Janus Kinase/signal Transducer And Activator Of Transcription Research Articles

One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway contributes to the defense against bacterial infection in the pea aphid

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is activated by infections of bacteria, fungi, viruses and parasites and mediated cellular and humoral immune responses. In the pea aphid Acyrthosiphon pisum little is known about the function of JAK/STAT signaling in its immune system. In this study, we first showed that expression of genes in the JAK/STAT signaling, including the receptors Domeless1/2, Janus kinase (JAK) and transcriptional factor Stat92E, is up-regulated upon bacteria Escherichia coli and Staphylococcus aureus and fungus Beauveria bassiana infections. After knockdown of expression of these genes by means of dsRNA injection, the aphids harbored more bacteria and suffered more death after infected with E. coli and S. aureus, but showed no significant change after B. bassiana infection. Our study suggests the JAK/STAT signaling contributes to the defense against bacterial infection in the pea aphid.

Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the principal culprit behind chronic kidney disease (CKD), ultimately developing end-stage renal disease (ESRD) and necessitating costly dialysis or kidney transplantation. The limited therapeutic efficiency among individuals with DKD is a result of our finite understanding of its pathogenesis. DKD is the result of complex interactions between various factors. Oxidative stress is a fundamental factor that can establish a link between hyperglycemia and the vascular complications frequently encountered in diabetes, particularly DKD. It is crucial to recognize the essential and integral role of oxidative stress in the development of diabetic vascular complications, particularly DKD. Hyperglycemia is the primary culprit that can trigger an upsurge in the production of reactive oxygen species (ROS), ultimately sparking oxidative stress. The main endogenous sources of ROS include mitochondrial ROS production, NADPH oxidases (Nox), uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), cytochrome P450 (CYP450), and lipoxygenase. Under persistent high glucose levels, immune cells, the complement system, advanced glycation end products (AGEs), protein kinase C (PKC), polyol pathway, and the hexosamine pathway are activated. Consequently, the oxidant-antioxidant balance within the body is disrupted, which triggers a series of reactions in various downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), transforming growth factor beta/p38-mitogen-activated protein kinase (TGF-β/p38-MAPK), nuclear factor kappa B (NF-κB), adenosine monophosphate-activated protein kinase (AMPK), and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. The disease might persist even if strict glucose control is achieved, which can be attributed to epigenetic modifications. The treatment of DKD remains an unresolved issue. Therefore, reducing ROS is an intriguing therapeutic target. The clinical trials have shown that bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, blood glucose-lowering drugs, such as sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can effectively slow down the progression of DKD by reducing oxidative stress. Other antioxidants, including vitamins, lipoic acid, Nox inhibitors, epigenetic regulators, and complement inhibitors, present a promising therapeutic option for the treatment of DKD. In this review, we conduct a thorough assessment of both preclinical studies and current findings from clinical studies that focus on targeted interventions aimed at manipulating these pathways. We aim to provide a comprehensive overview of the current state of research in this area and identify key areas for future exploration.

Insulin-like growth factor 1 knockdown attenuates high glucose-induced podocyte injury by promoting the JAK2/STAT signalling-mediated autophagy.

Podocyte injury plays a crucial role in the development of diabetic nephropathy (DN). A high serum level of insulin-like growth factor 1 (IGF-1) has been observed in patients with DN. This paper is to study the role and mechanism of IGF-1 in high glucose (HG)-induced podocyte injury. Mouse podocytes MPC-5 were treated with HG to establish a DN model in vitro. db/db diabetic mice and db/m nondiabetic mice were used to evaluate the IGF-1 role in vivo. Western blotting was used for measuring protein levels of IGF-1 receptor, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway-related markers, podocyte markers podocin and nephrin, apoptosis- and autophagy-related markers in MPC-5 cells. Immunofluorescence staining was implemented for measuring the expression of nephrin and the autophagy marker LC3. Flow cytometry was used for detecting podocyte apoptosis. IGF-1 expression was increased in HG-stimulated MPC-5 cells and the kidney of db/db diabetic mice compared with corresponding controls. Knocking down IGF-1 downregulated IGF-1R and inhibited JAK2/STAT signalling pathway in HG-treated MPC-5 cells and db/db diabetic mice. IGF-1 silencing attenuated HG-induced podocyte injury, apoptosis and reduction in autophagy. Activating the JAK2/STAT signalling pathway or inhibiting autophagy reversed the effects of IGF-1 silencing on HG-treated MPC-5 cells. Knocking down IGF-1 alleviates HG-induced podocyte injury and apoptosis by inactivating the JAK2/STAT signalling pathway and enhancing autophagy.

