Inflammatory Signaling Pathways Research Articles

CCL4L2 participates in tendinopathy progression by promoting macrophage inflammatory responses: a single-cell analysis

BackgroundTendinopathy is very common in clinical practice, which is highly prevalent in athletes, sports enthusiasts and other people involved in high-load weight-bearing activities. Common types of tendinopathy include rotator cuff injury, Achilles tendinitis, tennis elbow and so on. Macrophages (Macs) are key immune cells in the pathogenesis of tendinopathy. In this study, CCL4L2+ M1-related signaling pathways were screened by combining single-cell RNA sequencing (scRNA-seq) to explore their significance in tendinopathy treatment.MethodsImmune cell populations were screened by Uniform Manifold Approximation and Projection (UMAP) downscaling, and Mac cell subsets were annotated using cell marker genes. The cellular communication mechanism between different cellular subsets such as Macs and tendon stem/progenitor cells (TSPCs) was demonstrated by cellular communication analysis. Based on cell marker genes of CCL4L2 + M1, Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to compare the expression differences in M1 and M2 between the Disease and Healthy groups. Associations between CCL4L2+ M1 and TSPCs were inferred by cell-cell communication analysis. The effects of CCL4L2 on Mac polarization and TSPCs were verified by enzyme-linked immunosorbent assay (ELISA) and real-time fluorescence quantitative PCR (qPCR).ResultsThe proportions of TSPCs, endothelial cells (ECs), smooth muscle cells (SMCs), and immune cells were significantly elevated in the Disease group. The proportion of M1 cells in the Disease group was higher than that in the Healthy group, while the proportion of M2 cells was lower than that in the Healthy group. M1 differentially expressed genes (DEGs) were mainly enriched to disease-related and immunoinflammation-related signaling pathways. Signaling intensities between M1 and TSPCs in pathways related to immunoinflammation and ischemic injury were significantly increased in the Disease group. The proportion of CCL4L2 + M1 in the Disease group was significantly higher than in the Healthy group, and communications between CCL4L2 + M1 and TSPCs varied significantly. Compared with the Control group, the expression levels of inflammatory cytokines were higher in the CCL4L2 group, and the expression levels of tendon differentiation markers (Egr1, Mkx, Scx, Type 1 collagen, Tnmd) were significantly down-regulated.ConclusionThe present study analyzed the heterogeneous alterations in the Healthy and Disease groups by scRNA-seq data and found that there was a significant inflammatory infiltrate in the Disease group with markedly increased Mac activity, which was associated with activation of the CCL4L2 + M1-associated signaling pathways. CCL4L2 promotes M1 polarization and inhibits TSPC differentiation through activating M1-related inflammatory signaling pathways. These findings contribute to a more comprehensive understanding of tendon injury progression and provide potential targets for tendinopathy treatment.

Comparative liver transcriptome analysis in hamsters infected with food-borne trematodes Opisthorchis felineus, Opisthorchis viverrini, or Clonorchis sinensis.

Epidemiologically important food-borne trematodes Opisthorchis viverrini and Clonorchis sinensis are recognized as biological carcinogens of Group 1A, while Opisthorchis felineus is in Group 3 as noncarcinogenic to humans. Mechanisms of the biological carcinogenesis are still elusive. Some studies highlight chronic inflammation as a key factor and common pathway for cancer initiation and progression. Nonetheless, the chronic inflammation alone does not explain why these three species differ in carcinogenicity. We focused this study on genome-wide landscapes of liver gene expression and activation of cellular pathways in Mesocricetus auratus golden hamsters infected with C. sinensis (South Korea), O. viverrini (Thailand), or O. felineus (Russia) at 1 and 3 months after infection initiation. Liver transcriptomes of golden hamsters (HiSeq Illumina, 2X150 bp) were sequenced at 1 and 3 months postinfection. Data processing was carried out using the following bioinformatic and experimental approaches: analysis of differential gene expression, estimates of proportions of affected liver cell types, liver histopathology, and examination of weighted gene coexpression networks. All infections caused enrichment with inflammatory response signaling pathways, fibrogenesis and cell proliferation, and IL2-STAT5, TNF-NF-κB, TGF-β, Hippo, MAPK, and PI3K-Akt signaling pathways. Nevertheless, species-specific responses to each infection were noted too. We also identified species-specific responses of liver cell types, differentially expressed gene clusters, and cellular pathways associated with structural liver damage (such as periductal fibrosis, epithelial neoplasia, and inflammation). This is the first comparative analysis of gene expression landscapes in the liver of experimental animals infected with O. viverrini, O. felineus, or C. sinensis. The trematodes have species-specific effects on the hepatobiliary system by triggering signaling pathways, thereby leading to differences in the severity of hepatobiliary structural lesions and contributing to the pathogenicity of closely related foodborne trematodes.

