Activator Of Transcription Pathway Research Articles

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

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

Current management of giant cell arteritis and its complications.

This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses and mitigate glucocorticoid (GC)-related morbidity. The standard of care for GCA has traditionally involved prolonged use of GC, and recent studies are exploring faster GC tapering regimens in an effort to reduce adverse effects while maintaining disease control. Randomized clinical trials have highlighted the efficacy of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in reducing disease flares and sparing GCs. However, the optimal treatment duration with TCZ is unknown and patients remain at risk of relapse after treatment discontinuation. An unmet therapeutic need persists for patients who are not candidates for TCZ, and for those who have inadequate response to this biologic. Therefore, investigations into alternative therapies such as targeting interleukin-17A, blocking T-cell activation or inhibiting the Janus kinase-signal transducer and activator of transcription pathway, showcase potential avenues for tailored treatments. While GCs remain the cornerstone of therapy, TCZ emerges as a promising GC-sparing agent. Ongoing research targeting different pathways implicated in GCA pathogenesis have led to encouraging results. However, the preliminary nature of these findings necessitates larger randomized controlled trials to establish their efficacy conclusively.

Drug Repurposing Using Molecular Network Analysis Identifies Jak as Targetable Driver in Necrobiosis Lipoidica

Drug repurposing is an attractive strategy for therapy development, particularly in rare diseases where traditional drug development approaches may be challenging owing to high cost and small numbers of patients. In this study, we used a drug identification and repurposing pipeline to identify candidate targetable drivers of disease and corresponding therapies through application of causal reasoning using a combination of open-access resources and transcriptomics data. We optimized our approach on psoriasis as a disease model, demonstrating the ability to identify known and, to date, unrecognized molecular drivers of psoriasis and link them to current and emerging therapies. Application of our approach to a cohort of tissue samples of necrobiosis lipoidica (an unrelated; rare; and, to date, molecularly poorly characterized cutaneous inflammatory disorder) identified a unique set of upstream regulators, particularly highlighting the role of IFNG and the Jak-signal transducer and activator of transcription pathway as a likely driver of disease pathogenesis and linked it to Jak inhibitors as potential therapy. Analysis of an independent cohort of necrobiosis lipoidica samples validated these findings, with the overall agreement of drug-matched upstream regulators above 96%. These data highlight the utility of our approach in rare diseases and offer an opportunity for drug discovery in other rare diseases in dermatology and beyond.

P10 Janus kinase inhibitors to restore skin barrier function in a mouse model of Harlequin ichthyosis

Abstract Introduction and aims The autosomal recessive congenital ichthyoses (ARCIs) are a group of chronic conditions where there is unmet therapeutic need. Harlequin ichthyosis (HI) is the most severe form of ARCI with aberrant differentiation of the epidermis leading to a severe barrier defect. It is caused by mutations in ABCA12, a lipid transporter involved in transport of glucosylceramides from the lamellar body to the lipid lamellae. Several Janus kinase (JAK) inhibitors inhibiting the JAK-signal transducer and activator of transcription pathway are now licensed for atopic dermatitis. Previous work from our group in an HI in vitro model showed that tofacitinib, a pan-JAK inhibitor, had a restorative effect on the lipid barrier. Methods Further selective JAKis were tested in three dimensional skin equivalents using ABCA12 CRISPR-Cas9 knockout and wildtype keratinocytes to identify the most promising JAKi for use in an HI murine model (ABCA12tm1c: Het Cre+). JAKi-A (5 mg kg−1) and vehicle (10% dimethylsulfoxide in corn oil) were tested on male and female HI-inducible and wildtype mice (N = 4). All mice were initially treated with 4-OH-Tamoxifen to induce the HI phenotype and after 1 day JAKi-A was administered via oral gavage for 9 days. All mice were killed, and skin was collected and processed for haematoxylin and eosin, Nile Red, ABCA12, glucosylceramide and immune cell marker staining. Results JAKi-A had a positive effect on HI epidermal morphology, showing a significantly reduced epidermal thickness in treated HI mice compared with controls. JAKi-A also had a positive effect on the epidermal barrier, restoring neutral and polar lipids compared with vehicle-treated mice as observed using Nile Red and glucosylceramide staining. Further analysis on immune cell infiltrates is in progress. Conclusions These Results suggest that JAKi-A restores the skin barrier in vivo and may be a promising treatment for severe ichthyosis.

