Search Results (2,292)

Brucella infection is associated with an increased risk of adverse obstetric outcomes in humans and animals. Decidualization, a process involving structural and functional changes in endometrial stromal cells, is essential for proper trophoblast implantation and placental development. Trophoblasts’ migration and their ability to invade the decidua and to undergo tubulogenesis, critical for proper implantation and placental development, are normally promoted by decidual cells. We evaluated whether Brucella infection of human endometrial stromal cells (T-HESC cell line) affects their ability to decidualize and to promote trophoblast functions. Infection of T-HESC cells with either B. abortus, B. suis, or B. melitensis resulted in deficient decidualization (as revealed by reduced prolactin levels) and an increased production of proinflammatory chemokines (C-X-C motif chemokine ligand 8 -CXCL8- and C-C motif chemokine ligand 2 -CCL2-) as compared to uninfected cells subjected to decidualization stimuli. In addition, conditioned media (CM) from infected decidualized T-HESC induced an inflammatory response (CXCL8, CCL2 and interleukin-6 -IL-6) in human trophoblasts (Swan-71 cell line) but reduced their ability to produce progesterone. Trophoblasts preincubated with this CM also had reduced migration, invasion, and tubulogenesis capacities, and this impairment was mediated, at least in part, by CXCL8 and CCL2. Moreover, infection of decidual stromal cells impaired the adhesion and spreading of blastocyst-like spheroids formed by Swan-71 cells. Brucella infection also affected the chemotactic capacity of decidual stromal cells for trophoblasts. Overall, these results suggest that Brucella infection of endometrial stromal cells impairs key processes required for successful implantation and placental development. Full article

Objective: Lithospermum erythrorhizon has been extensively used for the clinical treatment of skin diseases, but its material basis and mechanism of action remain unclear. This study integrates network pharmacology, untargeted metabolomics, and in vitro experimental validation to elucidate the anti-inflammatory effects and underlying mechanisms of β-acetoxyisovalerylalkannin, a bioactive naphthoquinone compound isolated from Arnebiae Radix, using inflammatory skin disease models. Methods: Core targets for β-Acetoxyisovalerylalkannin and skin inflammation were identified via network pharmacology and validated through molecular docking. In vitro assays assessed β-Acetoxyisovalerylalkannin’s impact on keratinocyte proliferation, migration, apoptosis, and inflammatory factors (CXCL1, CXCL2, CXCL8, CCL20, IFN-γ, MCP-1, TNF-α, NF-κB). Non-targeted metabolomics identified differential metabolites and pathways. Results: Network pharmacology revealed 66 common targets significantly enriched in the MAPK/STAT3 signaling pathway. In vitro, β-Acetoxyisovalerylalkannin suppressed proliferative viability and hypermigration and induced apoptosis in HaCaTs. Moreover, it downregulated the mRNA levels of inflammatory markers (CXCL1, CXCL2, CXCL8, CCL20, IFN-γ, MCP-1, TNF-α, and NF-κB) by inhibiting the activation of the MAPK/STAT3 signaling pathway. Metabolomics identified 177 modified metabolites, associating them with the arginine/proline, glycine/serine/threonine, glutathione, and nitrogen metabolic pathways. Conclusions: β-Acetoxyisovalerylalkannin exerts protective effects against skin inflammation by reducing abnormal cell proliferation and inflammatory responses, promoting apoptosis, and effectively improving the metabolic abnormalities of HaCaTs. β-Acetoxyisovalerylalkannin is, therefore, a potential therapeutic option for mitigating skin inflammation-related damage. Full article

Traumatic brain injury (TBI) is a major cause of long-term neurological impairment, with aging amplifying vulnerability and worsening recovery. Older individuals face greater cognitive and motor deficits post-TBI and respond less effectively to treatments, as both aging and TBI independently elevate neuroinflammation and cognitive decline. This study evaluated the therapeutic effects of human adipose-derived stem cell small extracellular vesicles (hASC-sEVs) on neurological recovery and neuroinflammation in a mouse model of TBI. Male C57BL/6 mice (3, 15, and 20 months old) underwent controlled cortical impact (CCI) and received intranasal hASC-sEVs 48 h post-injury; control groups received PBS. A dose–response study at 7 days post injury (dpi) identified 20 µg as the optimal therapeutic dose, improving motor function, reducing neuroinflammation, and enhancing neurogenesis. This was followed by a 30-dpi study assessing cognitive function, neuroinflammation, neurogenesis, and proteomic changes in microglia and astrocytes via mass spectrometry. hASC-sEV treatment significantly improved behavioral outcomes and reduced neuroinflammatory markers (GFAP, IBA-1, and MHC-II), with reduced efficacy observed in older mice. Proteomics revealed that hASC-sEVs reduce inflammatory proteins (TNF-α, IL-1β, IFNG, CCL2) and modulated mitochondrial dysfunction and reactive oxygen species. These results highlight hASC-sEVs as a promising cell-free therapy for improving TBI outcomes, especially in aging populations. Full article