Glucose-Sensing ChREBP Protein in the Pathogenesis of Dia-betic Retinopathy.

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRP mice with constitutively active (ca) ChREBP. These mice underwent retinal function testing, followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration as we observed diminished scotopic ERG amplitudes detected in caChREB-PRP mice at P35. The retinal proteomic landscape indicated a decline in KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific ca-ChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBP cells displayed a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprograming triggering retinal functional loss in mice.

Selectively Antagonizing the NOD1-Mediated Inflammatory Signaling Pathway Mitigates the Gastric Inflammation Induced by Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) infection is characterized by the complex interplay between H. pylori and gastric disorders. It has been established that NOD1 can be activated by the peptidoglycan (PGN) present in the cell wall of H. pylori, serving as a key mediator of inflammation and initiating the RIP2/NF-κB and MAPK inflammatory signaling pathways. In this article, we reported on the development of a 2-chloroquinazolin-4-ol derivative 66 as a potent and selective antagonist of both human and mouse NOD1, which effectively inhibited the expression of inflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL1, CXCL8) in immune and epithelial cells, as well as inflammatory cytokines (KC, IL-6) in a H. pylori-induced murine model of gastritis following oral administration. This study laid a foundation for treating gastritis induced by H. pylori infection.

The CCL5/CCR5/SHP2 axis sustains Stat1 phosphorylation and activates NF-κB signaling promoting M1 macrophage polarization and exacerbating chronic prostatic inflammation

Background and objectiveChronic prostatitis (CP) is a condition markered by persistent prostate inflammation, yet the specific cytokines driving its progression remain largely undefined. This study aims to identify key cytokines involved in CP and investigate their role in driving inflammatory responses through mechanistic and therapeutic exploration.MethodsA 48-cytokine panel test was conducted to compare the plasma cytokine profiles between participants with CP-like symptoms (CP-LS) and healthy controls. Experimental autoimmune prostatitis (EAP) models were used for functional validation, with further mechanistic studies performed through in vivo and in vitro assays. Pharmacological inhibition was applied using maraviroc, and pathway inhibitors to assess therapeutic potential.ResultsOur analysis identified CCL5 as one of the most prominently elevated cytokines in CP-LS patients. Further validation in the EAP model mice confirmed elevated CCL5 levels, highlighting its role in driving prostatic inflammation. Mechanistic studies revealed that CCL5 interacts with the CCR5 receptor, promoting M1 macrophage polarization and activating key inflammatory signaling pathways, including Stat1 and NF-κB, as indicated by increased phosphorylation of Stat1 and p65. In vitro, CCL5 combined with LPS stimulation amplified these effects, further promoting M1 polarization. CCL5 also sustained Stat1 activation by inhibiting its dephosphorylation through reduced interaction with SHP2, leading to prolonged inflammatory signaling. Single-cell transcriptomics confirmed high CCR5 expression in macrophages, correlating with inflammatory pathways. Pharmacological inhibition of CCR5, or its downstream signaling, significantly reduced macrophage-driven inflammation both in vivo and in vitro.ConclusionThese findings establish the CCL5/CCR5 axis as a critical driver of persistant prostatic inflammation and present it as a potential therapeutic target for CP.Graphic The graphic abstract illustrates the central role of the CCL5/CCR5 axis in promoting chronic prostatitis progression. CCL5 binds to the CCR5 receptor on macrophages, enhancing M1 polarization and activating key inflammatory pathways, including Stat1 and NF-κB, as shown by the increased phosphorylation of Stat1 and p65. The interaction also inhibits SHP2-mediated Stat1 dephosphorylation, sustaining prolonged inflammatory signaling. Pharmacological inhibition of CCR5 or its downstream pathways attenuates macrophage-driven inflammation, highlighting this axis as a critical driver and potential therapeutic target for chronic prostatitis.