A novel immune‑related lncRNA as a prognostic biomarker in HER2+ breast cancer.

Human epidermal growth factor receptor 2 (HER2)+ breast cancer is characterized by high malignancy and poor prognosis. Long non-coding (lnc)RNAs are crucial in breast cancer progression and prognosis, especially in tumor-associated immune processes. The present study aimed to elucidate novel lncRNAs related to immune function that could serve as biomarkers for both diagnosis and prognosis of this cancer subtype. Using data from The Cancer Genome Atlas and The Immunology Database and Analysis Portal, correlation analysis was performed to identify differentially expressed lncRNAs and immune-related genes. Through receiver operating characteristic analysis, the diagnostic value of specific lncRNAs was identified and evaluated, with a focus on their capacity to distinguish between cancerous and non-cancerous states. The present research revealed 22 differentially expressed lncRNAs and 23 differentially expressed immune-related genes, with 19 immune-related lncRNAs. A total of 13 of these lncRNAs demonstrated diagnostic relevance. In particular, it was demonstrated that the expression of lncRNA CTC-537E7.2 was significantly correlated with patient survival, suggesting its potential as a prognostic marker. Additionally, the expression of lncRNA CTC-537E7.2 was significantly correlated with clinical parameters, such as hormone receptor status and patient demographics. Moreover, it exhibited associations with four distinct immune cell types and demonstrated involvement in the Janus kinase-signal transducer and activator of transcription pathway. Further assessment by in situ hybridization confirmed the increased expression of lncRNA CTC-537E7.2 in samples from HER2+ patients, reinforcing its significance. In summary, the present study uncovered a novel prognostic biomarker for HER2+ breast cancer, thereby laying the groundwork for investigating the underlying molecular mechanisms driving the development of this subtype of breast cancer.

Sishen Pill and its active phytochemicals in treating inflammatory bowel disease and colon cancer: an overview.

The incidence of inflammatory bowel disease (IBD) and the associated risk of colon cancer are increasing globally. Traditional Chinese medicine (TCM) treatment has unique advantages. The Sishen Pill, a common Chinese patented drug used to treat abdominal pain and diarrhea, consists mainly of Psoraleae Fructus, Myristicae Semen, Euodiae Fructus, and Schisandra Chinensis. Modern research has confirmed that Sishen Pill and its active secondary metabolites, such as psoralen, myristicin, evodiamine, and schisandrin, can improve intestinal inflammation and exert antitumor pharmacological effects. Common mechanisms in treating IBD and colon cancer mainly include regulating inflammation-related signaling pathways such as nuclear factor-kappa B, mitogen-activated protein kinase, phosphatidylinositol 3-kinase, NOD-like receptor heat protein domain-related protein 3, and wingless-type MMTV integration site family; NF-E2-related factor 2 and hypoxia-inducible factor 1α to inhibit oxidative stress; mitochondrial autophagy and endoplasmic reticulum stress; intestinal immune cell differentiation and function through the Janus kinase/signal transducer and activator of transcription pathway; and improving the gut microbiota and intestinal barrier. Overall, existing evidence suggests the potential of the Sishen pill to improve IBD and suppress inflammation-to-cancer transformation. However, large-scale randomized controlled clinical studies and research on the safety of these clinical applications are urgently required.