Modulation of atherosclerosis-related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives.

Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), NF-E2-related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator-activated receptor (PPAR), nucleotide oligo-structural domain-like receptor thermoprotein structural domain-associated protein 3 (NLRP3), silencing information regulator 2-associated enzyme 1 (Sirt1), nuclear transcription factor-κB (NF-κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor-β (TGF-β), and Janus kinase-signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high-intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.

Molecular Characteristics of JAK2 and Its Effect on the Milk Fat and Casein Synthesis of Ovine Mammary Epithelial Cells.

In addition to its association with milk protein synthesis via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, JAK2 also affects milk fat synthesis. However, to date, there have been no reports on the effect of JAK2 on ovine mammary epithelial cells (OMECs), which directly determine milk yield and milk contents. In this study, the coding sequence (CDS) region of ovine JAK2 was cloned and identified and its tissue expression and localization in ovine mammary glands, as well as its effects on the viability, proliferation, and milk fat and casein levels of OMECs, were also investigated. The CDS region of ovine JAK2, 3399 bp in length, was cloned and its authenticity was validated by analyzing its sequence similarity with JAK2 sequences from other animal species using a phylogenetic tree. JAK2 was found to be expressed in six ovine tissues, with the highest expression being in the mammary gland. Over-expressed JAK2 and three groups of JAK2 interference sequences were successfully transfected into OMECs identified by immunofluorescence staining. When compared with the negative control (NC) group, the viability of OMECs was increased by 90.1% in the pcDNA3.1-JAK2 group. The over-expression of JAK2 also increased the number and ratio of EdU-labeled positive OMECs, as well as the expression levels of three cell proliferation marker genes. These findings show that JAK2 promotes the viability and proliferation of OMECs. Meanwhile, the triglyceride content in the over-expressed JAK2 group was 2.9-fold higher than the controls and the expression levels of four milk fat synthesis marker genes were also increased. These results indicate that JAK2 promotes milk fat synthesis. Over-expressed JAK2 significantly up-regulated the expression levels of casein alpha s2 (CSN1S2), casein beta (CSN2), and casein kappa (CSN3) but down-regulated casein alpha s1 (CSN1S1) expression. In contrast, small interfered JAK2 had the opposite effect to JAK2 over-expression on the viability, proliferation, and milk fat and milk protein synthesis of OMECs. In summary, these results demonstrate that JAK2 promotes the viability, proliferation, and milk fat synthesis of OMECs in addition to regulating casein expression in these cells. This study contributes to a better comprehension of the role of JAK2 in the lactation performance of sheep.

Identification of key genes and molecular mechanisms of chronic urticaria based on bioinformatics.