The Anti-Inflammatory Properties of Polysaccharides Extracted from Moringa oleifera Leaves on IEC6 Cells Stimulated with Lipopolysaccharide In Vitro

Moringa oleifera (M. oleifera) is a plant with significant medicinal and nutritional value and contains various bioactive compounds, particularly in its leaves (MOL). This study sought to explore the impact of M. oleifera leaf polysaccharides (MOLPs) on lipopolysaccharide (LPS)-activated intestinal epithelial cells (IEC6) and to uncover the mechanisms involved. The cytotoxicity of MOLP on IEC6 cells was assessed using the Cell Counting Kit-8 (CCK-8) assay, which demonstrated a safe concentration range of 0–1280 µg/mL. The impact of MOLP on cell viability was further evaluated over 12 to 48 h. IEC6 cells were treated with three concentrations of MOLP low (25 µg/mL), medium (50 µg/mL), and high (100 µg/mL) alongside LPS (50 µg/mL) stimulation for one day. The findings revealed that treatment with MOLP significantly promoted cell migration and increased the production of interleukin-10 (IL-10), while it simultaneously decreased cell apoptosis and the levels of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6). Additionally, MOLP treatments across all concentrations significantly reduced the expression of Toll-like receptor 4 (TLR-4), myeloid differentiation primary response 88 (MyD88), phosphorylated nuclear factor kappa B-alpha (pIκB-α), and phosphorylated NF-κB p65 signalling pathways. Moreover, MOLP restored the expression of tight junction proteins, such as zonula occludens-1 (ZO-1) and occludin, which had been disrupted by LPS. These results indicate that MOLP exhibits anti-inflammatory properties by inhibiting inflammatory signalling pathways and maintaining intestinal barrier integrity through the upregulation of tight junction proteins in IEC6 cells. This study enhances our understanding of the anti-inflammatory capabilities of MOLP.

Evaluation of the effect of phellodendrin application on rats creating an experimental model of non-compression lumbar disc herniation on the NF-κB-related inflammatory signaling pathway

ObjectiveTo explore the therapeutic effects of phellodendrine on non-compression lumbar disc herniation (NCLDH).MethodsThe Sprague Dawley rat model of NCLDH was established via autologous caudal nucleus pulposus transplantation. Behavioral observations and neurological function scoring were conducted in Sprague Dawley rats, and the serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured via enzyme-linked immunosorbent assay (ELISA). Real-time quantitative polymerase chain reaction (RT‒qPCR) was used to detect the expression of nuclear factor kappa-B (NF-κB) p65 mRNA in L5 nerve roots and surrounding tissues. Western blotting was used to assess the protein expression of NF-κB p65 and TNF-α. Immunofluorescence and immunohistochemical analyses were performed to investigate the distribution and expression of the NF-κB p65 protein in the L5 nerve and its surrounding tissues.ResultsIn this animal study, phellodendrine was found to downregulate the expression of p65 mRNA, decrease the release of inflammatory factors, and alleviate motor dysfunction caused by lumbar disc herniation(LDH). Therefore, the phellodendrine technique has potential value for the treatment of NCLDH.ConclusionIn this animal experiment, phellodendrine was found to significantly reduce the expression level of p65 mRNA, decrease the release of inflammatory cytokines, and alleviate lumbar disc pain.Clinical trial numberNot applicable.

Mechanistic Study of Purple Sweet Potato Anthocyanins: Multifaceted Anti-Fibrotic Effects and Targeting of PDGFRβ in Liver Fibrosis.

