAG population division can provide useful recommendations for clinical CAG treatment. This method is useful for CAG illness classification and genotyping investigations and can be used for other complicated chronic diseases. [ABSTRACT FROM AUTHOR]

Medicinal food varieties developed according to the theory of medical and edible homologues are effective at preventing and treating chronic diseases and in health care. As of 2022, 110 types of traditional Chinese medicines from the same source of medicine and food have been published by the National Health Commission. Inflammation is the immune system's first response to injury, infection, and stress. Chronic inflammation is closely related to many diseases such as atherosclerosis and cancer. Therefore, timely intervention for inflammation is the mainstay treatment for other complex diseases. However, some traditional anti-inflammatory drugs on the market are commonly associated with a number of adverse effects, which seriously affect the health and safety of patients. Therefore, the in-depth development of new safe, harmless, and effective anti-inflammatory drugs has become a hot topic of research and an urgent clinical need. Polysaccharides, one of the main active ingredients of medical and edible homologous traditional Chinese medicines (MEHTCMs), have been confirmed by a large number of studies to exert anti-inflammatory effects through multiple targets and are considered potential natural anti-inflammatory drugs. In addition, the structure of medical and edible homologous traditional Chinese medicines' polysaccharides (MEHTCMPs) may be the key factor determining their anti-inflammatory activity, which makes the underlying the anti-inflammatory effects of polysaccharides and their structure–efficacy relationship hot topics of domestic and international research. However, due to the limitations of the current analytical techniques and tools, the structures have not been fully elucidated and the structure–efficacy relationship is relatively ambiguous, which are some of the difficulties in the process of developing and utilizing MEHTCMPs as novel anti-inflammatory drugs in the future. For this reason, this paper summarizes the potential anti-inflammatory mechanisms of MEHTCMPs, such as the regulation of the Toll-like receptor-related signaling pathway, MAPK signaling pathway, JAK-STAT signaling pathway, NLRP3 signaling pathway, PI3K-AKT signaling pathway, PPAR-γ signaling pathway, Nrf2-HO-1 signaling pathway, and the regulation of intestinal flora, and it systematically analyzes and evaluates the relationships between the anti-inflammatory activity of MEHTCMPs and their structures. [ABSTRACT FROM AUTHOR]

Xiaoyankangjun tablet (XYKJP) is a traditional Chinese medicine formulation used to treat intestinal disorders in clinical practice. However, the specific therapeutic mechanism of action of XYKJP in colitis has not yet been elucidated. This study aimed to reveal the multifaceted mechanisms of action of XYKJP in treating colitis. The model established based on DSS-induced colitis in C57BL/6 mice was employed to estimate the effect of XYKJP on colitis, which was then followed by histological assessment, 16S rRNA sequencing, RT-qPCR, ELISA, and Western blot. XYKJP alleviated the symptoms of DSS-induced colitis mainly by reducing oxidative stress, inflammatory responses, and intestinal mucosal repair in colitis tissues. In addition, XYKJP regulated the intestinal flora by increasing the relative abundance of Akkermansia and Bifidobacterium and reducing the relative abundance of Coriobacteriaceae_UCG-002. Mechanistically, XYKJP increased the content of short-chain fatty acids (SCFAs) in the feces, particularly propanoic acid and butyric acid, activated their specific receptor GPR43/41, furthermore activated the Nrf2/HO-1 pathway, and suppressed the JAK2/STAT3 pathway. XYKJP significantly alleviated the symptoms of experimental colitis and functioned synergistically by regulating the intestinal flora, increasing the production of SCFAs, and activating their specific receptors, thereby repressing oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Background: Corneal neovascularization (CNV) is a sight-threatening condition that necessitates epigenetic control. The role of lysine-specific demethylase 1 (LSD1) in CNV remains unclear, despite its established significance in tumor angiogenesis regulation. Methods: An alkali burn-induced CNV mouse model was used in vivo. The effects of LSD1 inhibitor tranylcypromine hydrochloride (TCP) were examined through slit lamp, histological staining, and immunofluorescence. The expression of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were assessed in corneal tissues. Oxidative stress and ferrous ion expression during CNV were determined using 4-HNE, GPX4, and FerroOrange staining. In vitro, a hypoxia-reoxygenation (H/R) model was established using human umbilical vein endothelial cells (HUVECs) to study LSD1 or hypoxia-inducible factor (HIF-1α) knockdown and lentiviral overexpression of HIF-1α. The effects on HUVECs migration, invasion, and angiogenesis were evaluated through cell scratching assay, transwell migration assay and tube formation assay. The role of ferroptosis was investigated using ROS staining, FerroOrange staining, and key ferroptosis proteins. Further, The JAK2/STAT3 pathway's involvement in CNV regulation was explored through in vivo experiments with subconjunctival injection of AG490. Results: The results showed a substantial correlation between corneal damage and LSD1 levels. In addition, HIF-1α expression was also elevated after alkali burns, and subconjunctival injection of TCP reduced corneal inflammation and neovascularization. Corneal alkali burns increased ROS levels and reduced antioxidative stress indicators, accompanied by elevated ferrous ion levels, which were reversed by TCP injection. In vitro, TCP or siRNAs inhibited H/R-induced ferroptosis and angiogenesis in HUVECs by affecting specific protein expressions and MDA, SOD, and GSH levels. HIF-1α levels, associated with ROS production, ferroptosis, and angiogenesis, increased during H/R, but were reversed by TCP or siRNA administration. HIF-1α overexpression counteracted the effects of LSD1 inhibition. Additionally, AG490 injection effectively reduced HIF-1α and VEGFA expression in the CNV model. Discussion: These findings suggest that LSD1 inhibition via the HIF-1α-driven pathway prevents angiogenesis, oxidative stress, and ferroptosis in corneal alkali burn-induced CNV, highlighting LSD1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

• AG490 ameliorated EAE severity and attenuated its typical symptoms. • The neuroprotective effect of AG490 is related to the regulation of JAK2/STAT3 pathway and autophagy. • AG490 may be a potential therapeutic in multiple sclerosis. Multiple sclerosis (MS) is an autoimmune inflammatory condition affecting the central nervous system, and experimental autoimmune encephalomyelitis (EAE) animal models have been extensively used to study it. T-helper 17 cells, which produce interleukin-17(IL-17), play crucial roles in MS pathogenesis, and the JAK2/STAT3 pathway has an essential function in their differentiation from naive CD4 + T cells. This study investigated the effects of the JAK2/STAT3 pathway inhibitor AG490 on EAE in vivo and in vitro , as well as the underlying mechanisms. AG490 ameliorated EAE severity and attenuated its typical symptoms by downregulating proteins associated with the JAK2/STAT3 pathway. Furthermore, it decreased T-helper 17 cell differentiation from naive CD4 + T cells by inactivating STAT3. In addition, it conferred protective effects against EAE by restoring autophagy. These findings indicate the potential of AG490 as a candidate anti-MS therapeutic. [ABSTRACT FROM AUTHOR]