Psoriasis is a chronic inflammatory skin disease driven by genetic, environmental, and immune factors. While biologics like adalimumab (anti-TNFα) and risankizumab (anti-IL-23) have improved outcomes, patient response variability remains unclear. This study examined immune-related transcriptomic differences between lesional (L) and non-lesional (NL) psoriatic skin, focusing on immune-related hub genes, their plasma levels, and their correlations with severity and treatment response. Patients with moderate-to-severe psoriasis were enrolled before treatment with anti-TNFα (n = 16) or anti-IL-23 (n = 18). Plasma and paired L and NL skin biopsies were collected for RNA sequencing. Gene ontology enrichment analysis found four immune-related terms enriched in L skin: T-helper 17, granulocyte and lymphocyte chemotaxis, and antimicrobial humoral response. A protein–protein interaction network identified ten immune-related hub genes upregulated in L skin that correlated with clinical severity. Patients with prior treatments expressed distinctive gene profiles. Plasma levels of CCL20 strongly correlated with disease severity. Decision tree models identified CCL20 expression in skin and plasma levels of IL-6 and CXCL8 as candidate predictors for anti-TNFα response. Similarly, skin expression of CXCL8, IL-6, and CXCL10, alongside plasma levels of CCL20, IL-6, and CXCL8, may predict anti-IL-23 response. Ten immune-related hubs may serve as possible biomarkers for disease severity and therapeutic response in psoriasis. Full article

Oral squamous cell carcinoma (OSCC) is a malignancy with a poor prognosis, and early diagnosis is essential for improving patient survival and quality of life. This study aimed to develop a non-invasive screening method based on salivary gene expression and microbiome analysis. Unstimulated saliva samples were collected from patients with OSCC, patients with oral potentially malignant disorders, and healthy controls. Microbiome profiling was performed using 16S ribosomal RNA gene sequencing. The OSCC group showed a significant increase in Fusobacterium and Bacteroidetes and a decrease in Streptococcus. LEfSe analysis indicated microbial changes associated with disease progression. Receiver operating characteristic analysis demonstrated high diagnostic accuracy when multiple bacterial species were combined. An increase in Fusobacteria was also associated with a higher risk of recurrence. Gene expression analysis revealed that NUS1, RCN1, CPLANE1, and CCL20 were significantly upregulated in OSCC, as confirmed by qRT-PCR and tissue expression data. Notably, CCL20 expression positively correlated with Fusobacterium abundance. These findings suggest that integrated analysis of the salivary microbiome and gene expression may offer a useful non-invasive approach for early OSCC detection and disease monitoring. Furthermore, we integrated current evidence from the literature to provide a comprehensive overview. Full article

Background: Methamphetamine use, which is disproportionately prevalent among people with HIV, increases risk for cardio- and neurovascular pathology through persistent immune activation and inflammation. Preclinical studies indicate that cannabinoids may reduce markers of pro-inflammatory processes, but data from people with chronic inflammatory conditions are limited. We examined potentially interacting associations of lifetime methamphetamine use disorder (MUD), recent cannabis use, and HIV with four plasma markers of immune and inflammatory functions. Method: Participants with HIV (PWH, n = 86) and without HIV (PWoH, n = 148) provided urine and blood samples and completed neuromedical, psychiatric, and substance use assessments. Generalized linear models examined main and conditional associations of lifetime MUD, past-month cannabis use, and HIV with plasma concentrations of CXCL10/IP-10, CCL2/MCP-1, ICAM-1, and VCAM-1. Results: PWH displayed higher CXCL10/IP-10 than PWoH. Past-month cannabis use was independently associated with lower CXCL10/IP-10 levels and conditionally lower CCL2/MCP-1, ICAM-1, and VCAM-1 levels among people with lifetime MUD, but only PWoH displayed cannabis-associated lower VCAM-1 levels. Conclusions: Human plasma sample evidence suggests that cannabis use is associated with lower levels of immune and inflammatory molecules in the context of MUD or HIV. Cannabinoid pathways may be worthwhile clinical targets for treating sequelae of chronic inflammatory conditions. Full article