The purple sweet potato anthocyanins (PSPA) are known for their diverse health benefits, yet their hepatoprotective effects and the mechanisms by which they combat liver fibrosis have not been thoroughly investigated. This study aimed to elucidate these effects by employing a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. We conducted a comprehensive analysis of the effects of PSPA on liver injury, oxidative stress, inflammation, and fibrosis-related signaling pathways. Our results demonstrate that PSPA can mitigate liver damage in mice, regulate key antioxidant enzymes such as catalase and SOD, and reduce oxidative stress as indicated by lowered MDA levels. PSPA also decrease the expression of inflammatory proteins, including CD3, CD4, CD45, IL-1β, TNF-α, and IL-17A, and reduce the accumulation of fibrotic markers like type I and III collagens and α-SMA. Additionally, PSPA have demonstrated the ability to inhibit key fibrogenic signaling proteins, including TGFβR2, p-Smad2, p-Smad3, p-PDGFRβ, p-AKT, p-ERK1/2, p-JNK1/2, and p-p38. Furthermore, we identified two potent monomers, PSPA-1 and PSPA-2, which directly target the PDGFRβ, a key player in fibrosis. The mechanism of action involves the inhibition of PDGF-B binding to PDGFRβ, thus disrupting the PDGF-B/PDGFRβ signaling pathway. These findings suggest that the hepatoprotective and antifibrotic effects of PSPA are due to their multifunctional bioactivities and the presence of specific active components that can effectively target fibrogenic protein.

Chitooligosaccharide-modified PLGA-loaded PPD nanoparticles ameliorated sepsis-associated acute kidney injury via the NF-κB signaling pathway

Objectives Sepsis-associated acute kidney injury (SA-AKI) is a significant clinical challenge with high morbidity and mortality. Low bioavailability of protopanaxadiol (PPD) limits its clinical application. In this study, PPD was encapsulated with chitooligosaccharide (COS) modified polylactic-co-glycolic acid (PLGA) to develop novel nanomedicines for the treatment of SA-AKI. Methods COS-PLGA-PPD nanoparticles were prepared by emulsified solvent evaporation method, and their properties were evaluated. In vitro, the anti-inflammatory and protective effects of COS-PLGA-PPD NPs were investigated in a cellular model of LPS-induced NRK-52E cells and their uptake in Caco-2 cells. Indicators of renal injury, inflammation, and NF-κB signaling pathway were evaluated by injecting LPS into SD rats and inducing SA-AKI model in vivo. The oral bioavailability of nanoparticles was evaluated by pharmacokinetics. Results Compared with PPD and unmodified nanoparticles, COS-PLGA-PPD NPs were more stable, with a particle size of 139.69 nm, which enhanced the viability of NRK-52E cells, increased the uptake of Caco-2 cells, alleviated the symptoms of SA-AKI in rats, inhibited the NF-κB signaling pathway, reduced the expression of inflammatory factors, and had a bioavailability 1.7-fold that of PPD. Conclusion COS-PLGA-PPD NPs ameliorate LPS-induced SA-AKI in rats by inhibiting the NF-κB signaling pathway, providing a basis for the treatment of SA-AKI.

Implication of Let7b/AhR/ARNT/HMGB1/RAGE cascade in neuroplasticity disturbances induced by glucocorticoids and the promising reversible effect of 3,3 diindolymethane: Bidirectional crosstalk of Aryl hydrocarbon receptors

Prolonged exposure to glucocorticoids (GC) disrupts neuronal architecture, hinders neuroplasticity, and triggers neuroinflammation. However, the precise underlying mechanisms have not been studied yet. The current study aimed to investigate the mechanisms of GC-induced neuroinflammatory effects by stimulating the miRNA let7b, aryl hydrocarbon receptor (AhR)/ARNT, HMGB1/RAGE, and other downstream targets. Rats were divided into 4 groups; control, GC (20 mg/kg, S.C.), 3,3′-diindolylmethane (DIM) 50 mg/kg/day, and donepezil (DNZ) 4 mg/kg/day for 21 days. Behavioral tests and histopathological investigations of cerebral cortex were done. Let7b, AhR, ARNT, and cytochrome A1A were estimated using qRT-PCR. HMGB1, RAGE, NQO1and NRF2 were estimated using ELISA, whereas GFAP and TNF-α by immunohistochemical analysis. Keap1 was estimated using Western technique. GSH and TBARS were assessed by colorimetric assay. In the current study, GC elevates the gene expressions of let7b, AhR, ARNT, and cytochrome A1A, along with the protein contents of HMGB1, RAGE, NQO1and NRF2. In addition, GC showed increased GFAP, TNF-α, and TBARS, together with decreased Keap1 and GSH. On the other side, DIM and DNZ reversed all the above-mentioned findings. Collectively, the study documents for the first time the effect of GC in upregulating let7b and activating the AhR/ARNT loop which subsequently stimulates RAGE/HMGB1 and NRF2/Keap1 cascade leading to stimulating further inflammatory and oxidative signaling pathways. Certainly, these effects are responsible for the behavioral fluctuations, the brain’s histological disruption, altered neuroplasticity, and neuroinflammation induced by GC. Moreover, DIM conquers GC-induced neuroinflammation due to its characteristic role in modulating AhR and its downstream targets.

