Search Results (68)

Objectives: (1) To compare cytokine levels in participants with serum urate (SU) < 360 µmol/L, SU ≥ 360 µmol/L with and without monosodium urate (MSU) crystal deposition, respectively, and inter-critical gout. (2) To explore the association of IL-1β, IL-6 and high-sensitivity (hs) CRP with disease duration and the frequency of self-reported gout flares. Methods: Samples and data from 184 participants from studies conducted at Academic Rheumatology, Nottingham City Hospital, were included. Serum high-sensitivity CRP and cytokines involved in the pathogenesis of gouty inflammation were measured. MANCOVA and multivariate linear regression were used, as appropriate, and were adjusted for age, sex, body mass index and self-reported comorbidities. p values were adjusted for multiple testing using a 5% false-discovery rate. Results: Participants with inter-critical gout had greater levels of IL-1β (p_corr = 0.009), IL-18 (p_corr = 0.02), IL-6 (p_corr < 0.0001), IP-10 (p_corr < 0.0001), TNF-α (p_corr < 0.0001), GRO-α (p_corr = 0.0006) and hsCRP (p_corr = 0.009) compared to other groups in multivariate analyses and after correcting for multiple testing. There were no differences in cytokine and hsCRP levels in participants with SU < 360 µmol/L and in participants with SU ≥ 360 µmol/L with or without MSU crystal deposition. There was a statistically non-significant trend for association between IL-6 levels and number of self-reported gout flares. Conclusions: Our findings suggest that gout is a chronic inflammatory condition. The pre-clinical phases of gout were not associated with systemic inflammation, potentially due to the modest sample size. Further research is required to understand whether treating gout by targeting the complete dissolution of MSU crystals would reduce systemic inflammation in inter-critical gout. Full article

CXCL1 (Gro-α, MGSA) is a chemokine functionally similar to CXCL8/IL-8, as both activate the same receptor, CXCR2. CXCL1 levels are frequently elevated in tumors compared to healthy tissue, where they play a key role in promoting cancer cell migration, angiogenesis, and neutrophil recruitment. While the involvement of CXCL1 in tumor progression is well established, its relevance to cancer therapy remains underexplored. This review examines the therapeutic potential of targeting CXCL1 and its receptor, CXCR2, in cancer treatment. It discusses anti-CXCL1 antibodies and CXCR2 antagonists, including AZD5069, SB225002, SCH-479833, navarixin/SCH-527123, ladarixin/DF2156A, and reparixin, as well as strategies to enhance CXCR2 expression in lymphocytes during adoptive cell therapy to improve immunotherapy outcomes. Particular attention is given to the role of CXCL1 in treatment resistance, including resistance to chemotherapy, radiotherapy, and anti-angiogenic therapy. Cancer therapies often upregulate CXCL1 expression, which in turn drives treatment resistance. Additionally, this review explores the contribution of CXCL1 to therapy-induced side effects, such as chemotherapy-induced metastasis, neuropathy, nephrotoxicity, diarrhea, and cardiotoxicity. CXCR2 inhibitors are well tolerated by patients in clinical trials. However, the limited number of studies evaluating these agents in combination with standard chemotherapy precludes any definitive conclusions. Full article

Glioblastoma is the most common primary brain tumor in adults. Our previous studies revealed a functional interplay of myelin transcription factor 1-like (MYT1L) with the DNA-dependent protein kinase (DNA-PK) in the regulation of p21 transcription. However, the contributing role of this functional interplay in glioblastoma remains largely unknown. Here, we used cell lines with normal DNA-PK (HEK293 and M059K) or deficient DNA-PK (M059J) as a model system to demonstrate the importance of the DNA-PK-dependent activation of MYT1L in controlling the transcription of CXC chemokine receptor 1 (CXCR1) in a positive-feedback proliferative signaling loop in glioblastoma with numerous conventional techniques. In normal DNA-PK cells, MYT1L acted as an oncogene by promoting cell proliferation, inhibiting apoptosis, and shortening a cell cycle S phase. However, in DNA-PK-deficient cells, MYT1L functioned as a tumor suppressor by inhibiting cell proliferation and inducing a G1 arrest. The enforced expression of MYT1L promoted CXCR1 transcription in DNA-PK-normal cells but attenuated transcription in DNA-PK-deficient cells. Bioinformatics analysis predicted a MYT1L-binding sequence at the CXCR1 promoter. The functional dependence of MYT1L on DNA-PK in CXCR1 transcription was validated by luciferase assay. Although the expression of CXCR1 was lower in M059J cells as compared to M059K cells, it was higher than in normal brain tissue. The CXCR1 ligands interleukin 8 (IL-8) and GRO protein alpha (GROα) expressed in M059J and M059K cells may signal through the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway that can be blocked by CXCR1 siRNA. Our findings demonstrate the existence of a positive feedback DNA-PK/MYT1L-CXCR1-ERK1/2 proliferation loop in glioblastoma cells that may represent a pharmacological target loop for therapeutic intervention. Full article