Ponatinib and STAT5 Inhibitor Pimozide Combined Synergistic Treatment Applications Potentially Overcome Drug Resistance via Regulating the Cytokine Expressional Network in Chronic Myeloid Leukemia Cells.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative hematological disease characterized by the chimeric breakpoint-cluster region/Abelson kinase1 (BCR::ABL1) oncoprotein; playing a pivotal role in CML molecular pathology, diagnosis, treatment, and possible resistance arising from the success and tolerance of tyrosine kinase inhibitor (TKI)-based therapy. The transcription factor STAT5 constitutive signaling, which is influenced by the cytokine signaling network, triggers BCR::ABL1-based CML pathogenesis and is also relevant to acquired TKI resistance. The unsuccessful therapeutic approaches targeting BCR::ABL1, in particular third-line therapy with ponatinib, still need to be further developed with alternative combination strategies to overcome drug resistance. As treatment with the STAT5 inhibitor pimozide in combination with ponatinib resulted in an efficient and synergistic therapeutic approach in TKI-resistant CML cells, this study focused on identifying the underlying amplification of ponatinib response mechanisms by determining different cytokine expression profiles in parental and ponatinib-resistant CML cells, in vitro. The results showed that expression of interleukin (IL) 1B, IL9, and IL12A-B was increased by 2-fold, while IL18 was downregulated by 2-fold in the ponatinib-resistant cells compared to sensitive ones. Importantly, ponatinib treatment upregulated the expression of 21 of the 23 interferon and IL genes in the ponatinib-resistant cells, while treatment with pimozide or a combination dose resulted in a reduction in the expression of 19 different cytokine genes, such as for example, inflammatory cytokines, IL1A-B and IL6 or cytokine genes associated with supporting tumor progression, leukemia stem cell growth or poor survival, such as IL3, IL8, IL9, IL10, IL12, or IL15. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis results showed that the genes were mainly enriched in the regulation of receptor signaling through the Janus kinase/signal transducer and activator of transcription pathway, cytokine-cytokine receptor interaction, and hematopoietic cell lineage. Protein-protein interaction analysis showed that IL2, IL6, IL15, IFNG, and others appeared in the top lists of pathways, indicating their high centrality and importance in the network. Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.

Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease.

Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) causes neurological disease in the peripheral and central nervous system (PNS and CNS, respectively) of some patients. It is not clear whether SARS-CoV-2 infection or the subsequent immune response are the key factors that cause neurological disease. Here, we addressed this question by infecting human induced pluripotent stem cell-derived CNS and PNS neurons with SARS-CoV-2. SARS-CoV-2 infected a low number of CNS neurons and did not elicit a robust innate immune response. On the contrary, SARS-CoV-2 infected a higher number of PNS neurons. This resulted in expression of interferon (IFN) λ1, several IFN-stimulated genes and proinflammatory cytokines. The PNS neurons also displayed alterations characteristic of neuronal damage, as increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and α-synuclein, and lower levels of cytoskeletal proteins. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neuronal damage, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS. Our results provide a basis to study coronavirus disease 2019(COVID-19) related neuronal pathology and to test future preventive or therapeutic strategies.

Identification and Expression Analysis of Suppressors of Cytokine Signaling from Spotted Seabass (Lateolabrax maculatus)

The suppressor of cytokine signaling (SOCS) plays a negative role in the cytokine signaling pathway, preventing excessive signaling from interfering with the metabolic homeostasis of the body. By regulating the Janus kinase-signal transducer and activator of transcription pathway through negative feedback, SOCS have a significant impact on the regulation of both innate and adaptive immunity against pathogens, thus playing a crucial role in the immune response, growth, and development of the body. In this study, the cDNA sequences of SOCS1, 2, 3a, 3b, 4, 5b, 6, 7, 8, 9, and CISH genes of spotted seabass (Lateolabrax maculatus), an important marine economic fish in China, were cloned using RT-PCR, nested PCR, and RACE techniques. Multiple sequence alignment showed that the SOCS family members shared highly conserved functional structural domains, including the SRC homology 2 domain (SH2 domain) and the SOCS-box domain. The phylogenetic analysis showed that SOCS1, 2, 3a, 3b, 8, and CISH belonged to the type II subfamily of SOCS genes, while SOCS4, 5b, 6, 7, and SOCS9 belonged to the type I subfamily. Furthermore, gene organization and syntenic analysis confirmed the phylogenetic analysis and protein annotation of the SOCS gene family in spotted seabass. Constitutive expression of spotted seabass SOCS genes was observed in various tissues of healthy fish, with varying expression levels. Following the lipopolysaccharide and Edwardsiella tarda challenge, the expression profiles of spotted seabass SOCS genes were differently regulated in the gill, head kidney, intestine, and spleen. These findings provide a basis for future research on the functional properties of SOCS genes in spotted seabass.

Investigation of the mutations in the genes involved in Janus kinase/signal transducer and activator of transcription pathway in canine large cell gastrointestinal lymphoma.