New insight on the potential detrimental effect of metabolic syndrome on the Alzheimer disease neuropathology: Mechanistic role.

The metabolic syndrome or syndrome X is a clustering of different components counting insulin resistance (IR), glucose intolerance, visceral obesity, hypertension and dyslipidemia. It has been shown that IR and dysregulation of insulin signalling play a critical role in the development of metabolic syndrome by initiating the pathophysiology of metabolic syndrome through induction of glucolipotoxicity, impairment of glucose disposal and triggering of pro-inflammatory response. Furthermore, metabolic syndrome unfavourably affects the cognitive function and the development of different neurodegenerative diseases such as Alzheimer disease (AD) by inducing oxidative stress, neuroinflammation and brain IR. These changes together with brain IR impair cerebrovascular reactivity leading to cognitive impairment. In addition, metabolic syndrome increases the risk for the development of AD. However, the central mechanisms by which metabolic syndrome amplify AD risk are not completely elucidated. Consequently, this narrative review aims to revise from published articles the association between metabolic syndrome and AD regarding cellular and subcellular pathways. In conclusion, metabolic syndrome is regarded as a potential risk factor for the induction of AD neuropathology by different signalling pathways such as initiation of brain IR, activation of inflammatory signalling pathways and neuroinflammation.

Neohesperidin Dihydrochalcone Alleviates Lipopolysaccharide-Induced Vascular Endothelium Dysfunction by Regulating Antioxidant Capacity.

Endothelial dysfunction is one of the important mechanisms of organ and tissue damage in sepsis. In this study, we evaluated the effects of neohesperidin dihydrochalone (NHDC) on lipopolysaccharide (LPS)-induced vascular dysfunction and explored the potential mechanisms. In vivo, we assessed vascular leakage in mice by injecting Evans blue dye. In vitro, cell counting kit-8 (CCK-8) assay and flow cytometry were used to assess the activity of HUVEC and apoptosis. The effect of LPS on HUVEC barrier was assessed using FITC-extend membrane assay. The adhesion ability of HUVEC was tested by THP-1 cell adhesion assay. The antioxidant capacity of cells was measured by detecting the level of mitochondrial membrane potential, ROS, and content of CAT, SOD, GSH, and MDA within the cells. Furthermore, the release of endothelial IL-1β, IL-6, and TNF-α were detected by ELISA, and the expression level of TAK1, ERK1/2, and NFκB were detected by western blot. Treatment with NHDC effectively alleviated LPS-induced endothelial permeability and organ damage by reducing reactive oxygen species production and enhancing the antioxidant response. Further investigation suggested that NHDC may exert its protective effects by inhibiting the release of IL-1β, IL-6, and TNF-α, and by decreasing the phosphorylation of key inflammatory signaling molecules, including transforming growth factor-β-activated kinase 1 (TAK1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor kappa B (NFκB). Our study indicate that pretreatment with NHDC may provide protection against LPS-induced vascular dysfunction by reducing oxidative stress and activation of inflammatory signaling pathways.