The purpose of this study was to examine whether supplementation of ultra- and nanofiltered colostrum-based products, combined with egg yolk extract, nicotinamide mononucleotide (NMN), quercetin, alpha-ketoglutarate, white button mushroom, and celery seed extracts (the formula was patented by 4Life Research Company, USA and named as AgePro), modulate the functional activity of natural killer (NK) cells in vivo. We found that this supplement, taken orally in two capsules twice a day for 30 days, significantly enhanced the cytotoxic activity of NK cells. This was evidenced by the increased NK cell-mediated killing of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled K562 human myeloid leukemia cells. As expected, this effect was dependent on the ratio between the effector (E) (e.g., peripheral blood mononuclear cells (PBMCs)) and target (T) (e.g., K562) cells, illustrating maximal killing of K562 cells at a 50:1 E/T ratio. Of note, increased NK-mediated killing of K562 cells after taking AgePro correlated with increased perforin release, evidenced by the CD107a degranulation assay. In concordance with these findings, taking of AgePro for 1 month increased production of several cytokines and chemokines, including IL-1β, IL-1Rα, IL-6, IL-8, IL-10, IFN-γ, TNF-α, G-CSF, PDGF-AA, PDGF-AB/BB, GRO, MCP-1, MCP-3, and MIP-1α, in PBMCs co-cultured with K562 cells. Of note, increased production of the cytokines correlated with the activation state of PBMCs, as evidenced by increased expression of the surface activation markers (e.g., the interleukin-2 receptor alpha chain—CD25). A strong correlation was found between NK-based cytotoxic activity and the production of IL-1β, IL-6, TNF-α, and MIP-1α. Importantly, no increase in the aforementioned soluble factors and activation markers was detected in PBMCs cultured alone, thereby illustrating the potent immunoregulatory activity of AgePro only in the presence of the harmful target cells. Hematological parameters also remained unchanged over the entire study period. Collectively, we show herein the significant enhancement of the cytotoxic activity of NK cells against target tumor cells after taking AgePro for 1 month. Notably, this effect was observed for all age groups, including young, adult, and elderly participants. Moreover, a significant improvement in NK cytotoxic activity was also detected for participants with low basal (e.g., before taking AgePro) numbers of NK-mediated killing. The enhancement of NK-based cytotoxicity was associated with an increased release of several cytokines and chemokines involved in regulating a broad spectrum of mechanisms outside the cell-mediated cytotoxicity and killing of target cells. Of note, spontaneous activation of PBMCs, particularly NK cells, was not detected after taking AgePro. Given that spontaneous activation of autoreactive lymphocytes is a feature associated with autoimmunity and taking into account our data illustrating the AgePro-induced activation of NK cells detected only in the presence of the potentially harmful cells, we conclude that our innovative product exhibits potent immunoregulatory activity and high safety profile. Full article

Tungsten disulfide (WS₂) nanoparticles have emerged in the biomedical field as potential theranostic agents due to their unique properties, including biocompatibility. However, their impact on the immune response remains unexplored. This study aimed to evaluate the effects of inorganic fullerene-like WS₂ (IF-WS₂) nanostructures on human peripheral blood mononuclear cells (PBMCs) in vitro. The study investigated several parameters to evaluate the effects of IF-WS₂ nanoparticles. Cytotoxicity was assessed by measuring cell viability, apoptosis, and necrosis. Internalization of IF-WS₂ by PBMCs was analyzed using morphological and flow cytometric techniques. Proliferation was studied in CellTrace Far Red-prestained total PBMCs stimulated with phytohemagglutinin (PHA) and in isolated T cell cultures stimulated with CD3/CD28-coated beads. Additionally, the production of cytokines and chemokines was measured in culture supernatants of total PBMCs and T cells. IF-WS₂ nanoparticles were non-cytotoxic up to a concentration of 200 µg/mL. Concentrations ≥25 µg/mL inhibited PHA-stimulated PBMC proliferation but did not affect T cell proliferation. Morphological and flow cytometric analysis demonstrated dose- and time-dependent internalization of IF-WS₂ by macrophages. Additionally, IF-WS₂ significantly reduced the production of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8, MCP-1, and GRO-α) in PHA-stimulated PBMCs. Th1, Th17, and Th21 cytokines were downregulated, while Th2, Th9, and T regulatory cytokines were upregulated. In conclusion, this study demonstrated for the first time that pristine IF-WS₂ nanoparticles, at non-cytotoxic concentrations, exhibit notable anti-inflammatory and immunomodulatory properties on activated PBMCs in vitro. Full article