Chronic urticaria (CU) is characterized by persistent skin hives, redness, and itching, enhanced by immune dysregulation and inflammation. Our main objective is identifying key genes and molecular mechanisms of chronic urticaria based on bioinformatics. We used the Gene Expression Omnibus (GEO) database and retrieved two GEO datasets, GSE57178 and GSE72540. The raw data were extracted, pre-processed, and analyzed using the GEO2R tool to identify the differentially expressed genes (DEGs). The samples were divided into two groups: healthy samples and CU samples. We defined cut-off values of log2 fold change ≥1 and p<.05. Analyses were performed in the Kyoto Encyclopaedia of Genes and Genomes (KEGG), theDatabasefor Annotation, Visualization and Integrated Discovery (DAVID), Metascape, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and CIBERSOFT databases. We obtained 1613 differentially expressed genes. There were 114 overlapping genes in both datasets, out of which 102 genes were up-regulated while 12 were down-regulated. The biological processes included activation of myeloid leukocytes, response to inflammations, and response to organic substances. Moreover, the KEGG pathways of CU were enriched in the Nuclear Factor-Kappa B (NF-kB) signaling pathway, Tumor Necrosis Factor (TNF) signaling pathway, and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway. We identified 27 hub genes that were implicated in the pathogenesis of CU, such as interleukin-6 (IL-6), Prostaglandin-endoperoxide synthase 2 (PTGS2), and intercellular adhesion molecule-1 (ICAM1). The complex interplay between immune responses, inflammatory pathways, cytokine networks, and specific genes enhances CU. Understanding these mechanisms paves the way for potential interventions to mitigate symptoms and improve the quality of life of CU patients.

Increased Interferon Signaling in Vaginal Tissue of Patients With Primary Sjögren Syndrome.

Vaginal dryness is an important factor influencing sexual function in women with primary Sjögren syndrome (pSS). Previous studies showed a higher degree of inflammation in vaginal biopsies from patients with pSS compared to non-pSS controls. However, the molecular pathways that drive this inflammation remain unclear. Therefore, the aim of this study was to investigate inflammatory pathway activity in the vaginal tissue of patients with pSS. Vaginal biopsies of 8 premenopausal patients with pSS experiencing vaginal dryness and 7 age-matched non-pSS controls were included. Expression of genes involved in inflammation and tissue homeostasis was measured using NanoString technology and validated using TaqMan Real-Time PCR. Vaginal tissue sections were stained by immunohistochemistry for myxovirus resistance protein 1 (MxA) and CD123 (plasmacytoid dendritic cells [pDCs]). The most enriched pathway in vaginal biopsies from patients with pSS compared to non-pSS controls was the interferon (IFN) signaling pathway (P < 0.01). Pathway scores for Janus kinase and signal transducer and activator of transcription (JAK-STAT) and Notch signaling were also higher (P < 0.01 for both pathways). Conversely, transforming growth factor-β signaling and angiogenesis pathway scores were lower in pSS (P = 0.02 and P = 0.04, respectively). Differences in IFN signaling between patients with pSS and non-pSS controls were confirmed by PCR and MxA tissue staining. No CD123+ pDCs were detected in vaginal biopsies. IFN-stimulated gene expression levels correlated positively with CD45+ cell numbers in vaginal biopsies and serum anti-SSA/Ro positivity. Upregulation of IFN signaling in vaginal tissue of women with pSS, along with its association with tissue pathology, suggests that IFNs contribute to inflammation of the vaginal wall and potentially also to clinical symptomatology (ie, vaginal dryness).

Inorganic ions activate lineage-specific gene regulatory networks

Inorganic biomaterials have been shown to direct cellular responses, including cell−cell and cell−matrix interactions. Notably, ions released from these inorganic biomaterials play a vital role in defining cell identity, and promoting tissue-specific functions. However, the effect of inorganic ions on cellular functions have yet to be investigated at the transcriptomic level, representing a critical knowledge gap in the development of next-generation bioactive materials. To address this gap, we investigated the impact of various inorganic ions including silver, copper, titanium, and platinum on human mesenchymal stem cells (hMSCs). Our finding showed that silver and copper induce osteogenic and chondrogenic differentiation respectively, through enrichment of lineage-specific gene expression program. In particular, silver effectively induced Wingless/Integrated (Wnt) and mitogen-activated protein kinase (MAPK) signaling, which are vital for osteogenesis. On the other hand, copper specifically stimulated Transforming growth factor beta (TGFβ) signaling, while suppressing Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling, thereby promoting chondrogenesis. In contrast, platinum, and tantalum, ions didn't stimulate regenerative responses. Together, our findings highlight the potential of inorganic biomaterials in tissue regeneration strategies, which currently rely largely on growth factors and small molecule therapeutics. Statement of significanceThis research emphasizes the critical role of bioactive inorganic ions in controlling lineage-specific gene expression patterns in mesenchymal stem cells, effectively modulating the transcriptome landscape and directing cell fate. The study lays the foundation for a systematic database of biomaterial candidates and their effects on cellular functions, which will ultimately streamline the translation of new biomaterials into clinical applications.

NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury.

Spinal cord injury (SCI) leads to significant functional impairments below the level of the injury, and astrocytes play a crucial role in the pathophysiology of SCI. Astrocytes undergo changes and form a glial scar after SCI, which has traditionally been viewed as a barrier to axonal regeneration and functional recovery. Astrocytes activate intracellular signaling pathways, including nuclear factor κB (NF-κB) and Janus kinase-signal transducers and activators of transcription (JAK/STAT), in response to external stimuli. NF-κB and STAT3 are transcription factors that play a pivotal role in initiating gene expression related to astrogliosis. The JAK/STAT signaling pathway is essential for managing secondary damage and facilitating recovery processes post-SCI: inflammation, glial scar formation, and astrocyte survival. NF-κB activation in astrocytes leads to the production of pro-inflammatory factors by astrocytes. NF-κB and STAT3 signaling pathways are interconnected: NF-κB activation in astrocytes leads to the release of interleukin-6 (IL-6), which interacts with the IL-6 receptor and initiates STAT3 activation. By modulating astrocyte responses, these pathways offer promising avenues for enhancing recovery outcomes, illustrating the crucial need for further investigation into their mechanisms and therapeutic applications in SCI treatment.

Inhibition of JAK-STAT pathway corrects salivary gland inflammation and interferon driven immune activation in Sjögren’s disease

ObjectivesInflammatory cytokines that signal through the Janus kinases–signal transducer and activator of transcription (JAK-STAT) pathway, especially interferons (IFNs), are implicated in Sjögren’s disease (SjD). Although inhibition of JAKs is effective...

CD146+CAFs promote progression of endometrial cancer by inducing angiogenesis and vasculogenic mimicry via IL-10/JAK1/STAT3 pathway

Heterogeneous cancer-associated fibroblasts (CAFs) play important roles in cancer progression. However, the specific biological functions and regulatory mechanisms involved in endometrial cancer have yet to be elucidated. We aimed to explore the potential mechanisms of heterogeneous CAFs in promoting endometrial cancer progression. The presence of melanoma cell adhesion molecule (MCAM; CD146) positive CAFs was confirmed by tissue multi-immunofluorescence (mIF), and fluorescence activated cell sorting (FACS). The biological functions were determined by wound healing assays, tuber formation assays and cord formation assays. The effects of CD146+CAFs on endometrial cancer cells were studied in vitro and in vivo. The expression level of interleukin 10 (IL-10) was measured by quantitative real time polymerase chain reaction (qRT-PCR), western boltting and enzyme linked immunosorbent assays (ELISAs). In addition, the transcription factor STAT3 was identified by bioinformatics methods and chromatin immunoprecipitation (ChIP). A subtype of CAFs marked with CD146 was found in endometrial cancer and correlated with poor prognosis. CD146+CAFs promoted angiogenesis and vasculogenic mimicry (VM) in vitro. A xenograft tumour model also showed that CD146+CAFs can facilitate tumour progression. The expression of IL-10 was elevated in CD146+CAFs. IL-10 promoted epithelial-endothelial transformation (EET) and further VM formation in endometrial cancer cells via the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signalling pathway. This process could be blocked by the JAK1/STAT3 inhibitor niclosamide. Mechanically, STAT3 can bind to the promoter of cadherin5 (CDH5) to promote its transcription which may be stimulated by IL-10. We concluded that CD146+CAFs could promote angiogenesis and VM formation via the IL-10/JAK1/STAT3 signalling pathway. These findings may lead to the identification of potential targets for antiangiogenic therapeutic strategies for endometrial cancers.