sEVs-Que promoted the recovery of motor function in rats with spinal cord injury. [Display omitted] • sEVs reduce the degradation of Que and accumulate at the SCI site. • sEVs-Que reduce inflammation via the TLR4/NF-κB pathway. • sEVs-Que reduce the astrocyte scar through the JAK2/STAT3 pathway. • sEVs-Que promote the recovery of motor function in rats with SCI. Following spinal cord injury, the inflammatory environment at the injury site causes local microglia and astrocytes to activate, which worsens the nerve damage in the affected area. Quercetin, an anti-inflammatory agent, has been limited in spinal cord injury due to its poor water solubility and easy degradation. Stem cell-derived extracellular vesicles can go through the blood–brain barrier and are an ideal drug delivery system. In this study, umbilical cord mesenchymal stem cell-derived extracellular vesicles were used to load quercetin to prevent its degradation and allow it to accumulate at the site of spinal cord injury. Our results showed that quercetin-loaded extracellular vesicles could inhibit the activation of microglia to M1 phenotype through the TLR4/NF-κB pathway, and the activation of astrocytes to A1 phenotype through the JAK2/STAT3 pathway. This reduced the production of inflammatory factors, mitigated neuronal damage, and inhibited the growth of astroglial scar, but promoted the recovery of motor function in rats with spinal cord injury. [ABSTRACT FROM AUTHOR]

Purpose: Exosomal microRNAs have been identified as important mediators of communication between tumor cells and macrophages in the microenvironment. miR-541-5p was reported to be involved in hepatocellular carcinoma progression, but its role in gastric cancer (GC) and in GC cell-macrophage crosstalk is unknown. Methods: Cell proliferation, migration and invasion were respectively assessed by CCK-8 assay, scratch and Transwell assays. RT-qPCR was used to detect the level of miR-541-5p, macrophage markers and DUSP3. The percentage of CD11b+CD206+ cell population was analyzed by flow cytometry. Western blotting was employed to evaluate DUSP3-JAK2/STAT3 pathway proteins and exosome markers. The interaction between miR-541-5p and DUSP3 was verified by luciferase assay. Results: The results showed that miR-541-5p was upregulated in GC tissues and cells, and stimulated GC cell growth, migration and invasion in vitro. GC cells induce M2 macrophage polarization by secreting the exosomal miR-541-5p. Exosomal miR-541-5p maintained JAK2/STAT3 pathway activation in macrophages by targeting negative regulation of DUSP3. Inhibiting miR-541-5p significantly limited tumor growth in vivo. Conclusion: In conclusion, miR-541-5p promotes GC cell progression. GC cells may induce macrophage M2 polarization through the exosomal miR-541-5p-mediated DUSP3/JAK2/STAT3 pathway. miR-541-5p may be a potential therapeutic target for GC. [ABSTRACT FROM AUTHOR]

Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase Set1 regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of Set1 results in temporally progressive defects, arising as germ cell loss and developing into overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage non-cell-autonomously. Additionally, wild-type Set1, but not the catalytically inactive Set1, rescues the Set1 knockdown phenotypes, highlighting the functional importance of the methyltransferase activity of Set1. Further, RNA-sequencing experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene Stat92E and the BMP pathway gene Mad, which are upregulated upon Set1 knockdown. Genetic interaction assays support the functional relationships between Set1 and JAK-STAT or BMP pathways, as both Stat92E and Mad mutations suppress the Set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The phenotype of germ cell loss followed by over-proliferation when inhibiting a histonemethyltransferase also raises concerns about using their inhibitors in cancer therapy. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of large B‐cell lymphoma that primarily affects individuals with immunodeficiency, particularly those who are HIV positive. PBL commonly presents in males at an advanced stage and often affects extranodal regions such as the oral cavity and gastrointestinal tract. The prognosis for PBL is poor, with limited treatment options and low overall survival rates. This article discusses the potential use of bispecific antibodies, specifically teclistamab, in the treatment of refractory PBL in an HIV-positive patient. The case study highlights the efficacy of teclistamab and the importance of donor selection for allogeneic stem cell transplantation in EBV-positive lymphomas. However, further research is needed to establish standardized treatment guidelines for PBL. [Extracted from the article]

Objective: Gastric cancer is a malignant tumor with high morbidity and mortality all around the world. Because of its poor prognosis and low survival rate, the treatment of gastric cancer has received extensive attention. Cinnamaldehyde (CA) is the main single active component of the Chinese herbal medicine cinnamon, which has a variety of pharmacological effects. The inhibitory effect of CA on the growth of some tumor cells has been proven, but its therapeutic effect on gastric cancer has rarely been reported. Methods: Through network pharmacology, bioinformatics methods, and molecular docking technology, we predicted the interaction targets of CA and gastric cancer. Moreover, we found that apoptosis is an important mode of action of CA on gastric cancer cells. Subsequently, we validated it in gastric cancer cell lines cultured in vitro. Results: The results showed that in the presence of CA, the Jak2/Stat3 pathway was inhibited, the ratio of Bcl-2/Bax decreased, and the apoptosis of gastric cancer cells was promoted in a concentration-dependent. Conclusion: In conclusion, CA can promote the apoptosis of gastric cancer cells by inhibiting the activity of the Jak2/Stat3 pathway, which may achieve the effect of treating gastric cancer. [ABSTRACT FROM AUTHOR]

Baicalin is an active compound extracted from Scutellaria baicalensis with antioxidant and anti‐inflammatory properties. Bone mesenchymal stem cells (BMSCs)‐derived exosomes have shown promise for the treatment of hepatic ischemia–reperfusion (I/R) injury. This study aims to investigate the role of Baicalin‐pretreated BMSCs‐derived exosomes in hepatic I/R injury and its mechanisms. BMSCs were pretreated with or without Baicalin, and their exosomes (Ba‐Exo and Exo) were collected and characterized. These exosomes were administered to mice via tail vein injection. Treatment with Exo and Ba‐Exo significantly suppressed the elevation of ALT and AST induced by hepatic injury. Additionally, both Exo and Ba‐Exo treatments resulted in a reduction in the liver weight‐to‐body weight ratio. RT‐PCR results revealed a significant downregulation of pro‐inflammatory cytokines with Exo and Ba‐Exo treatment. Both Exo and Ba‐Exo treatment improved the Th17/Treg cell imbalance induced by I/R and reduced hepatic injury. Additionally, exosomes were cocultured with normal liver cells, and the expression of fibroblast growth factor 21 (FGF21) in liver cells was elevated through Ba‐Exo treatment. After treatment, the JAK2/STAT3 pathway was inhibited, and FOXO1 expression was upregulated. Finally, recombinant FGF21 was injected into mouse tail veins to assess its effects. Recombinant FGF21 injection further inhibited the JAK2/STAT3 pathway, increased FOXO1 expression, and improved the Th17/Treg cell imbalance. In conclusion, this study confirms the protective effects of Exo and Ba‐Exo against hepatic I/R injury. Ba‐Exo mitigates hepatic I/R injury, achieved through inducing FGF21 expression in liver cells, inhibiting the JAK2/STAT3 pathway, and activating FOXO1 expression. Therefore, baicalin pretreatment emerges as a promising strategy to enhance the therapeutic capability of BMSCs‐derived exosomes for hepatic I/R. [ABSTRACT FROM AUTHOR]