Dorzolamide Intermediates with Potential Anti-Inflammatory Activity

Dorzolamide (DZD), a Carbonic anhydrase (CA) inhibitor clinically used to lower intraocular pressure, exhibits anti-inflammatory effects owing to the drug’s ability to inhibit the TIR domain-containing adaptor protein (TIRAP)-mediated signalling in macrophages. Here, we investigated whether DZD intermediates also demonstrate any anti-inflammatory property like DZD but with a reduced inhibition of CA. We found that several intermediates of DZD show increased binding to TIRAP at the common interface of kinases, such as Protein kinase C-delta (PKCδ) and Bruton's tyrosine kinase (BTK). Such binding results in a decreased activity of TIRAP, p38 Mitogen-activating protein kinases (MAPK), and p65, which are essential for major inflammatory signaling pathways. Remarkably, the DZD intermediates were more effective than DZD in decreasing the mRNA expression levels of pro-inflammatory cytokines in Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The DZD intermediates also exhibit a reduced binding energy to CA II and CA IV, highlighting their improved specificity as anti-inflammatory compounds with decreased unwanted biological effects. Furthermore, we validated the anti-inflammatory effect of the most efficient DZD intermediate, DRZ V, in a model of mouse sepsis. DRZ V-treated septic mice exhibited improved survival compared to DZD-treated septic mice. Our data indicate that the tested DZD intermediates are more effectual in dampening TIRAP-mediated inflammatory signaling as compared to DZD. Thus, DZD intermediates may be a promising option for developing novel anti-inflammatory therapeutics.

Exploring the mechanism of Jianpi Lishi Jiedu Granules against postoperative recurrence of colorectal adenoma based on IL-6/JAK/STAT3 signaling pathway

Globally, colorectal cancer (CRC) is the primary cause of cancer-related fatalities. Our previous study demonstrated the efficacy of Jianpi Lishi Jiedu Granules (JLJG) in preventing postoperative recurrence of colorectal adenoma (CRA). Building on this foundation, the current study aims to elucidate whether the mechanism by which JLJG prevents postoperative recurrence of CRA involves the classical JAK/STAT inflammatory signaling pathway and to assess its specific impact on this pathway. Utilizing proteomics, we discerned 143 differentially expressed proteins (DEPs) regulated by JLJG, whose functional roles are intimately linked to the JAK/STAT signaling pathway. Among these, we identified key proteins such as IL-6, JAK1, JAK2, STAT3, CCND1, MYC, Bcl-XL, and SOCS3 that are regulated by JLJG and play pivotal roles in the JAK/STAT signaling cascade. Our findings indicate that the sustained activation of the IL-6/JAK/STAT3 signaling pathway is significantly associated with CRA recurrence. JLJG was found to effectively modulate the expression levels of these proteins, as well as the expression of downstream genes including BCL2, MCL1, P21, and JAK1, STAT3, thereby inhibiting the IL-6/JAK/STAT3 signaling pathway. Consequently, this study demonstrates that JLJG prevents the postoperative recurrence of CRA by inhibiting the IL-6/JAK/STAT3 signaling pathway and its negative feedback loops.

Emerging functions of FMNL1 in myeloid neoplasms: insights from bioinformatics to biological and pharmacological landscapes.

Myeloid neoplasms encompass disorders characterized by abnormal myeloid cell proliferation and differentiation, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Formin-like protein 1 (FMNL1) is involved in the regulation of the actin cytoskeleton and is predominantly expressed in hematopoietic cells. Given its role in leukemia cell proliferation, survival, migration, and invasion, this study investigates FMNL1 expression in normal hematopoiesis and myeloid neoplasms and explores associations with clinical-laboratory characteristics, mutational status, and survival outcomes in AML. Transcript levels of FMNL1 from several blood-forming cell populations and myeloid neoplasms were extracted from publicly available databases. Myeloid neoplasm cell lines were used for gene/protein expression and cell differentiation studies. Functional genomics analysis was performed using RNA-seq data from The Cancer Genome Atlas (TCGA) AML study, and drug sensitivity predictions were investigated using Beat AML and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Statistical analyses assessed the impact of FMNL1 expression on clinical outcomes. FMNL1 was highly expressed in metamyelocytes, neutrophils, and monocytes compared to hematopoietic stem cells, and its expression increased with granulocytic differentiation. FMNL1 expression was elevated in AML and CML patients compared to healthy donors. FMNL1 expression was not significantly associated with clinical-laboratory characteristics or survival outcomes but showed a higher frequency of WT1 transcription factor (WT1) mutations with low FMNL1 expression in AML patients. High FMNL1 expression in AML correlated with immune response and inflammatory activity pathways. FMNL1 mRNA levels influenced drug sensitivity in AML models, with correlations observed for specific antineoplastic agents. FMNL1 plays a potential role in granulocyte differentiation and function, and its differential expression is linked to critical signaling pathways in leukemogenesis and inflammation. These findings highlight FMNL1's potential therapeutic implications in myeloid neoplasia, warranting further investigation.

