The JAK-STAT signaling pathway is a common pathway of many cytokine signal transductions, closely related to cell proliferation, apoptosis, differentiation, and inflammatory response. It is essential for inhibiting the inflammatory response, initiating innate immunity, and coordinating adaptive immune mechanisms. Owing to the nature of this pathway and its potential cross-epitopes with multiple alternative pathways, the long-term efficacy of monotherapy-based adaptive targeting therapy is limited, and the majority of drugs targeting STATs are still in the preclinical phase. Meanwhile, curcumin, quercetin, and several kinds of plant polyphenol chemicals play roles in multiple sites of the JAK-STAT pathway to suppress abnormal activation. Polyphenol compounds have shown remarkable effects by acting on the JAK-STAT pathway in anti-inflammatory, antitumor, and cardiovascular disease control. This review summarizes the pharmacological effects of more than 20 kinds of phytochemicals on JAK-STAT signaling pathway according to the chemical structure of polyphenolic phytochemicals.

Inflammatory bowel disease (IBD) represents a group of recurrent chronic inflammatory disorders associated with autoimmune dysregulation, typically characterized by neutrophil infiltration and mucosal inflammatory lesions. Neutrophils, as the earliest immune cells to arrive at inflamed tissues, play a dual role in the onset and progression of mucosal inflammation in IBD. Most of these cells specifically express CD177, a molecule increasingly recognized for its critical role in the pathogenesis of IBD. Under IBD-related inflammatory stimuli, CD177 is highly expressed on neutrophils and promotes their migration. CD177 + neutrophils activate bactericidal and barrier-protective functions at IBD mucosal inflammation sites and regulate the release of inflammatory mediators highly correlated with the severity of inflammation in IBD patients, thus playing a dual role. However, mitigating the detrimental effects of neutrophils in inflammatory bowel disease remains a challenge. Based on these data, we have summarized recent articles on the role of neutrophils in intestinal inflammation, with a particular emphasis on CD177, which mediates the recruitment, transepithelial migration, and activation of neutrophils, as well as their functional consequences. A better understanding of CD177 + neutrophils may contribute to the development of novel therapeutic targets to selectively modulate the protective role of this class of cells in IBD.

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 in clinical diagnosis. About 60% patients are over 60 years old. There are various treatment options for AML patients. But for elderly patients, the complete remission rates are disappointing due to genetic, molecular, and age-related factors. Development of next-generation sequencing technologies makes it possible to seek individual strategies for patients in different ages. This study analyzed transcriptome profiles in platelets of AML patients in different ages for the first time. Methods: Platelet RNA sequencing in AML of ten elderly and seven young patients were performed with Illumina TruSeq Stranded mRNA library Prep Kit and Illumina HiSeq4000 sequencing instrument. With the FASTQ sequencing data obtained, statistical analyses between elderly with young AML patients were analyzed by R program. GO and KEGG enrichment analyses were performed via R package clusterProfiler. TOP 10 down-regulated/up-regulated genes in elderly patients compared to young patients were selected with the threshold of |L2FC| > 2 and padj ≤ 0.0001. The down-regulated gene ATF4 was chosen by GSEA analysis and ROC analysis with AUC > 0.95. Results: We found 3059 genes with differential transcript levels (GDTLs) in AML patients of different age. Among them, 2048 genes are down-regulated and 651 genes are up-regulated in elderly patients. We found that gene transcript profiles in elderly patients is obviously different from those in young patients, including a collection of down-regulated genes related to proteins processing in endoplasmic reticulum and immunity. We further identified that genes of pathway in cancer and mitogen activated protein kinase (MAPK) pathway, involved in natural immunity and metabolism, are significantly down-regulated in elderly patients. Among all screened genes with decreased transcript levels, we believe that activating transcription factor 4 (ATF4) is a biomarker indicating different chemotherapy strategies for elderly patients. Conclusions: In summary, gene transcript profiles are different in platelets of elderly and young AML patients. And ATF4 can be a useful biomarker indicating different chemotherapy strategies for AML patients with different ages.