We recently found that myometrial distension stimulates maternal uterine vascular remodeling, and hypothesized that this may be a previously unrecognized mechanism for inducing arterial growth during pregnancy. The aim of this study was to further characterize a recently developed surgical model in which medical-grade silicone was infused into one uterine horn of a non-gravid rat to induce acute myometrial stretch, followed by an additional, gradual distension due to the secretion of an exudate into the uterine lumen. Our objectives were to better understand the effects of stretch on the myometrium and to look for the expression of proangiogenic and proinflammatory factors that may stimulate uterine vascular remodeling. Morphometric analysis showed hypertrophy of the uterine corpus that was primarily due to axial growth since the myometrial cross-sectional area was unchanged due to a thinning of the uterine wall secondary to stretch. This finding was supported by significantly increased myometrial smooth muscle cell mitosis. There was also an increase in the concentration of myometrial elastin but not collagen. The analysis showed modest increases in neutrophils, activated and unactivated macrophages, and the proinflammatory cytokines RANTES, MIP-3α, GRO-KC, and TNFα. The most dramatic change was the extremely high level of VEGF in the exudate, which was increased >900× above circulating levels. Full article

Drug resistance is a significant challenge in pancreatic ductal adenocarcinoma (PDAC), where stromal elements such as adipose-derived mesenchymal stem cells (ASCs) contribute to a chemoresistant tumor microenvironment (TME). This study explored the effects of oxaliplatin (OXP) and 5-fluorouracil (5-FU) on PDAC cells (Capan-1) and ASCs to investigate the mechanisms of chemoresistance. While OXP and 5-FU reduced Capan-1 viability in a dose- and time-dependent manner, ASCs demonstrated high resistance, maintaining > 90% viability even at cytotoxic doses. Transcriptomic analyses revealed OXP-induced transcriptional reprogramming in ASCs, with over 7000 differentially expressed genes, highlighting the pathways related to DNA damage response, cell cycle regulation, and stress-related signaling. In contrast, 5-FU elicited limited transcriptional changes, affecting only 192 genes. Cytokine proteome profiling revealed that OXP-treated ASCs significantly influenced the tumor microenvironment by promoting immune evasion (via IL-4, GM-CSF, IP-10, and GROα) and driving extracellular matrix remodeling (through EMMPRIN and DPPIV). In contrast, 5-FU induced comparatively weaker effects, primarily limited to hypoxia-related pathways. Although OXP reduced angiogenic factors, it paradoxically activated pro-survival pathways, thereby enhancing ASC-mediated tumor support. These findings underscore ASCs as modulators of chemoresistance via secretome alterations and stress adaptation. Therefore, future strategies should prioritize the precise targeting of tumor cells while also focusing on the development of personalized treatments to achieve durable therapeutic responses in PDAC. Full article

Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications. Full article

Skin inflammation and immune regulation have been suggested to be associated with allergic contact dermatitis (ACD) progression, but whether the system’s immune regulation is a cause or a potential mechanism is still unknown. This study aims to assess the upstream and downstream of systemic immune factors on ACD within a bidirectional Mendelian-randomization design. A bidirectional two-sample MR analysis was employed to implement the results from genome-wide association studies for 52 system immune factors and ACD. Genetic associations with systemic immune factors and ACD were obtained from the IEU Open GWAS project database. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis, MR-Egger, weighted median, MR-pleiotropy residual sum, and outlier (MR-PRESSO) was also used as the sensitivity analyses. Only Tumor necrosis factor ligand superfamily member 11 (TNFS11) from among 52 systemic immune factors was associated with a protective effect of ACD. However, ACD was associated with a decrease in Interleukin-9 (IL9) and an increase in C-X-C motif chemokine 1 (GROα), Tumor necrosis factor ligand superfamily member 10 (TRAIL), C4, and complement factor B of the assessed systemic immune factors. This study identified TNFS11 as the upstream regulator and IL9, GROα, TRAIL, C4, and complement factor B as the downstream regulator of ACD, providing opportunities for new therapeutic exploitation of ACD. Nonetheless, these associations of systemic immune factors need to be verified in vivo. Full article