Drosophila melanogaster is an ideal model organism for investigating spermatogenesis due to its powerful genetics, conserved genes and visible morphology of germ cells during sperm production. Our previous work revealed that ocnus (ocn) knockdown resulted in male sterility, and CG9920 was identified as a significantly downregulated protein in fly abdomen after ocn knockdown, suggesting a role of CG9920 in male reproduction. In this study, we found that CG9920 was highly expressed in fly testes. CG9920 knockdown in fly testes caused male infertility with no mature sperms in seminal vesicles. Immunofluorescence staining showed that depletion of CG9920 resulted in scattered spermatid nuclear bundles, fewer elongation cones that did not migrate to the anterior region of the testis, and almost no individualization complexes. Transmission electron microscopy revealed that CG9920 knockdown severely disrupted mitochondrial morphogenesis during spermatogenesis. Notably, we found that CG9920 might not directly interact with Ocn, but rather was inhibited by STAT92E, which itself was indirectly affected by Ocn. We propose a possible novel pathway essential for spermatogenesis in D. melanogaster , whereby Ocn indirectly induces CG9920 expression, potentially counteracting its inhibition by the JAK-STAT signaling pathway. [Display omitted] • CG9920 knockdown in germline caused male sterility with no mature sperms. • Depletion of CG9920 resulted in scattered spermatid nuclear bundles. • CG9920 knockdown led to fewer elongation cones and almost no ICs. • CG9920 knockdown disrupted mitochondrial morphogenesis during spermatogenesis. • CG9920 might be regulated by Ocnus through the JAK-STAT pathway. [ABSTRACT FROM AUTHOR]

The spleen has an essential role in immune responses regulation and is considered the biggest peripheral immune organ. Citicoline is used for various brain disorders management. This study aimed to examine the using possibility of citicoline to treat γ-radiation-induced splenic inflammation in rats. Eighteen male albino rats were classified into: Group 1 (control) animals were kept as control. Group 2 (γ-radiation) animals were total-body γ-irradiated with 6 Gy. Group 3 (γ-radiation + citicoline) rats were γ-irradiated with 6 Gy, then injected intraperitoneally with citicoline (300 mg/kg/d) 5 min after irradiation for one week. Levels of TNF-α, IL-1β, iNOS, NF-κB, JAK2, and STAT3 were determined in spleen tissue, along with histopathological examination. Rats exposure to gamma-radiation led to elevation in splenic TNF-α, IL-1β, NF-κB, iNOS, JAK2, and STAT3 levels significantly. Treatment with citicoline after gamma-radiation exposure improved this elevation, and modulated gamma-radiation-induced histopathological alterations. This data showed that citicoline inhibited γ-radiation-induced splenic inflammation via suppressing NF-κB and JAK2/STAT3 signaling pathways in spleen tissue. [ABSTRACT FROM AUTHOR]

Radiation resistance is a crucial factor influencing therapeutic outcomes in colorectal cancer (CRC). Baicalein (BE), primarily derived from Scutellaria baicalensis, has demonstrated anti‐CRC properties. However, the impact of BE on the radiosensitivity of CRC remains unclear. This study aimed to evaluate the radiosensitization effects of BE and elucidate its mechanism in CRC radiotherapy. We established an in vitro radioresistant cell model (CT26‐R) using parental CRC cells (CT26) subjected to ionizing radiation (IR). CT26‐R cells were pretreated with or without BE, followed by transfection with pcDNA‐NC and pcDNA‐JAK2. The proliferation of CT26‐R cells treated with BE and IR was assessed using a colony formation assay. A CRC animal model was developed in BALB/c mice via CT26‐R cell transplantation. The radiosensitizing effect of BE on CRC was evaluated in vivo. TUNEL assay was conducted to detect apoptosis in tumor tissue. The expression levels of p‐STAT3, JAK2, PD‐L1, and SOCS3 in vitro and in vivo were measured by western blotting. Our results demonstrated that BE significantly increased radiosensitivity in vitro and in vivo and enhanced apoptosis in tumor tissues. Additionally, BE significantly downregulated the expression of p‐STAT3, JAK2, and PD‐L1, and significantly upregulated SOCS3 expression. These in vivo effects were reversed by pcDNA‐JAK2. In summary, our data suggest that BE enhances CRC radiosensitivity by inhibiting the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

This article discusses the differences between checkpoint inhibitor-induced bullous pemphigoid (irBP) and spontaneous bullous pemphigoid (BP). The study compared patients with irBP to patients with BP and found that irBP patients were younger, had a shorter duration of disease, and had a better therapeutic response. However, irBP patients required permanent discontinuation of ICI therapy in 78% of cases. The article provides clinical characteristics and treatment information for both irBP and BP patients. The study also identified differentially expressed genes in irBP compared to BP and normal skin tissue, suggesting potential targets for irBP treatment. The JAK-STAT signaling pathway was found to be enriched in both irBP and BP, indicating that JAK inhibitors could be potential treatment options. The study was funded by grants and the authors declare potential conflicts of interest. [Extracted from the article]

Alopecia areata affects over 140 million people worldwide and causes severe psychological distress. The Janus kinase (JAK) inhibitor, tofacitinib, shows significant potential in therapeutic applications for treating alopecia areata; however, the systemic adverse effects of oral administration and low absorption rate at the target site limit its application. Hence, to address this issue, we designed topical formulations of tofacitinib-loaded cationic lipid nanoparticles (TFB-cNLPs) with particle sizes of approximately 200 nm. TFB-cNLPs promoted percutaneous absorption and hair follicle targeting in an ex vivo pig ear model. TFB-cNLP decreased IFN-γ-induced alopecia areata symptoms in an in vitro follicle model by blocking the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. It also reduced the number of CD8+NKG2D+T cells in a C3H mouse model of alopecia areata in vivo, thereby inhibiting the progression of alopecia areata and reversing hair loss. These findings suggest that TFB-cNLP enhanced hair follicle targeting and has the potential for topical treatment or prevention of alopecia areata. Reversal of alopecia areata with topical TFB NPs treatment by blocking the JAK-STAT signaling pathways, reduced the expression levels of IFN-γ and the frequencies of NKG2D+CD8+ T cells, restored immune environment and promoted hair regrowth. [Display omitted] • Ex vivo mouse hair follicles model was used to assess formulations. • Hair follicles blocked skin model was used to evaluate drug permeation. • Cationic nanostructured carriers minimize systemic circulation and maximize hair follicle targeting. • The formulation restored immune privilege and ensured safe topical delivery for the treatment of alopecia areata. [ABSTRACT FROM AUTHOR]