Background/Objectives: Eupatorium lindleyanum DC (Eup), a traditional Chinese medicinal herb, is widely used for treating inflammation-mediated diseases, including pneumonia. However, its potential therapeutic effects on inflammation-driven liver fibrosis remain to be elucidated. This study aimed to investigate the effects of Eup on carbon tetrachloride (CCl₄)-induced liver fibrosis and elucidate its underlying mechanisms. Methods: The chemical constituents of Eup were analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-LC/MS). A CCl₄-induced liver fibrosis murine model and LX-2 cells were used in study. Serum biochemical assays, histological analysis, qRT-PCR, ELISA, and Western blot were used to assess Eup’s anti-inflammatory and anti-fibrotic properties. RNA sequencing (RNA-seq) was employed to identify potential mechanisms, with validation by Western blot. Results: 89 and 49 compounds were identified in Eup under positive and negative ion modes, respectively. In vivo, Eup treatment decreased collagen deposition and expression levels of fibrosis-related genes, including collagen I and α-smooth muscle actin. Additionally, Eup alleviated hepatic inflammation. In vitro, Eup inhibited FBS-induced hepatic stellate cell (HSCs) activation. Gene set enrichment analysis (GSEA) indicated that Eup significantly downregulated the platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor-beta (PDGFR-β) signaling pathway, which was further validated in both CCl₄-induced fibrotic livers and PDGF-BB-activated HSCs using western blot. Conclusions: Eup attenuated liver fibrosis by inhibiting inflammation and suppressing HSCs activation via downregulating PDGF/PDGFR-β signaling pathway. Full article

Background: EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment. Methods: Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in murine models of non-small cell lung cancer (NSCLC). Results: Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrates via flow cytometry revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T-cell activation, particularly in CD8+ T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1 in RNA expression analyses. Conclusions: Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit the activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape. Full article

The ileum serves as the primary site for nutrient digestion and absorption in the intestine, with villus height representing a critical indicator of intestinal absorptive capacity. To investigate the regulatory mechanisms underlying ileal villus development, we conducted a feeding trial using crossbred pigs (Duroc × Landrace × Yorkshire) with an initial body weight of 27.74 ± 0.28 kg, stratifying them into high-villus and low-villus groups based on ileal villus height (n = 4). The results revealed 849 differentially RNA-edited genes (REGs) between the two groups, including 472 hyper-edited genes in the low-villus group and 377 in the high-villus group. Functional enrichment analysis showed that these REGs were significantly enriched in inflammation-related pathways, particularly the TNF signaling pathway and IL-17 signaling pathway, with TNF pathway genes exhibiting notably higher editing levels in the high-villus group. Additionally, 46 differentially expressed genes (DEGs) were identified, comprising 22 upregulated in the low-villus group and 24 in the high-villus group, which were similarly enriched in TNF and IL-17 signaling pathways. Integrated quadrant analysis of the RNA editing and transcriptomic profiles demonstrated that pro-inflammatory genes CXCL10 (C-X-C motif chemokine 10), CCL2 (C-C motif chemokine ligand 2), CREB3L2 (CAMP-responsive element-binding protein 3-like 2), and PIK3R1 (Phosphoinositide-3-kinase regulatory subunit 1) were highly expressed in the low-villus group but exhibited significantly lower RNA editing levels compared to the high-villus group. Furthermore, the expression of the inflammation-suppressive RNA editing enzyme APOBEC1 (apolipoprotein B mRNA editing enzyme catalytic subunit 1) showed correlation with villus height (R = 0.81, p < 0.05). Collectively, our findings indicate that RNA editing dynamics influence the variation in ileal villus height within inflammation-associated pathways, particularly the TNF signaling pathway. Enhanced RNA editing of this pathway may mitigate intestinal inflammation and promote healthy ileal villus developments. Full article