Cerebral malaria in young African children is associated with high mortality, and persisting neurological deficits often remain in survivors. Sequestered Plasmodium-infected red blood cells lead to cerebrovascular inflammation and subsequent neuroinflammation. Brain inflammation can play a role in the pathogenesis of neurologic sequelae. Therefore, we assessed a select set of proinflammatory analytes (IP10, IL23, MIP3α, GRO, MCP-1, and osteopontin in both the plasma and cerebrospinal fluid(CSF) of Zambian children with cerebral malaria and compared this with children with neurological symptoms that were negative for Plasmodium falciparum (non-cerebral malaria). Several similarities in plasma and CSF levels were found, as were some striking differences. We confirmed that IP10 levels were higher in the plasma of cerebral malaria patients, but this was not found in CSF. Levels of osteopontin were elevated in both the plasma and CSF of CM patients compared to the non-CM patients. These results show again a highly inflammatory environment in both groups but a different profile for CM when compared to non-cerebral malaria. Osteopontin may play an important role in neurological inflammation in CM and the resulting sequelae. Therefore, osteopontin could be a valid target for further biomarker research and potentially for therapeutic interventions in neuroinflammatory infections. Full article

Chemokines play a key role in cancer processes, with CXCL1 being a well-studied example. Due to the lack of a complete summary of CXCL1’s role in cancer in the literature, in this study, we examine the significance of CXCL1 in various cancers such as bladder, glioblastoma, hemangioendothelioma, leukemias, Kaposi’s sarcoma, lung, osteosarcoma, renal, and skin cancers (malignant melanoma, basal cell carcinoma, and squamous cell carcinoma), along with thyroid cancer. We focus on understanding how CXCL1 is involved in the cancer processes of these specific types of tumors. We look at how CXCL1 affects cancer cells, including their proliferation, migration, EMT, and metastasis. We also explore how CXCL1 influences other cells connected to tumors, like promoting angiogenesis, recruiting neutrophils, and affecting immune cell functions. Additionally, we discuss the clinical aspects by exploring how CXCL1 levels relate to cancer staging, lymph node metastasis, patient outcomes, chemoresistance, and radioresistance. Full article

Background: Comorbid chronic diseases, such as obesity, Type-2 Diabetes (T2D), and hypertension (HTN), are major public health issues and highly prevalent among underserved African Americans (AA) and Latin Americans (LA). Elevated inflammatory cytokines are underlying processes in comorbidities (obesity, T2D, and HTN) that could contribute to tumorigenesis and adverse cancer outcomes. Methods: A panel of 19 cytokines was measured by Luminex assay from 570 AA and LA women’s serum samples. The comorbidities and breast cancer information were extracted from our existing clinical database. Comorbidity-associated cytokines were identified by linear regression analysis, and the odds ratios of increasing cytokines for breast cancer were evaluated by Logistic regression. Results: Women with obesity, T2D, and HTN elevated specific groups of cytokines. EGF, MCP1, MDC, MIP-1b, and Groα were independent of T2D and HTN significantly associated with obesity. TGFβ1 and TGFβ2 were T2D-associated cytokines, and MIB-1b, TNFα, and VEGFα were HTN-associated cytokines. Among those comorbidity-associated cytokines, CXCL1, CCL4, CXCL10, TNFα, TGFβ1, and TGFβ2 were also significantly associated with breast cancer diagnosed at age < 50. Two or more comorbidities further increased the levels of Groα, MIP-1b, TNFα, and TGFβs. Conclusions: Comorbidity-associate cytokines could augment the risk of breast cancer for AA and LA women. Full article