Acquired pure red cell aplasia (PRCA) is a rare syndrome characterized by normocytic normochromic anemia with severe reticulocytopenia and absence of erythroid precursors in the bone marrow. For refractory PRCA patients, the low response rate and high toxicity of alternative therapies pose a great challenge. T-cell large granular lymphocyte (T-LGL) leukemia is one of the most common conditions in secondary PRCA and also the most difficult form to manage with an inferior treatment response to other secondary PRCA forms. T-LGL leukemia exhibits sustained activation of the intracellular JAK-STAT signaling pathway. We herein report a case of PRCA associated with T-LGL leukemia that had been refractory to multiple lines of therapies and was successfully treated by ruxolitinib. The patient achieved complete remission and tolerated ruxolitinib well without occurrence of neutropenia or thrombocytopenia. This preliminary finding favors ruxolitinib as a potential salvage therapy for refractory PRCA associated with T-LGL leukemia. [ABSTRACT FROM AUTHOR]

The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR. [ABSTRACT FROM AUTHOR]

Background: Shengxuebao mixture (SXBM) is a novel herbal drug approved by China State Food and Drug Administration for the treatment of Leukopenia and iron deficiency anemia caused by radiotherapy and chemotherapy. Methods: To explore the mechanism of SXBM in treating blood deficiency syndrome (BDS). Firstly, network pharmacology and in vivo experiments were used to screen candidate targets and important signaling pathways of SXBM, GO functional enrichment and KEGG pathway analysis were performed. Secondly, a BDS rat model was established to verify the results of the analysis of network pharmacological enrichment. Histopathology and routine peripheral blood examination were observed. The expressions of tumor necrosis factor-α, interleukin (IL)-6, HIF-1α and NF-κB were detected by Western blot, and the expressions of IL-6, IL-1β were detected by ELISA. Results: 62 bioactive components, 66 potential targets and 131 signaling pathways of BDS were successfully identified by network pharmacology. Molecular docking simulation techniques showed that key targets tumor necrosis factor-α, IL-6, IL-1β can dock well with crucial components, and the BDS-related signaling pathways HIF-1 and JAK-STAT play a vital role. The combined model experiment of acetylphenylhydrazine and cyclophosphamide showed that the model group had obvious blood deficiency, and the histopathology and blood routine were effectively restored after administration. Our findings indicate that SXBM's therapeutic effect on BDS primarily involves the mediation of the HIF-1α/NF-κB signaling pathway and the regulation of hematopoietic factor expression. Conclusion: This study not only affirmed the protective properties of SXBM against BDS but also provided insights into a potential mechanism for blood replenishment in the treatment of BDS using SXBM. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) inhibitors have been developed and are clinically available for management of active UC patients although most studies have been conducted for the outpatients and few studies have demonstrated its efficacy in endoscopic and histological remission of hospitalized patients with UC. The aim of the present study was to investigate the efficacy of upadacitinib, which is a novel selective JAK1 inhibitor, in the treatment of ulcerative colitis. We present the cases of three hospitalized patients with ulcerative colitis who achieved clinical remission after significant and rapid improvement with upadacitinib. While upadacitinib was used as the second-line treatment for patients with insufficient treatment effects for corticosteroids or ustekinumab, a patient received it just after admission because they were steroid dependent and previously used advanced therapy before hospitalization. All patients demonstrated rapid clinical responses within 7 days and the partial Mayo scores were 0 at week 8. All patients achieved confirmed endoscopic and histological remissions. We conclude that upadacitinib is a potential treatment option for hospitalized patients with an inadequate response to other biologics and JAK inhibitors. [ABSTRACT FROM AUTHOR]

Integrin β6 (ITGB6) is upregulated in multiple tumor types and elevated ITGB6 levels have been detected in patients with chronic pancreatitis. However, the role of ITGB6 in pancreatic fibrosis and cancer remains to be elucidated. In the present study, ITGB6 expression was assessed using western blotting and qRT-PCR. Besides, cell proliferation, cycling, migration, and invasion were evaluated using CCK-8, flow cytometry, wound healing, and transwell assays, respectively. The expression of fibrosis and JAK2/STAT3 signaling markers was detected by western blotting and immunofluorescence analysis. Moreover, nude mice were subcutaneously injected with co-cultured cell suspensions to establish an in vivo model. The results showed that ITGB6 was highly expressed in pancreatic cancer tissues and TGF-β-induced pancreatic stellate cells (PSCs). Inhibition of ITGB6 expression in PSCs resulted in clear inhibition of activated PSC proliferation, migration, and fibrogenesis. Additionally, reduced ITGB6 expression inhibits the JAK2/STAT3 signaling pathway. Interestingly, activators of the JAK2/STAT3 signaling pathway reversed the effects of ITGB6 disruption on PSCs. Activated PSCs notably promoted the proliferation, invasion, and migration of pancreatic cancer cells in a co-culture assay. In contrast, activated PSCs with low ITGB6 expression failed to significantly affect the malignancy of pancreatic cancer cells. Moreover, in vivo results showed that interference with ITGB6 inhibited the activation of PSCs and promoted the development of pancreatic cancer. Silencing ITGB6 inhibited the proliferation, migration, and fibrosis-like effects of activated PSCs and indirectly inhibited the metastasis and malignant process of pancreatic cancer by inhibiting the JAK2/STAT3 signaling pathway. Therefore, ITGB6 is a potential candidate target for pancreatic cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Increased production of Prostaglandin D2 (PGD2) is linked to development and progression of asthma and allergy. PGD2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD2 receptor 2 (DP2)-dependent manner. Blockade of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (Δ12-PGJ2, Δ12-PGD2, 15-deoxyΔ12,14-PGD2, 9α,11β-PGF2) with or without the selective DP2 antagonist fevipiprant. Total RNA was sequenced, and differentially expressed genes (DEG) were identified by DeSeq2. Differential gene expression analysis revealed an upregulation of pro-inflammatory DEGs in ILC2s stimulated with PGD2 (14 DEGs), Δ12-PGD2 (27 DEGs), 15-deoxyΔ12,14-PGD2 (56 DEGs) and Δ12-PGJ2 (136 DEGs), but not with 9α,11β-PGF2. Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP2 via fevipiprant mainly resulted in downregulation of pro-inflammatory genes such as DUSP4, SPRED2, DUSP6, ETV1, ASB2, CD38, ADGRG1, DDIT4, TRPM2, or CD69. DEGs were related to migration and various immune response-relevant pathways such as "chemokine (C-C motif) ligand 4 production", "cell migration", "interleukin-13 production", "regulation of receptor signaling pathway via JAK-STAT", or "lymphocyte apoptotic process", underlining the pro-inflammatory effects of PGD2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP2 inhibition via fevipiprant. Furthermore, PGD2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP2 initiated ILC2 activity. [ABSTRACT FROM AUTHOR]