Canine gastrointestinal lymphoma is known to be of T-cell origin in most cases, but the molecular biological aberrations have not been clarified. In human intestinal T-cell lymphoma, the mutations in the genes associated with Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway have been frequently observed. In this study, the gene mutations were investigated in 31 dogs with large cell gastrointestinal lymphoma (LCGIL) by focusing on the genes involved in JAK-STAT pathway. Next-generation sequencing analysis to examine the mutations in STAT3, STAT5B, and JAK1 genes throughout the exon regions revealed the mutations in STAT3 gene in two dogs and JAK1 gene in one dog. In conclusion, this study could not indicate the associations of gene mutations in JAK-STAT pathway with LCGIL in most canine cases.

E74-like ETS transcription factor 1 promotes the progression of pancreatic cancer by regulating doublecortin-like kinase 1/Janus kinase/signal transducer and activator of transcription pathway

E74-like ETS transcription factor 1 promotes the progression of pancreatic cancer by regulating doublecortin-like kinase 1/Janus kinase/signal transducer and activator of transcription pathway

Effect of Angiotensin II-Mediated Janus Kinase/Signal Transducers and Activators of Transcription Pathways on Thoracic Aortic Smooth Muscle Cells

Effect of Angiotensin II-Mediated Janus Kinase/Signal Transducers and Activators of Transcription Pathways on Thoracic Aortic Smooth Muscle Cells

MicroRNA-122 protects against interferon-α-induced hepatic inflammatory response via the Janus kinase-signal transducer and activator of transcription pathway.

Significant overlap in the epidemiology and coinfection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) has been identified, which accelerates the development of severe liver cirrhosis and hepatocellular carcinoma worldwide. Interferon-α (IFN-α), a cytokine with antiviral properties, exerts profound physiological effects on innate immunity by regulating interferon-stimulated genes (ISGs) within cells. However, the underlying mechanism of IFN-α in hepatic inflammation remains to be fully elucidated. Here, we utilized LO2 cells treated with the recombinant IFN-α protein and conducted microRNA (miR) sequencing. MiR-122-3p and miR-122-5p_R+1 were the most enriched miRNAs involved in the pathogenesis of IFN-α-induced inflammatory responses and were significantly downregulated by IFN-α treatment. Furthermore, we identified interferon induced protein with tetratricopeptide repeats 1 (IFIT1) as a potential target gene of miR-122. IFN-α markedly increased the expression of proinflammatory cytokines and fibrogenic genes but decreased the mRNA expression of ISGs. Additionally, IFN-α significantly activated the NF-κB p-p65, MAPK p-p38, and Jak/STAT pathways to trigger inflammation. Importantly, supplementation with a miR-122 mimic significantly alleviated IFN-α-induced inflammation and induced IFIT1 expression in LO2 cells. Conversely, the suppression of miR-122 markedly exacerbated the inflammatory response triggered by IFN-α. Furthermore, silencing IFIT1 via an siRNA elicited an inflammatory response, whereas IFIT1 overexpression ameliorated hepatic inflammation and fibrosis in a manner comparable to that induced by IFN-α treatment. Taken together, our findings suggest that miR-122 and its target, IFIT1, reciprocally regulate the inflammatory response associated with IFN through the Jak/STAT pathway.

LncRNA STAT3-AS regulates endometrial receptivity via the STAT3 signaling pathway

Endometrial receptivity is critical for the successful establishment of pregnancy in ruminants. Interferon tau (IFNT) plays a key role in promoting embryo attachment by activating the Janus kinase/signal transducer and activator of transcription pathway, which induces the expression of a series of interferon-stimulated genes (ISGs). In our previous study, sequencing analysis of goat endometrial epithelial cells (gEECs) treated with 20 ng/mL IFNT revealed a differentially expressed long non-coding RNA located on the STAT3 antisense chain, which we designated STAT3-AS. The aim of this study was to investigate the role and mechanism of STAT3-AS in establishing endometrial receptivity in goats. The results showed that STAT3-AS was expressed in both the nucleus and cytoplasm of gEECs, and its expression increased significantly in the uterus on day 15 of pregnancy. STAT3-AS expression was upregulated in gEECs treated with IFNT alone or in combination with progesterone and estradiol. Knockdown of STAT3-AS using specific short interfering RNA significantly inhibited the expression of classical ISGs such as interferon-stimulated gene 15 and 2′,5′-oligodenylate synthetase 2, as well as uterine endometrial receptivity-related genes including homeobox gene A11, integrin beta 3, and vascular endothelial growth factor. Moreover, gEEC proliferation and the STAT3 pathway were suppressed in the absence of STAT3-AS. However, pretreatment with the STAT3 activator RO8191 restored the effect of silencing STAT3-AS on endometrial receptivity. Overall, these results suggest that STAT3-AS is an important regulator of endometrial receptivity in goats and that it regulates endometrial receptivity through the STAT3 pathway.