The mesenchymal stromal/stem cells (MSCs) are known to secrete pleiotropic paracrine factors, contributing to tissue regeneration. This unique ability makes MSCs promising therapeutic tools for many diseases, including even those that were previously untreatable. Thus, the development of preconditioning approaches aimed at enhancing the paracrine function of MSCs attracts great interest. In the present work, we studied how the extracellular matrix, the essential part of the native tissue microenvironment, affects the secretory capacity of MSCs of various origins. The MSC-derived decellularized extracellular matrix (dECM), used as the cell culture substrate, triggered strong upregulation of FGF-2, MMP-1, HGF, GRO-α, GRO-β, CXCL-5, CXCL-6, IL-6, IL-8, G-CSF and MCP-1. Functional in vitro tests revealed that conditioned media derived from MSCs cultured on dECM significantly improved 3T3 fibroblast and HaCaT keratinocyte scratch wound healing, stimulated THP-1 monocyte migration and promoted capillary-like HUVEC-based tube formation compared to conditioned media from MSCs grown on plastic. In addition, we found that FAK inhibition promoted dECM-induced upregulation of paracrine factors, suggesting that this kinase participates in the MSCs’ paracrine response to dECM. Together, these findings demonstrate that dECM provides cues that considerably enhance the secretory function of MSCs. Thus, dECM usage as a cell culture substrate alone or in combination with a FAK inhibitor may be viewed as a novel MSC preconditioning technique. Full article

Toll-like receptors (TLRs) are crucial to the innate immune response. They regulate inflammatory reactions by initiating the production of pro-inflammatory cytokines and chemokines. TLRs also play a role in shaping the adaptive immune responses. While this protective response is important for eliminating infectious pathogens, persistent activation of TLRs may result in chronic immune activation, leading to detrimental effects. The role of TLR2 in regulating HIV-1 infection in vivo has yet to be well described. In this study, we used an SIV-infected rhesus macaque model to simulate HIV infection in humans. We evaluated the plasma of the macaques longitudinally and found a significant increase in the soluble TLR2 (sTLR2) level after SIV infection. We also observed an increase in membrane-bound TLR2 (mb-TLR2) in cytotoxic T cells, B cells, and NK cells in PBMC and NK cells in the gut after infection. Our results suggest that sTLR2 regulates the production of various cytokines and chemokines, including IL-18, IL-1RA, IL-15, IL-13, IL-9, TPO, FLT3L, and IL-17F, as well as chemokines, including IP-10, MCP-1, MCP-2, ENA-78, GRO-α, I-TAC, Fractalkine, SDF-1α, and MIP-3α. Interestingly, these cytokines and chemokines were also upregulated after the infection. The positive correlation between SIV copy number and sTLR2 in the plasma indicated the involvement of TLR2 in the regulation of viral replication. These cytokines and chemokines could directly or indirectly regulate viral replication through the TLR2 signaling pathways. When we stimulated PBMC with the TLR2 agonist in vitro, we observed a direct induction of various cytokines and chemokines. Some of these cytokines and chemokines, such as IL-1RA, IL-9, IL-15, GRO-α, and ENA-78, were positively correlated with sTLR2 in vivo, highlighting the direct involvement of TLR2 in the regulation of the production of these factors. Our findings suggest that TLR2 expression may be a target for developing new therapeutic strategies to combat HIV infection. Full article

Pomegranate has shown a favorable effect on gingivitis/periodontitis, but the mechanisms involved are poorly understood. The aim of this study was to test the effect of pomegranate peel extract (PoPEx) on gingiva-derived mesenchymal stromal cells (GMSCs) under physiological and inflammatory conditions. GMSC lines from healthy (H) and periodontitis (P) gingiva (n = 3 of each) were established. The lines were treated with two non-toxic concentrations of PoPEX (low—10; high—40 µg/mL), with or without additional lipopolysaccharide (LPS) stimulation. Twenty-four genes in GMSCs involved in different functions were examined using real-time polymerase chain reaction (RT-PCR). PoPEx (mostly at higher concentrations) inhibited the basal expression of IL-6, MCP-1, GRO-α, RANTES, IP-10, HIF-1α, SDF-1, and HGF but increased the expression of IL-8, TLR3, TGF-β, TGF-β/LAP ratio, IDO-1, and IGFB4 genes in H-GMSCs. PoPEx increased IL-6, RANTES, MMP3, and BMP2 but inhibited TLR2 and GRO-α gene expression in P-GMSCs. LPS upregulated genes for proinflammatory cytokines and chemokines, tissue regeneration/repair (MMP3, IGFBP4, HGF), and immunomodulation (IP-10, RANTES, IDO-1, TLR3, COX-2), more strongly in P-GMSCs. PoPEx also potentiated most genes’ expression in LPS-stimulated P-GMSCs, including upregulation of osteoblastic genes (RUNX2, BMP2, COL1A1, and OPG), simultaneously inhibiting cell proliferation. In conclusion, the modulatory effects of PoPEx on gene expression in GMSCs are complex and dependent on applied concentrations, GMSC type, and LPS stimulation. Generally, the effect is more pronounced in inflammation-simulating conditions. Full article