Immune thrombocytopenia (ITP) is an autoimmune disease with the typical symptom of a low platelet count in blood. ITP demonstrated age and sex biases in both occurrences and prognosis, and adult ITP was mainly induced by the living environments. The current diagnosis guideline lacks the integration of molecular heterogenicity. This study recruited the largest cohort of platelet transcriptome samples. A comprehensive procedure of feature selection, feature engineering, and stacking classification was carried out to detect the ITP biomarkers using RNA sequencing (RNA-seq) transcriptomes. The 40 detected biomarkers were loaded to train the final ITP detection model, with an overall accuracy 0.974. The biomarkers suggested that ITP onset may be associated with various transcribed components, including protein-coding genes, long intergenic non-coding RNA (lincRNA) genes, and pseudogenes with apparent transcriptions. The delivered ITP detection model may also be utilized as a complementary ITP diagnosis tool. The code and the example dataset is freely available on http://www.healthinformaticslab.org/supp/resources.php

Background: For more than 30 years, Qian Ji Sheng Xue Pian (QJSXP) has been used clinically to treat primary immune thrombocytopenia (ITP) with good documented efficacy. However, nothing is known about its underlying mechanisms, effective components, and possible targets. To employ several methodologies to initially investigate the possible targets and therapeutic mechanisms of QJSXP in the treatment of ITP. Methods: Liquid chromatography-mass spectrometry (LC-MS) identified the principal chemical elements of QJSXP and assessed its probable active components based on ADME characteristics. The research incorporated multidimensional databases to pinpoint probable targets for the active components. Key pathogenic targets linked to ITP were aggregated from several illness databases, and the STRING and Metascape tools were utilized to examine protein interaction activities and related biological processes. Mendelian randomization (MR) was then utilized to determine beneficial targets for the therapy of ITP. The potential targets, including disease targets and MR-positive targets, were found at the intersection, while risk genes were excluded by heterogeneity, pleiotropy, and Steiger analysis to ascertain the core targets. Molecular docking and molecular dynamics simulations were conducted utilizing Schrodinger and Gromacs software to assess the binding affinity of compound-core targets. The toxicological effects of active molecules targeting critical sites were concurrently anticipated using several toxicity databases. Results: A total of 67 active components and 352 potential targets were discovered in QJSXP, of which 77 were associated with ITP disease targets. Through MR analysis, a total of 12 core genes were identified. Binding scores below − 4.25 kcal/mol constituted 82.0%; docking scores below − 5 kcal/mol represented 60.1%, with an average binding energy of -5.44 kcal/mol. The majority of targets demonstrated strong binding affinity with the components. Toxicity prediction initially highlighted potential hazards, including hepatotoxicity and nephrotoxicity, establishing a foundation for future clinical surveillance. Conclusion: This study has preliminarily identified the active constituents, associated pathways, and possible targets of QJSXP in the treatment of ITP, offering insights for additional experimental validation of QJSXP’s mechanism of action in ITP.

Primary immune thrombocytopenia (ITP) is characterized by the dual pathology of peripheral immune-mediated platelet clearance and restricted platelet production by megakaryocytes. The TPO-MPL axis is a central regulator of platelet homeostasis, and ligand-induced receptor activation is associated with downstream JAK2-STAT, MAPK, and PI3K-AKT signaling. This review summarizes the structural and functional features of TPO and MPL, the major immunopathogenic mechanisms of ITP, and the current clinical use of thrombopoietin receptor agonists (TPO-RAs) in ITP. Recent structural and functional studies suggest that TPO-RAs with distinct binding sites may not engage MPL in fully identical ways and may therefore be associated with differences in receptor conformation, dimer geometry, and downstream signaling output. Within this emerging structural and functional framework, these structural and signaling differences may help explain response heterogeneity and the clinical observation that some patients may still benefit after switching agents. However, direct experimental evidence linking switching outcomes to specific alterations in MPL dimer geometry remains lacking, and the available clinical evidence regarding switching comes mainly from retrospective and observational studies, with additional support from post hoc analyses. Overall, continued investigation of the TPO-MPL pathway and its structural basis may help refine our understanding of ITP pathogenesis, treatment-response heterogeneity, and the clinical observations associated with switching, although the proposed mechanistic links still require direct experimental validation.