Mechanisms of Shufeng Jiedu Capsule in treating bacterial pneumonia based on network pharmacology and experimental verification

ObjectiveThis study aimed to investigate the underlying mechanism of Shufeng Jiedu Capsule (SFJD) for treating bacterial pneumonia (BP) in vivo based on network pharmacology and experimental verification study. MethodsNetwork pharmacology was used to screen the active compounds and target genes of SFJD. Then, the multi drug resistance-Pseudomonas aeruginosa (MDR-PA) mice lethal model and MDR-PA pneumonia model were established to evaluate the therapeutic effects and underlying mechanisms of SFJD. Western blot and ELISA were used to determinate the protein expression level of the IL-17 signaling pathway and JAK/STAT signaling pathway. ResultsAfter screening, 172 potential components of SFJD were generated, based on which we constructed an SFJD-component-target-BP interaction network. The Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment revealed that SFJD could regulate the IL-17 signaling pathway and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Molecular docking showed that the potential target proteins had good combinations with the main active components. SFJD significantly reduced the mortality and prolonged survival days in lethal models. The lung index and pathological changes in the lung were also significantly decreased. SFJD could significantly decrease the expression of interleukin-17A (IL-17A), TNF receptor associated factor 6 (TRAF6), phospho-inhibitor of nuclear factor-kappa B (p-IκB)/inhibitor of NF-κB (IκB), phospho-NF-κB p65 (p-NF-κB p65), phospho-protein kinase B (p-AKT)/AKT, phospho-signal transducer and activator of transcription 3 (p-STAT3)/STAT3, phospho-signal transducer and activator of transcription 1 (p-STAT1)/STAT1, and the protein level of interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β. ConclusionCombined with network pharmacology and in vivo study, it was found that SFJD exerted its therapeutic effects on BP by inhibiting the IL-17 pathway and JAK/STAT signaling pathway. This study provides new evidence for SFJD in treatment of BP.

JAK/STAT3 signaling in cardiac fibrosis: a promising therapeutic target.

Cardiac fibrosis is a serious health problem because it is a common pathological change in almost all forms of cardiovascular diseases. Cardiac fibrosis is characterized by the transdifferentiation of cardiac fibroblasts (CFs) into cardiac myofibroblasts and the excessive deposition of extracellular matrix (ECM) components produced by activated myofibroblasts, which leads to fibrotic scar formation and subsequent cardiac dysfunction. However, there are currently few effective therapeutic strategies protecting against fibrogenesis. This lack is largely because the molecular mechanisms of cardiac fibrosis remain unclear despite extensive research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade is an extensively present intracellular signal transduction pathway and can regulate a wide range of biological processes, including cell proliferation, migration, differentiation, apoptosis, and immune response. Various upstream mediators such as cytokines, growth factors and hormones can initiate signal transmission via this pathway and play corresponding regulatory roles. STAT3 is a crucial player of the JAK/STAT pathway and its activation is related to inflammation, malignant tumors and autoimmune illnesses. Recently, the JAK/STAT3 signaling has been in the spotlight for its role in the occurrence and development of cardiac fibrosis and its activation can promote the proliferation and activation of CFs and the production of ECM proteins, thus leading to cardiac fibrosis. In this manuscript, we discuss the structure, transactivation and regulation of the JAK/STAT3 signaling pathway and review recent progress on the role of this pathway in cardiac fibrosis. Moreover, we summarize the current challenges and opportunities of targeting the JAK/STAT3 signaling for the treatment of fibrosis. In summary, the information presented in this article is critical for comprehending the role of the JAK/STAT3 pathway in cardiac fibrosis, and will also contribute to future research aimed at the development of effective anti-fibrotic therapeutic strategies targeting the JAK/STAT3 signaling.

Successful Treatment of Disseminated Granuloma Annulare with Upadacitinib.

Disseminated granuloma annulare (DGA) is an inflammatory skin disorder characterized by more than 10 erythematous, raised, ring-shaped plaques. Its treatment remains challenging, with conventional therapies showing variable efficacy. We report the case of a woman in her 50s with a 2-year history of DGA refractory to multiple treatments. Given the recent evidence of the role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in the granuloma annulare pathophysiology, treatment with upadacitinib 30mg per day was started with rapid effectiveness and good tolerance. This case underscores the potential of JAK inhibitors as promising therapeutic options for recalcitrant granuloma annulare.