Transcriptomic analysis of skin immunity genes in the Chinese spiny frog (Quasipaa spinosa) after Proteus mirabilis infection

Recently, populations of Chinese spiny frogs (Quasipaa spinosa), an important amphibian species in China, have decreased, mainly due to a disease caused by the gram-negative bacteria Proteus mirabilis. To elucidate the immune response of the frogs, this study aimed to identify novel candidate genes functionally associated with P. mirabilis infection-induced “rotting skin” disease. Chinese spiny frogs were infected with P. mirabilis, and the skin transcriptome was sequenced using the MGISEQ-2000 platform. A total of 233,965 unigenes were obtained by sequencing, of which 27.23 % were known genes. Screening of differentially expressed genes (DEGs) indicated 210 unigenes differentially expressed after P. mirabilis infection, of which 132 unigenes were up-regulated, and 78 unigenes were down-regulated. Using Kyoto Encyclopedia of Genes and Genomes enrichment analysis, DEGs were identified as enriched in signal pathways, such as oxidative phosphorylation, apoptosis, and the Janus kinase-signal transducer and activator of transcription pathway. Of the DEGs, there was a significant upregulation of the colony stimulating factor 2 receptor beta common subunit, interleukin 2 receptor subunit gamma, cathelicidin antimicrobial peptide, interleukin-17 receptor E, receptor-interacting serine/threonine-protein kinase 3, and pulmonary surfactant-associated protein D immune genes following P. mirabilis infection. Conversely, scavenger receptor cysteine-rich domain-containing group B protein, tumor protein p53 inducible nuclear protein 2, suppressor of cytokine signaling 2, and metalloreductase STEAP3 were significantly downregulated. In conclusion, the first skin transcriptome database of Chinese spiny frogs was established, and several immune genes were identified to elucidate the pathogenic mechanism of “skin rot” in Chinese spiny frogs and other cultured frogs.

Knockdown of Slfn5 alleviates lipopolysaccharide-induced pneumonia by regulating Janus kinase/signal transduction and activator of transcription pathway.

In recent years, the incidence of pneumonia has been increasing, which is the main cause of death and morbidity of children and the elderly in the world. Slfn5 is implicated in multiple cancers, and Slfn5 promotes epithelial-mesenchymal transition and metastasis in lung cancer. However, the influences of Slfn5 in pneumonia have not yet been completely cleared. Herein, we aimed to explore the underlying effects and regulatory mechanisms of Slfn5 in lipopolysaccharide (LPS)-induced pneumonia in mice and A549 cells. Mice were intratracheally administered 5 mg/kg LPS to construct pneumonia model. In vitro, A549 cells were treated with 10 µg/mL LPS to construct cellular pneumonia model. Slfn5 expression was detected using immunohistochemistry and western blotting. Haematoxylin and eosin staining, TUNEL (terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate‑biotin nick end‑labelling), and western blotting were performed to assess pathological injury and inflammation. MTT [3(4,5‑dimethyl‑2‑thiazolyl)‑2,5‑diphenyl‑2‑H‑tetrazolium bromide], flow cytometry, and enzyme-linked immunosorbent assay analysis were performed to analyze cell viability, apoptosis, and inflammation. Gene set enrichment analysis was performed to explore the mechanism of Slfn5 in pneumonia. Slfn5 expression was upregulated in LPS-induced pneumonia in mice and A549 cells. In mice, knockdown of Slfn5 weakened LPS-induced lung injury and inflammation and decreased the expression of p-JAK2, p-JAK3, and p-STAT3. In LPS-stimulated A549 cells, downregulation of Slfn5 expression increased and Slfn5 overexpression decreased cell viability. Downregulation of Slfn5 expression decreased and Slfn5 overexpression increased cell apoptosis, inflammation and the expression of p-JAK2, p-JAK3, and p-STAT3. AG490, an inhibitor of the JAK/STAT pathway, reversed the damaging effects of Slfn5 overexpression. In the LPS-induced pneumonia model, Slfn5 knockdown alleviated LPS-induced lung injury by regulating the JAK/STAT pathway.