Background/Objectives: Controlled release systems, such as polymeric microparticles (MPs), have emerged as a promising solution to extend the bioavailability and reduce dosing frequency for biologic drugs; however, the formulation of these systems to encapsulate highly sensitive, hydrophilic biologic drugs within hydrophobic polymers remains a nontrivial task. Although scalable manufacturing and FDA approval of single emulsion processes encapsulating small molecules has been achieved, scaling more complex double emulsion processes to encapsulate hydrophilic biologics remains more challenging. Methods: Here, we demonstrate that two hydrophilic, low-molecular-weight, recombinant chemokines, CCL22 and CCL2, can be encapsulated in poly(lactic-co-glycolic acid) (PLGA) MPs using a single emulsion method where the proteins are dissolved in an organic solvent during formulation. Results: As expected, we observed some differences in release kinetics from single emulsion MPs compared to double emulsion MPs, which traditionally have been used to encapsulate proteins. Single emulsion MPs exhibited a substantially reduced initial burst. Importantly, protein released from single emulsion CCL22-MPs also retained biological activity, as determined by a cell-based functional assay. Decreasing particle size or changing the polymer end group from PLGA-COOH to PLGA-OH increased the initial burst from single emulsion MPs, demonstrating tunability of release kinetics for protein-loaded, single emulsion MPs. Finally, to improve scalability and enable more precise control over MP formulations, the single emulsion process was adapted to a microfluidic, continuous manufacturing system, and the resulting MPs were evaluated similarly. Conclusions: Altogether, this study demonstrates the feasibility of using a single emulsion encapsulation method for at least some protein biologics. Full article

The aim of this paper is to obtain ethyl (2-(methylcarbamoyl)phenyl)carbamate and its metal complexes as promising antimicrobial agents. The title compound was synthesized using the ring-opening of isatoic anhydride with methylamine and further acylation with ethyl chloroformate. All metal complexes were successfully obtained after mixing the ligand dissolved in DMSO and water solutions of the corresponding metal salts and sodium hydroxide, in a metal-to-ligand-to base ratio 1:2:2. As a result, mixed ligand complexes of ethyl 2-(methylcarbamoyl)phenyl)carbamate and 3-methylquinazoline-2,4(1H,3H)-dione were obtained. The obtained complexes were characterized by their melting points, FTIR, NMR spectroscopy, and MP-AES. Then, the antimicrobial effect of the compounds against both Gram-negative and Gram-positive bacteria, yeasts, and fungi was studied. Only the Co(II) complex showed antimicrobial activity against almost all Gram-positive and Gram-negative bacteria. The cobalt complex exhibited promising antimicrobial activity against Gram-positive Micrococcus luteus with inhibition zones of 20 mm, Listeria monocytogenes (15 mm), Staphylococcus aureus (13 mm), as well as Gram-negative Klebsiella pneumoniae (13 mm) and Proteus vulgaris (13 mm). Given the potential of metal complexes as antimicrobial agents, understanding their cytotoxic effects is crucial for evaluating their therapeutic safety. To assess the in vitro biocompatibility of the experimental compounds, a range of cell viability assays was conducted using human malignant leukemic cell lines (LAMA-84, K-562) and normal murine fibroblast cells (CCL-1). The Ni(II) complex shows IC₅₀ = 105.1 µM against human malignant leukemic cell lines LAMA-84. Based on the reported results, it may be concluded that the mixed cobalt complex of 2-(methylcarbamoyl)phenyl)carbamate and 3-methylquinazoline-2,4(1H,3H)-dione can be attributed as a promising antimicrobial agent. Future in vivo tests will contribute to establishing the antimicrobial properties of this complex. Full article

Background: Sepsis-induced myocardial injury (SIMI) significantly contributes to sepsis-related mortality, yet effective therapies remain limited. This study investigated the cardioprotective potential of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP), a bioactive metabolite from Salvia miltiorrhiza, focusing on its mechanism via the GAS6/Axl signaling axis in lipopolysaccharide (LPS)-induced myocardial injury. Methods: Using an in vitro HL-1 cardiomyocyte model, IDHP’s cytotoxicity was assessed (0–20 μM). Cells were pretreated with IDHP (10 μM, optimal concentration) before LPS exposure. Inflammatory cytokines (IL-6/TNF-α/IL-1β/IL-18), chemokines (CCL2/CCR2, CCL25/CCR9), ROS levels (Nrf2 pathway), and apoptosis markers (Bax) were quantified. GAS6/Axl-AMPK signaling was evaluated via GAS6 knockout experiments. Results: IDHP (≤20 μM) showed no cytotoxicity. At 10 μM, it exhibited anti-inflammatory effects by reducing LPS-induced cytokine/chemokine release, demonstrated antioxidant activity through lowering ROS via Nrf2 activation, and exerted anti-apoptotic action by downregulating Bax. Mechanistically, IDHP restored GAS6/Axl-AMPK phosphorylation, an effect abolished in GAS6-knockout cells. Conclusions: IDHP mitigates LPS-induced cardiomyocyte injury by concurrently targeting inflammation, oxidative stress, and apoptosis via GAS6/Axl-AMPK signaling, proposing a novel therapeutic avenue for SIMI. Full article