Based on network pharmacology and molecular docking, the mechanism of action of Chinese herbal compound on mycoplasma synovial sac of chicken was studied

Mycoplasma synoviae (MS) is a wall-less pathogen primarily transmitted through the respiratory tract, causing synovitis and airsacculitis in poultry, which leads to substantial economic losses in the poultry industry. China has a long-standing tradition of Chinese medicine with abundant medicinal resources, renowned for its safety, efficacy, and holistic regulatory effects. This study aims to screen a traditional Chinese medicine (TCM) compound with anti-inflammatory and immunoregulatory properties and preliminarily validate its in vitro efficacy against MS infections. Based on the research foundation of this experiment and findings from previous studies, this study utilized network pharmacology analysis and molecular docking techniques to identify the anti-inflammatory and immunoregulatory effects of traditional Chinese medicinal herbs, including Rhizoma Coptidis, Honeysuckle (Flos Lonicerae Japonicae), Radix Codonopsis, and Radix Glycyrrhizae.The primary active components and potential targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and other platforms. Protein-protein interaction (PPI) networks, Gene Ontology (GO) functional annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to identify critical therapeutic targets. The AutoDock software was used for molecular docking between active components and core targets. Subsequently, in vitro experiments were conducted to validate the effects of key active components on MS targets. The analysis revealed that this TCM compound contains 122 active components, including flavonoids (e.g., quercetin, trimethylisoflavone), chromones (e.g., anti-inflammatory coumarin A), and triterpenes (e.g., glycyrrhizic acid B). These components act on 739 pharmacological targets, and Venn analysis identified 23 intersection targets related to MS. Further analysis indicated that STAT3, IL6, and IL1B were potential core targets. KEGG pathway enrichment analysis showed that MAPK, FoxO, and Toll-like receptor signaling pathways played critical roles in the pathology and treatment of MS, while GO analysis emphasized the significance of the NF-κB signaling pathway and VEGF receptor pathway in immune regulation, inflammation, and tissue repair. Molecular docking results demonstrated that lignans and quercetin in this TCM compound exhibited strong binding affinities to IL1B, IL6, and STAT3, potentially modulating these key targets to exert anti-inflammatory and immunoregulatory effects. In vitro experiments further validated the significant inhibitory effects of quercetin and glycyrrhizic acid on MS infection. The findings suggest that this TCM compound may exert therapeutic effects on MS infection by regulating targets such as CASP3, TLR4, STAT3, IL6, and IL1B, and modulating signaling pathways including MAPK, NF-κB, and FoxO.

Bushen Zhuyun Decoction Enhances Endometrial Receptivity via the IL-6/STAT3 Signaling Pathway in Rats

Background: Reproductive endocrine disorder can impair endometrial receptivity, preventing embryo implantation and increasing miscarriage risk. Impaired endometrial receptivity contributes significantly to female infertility. Inflammatory signaling pathways including the IL-6/STAT3 pathway help embryos implant. Therefore, it is crucial to explore the relationship between the IL-6/STAT3 signaling pathway and endometrial receptivity. Objective: To investigate the mechanism by which Bushen Zhuyun decoction (BSZY) enhances endometrial receptivity in rats through the IL-6/STAT3 signaling pathway. Methods: Mifepristone-induced poor endometrial receptivity models of female SD rats were established, followed by histopathological observation. ELISA was used to measure serum sex hormones and VEGF. Western blotting or IHC was used to measure steroid receptors, IGFBP1, and IL-6/STAT3 pathway activation in the uterus during each estrus cycle and early gestation of normal rats. The Treg/Th17 balance was assessed using flow cytometry. Results: Significant differences were found in the protein expressions of steroid receptors, IL6, STAT3, and p-STAT3 during each estrus cycle and early gestation of normal rats. The protein expressions of STAT3 and PR were strongly correlated with each other. BSZY notably improved uterine morphology increased the expression of implantation markers and raised the serum concentrations of sex hormones and VEGF. BSZY enhanced the expressions of IL-6 and its receptors and restored the expressions of STAT3 and p-STAT3 in the uterus of pregnant rats. In addition, BSZY effectively restored the Treg/Th17 balance in the peripheral blood of pregnant rats. Conclusion: BSZY enhances endometrial receptivity and promotes decidualization in SD rats via the IL-6/STAT3 signaling pathway.