Nuclear Matrix-associated Protein SMAR1 Attenuated Acute Graft-versus-host Disease by Targeting JAK-STAT Signaling in CD4 + T Cells.

Acute graft-versus-host disease (aGVHD) mediated by alloreactive T cells remains a serious and life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). The contribution of the different CD4 + T helper cell subtypes to the pathogenesis and regulation of aGVHD is a central point in current research. The specialized effector subsets of T cells that differentiate from naive T cells into mature cells are closely related to scaffold/matrix-associated region-1-binding protein (SMAR1). However, the role of SMAR1 in aGVHD is unclear. Peripheral blood was collected from the patients with or without aGVHD after allo-HCT. The differences in CD4 + T cells transduced with the SMAR1 lentivirus vector and empty vector were analyzed. A humanized aGVHD mouse model was constructed to evaluate the function of SMAR1 in aGVHD. The expression of SMAR1 was significantly reduced in the CD4 + T cells from aGVHD patients and related to the occurrence of aGVHD. SMAR1 overexpression in human CD4 + T cells regulated CD4 + T-cell subsets differentiation and inflammatory cytokines secretion and inhibited the Janus kinase/signal transducer and activator of transcription pathway. Moreover, SMAR1 changed chromatin accessibility landscapes and affected the binding motifs of key transcription factors regulating T cells. Additionally, upregulation of SMAR1 expression in CD4 + T cells improved the survival and pathology in a humanized aGVHD mouse model. Our results showed that upregulation of SMAR1 regulated the CD4 + T-cell subpopulation and cytokines secretion and improved survival in a humanized aGVHD mouse model by alleviating inflammation. This study provides a promising therapeutic target for aGVHD.

FGFR families: biological functions and therapeutic interventions in tumors.

There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1-FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well-known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.

Case control study: G-allele of rs4244165 in JAK1 gene correlated with high-level brief psychiatric rating scale in bipolar patients.

Bipolar disorder (BD) is a chronic and clinically complex disease, characterized by pathological disturbances in mood and energy. Cytokines can access the brain and their signaling pathways affect brain functions, such as neurotransmitter metabolism, neuroendocrine function, neural/synaptic plasticity, and mood neural circuitry. JAK 1 is the most common phosphorylation protein combined with the tyrosine kinase cytokine receptors; therefore, we investigated the association between the Janus family kinase 1 (JAK1) gene polymorphisms (rs2780895, rs4244165, and rs17127024) and susceptibility to BD. The case study population included 93 patients diagnosed with BD and 112 healthy controls, selected from the central coastal region of Tunisia. Polymerase chain reaction-restriction fragment length polymorphism was used to investigate these 3 JAK1 polymorphisms. We compared the sociodemographic and clinical parameters of 3 genotypes of this single nucleotide polymorphisms rs2780895, rs4244165, and rs17127024 of the JAK1 gene. The frequencies of the 3 genotypes were similar in the patient and control groups. One-way analysis of variance revealed a significant variation in rs4244165. After hospitalization, the average of the brief psychiatric rating scale score was significantly higher for the wild-type GG genotype than that for the double-mutation TT genotype (31.23% vs 22.85%, P = .043). The least significant difference post hoc test also showed a significant difference between the GG and TT genotypes at both hospital admission (P = .001) and after hospitalization (P = .012), with the GG genotype being associated with a higher brief psychiatric rating scale score. Haplotypic analysis revealed that the wild-type haplotype with the highest frequency (46.62%) was CTG. Our results showed no association between the 3 studied positions and bipolar disorder. However, the G-allele of rs4244165 in JAK1 is associated with the highest level of the brief psychiatric rating scale in patients with bipolar disorder. The JAK/signal transducer and activator of transcription pathway is an interesting therapeutic route that requires further investigations. Studying their regulatory regions can provide a clearer picture of all the interactions involved in the regulation of genetic expression in response to treatment.