Background/Objectives: Neutrophils have recently gained significant attention due to their heterogeneity in tumor settings. Recent data showed neutrophil pro- and anti-tumor profiles during tumor progression. However, the concessive causes of neutrophil skewing toward one or another profile are not fully understood. Methods: In this study, using RT-qPCR, flowcytometry, and confocal microscopy, we investigated the phenotype of splenic neutrophils of mice bearing Lewis lung carcinoma LLC, RLS₄₀ lymphosarcoma, and B16 melanoma. Results: Our data showed an immunosuppressive phenotype in the case of the LLC model with PD-L1 and IL10 expression. In the B16 model, minimal changes in the neutrophil phenotype were observed, regardless of tumor size. In the RLS₄₀ model, the neutrophil phenotype was associated with the tumor growth rate, where, in aggressively progressed tumors (RLS₄₀^High), CCL17 was expressed, while, in mice with controlled tumor growth (RLS₄₀^Low), anti-tumor markers were expressed (FAS, ICAM-1, PD-L1). DNase I treatment significantly reduced tumor growth and metastasis in the RLS₄₀ model but not in B16, enhanced the anti-tumor profile in RLS₄₀ neutrophils, and tended to reduce NET formation induced by A23187. Conclusions: The phenotype of neutrophils from tumor-bearing mice is influenced by the tumor type and progression stage. DNase I had anti-tumor, antimetastatic, and immunostimulatory effects and significantly modified the neutrophil profile in the immunogenic model RLS₄₀. Full article

Cardiovascular disease (CVD) remains the leading global cause of morbidity and mortality, largely driven by atherosclerosis, a chronic inflammatory process involving lipids and immune cells. Although traditional lipid biomarkers such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL) are well-established in CVD risk stratification, the interplay between cytokines, chemokines, growth factors (CCGFs), lipid metabolism, and hematological parameters in non-cardiac populations remains underexplored. We investigated associations between plasma cytokines and lipid-related biomarkers and their relationships with circulating blood cell counts in a cohort of 164 essentially healthy adults aged 18–44 years. CCGF profiling was performed using a proximity extension assay (PEA), and statistical correlations were adjusted for multiple testing using false discovery rate (FDR) correction. The CCGFs that were associated with HDL and apolipoprotein A1 all displayed negative associations. Several pro-inflammatory cytokines, including CCL3, IL-6, and TNFSF10, showed strong positive associations with triglycerides, remnants, non-HDL, and body mass index (BMI). Furthermore, triglycerides and remnants were consistently correlated with elevated leukocyte, neutrophil, and platelet counts. HGF and FGF-21, mainly considered as anti-inflammatory, were positively associated with BMI and negatively associated with HDL, which is compliant with a multitude of actions, depending on the local milieu and the cellular interplay. Our results support the existence of a complex immunometabolic network involving lipids, CCGFs, and blood cells, even in non-diseased individuals. The observed patterns underscore the importance of understanding the intricate cytokine–lipid–cell interactions that may occur in early pathophysiological processes and highlight their potential utility in refining cardiovascular risk assessment beyond traditional lipid metrics. Full article

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disorder affecting 10–20% of the population. In this study, we investigate the anti-inflammatory effect on the skin of eight compounds isolated from Digitalis purpurea L., using tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-stimulated human keratinocytes (HaCaT cells) and a three-dimensional (3D) reconstructed human skin model. Among the tested compounds, desrhamnosyl acteoside exhibited the most potent activity, significantly reducing the secretion of pro-inflammatory cytokines (IL-6, IL-8) and chemokines (CCL17, CCL22), suppressing the expression of inflammatory proteins, and modulating key signaling pathways, including NF-κB, JAK2/STAT1, and MAPK. Notably, this is the first report demonstrating that desrhamnosyl acteoside simultaneously targets all three pathways, indicating a multi-modal mechanism distinct from conventional single-target approaches. In the 3D skin model, desrhamnosyl acteoside further exhibited barrier-protective effects by downregulating inflammatory mediators and upregulating epidermal differentiation markers such as involucrin and loricrin. These findings reveal a previously uncharacterized phytochemical with dual anti-inflammatory and barrier-restorative activities, supporting its potential as a novel therapeutic candidate for AD and other inflammatory skin diseases. Full article