Potential Effect of Etoricoxib in Reducing Inflammation in Methotrexate-Induced Pulmonary Injury in Rats: Role of Oxidative Stress and the TLR4/p38-MAPK/NF-κB Signaling Pathway.

Numerous chemotherapeutic medications can have hazardous effects on the lungs, which can result in severe lung diseases. Methotrexate (MTX) is prescribed for cancer and inflammation-related disorders; nevertheless, it is exceptionally highly toxic and has multiple kinds of adverse reactions, including pulmonary injury. Our work was designed to demonstrate the ability of etoricoxib (ETO) to mitigate MTX-induced lung injury in experimental animals. Adult male Wistar rats were separated into four groups. The first group consisted of healthy controls that received carboxymethyl cellulose (1 ml/day, p.o.), the second group received a single dose of MTX (20 mg/kg/day, i.p.), the third group received ETO (10 mg/kg/day, p.o.) for three weeks, and the fourth group first received a single MTX (20 mg/kg, i.p.) and then was treated with ETO for three weeks. Concomitant treatment with ETO and MTX improved the histological structure of the lung tissue. It significantly altered the levels of oxidant/antioxidant markers, such as malondialdehyde (MDA), heme oxygenase-1 (HO-1), reduced glutathione (GSH), and nuclear factor erythroid 2-related factor 2 (Nrf-2), in favor of antioxidants. Moreover, ETO can normalize the proinflammatory cascade, which includes tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). At the molecular level, ETO downregulated the protein expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), and p38 mitogen-activated protein kinase(p38 MAPK) in inflamed rat lungs. In conclusion, our findings indicate that oral administration of ETO ameliorates MTX-induced lung injury by inhibiting oxidative stress and suppressing the TLR4/NF-κB and TLR4/p38-MAPK inflammatory signaling pathways.

Inflammation and Related Signaling Pathways in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, and inflammatory signaling is involved in its pathogenesis. Cytokines exert a robust effect on the progression of AML and affect survival outcomes. The dysregulation in the cytokine network may foster a pro-tumorigenic microenvironment, increasing leukemic cell proliferation, decreasing survival and driving drug resistance. The dominance of pro-inflammatory mediators such as IL-11β, TNF-α and IL-6 over anti-inflammatory mediators such as TGF-β and IL-10 has been implicated in tumor progression. Additionally, inflammatory cytokines have favored certain populations of hematopoietic stem and progenitor cells with mutated clonal hematopoiesis genes. This article summarizes current knowledge about inflammatory cytokines and signaling pathways in AML, their modes of action and the implications for immune tolerance and clonal hematopoiesis, with the aim of finding potential therapeutic interventions to improve clinical outcomes in AML patients.

Neuroinflammation in Age-Related Neurodegenerative Diseases: Role of Mitochondrial Oxidative Stress

A shared hallmark of age-related neurodegenerative diseases is the chronic activation of innate immune cells, which actively contributes to the neurodegenerative process. In Alzheimer’s disease, this inflammatory milieu exacerbates both amyloid and tau pathology. A similar abnormal inflammatory response has been reported in Parkinson’s disease, with elevated levels of cytokines and other inflammatory intermediates derived from activated glial cells, which promote the progressive loss of nigral dopaminergic neurons. Understanding the causes that support this aberrant inflammatory response has become a topic of growing interest and research in neurodegeneration, with high translational potential. It has been postulated that the phenotypic shift of immune cells towards a proinflammatory state combined with the presence of immunogenic cell death fuels a vicious cycle in which mitochondrial dysfunction plays a central role. Mitochondria and mitochondria-generated reactive oxygen species are downstream effectors of different inflammatory signaling pathways, including inflammasomes. Dysfunctional mitochondria are also recognized as important producers of damage-associated molecular patterns, which can amplify the immune response. Here, we review the major findings highlighting the role of mitochondria as a checkpoint of neuroinflammation and immunogenic cell deaths in neurodegenerative diseases. The knowledge of these processes may help to find new druggable targets to modulate the inflammatory response.