The objective of this study was to elucidate the protective role of quercetin in atherosclerosis by examining its effect on the phenotypic switch of vascular smooth muscle cells (VSMCs) to macrophage-like cells and the underlying regulatory pathways. Aorta tissues from apolipoprotein E-deficient (ApoE KO) mice fed a high-fat diet (HFD), treated with or without 100 mg/kg/day quercetin, were analyzed for histopathological changes and molecular mechanisms. Quercetin was found to decrease the size of atherosclerotic lesions and mitigate lipid accumulation induced by HFD. Fluorescence co-localization analysis revealed a higher presence of macrophage-like vascular smooth muscle cells (VSMCs) co-localizing with phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 3 (p-STAT3), and Krüppel-like factor 4 (KLF4) in regions of foam cell aggregation within aortic plaques. However, this co-localization was reduced following treatment with quercetin. Quercetin treatment effectively inhibited the KLF4-mediated phenotypic switch in oxidized low-density lipoprotein (ox-LDL)-loaded mouse aortic vascular smooth muscle cells (MOVAS), as indicated by decreased expressions of KLF4, LGALS3, CD68, and F4/80, increased expression of alpha smooth muscle actin (α-SMA), reduced intracellular fluorescence Dil-ox-LDL uptake, and decreased lipid accumulation. In contrast, APTO-253, a KLF4 activator, was found to reverse the effects of quercetin. Furthermore, AG490, a JAK2 inhibitor, effectively counteracted the ox-LDL-induced JAK2/STAT3 pathway-dependent switch to a macrophage-like phenotype and lipid accumulation in MOVAS cells. These effects were significantly mitigated by quercetin but exacerbated by coumermycin A1, a JAK2 activator. Our research illustrates that quercetin inhibits the KLF4-mediated phenotypic switch of VSMCs to macrophage-like cells and reduces atherosclerosis by suppressing the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. Methods: Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. Results: CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. Conclusion: CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications. [ABSTRACT FROM AUTHOR]

Objectives Methodology Results Conclusions Common Variable Immunodeficiency Disorders (CVID) and Large Granular Lymphocytes leukemia (LGLL) exhibit diverse clinical manifestations including infections, dysimmunity, and lymphoproliferation. Recent decades have seen the discovery of new genes in the lymphopoiesis pathway, such as JAK–STAT. This case series supplemented by a literature review aims to describe clinical and biological characteristics of patients with both CIVD and LGLL.Patients were included through a call for comments to French and Belgian centers and through a literature review via PubMed. Clinical characteristics were compared to two large French cohort involving CVID and LGLL patients.Twelve patients were included. In all cases, CVID precedes LLGL (median diagnosis delay for LLGL was 7 years). Most cases presented with splenomegaly and autoimmune cytopenia. Ten out of 12 patients underwent splenectomy during follow up.Patients with LGLL and CVID differ from patients without immune deficiency in term of clinical presentation and prognosis. We suggest CVID may act as a trigger of LGL lymphocytosis, due to endogenous and exogenous antigenic pressure leading to the selection of a dominant LGL clone and stimulation of the JAK–STAT pathway. The role of splenomegaly and splenectomy in LGLL onset warrant further investigation in future studies. [ABSTRACT FROM AUTHOR]

Radiotherapy (RT) and immune checkpoint inhibitor (ICI) are important treatments for esophageal cancer. Some studies have confirmed the safety and effectiveness of using RT in combination with ICI, while serious side effects have been exhibited by some patients. We report a patient with metastatic esophageal cancer who received RT combined with ICI. The patient experienced severe thrombocytopenia, and treatment with thrombopoietin and corticosteroids were ineffective. Finally, the patient developed abscopal hyperprogression outside the radiation field. Interestingly, next-generation sequencing revealed increased JAK2 gene copies in the surgical slices. The JAK2/STAT3 pathway is involved in the regulation of megakaryocyte development. Recurrent thrombocytopenia may activate the JAK2/STAT3 pathway, leading to megakaryocyte differentiation and platelet biogenesis. However, persistent activation of the JAK2/STAT3 pathway has been associated with immune ICI resistance and tumor progression. This case indicates that thrombocytopenia and increased JAK2 gene copies may be risk factors for poor prognosis after ICI and RT treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Simple Summary: Plant essential oils are currently gaining increasing attention for their roles in mood regulation and neuroprotection. Dalbergia pinnata (Lour.) Prain (DP) is a traditional aromatic medicinal plant in China, primarily containing elemicin and methyl eugenol. Despite limited research, the potential neurological effects of aromatherapy are acknowledged, particularly in Alzheimer's Disease. The pathogenesis of AD involves amyloid-beta (Aβ) deposition and Tau protein hyperphosphorylation, leading to neuronal dysfunction and inflammation. This study aims to document changes in brainwave power in male and female subjects following inhalation of DP essential oil (DPEO) and to investigate its impact on mood and brain function across genders. Additionally, the study examines the efficacy of DPEO in mitigating Aβ1–42-induced neurotoxicity using an in vitro Alzheimer's Disease neural cell model. Alzheimer's disease (AD) is a neurodegenerative disorder that is projected by the WHO to affect over 100 million people by 2050. Clinically, AD patients undergoing long-term antipsychotic treatment often experience severe anxiety or depression in later stages. Furthermore, early-stage AD manifests with weakened α waves in the brain, progressing to diminished α and β waves in late-stage disease, reflecting changes in emotional states and disease progression. In this study, EEG signal analysis revealed that inhalation of Dalbergia pinnata (Lour.) Prain essential oil (DPEO) enhanced δ, θ, α and β wave powers in the frontal and parietal lobes, with a rising trend in the β/α ratio in the temporal lobe. These findings suggest an alleviation of anxiety and an enhancement of cognitive functions. Treatment of the AD SH-SY5Y (human neuroblastoma cells) cell model with DPEO resulted in decreased intracellular levels of Aβ, GSK-3β, P-Tau, IL-1β, TNF-α, IL-6, COX-2, OFR, and HFR, alongside reduced AchE and BchE activities and increased SOD activity. Network pharmacology analysis indicated a potential pharmacological mechanism involving the JAK-STAT pathway. Our study provides evidence supporting DPEO's role in modulating anxiety and slowing AD pathological progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Liver cancer remains a serious health issue worldwide, necessitating the development of novel treatments. Yadanziolide A (Y-A) has shown potential in treating liver cancer. Our research evaluated Y-A's effects on liver cancer cells and in a mouse model. We discovered that Y-A not only kills liver cancer cells but also prevents their spread and induces programmed cell death at effective doses. In animal models, Y-A reduced tumor growth and improved health markers. Our study also identified that Y-A targets specific pathways related to cancer cell survival and growth, offering insights into its mechanism. These findings support Y-A as a promising candidate for liver cancer therapy, highlighting its effectiveness and potential clinical application. Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. Yadanziolide A (Y-A), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver cancer remain incompletely understood. In this study, we conducted a comprehensive evaluation of Y-A's effects on liver cancer cells using a range of in vitro assays and an orthotopic liver cancer mouse model. Our findings reveal that Y-A exerts dose-dependent cytotoxic effects on liver cancer cells, significantly inhibiting proliferation, migration, and invasion at concentrations ≥ 0.1 μM. Furthermore, Y-A induces apoptosis, as evidenced by increased apoptotic cell populations and apoptosome formation. In vivo studies confirm that Y-A inhibits tumor growth and reduces liver damage in mouse models. Mechanistically, Y-A targets the TNF-α/STAT3 pathway, inhibiting STAT3 and JAK2 phosphorylation, thereby activating apoptotic pathways and suppressing tumor cell growth. These results suggest that Y-A has promising anticancer activity and potential utility in liver cancer therapy. [ABSTRACT FROM AUTHOR]