Mechanism of Yuxuebi Tablets in treating synovial inflammation in rheumatoid arthritis based on transcriptomics

This study investigated the mechanism of Yuxuebi Tablets(YXB) in the treatment of synovial inflammation in rheumatoid arthritis(RA) based on transcriptomic analysis. Transcriptome sequencing technology was employed to analyze the gene expression profiles of joint tissues from normal rats, collagen-induced arthritis(CIA) rats(an RA model), and YXB-treated rats. Common diffe-rentially expressed genes(DEGs) were subjected to Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses. RA synovial inflammation-related target genes were retrieved from the OMIM and GeneCards databases. Venny 2.1 software was used to identify the intersection of YXB target genes and RA synovial inflammation-related target genes, and GO and KEGG enrichment analyses were performed on the intersecting target genes. Immunohistochemistry was used to assess the protein expression levels of the inflammatory factors interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in rat joint tissues. Western blot analysis was employed to measure the expression levels of key proteins in the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway. A total of 2 058 DEGs were identified by intersecting the genes from the normal group vs model group and the model group vs YXB treatment group. A search in OMIM and GeneCards databases yielded 1 102 RA synovial inflammation-related target genes. After intersecting with the DEGs in the YXB treatment group, 204 intersecting target genes were identified, primarily involving biological processes such as immune response, signal transduction, and inflammatory response; cellular components including plasma membrane, extracellular space, and extracellular region; molecular functions like protein binding, identical protein binding, and receptor binding. These target genes were mainly enriched in signaling pathways such as PI3K/Akt, cytokine-cytokine receptor interaction, and Janus kinase/signal transducer and activator of transcription(JAK/STAT). Western blot results showed that YXB at low, medium, and high doses could significantly inhibit the expression levels of key proteins in the PI3K/Akt signaling pathway in rat joint tissues in a dose-dependent manner. Immunohistochemistry further confirmed these findings, showing that YXB not only suppressed the protein expression levels of the inflammatory factors IL-1β and TNF-α in the joint synovial tissues of CIA rats, but also inhibited p-Akt protein expression. In conclusion, this study used transcriptomic analysis to uncover the key mechanisms of YXB in inhibiting synovial inflammation and alleviating the progression of RA, with a focus on its role in suppressing the PI3K/Akt signaling pathway.

PJ‑001, a small‑molecule proteolysis‑targeting chimera, ameliorates atopic dermatitis‑like inflammation in mice by inhibiting the JAK2/STAT3 pathway and repairing the skin barrier.

Atopic dermatitis (AD) is a common allergic skin disease, and its pathogenesis involves genetic and environmental factors, as well as the immune response and skin barrier. PJ-001 is a small-molecule proteolysis-targeting chimera, which can degrade proteins related to the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. In the present study, 0.5% 2,4-dinitrofluorobenzene was used to induce a mouse model of AD. Following treatment with PJ-001, the number of scratches and the severity of skin damage in the AD mice were recorded. Pathological changes in skin lesions were observed with hematoxylin and eosin staining. The expression levels of JAK2/STAT3, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB), Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3) were detected using western blotting. Furthermore, reverse transcription-PCR was used to detect the mRNA expression levels of filaggrin (FLG) and keratin 17, and the change in interleukin-10 levels in the splenic tissue of the mice. Compared with in the control group, the model group exhibited severe skin lesions. Following treatment with PJ-001, the AD-like inflammation in mice decreased. The expression levels of LC3 II/LC3 I and Beclin 1 were significantly reduced (P<0.01), and the expression levels of JAK2, STAT3, TLR4 and NF-κB were significantly downregulated (P<0.001). Additionally, the mRNA expression levels of FLG were significantly upregulated (P<0.001). These results indicated that PJ-001 may alleviate the skin condition in a mouse model of AD. The underlying mechanism may involve inhibition of the JAK/STAT signaling pathway, thereby suppressing the release of inflammatory factors, reducing excessive autophagy at the site of skin lesions, and enhancing the skin barrier function. In conclusion, PJ-001 could be considered a potential therapeutic option for AD.