As a Gram‐negative anaerobic bacterium, Akkermansia muciniphila (AKK) participates in the immune response in many cancers. Our study focused on the factors and molecular mechanisms of AKK affecting immune escape in lung adenocarcinoma (LUAD). We cultured AKK bacteria, prepared AKK outer membrane protein Amuc_1100 and constructed a subcutaneous graft tumour mouse model. A549, NCI‐H1395 cells and mice were respectively treated with inactivated AKK, Amuc_1100, Ruxolitinib (JAK inhibitor) and RO8191 (JAK activator). CD8+ T cells that penetrated the membrane were counted in the Transwell assay. The toxicity of CD8+ T cells was evaluated by lactate dehydrogenase assay. Western blot was applied to determine JAK/STAT‐related protein and PD‐L1 expression, whilst CCL5, granzyme B and INF‐γ expression were assessed through enzyme‐linked immunosorbent assay (ELISA). The proportion of tumour‐infiltrating CD8+ T cells and the levels of granzyme B and INF‐γ were determined by flow cytometry. AKK markedly accelerated A549 and NCI‐H1395 recruiting CD8+ T cells and enhanced CD8+ T cell toxicity. Amuc_1100 purified from AKK exerted the same promoting effects. Besides, Amuc_1100 dramatically suppressed PD‐L1, p‐STAT and p‐JAK expression and enhanced CCL5, granzyme B and INF‐γ expression. Treatment with Ruxolitinib accelerated A549 and NCI‐H1395 cells recruiting CD8+ T cells, enhanced CD8+ T cell toxicity, CCL5, granzyme B and INF‐γ expression, and inhibited PD‐L1 expression. In contrast, the RO8191 treatment slowed down the changes induced by Amuc_1100. Animal experiments showed that Amuc_1100 was found to increase the number of tumour‐infiltrating CD8+ T cells, increase the levels of granzyme B and INF‐γ and significantly inhibit the expression of PD‐L1, p‐STAT and p‐JAK, which exerted an antitumour effect in vivo. In conclusion, through inhibiting the JAK/STAT signalling pathway, AKK outer membrane protein facilitated the recruitment of CD8+ T cells in LUAD and suppressed the immune escape of cells. [ABSTRACT FROM AUTHOR]

Innate immune responses that allow hosts to survive infection depend on the action of multiple conserved signaling pathways. Pathogens and parasites in turn have evolved virulence factors to target these immune signaling pathways in an attempt to overcome host immunity. Consequently, the interactions between host immune molecules and pathogen virulence factors play an important role in determining the outcome of an infection. The immune responses of Drosophila melanogaster provide a valuable model to understand immune signaling and host-pathogen interactions. Flies are commonly infected by parasitoid wasps and mount a coordinated cellular immune response following infection. This response is characterized by the production of specialized blood cells called lamellocytes that form a tight capsule around wasp eggs in the host hemocoel. The conserved JAK-STAT signaling pathway has been implicated in lamellocyte proliferation and is required for successful encapsulation of wasp eggs. Here we show that activity of Stat92E, the D. melanogaster STAT ortholog, is induced in immune tissues following parasitoid infection. Virulent wasp species are able to suppress Stat92E activity during infection, suggesting they target JAK-STAT pathway activation as a virulence strategy. Furthermore, two wasp species (Leptopilina guineaensis and Ganaspis xanthopoda) suppress phenotypes associated with a gain-of-function mutation in hopscotch, the D. melanogaster JAK ortholog, indicating that they inhibit the activity of the core signaling components of the JAK-STAT pathway. Our data suggest that parasitoid wasp virulence factors block JAK-STAT signaling to overcome fly immune defenses. Author summary: Following infection, host immune responses are triggered to provide protection against the invading pathogen. The proper function of these responses depends on the activity of multiple immune signaling pathways. These pathways act in a coordinated manner to orchestrate the immune response, and any disruption can render the host susceptible to infection. Because of this sensitivity, many pathogen species have evolved virulence mechanisms that target host signaling pathways and disrupt their function. We are using the interaction between Drosophila melanogaster and Drosophila-infecting parasitoid wasps to study this relationship between host signaling and pathogen virulence. Parasitoids infect fly larvae, and during infection, transfer virulence protein containing venom into the host, providing a mechanism to alter host signaling. This study is focused on one key immune signaling pathway, the highly conserved JAK-STAT pathway. We find that many virulent parasitoid species restrict the activity of the host JAK-STAT pathway, providing a clue as to their virulence strategy. JAK-STAT signaling plays many additional roles in health and disease, and so this system provides a good model to further understand this important pathway. [ABSTRACT FROM AUTHOR]

Postmenopausal osteoporosis (OP) is a prevalent skeletal disease with not fully understood molecular mechanisms. This study aims to investigate the role of circular RNA (circRNA) in postmenopausal OP and to elucidate the potential mechanisms of the circRNA--miRNA--mRNA regulatory network. We obtained circRNA and miRNA expression profiles from postmenopausal OP patients from the Gene Expression Omnibus database. By identifying differentially expressed circRNAs and miRNAs, we constructed a circRNA--miRNA--mRNA network and identified key genes associated with OP. Further, through a range of experimental approaches, including dual-luciferase reporter assays, RNA pull-down experiments, and qRT-PCR, we examined the roles of circ_0134120, miR-590-5p, and STAT3 in the progression of OP. Our findings reveal that the interaction between circ_0134120 and miR-590-5p in regulating STAT3 gene expression is a key mechanism in OP, suggesting the circRNA--miRNA--mRNA network is a potential therapeutic target for this condition. [ABSTRACT FROM AUTHOR]

Entomopathogenic fungi may interact with insects’ symbiotic bacteria during infection. We hypothesized that topical infection with Beauveria bassiana may alter the microbiota of the Colorado potato beetle (CPB) and that these modifications may alter the course of mycoses. We used a model with two concentrations of conidia: (1) high concentration that causes rapid (acute) pathogenesis with fast mortality followed by bacterial decomposition of insects; (2) lower concentration that leads to prolonged pathogenesis ending in conidiation on cadavers. The fungal infections increased loads of enterobacteria and bacilli on the cuticle surface and in hemolymph and midgut, and the greatest increase was detected during the acute mycosis. By contrast, stronger activation of IMD and JAK–STAT signaling pathways in integuments and fat body was observed during the prolonged mycosis. Relatively stable (nonpathogenic) conditions remained in the midgut during both scenarios of mycosis with slight changes in bacterial communities, the absence of mesh and stat expression, a decrease in reactive oxygen species production, and slight induction of Toll and IMD pathways. Oral administration of antibiotic and predominant CPB bacteria (Enterobacteriaceae, Lactococcus, Pseudomonas) led to minor and mainly antagonistic effects in survival of larvae infected with B. bassiana. We believe that prolonged mycosis is necessary for successful development of the fungus because such pathogenesis allows the host to activate antibacterial reactions. Conversely, after infection with high concentrations of the fungus, the host's resources are insufficient to fully activate antibacterial defenses, and this situation makes successful development of the fungus impossible. [ABSTRACT FROM AUTHOR]

The reproductive system of males is adversely impacted by lead (Pb), a toxic heavy metal. The present study examined arbutin, a promising hydroquinone glycoside, for its potential ameliorative impact against Pb-induced testicular impairment in rats. The testicular injury was induced by the intraperitoneal administration of Pb acetate (20 mg/kg/day) for 10 consecutive days. Thirty-six rats were divided into six experimental groups (n = 6 per group): control, control treated with oral arbutin (250 mg/kg), control treated with intraperitoneal arbutin (75 mg/kg), untreated Pb, Pb treated with oral arbutin, and Pb treated with intraperitoneal arbutin. The treatments were administered daily for 10 days. Arbutin was administered by the oral and intraperitoneal routes to compare the efficacy of both routes in mitigating Pb acetate-induced testicular dysfunction. The current data revealed that both oral and intraperitoneal administration of arbutin significantly enhanced serum testosterone and sperm count/motility, indicating the amelioration of testicular dysfunction. In tandem, both routes lowered testicular histopathological aberrations and Johnsen's damage scores. These favorable outcomes were driven by dampening testicular oxidative stress, evidenced by lowered lipid peroxidation and increased glutathione and catalase antioxidants. Moreover, arbutin lowered testicular p-JAK2 and p-STAT3 levels, confirming the inhibition of the JAK2/STAT3 pro-inflammatory pathway. In tandem, arbutin suppressed the testicular NLRP3/caspase-1/NF-B axis and augmented the cytoprotective PK2/PKR2 pathway. Notably, intraperitoneal arbutin at a lower dose prompted a more pronounced mitigation of Pb-induced testicular dysfunction compared to oral administration. In conclusion, arbutin ameliorates Pb-evoked testicular damage by stimulating testicular antioxidants and the PK2/PKR2 pathway and inhibiting the JAK2/STAT3 and NLRP3/caspase-1 pro-inflammatory pathways. Hence, arbutin may be used as an adjunct agent for mitigating Pb-induced testicular impairment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the mechanism of nucleotides binding oligomeric domain like receptor protein 3 (NLRP3) inflammasome on the intestinal inflammatory response and intestinal mucosal injury in septic rats through the JAK/STAT3 signaling pathway. Methods: Thirty healthy and clean grade male Wistar rats were chosed and randomly divided into three groups: sham surgery group, model group, and NLRP3 inhibitor group, with 10 rats in each group. The model group and inhibitor group were subjected to cecal ligation and perforation for modeling. The inhibitor group was intraperitoneally injected with NLRP3 inhibitor MCC950 (10 mg/kg) 30 minutes before modeling, and the model group was injected with equal amount of physiological saline. The 24-hour survival status of rats in each group were observed, ileal pathological score was performed with HE staining, serum tumor necrosis factor-α(TNF-α) and interleukin-1β (IL-1β) were detected using ELISA method, NF-κB p65, NLRP3, apoptosis related spot protein (ASC), aspartate specific cysteine protease-1(Caspase-1), p-JAK, and p-STAT3 proteins levels in small intestine tissues were detected by Western blot method. Results: ① Compared with the sham surgery group, the mortality rate and pathological score of the model group rats significantly increased, serum TNF-α and IL-1β levels were higher, tissue NF-κB p65, NLRP3, ASC, Caspase-1, p-JAK, and p-STAT3 proteins relative expressions were significantly higher, too (P<0.05). ② Compared with the model group, the mortality rate and pathological score of the inhibitor group rats significantly reduced, serum TNF-α and IL-1β was significantly lower, levels of NF-κB p65, NLRP3, ASC, Caspase-1, p-JAK, and p-STAT3 proteins were significantly less, too(P<0.05). There were still significantly statistical differences between the inhibitor group and the sham surgery group in the above indicators (P<0.05). Conclusion: NLRP3 inflammasome may enhance the intestinal inflammatory response and injury intestinal mucosal in septic rats by activating JAK/STAT3 signaling pathway, targeting intervention of NLRP3 could reverse intestinal injury. [ABSTRACT FROM AUTHOR]

Sheep are important herbivorous domestic animal globally, and the Chinese indigenous sheep breed has a multitude of economically significant variations due to the diverse geographical and ecological conditions. In particular, certain native breeds exhibit a visible high litter size phenotype due to the selection pressure of natural and artificial for thousands of years, offering an ideal animal model for investigating sheep's fecundity. In this study, selective signal analysis was performed on public whole‐genome sequencing data from 60 sheep across eight breeds to identify candidate genes related to litter size. Results revealed that a total of 34,065,017 single‐nucleotide polymorphisms (SNPs) were identified from all sheep, and 65 candidate genes (CDGs) were pinpointed from the top 1% of interacted windows and SNPs between the pairwise fixation index (FST, >0.149543) and cross‐population extended haplotype homozygosity (XP‐EHH, >0.701551). A total of 41 CDGs (e.g. VRTN, EYA2 and MCPH1) were annotated to 576 GO terms, of which seven terms were directly linked to follicular and embryonic development (e.g. TBXT, BMPR1B, and BMP2). In addition, 73 KEGG pathways were enriched by 21 CDGs (e.g. ENTPD5, ABCD4 and RXFP2), mainly related to Hippo (TCF4, BMPR1B and BMP2), TGF‐β (BMPR1B and BMP2), PI3K‐Akt (ITGB4, IL4R and PPP2R5A) and Jak–STAT signalling pathways (IL20RA and IL4R). Notably, a series of CDGs was under strong selection in sheep with high litter size traits. These findings result could improve the comprehension of the genetic underpinnings of sheep litter size. Furthermore, it provides valuable CDGS for future molecular breeding. [ABSTRACT FROM AUTHOR]

Senecavirus A (SVA), a picornavirus, causes vesicular diseases and epidemic transient neonatal losses in swine, resulting in a multifaceted economic impact on the swine industry. SVA counteracts host antiviral response through multiple strategies facilitatng viral infection and transmission. However, the mechanism of how SVA modulates interferon (IFN) response remains elusive. Here, we demonstrate that SVA 3C protease (3Cpro) blocks the transduction of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway to antagonize type I IFN response. Mechanistically, 3Cpro selectively cleaves and degrades STAT1 and STAT2 while does not target JAK1, JAK2, and IRF9, through its protease activity. Notably, SVA 3Cpro cleaves human and porcine STAT1 on a Leucine (L)-Aspartic acid (D) motif, specifically L693/ D694. In the case of STAT2, two cleavage sites were identified: glutamine (Q) 707 was identified in both human and porcine, while the second cleavage pattern differed, with residues 754–757 (Valine-Leucine-Glutamine-Serine motifs) in human STAT2 and Q758 in porcine STAT2. These cleavage patterns by SVA 3Cpro partially differ from previously reported classical motifs recognized by other picornaviral 3Cpro, highlighting the distinct characteristics of SVA 3Cpro. Together, these results reveal a mechanism by which SVA 3Cpro antagonizes IFN-induced antiviral response but also expands our knowledge about the substrate recognition patterns for picornaviral 3Cpro . IMPORTANCE Senecavirus A (SVA), the only member in the Senecavirus genus within the Picornaviridae family, causes vesicular diseases in pigs that are clinically indistinguishable from foot-and-mouth disease (FMD), a highly contagious viral disease listed by the World Organization for Animal Health (WOAH). Interferon (IFN)-mediated antiviral response plays a pivotal role in restricting and controlling viral infection. Picornaviruses evolved numerous strategies to antagonize host antiviral response. However, how SVA modulates the JAK-STAT signaling pathway, influencing the type I IFN response, remains elusive. Here, we identify that 3Cpro, a protease of SVA, functions as an antagonist for the IFN response. 3Cpro utilizes its protease activity to cleave STAT1 and STAT2, thereby diminishing the host IFN response to promote SVA infection. Our findings underscore the significance of 3Cpro as a key virulence factor in the antagonism of the type I signaling pathway during SVA infection. [ABSTRACT FROM AUTHOR]