Identification and validation of LINC01322 as a potential prognostic biomarker and oncogene promoting tumor progression in lung adenocarcinoma

Our study identified a novel long noncoding RNA, LINC01322, that acts as an oncogene in lung adenocarcinoma progression. Cytoplasmic and nuclear RNA purification assays indicated that LINC01322 was localized in the cytoplasm and nucleus. Gene set enrichment analysis revealed the involvement of LINC01322 in the regulation of cell proliferation, migration, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. LINC01322 may promote lung adenocarcinoma proliferation and migration through the Janus kinase/signal transducer and activator of transcription signaling pathway. In vitro experiments demonstrated that the knockdown of LINC01322 significantly suppressed lung adenocarcinoma cell proliferation, migration, and activation of the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, whereas overexpression had the opposite effects. Inhibition of the Janus kinase 2/signal transducer and activator of transcription 3 pathway activity partially reversed the enhancement of cell proliferation and migration caused by LINC01322 overexpression. In vivo experiments further verified the oncogene role of LINC01322. Altogether, our findings suggest that LINC01322 promotes lung adenocarcinoma progression by activating the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway and that it could be a therapeutic target.

Application of JAK inhibitors in paradoxical reaction through immune-related dermatoses.

Biologics play a positive and effective role in the treatment of immune-related dermatoses. However, many other immune-related diseases have also manifested along with biologics treatment. Paradoxical reaction through immune-related dermatoses refer to the new onset or exacerbation of other immune-mediated dermatoses (mainly psoriasis and atopic dermatitis) after biologics treatment of inflammatory dermatoses (mainly psoriasis and atopic dermatitis), such as new atopic dermatitis (AD) in psoriasis (PsO) treatment and new PsO in AD treatment. A common genetic background and Inflammatory pathway are possible pathogenesis. Faced with paradoxical reactions, the choice of therapy needs to be directed toward therapies effective for both diseases, such as Janus kinase (JAK) inhibitors. The Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway plays an important role in the inflammatory pathway, and has been widely used in the treatment of AD and PsO in recent years. This article focuses on JAK inhibitors such as tofacitinib, baricitinib, ruxolitinib, Abrocitinib, upadacitinib, and deucravacitinib, to explore the possible application in treatment of paradoxical reactions. Common side effects, baseline risk factors and safety use of JAK inhibitors were discussed.

Microarray Gene Expression Analysis of Lesional Skin in Canine Pemphigus Foliaceus.

Canine pemphigus foliaceus (PF) is considered the most common autoimmune skin disease in dogs; the mechanism of PF disease development is currently poorly understood. Therefore, this study aimed to characterize the molecular mechanisms and altered biological pathways in the skin lesions of canine PF patients. Using an RNA microarray on formalin-fixed, paraffin-embedded samples, we analyzed the transcriptome of canine PF lesional skin (n = 7) compared to healthy skin (n = 5). Of the 800 genes analyzed, 420 differentially expressed genes (DEGs) (p < 0.05) were found. Of those, 338 genes were significantly upregulated, including pro-inflammatory and Th17-related genes. Cell type profiling found enhancement of several cell types, such as neutrophils, T-cells, and macrophages, in PF skin compared to healthy skin. Enrichment analyses of the upregulated DEGs resulted in 78 statistically significant process networks (FDR < 0.05), including the Janus kinase signal transducer and activator of transcription (JAK-STAT) and mitogen-activated protein kinase (MAPK) signaling. In conclusion, canine PF lesional immune signature resembles previously published changes in human pemphigus skin lesions. Further studies with canine PF lesional skin using next-generation sequencing (e.g., RNA sequencing, spatial transcriptomics, etc.) and the development of canine keratinocyte/skin explant PF models are needed to elucidate the pathogenesis of this debilitating disease.