Porcine deltacoronavirus (PDCoV) is an enteric pathogenic coronavirus that causes acute and severe watery diarrhea in piglets and has the ability of cross-species transmission, posing a great threat to swine production and public health. The interferon (IFN)-mediated signal transduction represents an important component of virus-host interactions and plays an essential role in regulating viral infection. Previous studies have suggested that multifunctional viral proteins encoded by coronaviruses antagonize the production of IFN via various means. However, the function of these viral proteins in regulating IFN-mediated signaling pathways is largely unknown. In this study, we demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I IFN-mediated JAK-STAT signaling pathway. We identified that PDCoV infection stimulated but delayed the production of IFN-stimulated genes (ISGs). In addition, PDCoV inhibited JAK-STAT signal transduction by targeting the nuclear translocation of STAT1 and ISGF3 formation. Further evidence showed that PDCoV N is the essential protein involved in the inhibition of type I IFN signaling by targeting STAT1 nuclear translocation via its C-terminal domain. Mechanistically, PDCoV N targets STAT1 by interacting with it and subsequently inhibiting its nuclear translocation. Furthermore, PDCoV N inhibits STAT1 nuclear translocation by specifically targeting KPNA2 degradation through the lysosomal pathway, thereby inhibiting the activation of downstream sensors in the JAK-STAT signaling pathway. Taken together, our results reveal a novel mechanism by which PDCoV N interferes with the host antiviral response. IMPORTANCE Porcine deltacoronavirus (PDCoV) is a novel enteropathogenic coronavirus that receives increased attention and seriously threatens the pig industry and public health. Understanding the underlying mechanism of PDCoV evading the host defense during infection is essential for developing targeted drugs and effective vaccines against PDCoV. This study demonstrated that PDCoV and its encoded nucleocapsid (N) protein antagonize type I interferon signaling by targeting STAT1, which is a crucial signal sensor in the JAK-STAT signaling pathway. Further experiments suggested that PDCoV N-mediated inhibition of the STAT1 nuclear translocation involves the degradation of KPNA2, and the lysosome plays a role in KPNA2 degradation. This study provides new insights into the regulation of PDCoV N in the JAK-STAT signaling pathway and reveals a novel mechanism by which PDCoV evades the host antiviral response. The novel findings may guide us to discover new therapeutic targets and develop live attenuated vaccines for PDCoV infection. [ABSTRACT FROM AUTHOR]

Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction. Editor's summary: Neuroinflammation can cause symptoms outside of the central nervous system (CNS), including muscle pain and fatigue, yet how inflammatory signals in the brain are communicated to muscle remains to be determined. Using multiple models of CNS stress in fruit flies, Yang et al. identified that reactive oxygen species accumulation in the brain promoted expression of Upd3, a Drosophila ortholog of interleukin-6 (IL-6). IL-6 activated JAK-STAT signaling in skeletal muscle, resulting in mitochondrial dysfunction–impaired motor function. This axis was also activated in mice after CNS stress and evident in humans with neuroinflammation. This work identifies a conserved brain-to-muscle signaling axis that regulates muscle performance, which may be a promising therapeutic target. —Hannah Isles [ABSTRACT FROM AUTHOR]

Introduction: Porcine reproductive and respiratory syndrome virus (PRRSV) causes substantial economic losses in the global swine industry. The current vaccine options offer limited protection against PRRSV transmission, and there are no effective commercial antivirals available. Therefore, there is an urgent need to develop new antiviral strategies that slow global PRRSV transmission Methods: In this study, we synthesized a dicoumarol-graphene oxide quantum dot (DIC-GQD) polymer with excellent biocompatibility. This polymer was synthesized via an electrostatic adsorption method using the natural drug DIC and GQDs as raw materials. Results: Our findings demonstrated that DIC exhibits high anti-PRRSV activity by inhibiting the PRRSV replication stage. The transcriptome sequencing analysis revealed that DIC treatment stimulates genes associated with the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway. In porcine alveolar macrophages (PAMs), DIC-GQDs induce TYK2, JAK1, STAT1, and STAT2 phosphorylation, leading to the upregulation of JAK1, STAT1, STAT2, interferon-b (IFN-b) and interferon-stimulated genes (ISGs). Animal challenge experiments further confirmed that DIC-GQDs effectively alleviated clinical symptoms and pathological reactions in the lungs, spleen, and lymph nodes of PRRSV-infected pigs. Discussion: These findings suggest that DIC-GQDs significantly inhibits PRRSV proliferation by activating the JAK/STAT signalling pathway. Therefore, DICGQDs hold promise as an alternative treatment for PRRSV infection. [ABSTRACT FROM AUTHOR]

Domestic ducks (Anas platyrhynchos domesticus) are resistant to most of the highly pathogenic avian influenza virus (HPAIV) infections. In this study, we characterized the lung proteome and phosphoproteome of ducks infected with the HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala) at 12 h, 48 h, and 5 days post-infection. A total of 2082 proteins were differentially expressed and 320 phosphorylation sites mapping to 199 phosphopeptides, corresponding to 129 proteins were identified. The functional annotation of the proteome data analysis revealed the activation of the RIG-I-like receptor and Jak-STAT signaling pathways, which led to the induction of interferon-stimulated gene (ISG) expression. The pathway analysis of the phosphoproteome datasets also confirmed the activation of RIG-I, Jak-STAT signaling, NF-kappa B signaling, and MAPK signaling pathways in the lung tissues. The induction of ISG proteins (STAT1, STAT3, STAT5B, STAT6, IFIT5, and PKR) established a protective anti-viral immune response in duck lung tissue. Further, the protein–protein interaction network analysis identified proteins like AKT1, STAT3, JAK2, RAC1, STAT1, PTPN11, RPS27A, NFKB1, and MAPK1 as the main hub proteins that might play important roles in disease progression in ducks. Together, the functional annotation of the proteome and phosphoproteome datasets revealed the molecular basis of the disease progression and disease resistance mechanism in ducks infected with the HPAI H5N1 virus. [ABSTRACT FROM AUTHOR]